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Biomedical subjects

B Tait

Publications and source records attributed to B Tait.

At least 19 recordsLinked to original sources

Flagging the pain: preventing the burden of chronic pain by identifying and treating risk factors in acute pain.

Chronic pain represents a major public health problem that impacts negatively on quality-of-life issues and healthcare costs. Unrelieved acute post-traumatic and postoperative pains are risk factors in the development of chronic pain, although psychological and environmental factors are at work as well. Flagging pain (blue, yellow and red flags) helps to identify risk factors in acute pain that need attention to avoid the transition from acute postoperative pain to acute persistent and then on to chronic pain. This offers a unique opportunity for preventative medicine.

Acute Disease↗

Micro-Raman characterisation of the R to T state transition of haemoglobin within a single living erythrocyte.

We present the first recorded Raman spectra of haemoglobin in both the R and T states from within a single living erythrocyte using 632.8 nm excitation. Bands characteristic of low spin haems are observed in oxygenated and carboxylated erythrocytes at approx. 1636 (nu(10)), 1562-1565 (nu(2)), 1250-1245 cm(-1) (nu(13)) and 1226-1224 cm(-1) (nu(5)+nu(8)). The spectra of deoxygenated and methaemoglobin erythrocytes have characteristic high spin bands at approx. 1610-1606 cm(-1) (nu(10)), 1582-1580 (nu(37)), 1547-1544 (nu(11)), 1230-1220 cm(-1) (nu(13)) and 1215-1210 cm(-1) (nu(5)+nu(8)). Bands at 1172 (nu(30)), 976 (nu(45)) and 672 (nu(7)) cm(-1) appear to be enhanced at 632.8 nm in low spin haems. The oxidation state marker band (nu(4)) at 1364-1366 cm(-1) appeared invariant within this domain in all single cells and conditions investigated contrary to other resonance Raman studies on haem isolates. The information gained by in vivo single erythrocyte molecular analysis has important ramifications to the understanding of fundamental physiological processes and may have applications in the diagnosis and treatment of red blood cell disorders.

Erythrocytes↗

Unearthing the conflicts between carer and custodian: implications of participation in Section 16 hearings under the Mental Health (Compulsory Assessment and Treatment) Act (1992).

Mental health nursing occurs within a legal and ethical framework that presents conflicts between a paternalistic custodial role and an ethical commitment to autonomy. This paper considers the ethical conflict for nurses posed by acting as second health professional at judicial reviews under Section 16 of the Mental Health (Compulsory Treatment and Assessment) Act. Issues of advocacy and paternalism are discussed in light of the conflict between therapeutic and legislated roles. Strategies aimed at protecting the therapeutic relationship are outlined as a response to the current lack of guidelines in this area. Participation in legal processes of committal requires that nurses reflect carefully and critically on the ethical issues raised.

Authoritarianism↗

Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody.

AIMS/HYPOTHESIS: To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. METHODS: We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was sampled every 6 months for IAA, GADAb and IA2Ab. RESULTS: We did not find any antibodies in 263 (73%) infants; 50 (14%) were positive for a single antibody once, 19 (5%) for a single antibody more than once and 25 (7%) for two or more antibodies. Of the latter, 10 (2.8% overall) were persistently positive; they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64% of infants with two or more antibodies. CONCLUSION/INTERPRETATION: Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient 'self limited' islet autoimmunity in at risk infants.

Aging↗

Fourier-transform infrared spectroscopy as a tool for detecting early lymphocyte activation: a new approach to histocompatibility matching.

Fourier transform infrared (FT-IR) spectroscopy due to its speed and sensitivity is becoming an increasingly powerful tool in the study of cell composition. We outline the potential of FT-IR microspectroscopy in monitoring mitogenic and cell mediated lymphocyte activation. We demonstrate the potential of FT-IR spectroscopy in histocompatibility testing by showing that significant spectral differences (p < 0.001, for the mean integrated intensity of phosphodiester band located in the 1142-996 cm(-1) region) exist between lymphocyte cocultures from pairs of HLA matched and mismatched volunteers after only 90 min of incubation. The preliminary results indicate that early spectral changes measured are due to HLA differences between individuals, although the relative contribution of class I and class II differences has yet to be determined. FT-IR spectroscopy represents a novel approach to histocompatibility matching and the rapidity and sensitivity of the technique indicates a potential role in matching protocols for clinical use, particularly in allogeneic bone marrow transplantation.

