Biomedical subjects
Publications and source records attributed to M R Taylor.
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We report pediatric age- and sex-specific 95% reference intervals for procollagen type I C-terminal propeptide (PICP), the cross-linked C-terminal telopeptide of type I collagen (ICTP), and procollagen type III N-terminal propeptide (P3NP), measured in plasma from 302 schoolchildren (156 boys, 146 girls) ages 4-19 years. All three markers displayed a significant variation with age (ANOVA P < or = 0.0015). PICP showed no detectable increase during adolescence for either sex, but decreased towards adult concentrations after the age of puberty, with an earlier decrease for girls than for boys (P < 0.01). ICTP and P3NP both increased in pubertal-aged children (P < 0.05), with an earlier increase in girls than in boys (P < 0.05), before decreasing towards adult concentrations (P < 0.01). All three collagen markers were highly correlated with one another (P < 0.001). The patterns observed mirrored the childhood growth curve and reflected the high turnover of bone and soft tissue during childhood growth.
Micellar electrokinetic capillary chromatography (MECC) using diode array detection has been investigated for the determination of phase I and phase II metabolites of drugs in biofluids. Methods were optimised for the determination of morphine, morphine-3-glucuronide, morphine-6-glucuronide, normorphine, meclofenamic acid and its metabolites in equine urine. Solid-phase extraction procedure were developed to concentrate and purify the analytes from spiked and post administration urines for MECC analysis. A simple on-line procedure for monitoring the kinetics of hydrolysis of morphine-glucuronide conjugates by beta-glucuronidase was demonstrated.
In the lactose permease of Escherichia coli, transmembrane helix 10 has been shown to be functionally important. The structure of this helix has been examined in greater detail in this study. A total of 46 substitution and 8 insertional mutants were constructed and analyzed along the entire length of transmembrane helix 10. The results identified amino acids that are tolerant of substitutions by a variety of amino acids. Since a number of these amino acids (Thr-320, Val-331, Phe-325, and Ile-317) are clustered in one region in a helical wheel projection of transmembrane helix 10, it seems likely that this face of helix 10 is interacting with the membrane. The channel lining domain is thought to consist of the helical face containing Glu-325, Leu-318, Leu-329, His-322, Val-315, Cys-333, Val-326, and Lys-319 based on the results here and from earlier findings. Deleterious mutations along this face tended to greatly increase the Km value for lactose transport with only minor effects on the Vmax. Analysis of insertional mutants revealed that perturbation of the spatial relationship between amino acids at the periplasmic edge is less deleterious than perturbation in the center of the helix or the cytoplasmic edge. Using all of the above information, a detailed structural topology of transmembrane helix 10 is proposed.
Human butyrophilin was cloned and sequenced from a human breast cDNA library. The derived amino acid sequence shows 84% sequence identity and identical domain arrangements with the previously reported bovine sequence. Sequence analysis reveals an immunoglobulin constant (IgC) domain that was not previously identified in the bovine sequence. The extracellular domain composition of butyrophilin suggests a cell surface receptor function.
Fifty-two pairs of maternal and cord blood samples were examined for evidence of Toxocara canis antibodies. All the mothers in the study delivered normal babies at term. Seventeen (33%) of the mothers had Toxocara antibody titres of 1:50 or greater. No IgM isotype anti-Toxocara antibody was detected in the cord blood samples, evidence that transplacental toxocaral infection had not occurred. In the toxocara antibody-positive group it was found that six of 17 mothers (35%) had previously miscarried compared with three of 35 (8.6%) of the toxocara-negative mothers (P = 0.044).
