The molecules of mammalian fertilization.
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ADAM Proteins↗
Biomedical subjects
J M White
Publications and source records attributed to J M White.
The effect of an accelerated immunisation schedule on pertussis in England and Wales.
Notifications of pertussis in England and Wales have fallen dramatically from 65 810 during the epidemic year of 1982 to 3963 cases during the epidemic year of 1994, as vaccine coverage has risen. The incidence of pertussis has declined in all ages, including babies under 3 months of age who would have been at risk of disease from older siblings vaccinated under the accelerated schedule introduced in 1990 if immunity induced as result of this schedule had been short lived. To document the efficacy of the current whole cell vaccine under the accelerated schedule an enhanced surveillance scheme based on laboratory confirmed cases of pertussis was set up in 1994. Three deaths occurred in infants with confirmed pertussis, all of whom were under 8 weeks of age and unvaccinated. The overall vaccine efficacy for those over 6 months and under 5 years of age was 94%. This estimate may be inflated, as a number of biases could lead to the underascertainment of cases in vaccinated children, but it is similar to previous estimates obtained for children of the same age vaccinated under the 3, 5, and 10 month schedule. Vaccine efficacy was 89% for children aged over 5 and under 15 years. The enhanced surveillance scheme will enable us to monitor the duration of protection under the accelerated schedule and evaluate the continuing impact of pertussis infection.
Adolescent↗
Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway.
The JAK-STAT signaling pathway has been implicated in mediating biological responses induced by many cytokines. However, cytokines that promote distinct cellular responses often activate identical STAT proteins, thereby raising the question of how specificity is manifest within this signaling pathway. Here we report the generation and characterization of mice deficient in STAT1. STAT1-deficient mice show no overt developmental abnormalities, but display a complete lack of responsiveness to either IFN alpha or IFN gamma and are highly sensitive to infection by microbial pathogens and viruses. In contrast, these mice respond normally to several other cytokines that activate STAT1 in vitro. These observations document that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biologic responses and reveal an unexpected level of physiologic specificity for STAT1 action.
Animals↗
Dentin ablation with three infrared lasers.
BACKGROUND AND OBJECTIVE: Lasers are used for caries removal in enamel and dentin, but are currently limited in their ability to remove sound tooth structure. In this study plasma interaction regimes are investigated as the principal factor determining the ablation characteristics. STUDY DESIGN/MATERIALS AND METHODS: Three ablation parameters are considered: ablation rates (AR), surface temperatures (ST), and surface morphological characteristics. The three lasers investigated were Er:YSGG with wavelength (WL) of 2.94 mu m and pulse duration (PD) of 250 mu s, Ho:YSGG at 2.1 mu m and 250 mu s and an Nd:YAG with WL of 1.06 mu M and PD of 15ns. RESULTS: The highest surface temperatures were observed during Er:YSGG treatment (> 300 degrees C), moderate temperatures with the Ho:YSGG (150 degrees C), and lowest with the Nd:YAG (with highest surface temperature generally lower than 80 degrees C). Ablation rates were also compared and were shown to be highest with the Er:YSGG and Ho:YSGG, and lower with the Nd:YAG (< 3 mu m). In all systems, efficient ablation was observed only in the presence of plasma. In spite of their different wavelengths, for similar spot sizes, energy, and pulse duration, ablation rates of Ho:YSGG and Er:YSGG were found to be comparable. These were an order of magnitude larger than the ablation rates observed with the nanosecond system. CONCLUSION: Possible explanation for these observations is given in terms of plasma characteristics.
Dentin↗
Initial evaluation of fertilin as an immunocontraceptive antigen and molecular cloning of the cynomolgus monkey fertilin beta subunit.
Fertilin (PH-30) is a sperm surface protein that functions in sperm adhesion and fusion with the egg plasma membrane. Because of its essential function in fertilization, fertilin is a potential target for novel contraceptive approaches. In a pilot fertility trial, immunization of male guinea pigs with purified guinea pig fertilin resulted in complete infertility. The contraceptive effect was partial (two out of six animals were infertile) when female guinea pigs were immunized with the antigen. These results suggest that fertilin or domains of fertilin may be effective as immunocontraceptive antigens. As a step toward achieving this goal, we communicate the cDNA and deduced amino acid sequence of the monkey fertilin beta subunit.
ADAM Proteins↗
Spectroscopic changes in human dentine exposed to various storage solutions--short term.