Analysis of Variance↗

Clinical features and pathogenesis of thyrotoxicosis in adult Melanesians in Papua New Guinea.

OBJECTIVE: To investigate the cause of an apparent increase in the incidence of thyrotoxicosis in the Melanesian population of the coastal areas around Port Moresby, Papua New Guinea. DESIGN: Consecutive patients attending the thyroid clinic at Port Moresby General Hospital were included in the study which collected clinical and immunogenetic data. PATIENTS: One hundred and ninety-four patients with thyrotoxicosis were studied. The mean age was 31 years. The clinical features were typical for thyrotoxicosis apart from increased pigmentation, which occurred in the majority of patients and which reversed with treatment with antithyroid drugs and resolution of the thyrotoxicosis. MEASUREMENTS: Antibodies to thyroid peroxidase, thyroglobulin and the thyrotropin receptor were present in 99%, 52% and 69% of patients, respectively, confirming that all cases were caused by autoimmune thyroid disease. Fine needle aspirations in 42 of 43 patients were consistent with Graves' disease. CONCLUSIONS: The cause of this apparent sudden increase in Graves' disease in the coastal region around Port Moresby, an apparently iodine-replete area, remains unexplained.

Adult↗

Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity.

The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.

Aging↗

FTIR microspectroscopic study of cell types and potential confounding variables in screening for cervical malignancies.

FTIR microscopy was applied to the analysis of cell types and other variables present in Pap smears to ascertain the limitations of infrared spectroscopy in the diagnosis of cervical cancer and dysplasia. It was found that leukocytes, and in particular lymphocytes, have spectral features in the phosphodiester region (1300-900 cm[-1]) suggestive of what has previously been described as changes indicative of malignancy. Endocervical cells and fibroblasts have similar spectral features to HeLa cells and consequently could also confound diagnosis. The use of ethanol as a fixative and dehydrating agent results in retention of glycogen in cervical cell types and thus minimizes spectral changes in the glycogen region due to sampling technique. Spectra of seminal fluids exhibit strong bands in the phosphodiester/carbohydrate region; however, sperm contamination should be easily detectable by the presence of a distinctive doublet at 981/968 cm(-1). Erythrocyte spectra exhibit a reduction in glycogen band intensity, but can be discerned by a relatively low-intensity nu(s) PO2- band. Endocervical mucin spectra exhibit a reduction in glycogen bands and a very pronounced nu(s) PO2- band, which is similar in intensity to the corresponding band in HeLa cells. Thrombocytes have strong bands in the phosphodiester region, but thrombocytes can be discerned from other cell types by the presence of two small broad bands at 980 and 935 cm(-1). Candida albicans is characterized by strong bands in the polysaccharide region which could potentially obscure diagnostic bands if C. albicans is present in large numbers. Spectra of bacteria common to the female genital tract, in general, also have strong absorptions in the polysaccharide region; however, bacterial contamination is usually minimal and would not be expected to obscure cervical cell spectra. Nylon threads and bristles from cervical sampling implements produce characteristic IR profiles which allow for easy identification. Given the number of potential confounding variables associated with cervical cytology, a multivariate statistical or neural network analysis would appear to be necessary before the implementation of FTIR technology in clinical laboratories.

Biopsy↗

Hydrophobicity of HIV protease inhibitors by immobilized artificial membrane chromatography: application and significance to drug transport.

