Rates of first measles-mumps-rubella immunisation in Wales (UK)
Explore the source record for details and available documents.
Child, Preschool↗
Biomedical subjects
J King
Publications and source records attributed to J King.
The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.
BACKGROUND: Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. METHODS: Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. RESULTS: The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001). CONCLUSIONS: A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.
Administration, Intranasal↗
The joining of blunt DNA ends to 3'-protruding single strands in Escherichia coli.
In eukaryotic and prokaryotic organisms DNA double-strand breaks with non-complementary ends can be joined by mechanisms of illegitimate recombination. We examined the joining of 3'-protruding single strand (PSS) ends, which do not have recessed 3' hydroxyls that can allow for fill-in DNA synthesis, to blunt ends. End-joining was examined by electro-transforming Escherichia coli strains with linearized plasmid DNA, sequencing the resulting junctions, and determining the transformation frequencies. Three different E.coli strains were examined: MC1061, which has no known recombination or DNA repair defects, HB101 (rec A-) and SURE (recB- recJ-). No striking differences were found in either the spectrum of products observed or the efficiency of end-joining between these strains. As in vertebrate systems, the majority of the products were overlaps between directly repeated DNA sequences. 3'-PSS are frequently preserved in vertebrate systems, but they were not preserved in our experiments unless the transforming DNA was pretreated with a DNA polymerase.
Base Sequence↗
Cold rescue of the thermolabile tailspike intermediate at the junction between productive folding and off-pathway aggregation.
Off-pathway intermolecular interactions between partially folded polypeptide chains often compete with correct intramolecular interactions, resulting in self-association of folding intermediates into the inclusion body state. Intermediates for both productive folding and off-pathway aggregation of the parallel beta-coil tailspike trimer of phage P22 have been identified in vivo and in vitro using native gel electrophoresis in the cold. Aggregation of folding intermediates was suppressed when refolding was initiated and allowed to proceed for a short period at 0 degrees C prior to warming to 20 degrees C. Yields of refolded tailspike trimers exceeding 80% were obtained using this temperature-shift procedure, first described by Xie and Wetlaufer (1996, Protein Sci 5:517-523). We interpret this as due to stabilization of the thermolabile monomeric intermediate at the junction between productive folding and off-pathway aggregation. Partially folded monomers, a newly identified dimer, and the protrimer folding intermediates were populated in the cold. These species were electrophoretically distinguished from the multimeric intermediates populated on the aggregation pathway. The productive protrimer intermediate is disulfide bonded (Robinson AS, King J, 1997, Nat Struct Biol 4:450-455), while the multimeric aggregation intermediates are not disulfide bonded. The partially folded dimer appears to be a precursor to the disulfide-bonded protrimer. The results support a model in which the junctional partially folded monomeric intermediate acquires resistance to aggregation in the cold by folding further to a conformation that is activated for correct recognition and subunit assembly.
Bacteriophage P22↗
Chemical warfare agents: estimating oral reference doses.
Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other Uncertainty Factors, including (1) a UFH < or = 10 to ensure that the resulting RfD protects segments of the human population that may be more sensitive to the chemical than the average person; (2) a UFA < or = 10 to extrapolate from the experimental animal species to humans; (3) a UFS < or = 10 to extrapolate from an experimental subchronic exposure study to a potential chronic exposure; and (4) a UFD < or = 10 to ensure that the resulting RfD is protective for all possible adverse effects, particularly those that may not have been adequately evaluated in the available studies. A Modifying Factor (MF), based on a qualitative professional assessment of the data, may also be used to account for other factors (e.g., deficiencies in the critical study) that are not adequately covered by the standard Uncertainty Factors. 1. Agent HD (Sulfur Mustard). RfDe = 7 x 10(-6) mg kg-1 d-1. A LOAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be "mild" in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level.
Air Pollutants↗
The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene.
Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C, and L182F, which occur in patients in association with GAA expansions. These cases, and a further five reported cases of point mutations causing FRDA, demonstrate that splicing, nonsense, or initiation codon mutations (which cause a complete absence of functional frataxin) are associated with a severe phenotype. Missense mutations, even in highly evolutionally conserved amino acids, may cause a mild or severe phenotype.