OBJECTIVES: Tooth storage conditions in studies of dentine have not been standardized. The objective of this investigation was to determine the effects of storage solution and time on dentine, using spectroscopic methods. METHODS: Twenty-seven dentine disks (0.75 mm thick) were prepared from freshly extracted third molars with documented histories. The teeth were sectioned parallel to the occlusal plane using a diamond saw. Specimens were analysed non-destructively for surface chemical changes using specular reflectance infra-red Fourier transform spectroscopy (SRIFTS), and changes in optical properties were measured in the ultraviolet, visible and near-infra-red spectral ranges with an integrating sphere spectrophotometer (UV/VIS/NIR) before and after storage. A minimum of five specimens were stored in distilled water with 0.02% thymol, purified and filtered water, phosphate buffered saline with 0.02% thymol, 70% ethanol or 10% buffered formalin and evaluated at 0, 1, 2, 7, 14, 21 and 28 days. After each measurement, specimens were stored in fresh solutions. IR spectra were obtained from 4400 to 400 wave-numbers (cm-1). Optical properties of reflectance and transmittance were determined from 200 to 2500 nm, and absorbance was calculated. RESULTS: Analysis of the IR spectra indicated no significant differences in collagen or mineral peak positions for any solution at any time period. There were significant differences in peak intensities of dentine stored in distilled water, purified and filtered water and phosphate-buffered saline over time in the IR spectra. Furthermore, differences in optical properties of dentine disks were detected by UV/VIS/NIR. CONCLUSION: It was concluded that changes in surface chemistry and optical properties of dentine occur as a function of storage solution and time, which must be considered when studying dentine.
Anti-Infective Agents↗
ADAMs and cell fusion.
Members of the ADAM family (membrane proteins with a disintegrin and metalloprotease domain) have been implicated in several cell-interactive events, including cell-cell fusion. Recent evidence implicates three ADAMs, fertilin-alpha, fertilin-beta, and meltrin-alpha, in sperm-egg fusion and myoblast fusion. In light of the large number and wide tissue distribution of the ADAMs, they may also participate in other cell-cell fusion events. As ADAMs are also found in both vertebrates and invertebrates, some features of cell-cell fusion reactions may be conserved throughout the animal kingdom.
Amino Acid Sequence↗
Health status at entry to methadone maintenance treatment using the SF-36 health survey questionnaire.
This study used the SF-36 general health questionnaire to measure the health status of heroin users at entry to a public methadone maintenance programme. Their results were compared to those from the general population and from three clinical groups: patients with minor medical, major medical and psychiatric problems. One hundred consecutive clients were interviewed in the first week on the programme using the SF-36 health questionnaire. Data were also gathered on their drug use, use of medical services and HIV risk behaviour. The results showed that heroin users at entry to the methadone maintenance programme had significantly worse physical and psychological health than the general population. Their scores were most similar to the psychiatrically depressed patients, although they had worse physical health than this comparison group. The greater the amount of heroin used by clients before entering the programme, the more pain they reported. Alcohol and marijuana use were associated with better social and physical health. The relationship between general health status and amount or frequency of drug use is not a clear one. Heroin users experience severe emotional and physical problems at the time of entering methadone maintenance treatment.
Adolescent↗
Improvements in retention rates and changes in client group with methadone maintenance streaming.
This study evaluated changes in client population and in retention rates following the introduction of a system of methadone maintenance streaming. A low intervention and low supervision stream was combined with two abstinence-orientated streams. Privileges of take-home doses and local pharmacy dose collection were contingent on successful participation in the abstinence-orientated streams. The clinic also modified policy to allow clients greater control over dose levels. The case notes of the first 100 clients entering the programme in the year prior to the changes (1991) and in the year following the changes (1993) were compared. The results showed a significant increase in retention rates. The demographic and heroin using histories did not change, but the newer programme attracted a greater proportion of clients with no previous history of methadone maintenance treatment. Mean clinic dose increased from 45 mg to 63 mg when clients were allowed to exert control over dose. These findings reveal improved outcomes in a public methadone maintenance programme as a result of policy changes designed to give clients greater control of their treatment.
Journal Article↗
Pharmacological properties of ketamine.