PURPOSE: The feasibility of using hydrophobicity measurements as screens for intracellular availability in T-cells or intestinal permeability in Caco-2 cells was examined. METHODS: T-cell experiments: Cells were counted, collected, then incubated with drug solution at 37 degrees C. At selected time intervals, uptake was quenched by transferring a sample into oil, followed by rinsing, lysis of cells, protein precipitation and analysis by HPLC. Caco-2 cell experiments: Cells were grown on plastic dishes for 7-10 d, then rinsed and incubated with drug solution at 37 degrees C. Uptake was quenched, cells were lysed, protein precipitated and drug was analyzed by HPLC. IAM chromatography: Stock solutions were injected onto an IAM column for HPLC. Mobile phase consisted of varying amounts of acetonitrile in buffer (pH 7.4). The capacity factor, k'IAM, was calculated using citric acid to measure the void volume and was obtained by extrapolation to pure buffer. RESULTS: Nine HIV protease inhibitors were studied for uptake by CEM T-cell suspensions or Caco-2 cell monolayers. Capacity factors (log) between IAM and C-18 columns were positively correlated for this series. Caco-2 uptake rates correlated well with T-cell uptake rates when normalized by protein mass. Single-variable regression using IAM or C-18 columns was acceptable for analysis of T-cell data. Correlation coefficients between T-cell uptake and log k'IAM or log k'C-18 were not improved with multivariable regression. Correlation between Caco-2 uptake and log k'IAM was enhanced when molecular weight and hydrogen-bonding potential were included in multivariable regression analysis (from r2 of 0.39 to 0.91). Correlations obtained using log k'IAM, log k'C-18 or log distribution coefficient (log D) were comparable when regressed against Caco-2 uptake using this approach. Calculated log partition coefficient (ClogP) provided the poorest correlation in the multivariable analysis (r2=0.57 for T-cell uptake and r2=0.71 for Caco-2 cell uptake). CONCLUSIONS: Uptake of HIV protease inhibitors by T-cell suspensions or Caco-2 cell monolayers was positively correlated. Uptake by T-cell suspensions was adequately described by hydrophobicity alone. Description of uptake by Caco-2 cell monolayers required multivariable regression analysis in which molecular weight and hydrogen bonding were included. Experimental measures of hydrophobicity (log k'IAM, log k'C-18 and log D) were superior to ClogP in the correlation analysis.

Biological Transport↗

Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein.

Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.

Adenocarcinoma↗

Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties.

1. 15-Lipoxygenase (15-LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15-LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol-fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties. 2. PD 146176 inhibited rabbit reticulocyte 15-LO through a mixed noncompetitive mode with a Ki of 197 nM. The drug had minimal effects on either copper or 2,2'-azobis(2-amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the Ki. 3. Control New Zealand rabbits were fed a high-fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg-1, b.i.d.). Plasma concentrations of inhibitor were similar to the estimated Ki (197 nM). During the 12 week study, there were no significant differences in weight gain haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol. 4. The drug plasma concentrations achieved in vivo did not inhibit low-density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176-treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. 5. PD 146176 was very effective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15 +/- 4 to 0% (P < 0.02); esterified cholesterol content was reduced from 2.1 +/- 0.7 to 0 micrograms mg-1 (P < 0.02) in this region. Immunostainable lipid-laden macrophages present in aortic intima of control animals were totally absent in the drug-treated group. 6. Results of these studies are consistent with a role for 15-LO in atherogenesis.

Animals↗

Use of monoclonal antibodies to detect disease associated HLA-DRB1 alleles and the shared epitope in rheumatoid arthritis.