Adaptor Proteins, Signal Transducing↗
Role of the scaffolding protein in P22 procapsid size determination suggested by T = 4 and T = 7 procapsid structures.
Assembly of bacteriophage P22 procapsids requires the participation of approximately 300 molecules of scaffolding protein in addition to the 420 coat protein subunits. In the absence of the scaffolding, the P22 coat protein can assemble both wild-type-size and smaller size closed capsids. Both sizes of procapsid assembled in the absence of the scaffolding protein have been studied by electron cryomicroscopy. These structural studies show that the larger capsids have T = 7 icosahedral lattices and appear the same as wild-type procapsids. The smaller capsids possess T = 4 icosahedral symmetry. The two procapsids consist of very similar penton and hexon clusters, except for an increased curvature present in the T = 4 hexon. In particular, the pronounced skewing of the hexons is conserved in both sizes of capsid. The T = 7 procapsid has a local non-icosahedral twofold axis in the center of the hexon and thus contains four unique quasi-equivalent coat protein conformations that are the same as those in the T = 4 procapsid. Models of how the scaffolding protein may direct these four coat subunit types into a T = 7 rather than a T = 4 procapsid are presented.
Bacteriophage P22↗
Long-term outcome with the use of OKT3 induction therapy in heart transplant patients: a single-center experience.
Explore the source record for details and available documents.
Azathioprine↗
High incidence and clinical course of aggressive skin cancer in heart transplant patients: a single-center study.
Explore the source record for details and available documents.
Female↗
Effects of sulfanilamide and methotrexate on 13C fluxes through the glycine decarboxylase/serine hydroxymethyltransferase enzyme system in arabidopsis.
In C3 plants large amounts of photorespiratory glycine (Gly) are converted to serine by the tetrahydrofolate (THF)-dependent activities of the Gly decarboxylase complex (GDC) and serine hydroxymethyltransferase (SHMT). Using 13C nuclear magnetic resonance, we monitored the flux of carbon through the GDC/SHMT enzyme system in Arabidopsis thaliana (L.) Heynh. Columbia exposed to inhibitors of THF-synthesizing enzymes. Plants exposed for 96 h to sulfanilamide, a dihydropteroate synthase inhibitor, showed little reduction in flux through GDC/SHMT. Two other sulfonamide analogs were tested with similar results, although all three analogs competitively inhibited the partially purified enzyme. However, methotrexate or aminopterin, which are confirmed inhibitors of Arabidopsis dihydrofolate reductase, decreased the flux through the GDC/SHMT system by 60% after 48 h and by 100% in 96 h. The uptake of [alpha-13C]Gly was not inhibited by either drug class. The specificity of methotrexate action was shown by the ability of 5-formyl-THF to restore flux through the GDC/SHMT pathway in methotrexate-inhibited plants. The experiments with sulfonamides strongly suggest that the mitochondrial THF pool has a long half-life. The studies with methotrexate support the additional, critical role of dihydrofolate reductase in recycling THF oxidized in thymidylate synthesis.
Amino Acid Oxidoreductases↗
Efficacy of programmes based on Conductive Education for young children with cerebral palsy.
Conductive Education (CE)-based programmes have been introduced to Australia over the past 10 years. The aim of this project was to compare these programmes with traditional neurodevelopmental programmes of rehabilitation for young children (12 to 36 months, mean age 22 months 3 weeks) with cerebral palsy. Thirty-four children were matched by age, motor impairment, and cognitive ability and randomly allocated to CE-based or equivalent-intensity control programmes. Those unwilling to be randomized (32) were still studied but their outcomes were treated separately. Our results indicate that children involved in CE-based programmes made similar progress to those involved in traditional programmes. Statistically significant changes were spread among the four groups of subjects. The findings also endorsed the measures used and the expected maturational effect was detected. Although there were major difficulties in conducting this randomized trial, it was achieved by gathering parental and professional support, and adequate funding.
Cerebral Palsy↗
Clinical and economic outcomes of individuals with severe peptic ulcer hemorrhage and nonbleeding visible vessel: an analysis of two prospective clinical trials.