Ketamine is a dissociative anaesthetic that is being used in non-medical contexts. The effects of ketamine are very similar to those of phencyclidine, another dissociative anaesthetic that has enjoyed considerable popularity as a recreational drug. The effects of ketamine include analgesia, cardiovascular and respiratory stimulation, dissociation, hallucinations and anaesthesia. The potential dangers of uncontrolled ketamine use include psychosis and violence, accidents and marked psychomotor and cognitive impairment. Although studies have shown potential for tolerance to and physical dependence on ketamine, further investigation of these phenomena is needed. Ketamine is thought to produce most of its effects through antagonist activity at the PCP site of the NMDA receptor complex. Ketamine has sympathomimetic properties resulting from enhancement of catecholamine, and particularly dopamine, activity. While opioid receptor activity has been identified, this is relatively weak and the contribution to the effects of ketamine is not clear. Although much is known of the clinical uses and effects of ketamine, as yet little is understood of ketamine as a recreational drug and potential drug of dependence.
Journal Article↗
Membrane fusion mediated by the influenza virus hemagglutinin requires the concerted action of at least three hemagglutinin trimers.
In this study we tested the hypothesis that fusion mediated by the influenza virus hemagglutinin (HA) is a cooperative event. To so this we characterized 3T3 cell lines that express HA at nine different defined surface densities. HA densities ranged from 1.0 to 12.6 x 10(3) HA trimers/microns2 as determined by quantitative fluorescent antibody binding. The lateral mobility and percent mobile fraction of HA did not vary significantly among these cells, nor did the contact area between HA-expressing cells and target RBCs. The fusion reaction of each HA-expressing cell line was analyzed using a fluorescence dequenching assay that uses octadecylrhodamine (R18)-labeled RBCs. For each cell line we measured the lag time preceding the onset of fusion, the initial rate of fusion, and final extent of fusion. The final extent of fusion was similar for all cell lines, and the initial rate of fusion as a function of HA surface density displayed a Michaelis-Menten-type dependence. However, the dependence of the lag time preceding the onset of fusion on HA surface density was clearly sigmoidal. Kinetic analysis of the data for the reciprocal lag time vs HA surface density, by both a log/log plot and a Hill plot, suggested that the observed sigmoidicity does not reflect cooperativity at the level of formation of HA aggregates as a prerequisite to fusion. Rather, the cooperativity of the process(es) that occur(s) during the lag time arises at a later step and involves a minimum of three, and most likely four, HA trimers. A model is proposed to explain HA cooperativity during fusion.
3T3 Cells↗
Studies of HIV-1 envelope glycoprotein-mediated fusion using a simple fluorescence assay.
OBJECTIVE: To study HIV envelope glycoprotein (Env)-mediated entry using a sensitive fusion assay. DESIGN AND METHODS: CD4+ lymphocytes or T-cell lines were labelled with fluorescent cytoplasm or membrane markers. Fusion with Env-expressing adherent cells was monitored by observing dye transfer from CD4+ cells to Env cells. RESULTS: Cell-cell fusion began 20-30 min after co-cultivation at 37 degrees C. Pre-binding at 4 degrees C was observed not to decrease the lag phase before fusion. Cells expressing envelope glycoproteins from non-syncytium-inducing (NSI) HIV strains showed dye transfer between two cells without progression to syncytia. A glycosylphosphatidylinositol anchored Env was found to be incapable of mediating membrane fusion, as measured either by lipid or cytoplasm contents mixing. Primary mouse cells expressing human CD4 and mouse 3T3 cells stably expressing both human CD4 and human CD26 did not support fusion with our Env-expressing cells. CONCLUSIONS: Env-mediated cell-cell fusion is a relatively slow process, probably reflecting a multi-step process occurring after CD4 binding and requiring the transmembrane domain of gp41. Env proteins are able to mediate cell-cell fusion at least under some experimental conditions, indicating that lack of a syncytia phenotype does not rule out the possibility of fusion occurring between only two or a few cells.
3T3 Cells↗
Virus-cell and cell-cell fusion.
Significant progress has been made in elucidating the mechanisms of viral membrane fusion proteins; both those that function at low, as well as those that function at neutral, pH. For many viral fusion proteins evidence now suggests that a triggered conformational change that exposes a previously cryptic fusion peptide, along with a rearrangement of the fusion protein oligomer, allows the fusion peptide to gain access to the target bilayer and thus initiate the fusion reaction. Although the topologically equivalent process of cell-cell fusion is less well understood, several cell surface proteins, including members of the newly described ADAM gene family, have emerged as candidate adhesion/fusion proteins.