There is a reported association between antiepithelial cell (AEC) antibodies and increased renal allograft loss in paediatric recipients. Our unit experienced a dramatic fall in 1-year graft survival so we undertook a study to determine if AEC antibodies could account for such losses. We also studied healthy children and adults as well as a group of individuals with serologically proven viral infection in an attempt to determine the prevalence and possible aetiology of these antibodies. Sera were screened for AEC antibodies in a microcytotoxicity test using a lung epithelial cell line (A549) as target. The prevalence of these antibodies in our paediatric recipients was similar to that reported elsewhere but we found no correlation between the presence of AEC antibody and allograft loss. Within the control populations, we found the antibody was more prevalent in children than in adults (p < 0.0001). We also found a strong age banding pattern, with antibody being present in 50% of children under 10 years and declining with increasing age, so that by the age of 16 years the seroprevalence was similar to that found in our adults. However, AEC antibody had a significantly higher prevalence in individuals with active viral infection than in our healthy control groups (p = 0.00003). A positive association was noted between rubella and respiratory syncytial virus and AEC antibody presence and a negative association with varicella zoster. We conclude that AEC antibodies do not correlate with increased paediatric renal allograft loss but appear to be linked to certain viral infections.
The BA46 antigen of the human milk fat globule (HMFG) membrane is expressed in human breast carcinomas and has been used successfully as a target for experimental breast cancer radioimmunotherapy. To characterize this antigen further, we obtained the entire cDNA sequence and focused on its possible role in cell adhesion. The derived protein sequence of BA46 encodes a 387-residue precursor composed of a putative signal peptide, an amino-terminal epidermal growth factor (EGF)-like domain containing the cell adhesion tripeptide arginine-glycine-aspartic acid (RGD), and human factor V and factor VIII C1/C2-like domains. The EGF-like domain of BA46 is similar to the calcium-binding EGF-like domains of several coagulation factors, but the BA46 domain lacks a residue required for calcium binding and the coagulation factor domains do not include an RGD sequence. Assuming that all EGF-like domains fold into a similar structure, the RGD-containing sequence in BA46 is inserted between two antiparallel beta strands. This positioning suggests a novel function for the EGF-like domain as a scaffold for RGD presentation.
In an earlier report we showed that the 5' end of the gene for ataxia telangiectasia ATM is within 700 bp of the 5' end of a novel gene E14, and suggested that the CpG island that separates these genes functions as a bidirectional promoter. We have now determined the complete amino acid sequence of the E14 protein, defined the exon/intron structure of the gene and estimate that the complete gene is more than 55 kb in length. The E14 gene appears to be a housekeeping gene that is expressed in all tissues, including all parts of the brain. The E14/ATM promoter organisation is conserved in man, monkey and mouse, although the mouse promoter is more compact and appears to lack two of the four putative Sp1 boxes found in the human promoter. Reporter gene constructs showed that the human and mouse E14/ATM promoters were indeed bidirectional, that the ATM side of the human promoter was three times stronger than the E14 side, and that the mouse promoter (in human cells) directed transcription with equal efficiency in both directions, but at a lower level than the human promoter. Analysis of a small number of A-T patients for mutations in the promoter region or the E14 coding sequence did not provide evidence to suggest that E14 contributes to the A-T phenotype.
We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10%-15% of A-T families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize.