OBJECTIVE: We report the clinical outcomes and direct medical costs of 155 patients with severe peptic ulcer hemorrhage and a nonbleeding visible vessel at emergency endoscopy treated with endoscopic hemostasis or medical-surgical therapy. METHODS: In two consecutive, prospective, randomized, controlled trials, patients were randomly assigned to endoscopic hemostasis (heater probe, bipolar electrocoagulation, or injection sclerosis) or medical-surgical treatment. Study endpoints included the incidence of severe ulcer rebleeding and emergency surgery, length of hospital stay, blood transfusion requirements, mortality rate, and direct costs of utilized health care. Direct medical costs were estimated using combined fixed and variable institutional costs for consumed resources and Medicare reimbursement rates. RESULTS: Compared with medical-surgical treatment, endoscopically treated patients had significantly lower rates of severe ulcer rebleeding (p = 0.004), emergency surgery (p = 0.002 and p = 0.019, 0.024), and blood transfusions (p = 0.025). Observed inter-trial differences in ulcer rebleeding rates may be partially explained in a multivariate model by covariates of comorbid disease and inpatient ulcer bleeding. In both trials, length of hospital stay, mortality rates, and treatment-related complications were similar. Estimated median direct costs per patient differed: The first trial had lower costs with endoscopic hemostasis ($4254, vs $4620 for electrocoagulation and $5909 for medical-surgical treatment), yet the second trial yielded lower costs with medical-surgical treatment ($3169, vs $3477 for injection sclerosis and $4098 for heater probe). CONCLUSIONS: Compared with medical-surgical therapy, endoscopic hemostasis for severe ulcer hemorrhage and a nonbleeding visible vessel yielded significantly better patient outcomes and was safe. This procedure may or may not yield lower direct medical costs and cost savings.
Blood Transfusion↗
Uptake of measles containing vaccines in the measles, mumps, and rubella second dose catch-up programme in Wales.
A two dose schedule for measles, mumps, and rubella (MMR) vaccination was introduced in England and Wales on 1 October 1996 in order to prevent the accumulation of susceptible individuals and thus prevent future epidemics. A routine second dose of MMR vaccine is now offered with the diphtheria, tetanus and polio (DTPol) preschool booster. In addition a second dose of MMR is being offered to all children born since 1 January 1990 without documented histories of two doses of measles containing vaccine in a catch up programme due to end in March 1998. Progress in the catch up programme in Wales was assessed by examining uptake of all possible combinations of measles containing vaccines in four birth cohorts by 1 May 1997. Of 126,550 children born between January 1990 and March 1993 (aged 4 years, 1 month to 7 years, 3 months) and living in Wales on 1 May 1997, 63,855 (50.5%) had received two doses of measles containing vaccine and 120,668 (95.4%) had received at least one dose, but 5882 children (4.6%) had no record of having received any measles containing vaccine. Uptake of the preschool DTPol booster in the same cohort was 87.2%. Uptake of two measles containing vaccines varied between health authority (range: 35.4-58.3%) and between birth cohorts (range: 40.0-81.8%). Few (18.4%) previously unimmunised children had attended for the MMR catch-up dose. Successful elimination of measles may depend on targeting this group in order to improve coverage. Although this analysis was carried out during the catch-up programme, these data suggest that the programme may not reach the children who most need to be immunised.
Child↗
MGDS case presentation: hypodontia with retained deciduous teeth.
This case, which was presented as a log diary for the 1997 Diploma of Membership in General Dental Surgery (MGDS) examination, describes the examination, treatment planning, and subsequent treatment of a patient displaying mild hypodontia with retained deciduous teeth and lateral excursions guided by group function. It incorporates preventive treatment and management of early interproximal caries, prerestorative orthodontics, reorganisation to a canine-guided occlusion using conventional and adhesive cast restorations, and management of an occasional clenching habit.
Adult↗
A specific deficit of dorsal stream function in Williams' syndrome.
Williams' syndrome (WS) is a rare, genetically based disorder of cognitive development. Affected individuals show a severe deficit of spatial cognition but a relative sparing of language and face recognition. To examine the possible neural basis of the spatial deficit, we tested a group of WS children, aged 4-14 years, on two measures specific to dorsal cortical stream function: global motion coherence thresholds, in comparison with an analogous form-coherence test, and visuo-manual accuracy in posting a card through a slot, compared with matching the slot orientation. Deficits in these tasks provide the first evidence of specific involvement in WS of the dorsal stream, the cortical system believed to encode information about spatial relationships and the visual control of action.