Cell Membrane↗
The threshold effects of Nd and Ho: YAG laser-induced surface modification on demineralization of dentin surfaces.
Laser irradiation alters the structure of dentin and produces surface layers that give the appearance of being more enamel-like. The laser-modified surface may be more resistant to demineralization; hence, many investigators are proposing continued development of the laser as a possible preventive treatment for caries. The purpose of this study was to explore the morphological changes that occur in dentin when treated at threshold illuminance with two clinically interesting laser wavelengths, and to evaluate the effectiveness of the laser-treated surface at resisting demineralization in an acid-gel solution. The Nd: YAG laser (wavelength 1060 nm) produced significant recrystallization and grain growth of the apatite, without the formation of second phases such as beta-tricalcium phosphate. This recrystallized surface layer showed resistance to demineralization; however, the layer did not provide protection of the underlying dentin from demineralization because of cracks and macroscopic voids that allowed for penetration of the demineralizing gel. The Ho: YAG laser-treated surface (wavelength 2100 nm) did not show significant evidence of recrystallization and grain growth, and only a trace amount of an acid-resistant layer was observed with demineralization. It is speculated that the Ho:YAG laser is coupling with absorbed water, and that the heat transfer from the water to the mineral phase is inefficient. For the purposes of creating a demineralization-resistant layer, threshold illuminance with both Nd: YAG and Ho: YAG was ineffective.
Absorption↗
Membrane fusion by the influenza hemagglutinin: the fusion pore.
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Animals↗
Microhardness and scanning electron microscopy analysis of Nd:YAG laser and acid treatment effects in dentin.
Laser irradiation at and above parameters producing the modification threshold for dentin causes structural changes to the dentin surface. This study determined the microhardness of dentin before and after laser modification and acid treatment using a repeated-measures design. Seven dentin sections (4 mm in thickness) were cut from freshly extracted non-carious third molars using a diamond saw. The middle occlusal third was used as the test dentin surface. One section served as a control (C); three received laser modification (L) and then acid treatment (L + A); and three received acid (A) and then laser treatment (A + L). Laser modification was made using a pulsed (120 microseconds) fiber-optic-delivered (500 microns diameter) Nd:YAG (lambda = 1.06 microns) laser at the physical modification threshold of 207 J/cm2. Acid treatment consisted of 10% nitric acid applied for 45 seconds. Twenty Knoop indentation microhardness measurements (KHN) were obtained using 300 g force engaged for 15 seconds for each section before and after each treatment (n = 400). Knoop microhardness values recorded: C = 62 +/- 3; L = 149 +/- 35; A = 24 +/- 5; L + A = 40 +/- 16; and A + L = 33 +/- 5. Multifactor-repeated measures, with analysis of variance (ANOVA; p < or = 0.05), indicated significant differences between all treatment groups. Scanning electron microscopy analysis of dentin surfaces documented unique surface morphology for all treatment conditions. Laser modification of dentin before or after acid treatment increased dentin microhardness.
Adult↗
COVER/Körner 95-1 (April to June 1995). Vaccination coverage statistics for children up to 2 years old in the United Kingdom.
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Child, Preschool↗
Mouse egg integrin alpha 6 beta 1 functions as a sperm receptor.
Binding between sperm and egg plasma membranes is an essential step in fertilization. Whereas fertilin, a mammalian sperm surface protein, is involved in this crucial interaction, sperm receptors on the egg plasma membrane have not been identified. Because fertilin contains a predicted integrin ligand domain, we investigated the expression and function of integrin subunits in unfertilized mouse eggs. Polymerase chain reactions detected mRNAs for alpha 5, alpha 6, alpha v, beta 1, beta 3, and beta 5. Immunofluorescence revealed alpha 6 beta 1 and alpha v beta 3 on the plasma membrane. GoH3, a function-blocking anti-alpha 6 monoclonal antibody, abolished sperm binding, but a nonfunction-blocking anti-alpha 6 monoclonal antibody, a function-blocking anti-alpha v beta 3 polyclonal antibody, and an RGD peptide had no effect. Somatic cells bound sperm avidly, but only if they expressed alpha 6 beta 1. A peptide analog of the fertilin integrin ligand domain inhibited sperm binding to eggs and alpha 6 beta 1+ cells and diminished GoH3 staining of eggs. Our results indicate a novel role for the integrin alpha 6 beta 1 as a cell-cell adhesion receptor that mediates sperm-egg binding.
ADAM Proteins↗