Evidence is presented for two different breast epithelial antigens that some epitopes have greater tumor specificity and are more effective targets for radioimmunotherapy than others. The two antigens, which are major components of the human milk fat globule membrane, are breast mucin and a M(r) 46,000 glycoprotein (BA46). Of five monoclonal antibodies (Mc5, Mc1, BrE-1, BrE-2, and BrE-3) against breast mucin, all recognize overlapping amino acid epitopes on the tandem repeat domain. However, each have unique and different tissue and tumor specificities and unique epitope structures on the fully glycosylated breast mucin. In preclinical studies, radioimmunoconjugates of all five monoclonal antibodies inhibit growth of transplantable breast tumors in immunodeficient mice. In human clinical trials, radioiodinated Mc5 was very poor in localizing breast tumor metastases. On the other hand, 111In-labeled BrE-3 imaged almost 90% of breast tumors and showed promise in radioimmunotherapy when labeled with 90Y. The failure of Mc5 in clinical trials may be partly attributed to the high levels of its epitope on circulating mucin compared to the epitope of BrE-3. The Mc5 binding affinity increased significantly with glycosylation, while the BrE-3 epitope was masked by glycosylation. The BA46 glycoprotein is a breast tumor-associated membrane antigen containing an NH2-terminal, epidermal growth factor-like domain into which a cell adhesion sequence (RGD) is inserted and a COOH-terminal domain with homology to the phospholipid binding C1/C2 domain of coagulation factors V and VIII. It promotes cell attachment in an RGD-dependent manner. Monoclonal antibody Mc8, which binds to the C2-like domain, is only moderately effective in experimental radioimmunotherapy, while Mc3, which binds an epitope in the EGF-like RGD domain, was highly effective in destroying breast tumors in nude mice. With 90Y-labeled Mc3, 6 of 7 mice are cured of the tumors. These results indicate that by selecting appropriate monoclonal antibodies, a normal antigen can be used as a target for radioimmunotherapy.
In order to evaluate the diagnostic usefulness of Gram-staining films from petechial lesions in suspected meningococcal infection, data from 52 patients with confirmed infection were reviewed. Gram-negative diplococci were found in specimens from skin films in 80% (24/30) patients with petechiae. This is significantly better than results reported for Gram-staining of needle aspirates from petechiae (46%; 12/26). Positive skin films were obtained from 89% (17/19) blood culture negative cases and 85% (17/20) CSF negative cases. In 14 cases meningococcal infection was identified only by skin films. Skin film results were not significantly affected by previous antibiotic. Gram-staining of films from petechial lesions in suspected meningococcal infection is a very rapid and effective investigation. Blood culture, CSF examination and culture, and skin films each identified meningococcal infection not identified by the other two investigations.
The seroprevalence of toxocariasis was investigated in 2129 school children ranging in age from 4 to 19 years. Infection, as measured by titre, was found to be high compared to values obtained from children in other countries, with 31% having a titre of > or = 1:50 and 3.1% having titres of > or = 1:800. Relationships between seroprevalence and host factors including age, sex and location, and risk factors including geophagia, thumbsucking and pet ownership were explored. Age was found to be a significant factor in relation to infection with Toxocara. Males were significantly more infected than females, as were the inhabitants of rural schools versus urban schools. The percentage of seropositive children varied widely from school to school. Geophagia and pet ownership were found to be significantly associated with toxocariasis. Logistic regression analysis was used to model the relative contribution of these factors to infection with Toxocara. While this analysis identified factors which were highly significantly associated with Toxocara titre, the odds ratios were generally low indicating the low specificity of the model.
Scientific developments have increased awareness of possible links between diet and health within the scientific community and in the general public and have generated interest in the use of disease-related health claims on food labels. The enactment of the Nutrition, Labeling, and Education Act for the first time authorizes such claims if they are claims approved by FDA. From FDA's perspective, it is imperative that statements regarding potential health benefits of changes in nutrient intake also take into consideration potential health risk. The ultimate goal must be to capitalize on available scientific evidence and the communication capacity of the food label to assist the consumer in constructing healthier diets.
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A two part 8.5 month study was undertaken to see if peak expiratory flow rate (PEFR) could be used to guide casualty officers deciding whether to admit or discharge children with asthma. In part 1 PEFR, immediate treatment, and admission or discharge of all children attending because of asthma were recorded. In part 2 the same information was recorded after the introduction of admission and discharge guidelines based on PEFR. After the introduction of guidelines the proportion of children admitted with a PEFR > or = 40% expected after casualty treatment fell from 43% to 26% (part 1 44/101, part 2 38/145). For a PEFR > 60% the rate fell from 23% to 5% (part 1 12/52, part 2 4/80). There was no significant change in the reattendance rate. PEFR can help to reduce unnecessary admissions, provided appropriate normal values and guidelines are supplied.
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