Adolescent↗
Recombinational repair in yeast: functional interactions between Rad51 and Rad54 proteins.
Rad51p is a eukaryotic homolog of RecA, the central homologous pairing and strand exchange protein in Escherichia coli. Rad54p belongs to the Swi2p/Snf2p family of DNA-stimulated ATPases. Both proteins are also important members of the RAD52 group which controls recombinational DNA damage repair of double-strand breaks and other DNA lesions in Saccharomyces cerevisiae. Here we demonstrate by genetic, molecular and biochemical criteria that Rad51 and Rad54 proteins interact. Strikingly, overexpression of Rad54p can functionally suppress the UV and methyl methanesulfonate sensitivity caused by a deletion of the RAD51 gene. However, no suppression was observed for the defects of rad51 cells in the repair of gamma-ray-induced DNA damage, mating type switching or spontaneous hetero-allelic recombination. This suppression is genetically dependent on the presence of two other members of the recombinational repair group, RAD55 and RAD57. Our data provide compelling evidence that Rad51 and Rad54 proteins interact in vivo and that this interaction is functionally important for recombinational DNA damage repair. As both proteins are conserved throughout evolution from yeasts to humans, a similar protein-protein interaction may be expected in other organisms.
Adenosine Triphosphatases↗
Prevalence of temperature sensitive folding mutations in the parallel beta coil domain of the phage P22 tailspike endorhamnosidase.
Temperature sensitive mutations fall into two general classes: tl mutations, which render the mature protein thermolabile, and tsf (temperature sensitive folding) mutations, which destabilize an intermediate in the folding pathway without altering the functions of the folded state. The molecular defects caused by tsf mutations have been intensively studied for the elongated tailspike endorhamnosidase of Salmonella phage P22. The tailspike, responsible for host cell recognition and attachment, contains a 13 strand parallel beta coil domain. A set of tsf mutants located in the beta coil domain have been shown to cause folding defects in the in vivo folding pathway for the tailspike. We report here additional data on 17 other temperature sensitive mutants which are in the beta coil domain. Using mutant proteins formed at low temperature, the essential functions of assembling on the phage head, and binding to the O-antigen lipopolysaccharide (LPS) receptor of Salmonella were examined at high temperatures. All of the mutant proteins once folded at permissive temperature, were functional at restrictive temperatures. When synthesized at restrictive temperature the mutant chains formed an early folding intermediate, but failed to reach the mature conformation, accumulating instead in the aggregated inclusion body state. Thus this set of mutants all have the temperature sensitive folding phenotype. The prevalence of tsf mutants in the parallel beta coil domain presumably reflects properties of its folding intermediates. The key property may be the tendency of the intermediate to associate off pathway to the kinetically trapped inclusion body state.
Bacteriophage P22↗
Inhibition of hepatocellular carcinoma development in hepatitis B virus transfected mice by low dietary casein.
In a comprehensive human ecological study, primary liver cancer has been shown to be highly significantly associated with 1) the prevalence of persistent infection with hepatitis B virus (HBV) and 2) plasma cholesterol concentrations that are, in turn, associated with the consumption of animal based foods. In rat studies, aflatoxin-induced hepatocellular carcinoma is substantially prevented by decreasing the intake of animal based protein (casein), a hypercholesterolemic nutrient. Thus the development of primary liver cancer associated with persistent HBV infection or with aflatoxin exposure may be controlled by reduced intake of animal-based proteins. Transgenic mice transfected with an HBV gene fragment containing the viral transactivator of hepatis B virus, HBx, which induces the formation of hepatocellular carcinoma, were used to examine the ability of dietary casein to modify tumor formation. Reducing the concentration of dietary casein to 6% from the traditional level of 22% markedly inhibited (by 75%) hepatic tumor formation in these transgenic mice. Tumor development also was substantially altered by interchanging dietary casein concentration well after tumor development had begun (at 8 months), increasing by 173% from the expected yield when casein intake was increased and decreasing by 99% when casein was reduced. These findings suggest that the development of liver tumor formation among individuals persistently infected with HBV may be controlled by minimizing or eliminating the intake of animal protein-based foods.
Animals↗