OBJECTIVE: To use a panel of monoclonal antibodies (Mab) which recognise HLA class II alleles associated with rheumatoid arthritis for fluorescence activated cell sorter (FACS) analysis of peripheral blood mononuclear cells (PBMNC) from patients with early and established rheumatoid arthritis and to compare these results against DNA oligotyping of HLA class II molecules in the same patients. METHODS: 27 patients (18 from an early arthritis clinic, nine with established rheumatoid arthritis) were studied using both techniques. PBMNC were stained with Mab which recognise the shared epitope, the HLA-DRB1*04 molecule and its* 0401, *0404 subtypes in the presence of bound peptide. Mab stained cells were analysed by FACS. Genomic DNA was prepared from PBMNC and use for DNA oligotyping and sequencing by standard methods. RESULTS: FACS analysis of Mab stained PBMNC gave identical results to those obtained by DNA oligotyping in 26/27 patients. The antibodies identified the shared epitope in 14/14 cases and the presence of an HLA-DRB1*04 molecule in 12/12 cases. HLA-DRB1*0404 was identified in 4/4 cases. HLA-DRB1*0401 was identified in 5/6 cases. One patient oligotyped as HLA-DRB1*0401, but consistently failed to react with the *0401 Mab. DNA sequencing of the second exon of the HLA-DRB1*0401 allele in this patient confirmed a normal HLA-DRB1*0401 genotype. CONCLUSIONS: FACS analysis of PBMNC stained with Mab recognising the shared epitope and rheumatoid arthritis associated HLA susceptibility molecules provides a rapid, reliable, and more accessible alternative to DNA oligotyping. The apparent discordance between phenotypic and genetic analysis of HLA-DRB1*0401 in one patient, may reflect variability in HLA-DRB1*0401 gene expression or in class II peptide presentation.

Alleles↗

Immunosusceptibility genes in rheumatoid arthritis.

The polygenic predisposition to RA is conferred particularly by disease susceptibility sequences in the HVR3 of HLA DRB1 present in those subtypes of DR4 and DR1 that are associated with RA. The aim of this study was to examine predisposing interactions between genes encoding HLA and immunoglobulin molecules. Accordingly, we compared the genetic background of 114 Australian patients with RA with that of Australian controls of similar ethnic background. We identified HLA-A, B, and DR phenotypes serologically, HLA-DR, DQ alleles, and subtypes of DR4 by DNA typing, and Gm allogenotypes and immunoglobulin switch region polymorphisms by RFLP. For the subjects with RA, we confirmed previously reported observations that included an excess of females, 71%, a high frequency of HLA types DR4 or DR1 of 77% versus controls 47%, and a high frequency of the HVR3 susceptibility sequences of 76%, with 24% homozygous, and 52% heterozygous for the sequences. We observed other genetic correlations in RA that included increases in frequencies of DR4 in males, DR1 in females, the class I specificity HLA-B27 overall but more particularly in females, 24% in females, versus 5% of controls, HLA-DQB1*0302 (DQ8) in DR4*0401-positive patients, and the Gm allogenotype 1,2,3;23 +/- ; 5,10, 15% of patients versus 4% of controls. Examination of switch region genes gave no evidence of differences in the polymorphisms distributions. Thus, the major genetic risks for RA that are conferred by female gender and the HVR3 of HLA DRB1 are modulated by interactions between gender and HLA class I and class II alleles, and the Gm allogenotype.

Adult↗

Vogt-Koyanagi-Harada syndrome in patients of Vietnamese ancestry.

BACKGROUND: Vogt-Koyanagi-Harada syndrome (VKH), is an idiopathic, multisystem inflammatory disorder primarily involving the eye. HLA typing has shown a strong association between the HLA-DR4 antigen and people of Japanese, Han Chinese and Hispanic ancestry with VKH. This study reviewed the clinical features and HLA typing of Vietnamese patients with VKH. PATIENTS AND METHODS: A retrospective review of four unrelated Vietnamese patients with VKH seen in private practice and hospital clinic. The American Uveitis Society (1978) criteria for VKH diagnosis were satisfied. Standard microcytotoxic assays for Class I antigens and HLA-DNA typing of Class II DR antigens (DRB1 genotyping) by the PCR-SSO method were performed. RESULTS: The clinical features of VKH in Vietnamese were comparable to those seen in other Asian races. HLA-DR4 was present in three of the four VKH patients. Two of these patients also expressed the allele DRB1*0405. DISCUSSION: The strong association between HLA-DR4 and the DRB1*0405 allele and VKH seen in Japanese people, may well also exist in Vietnamese people. The HLA association suggests an immunogenetic predisposition to VKH.

Adult↗

Cell proliferation and expression of EGF, TGF-alpha, and EGF receptor in the developing primary palate.

Growth factors such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) play an important role in cell proliferation during embryogenesis. The purposes of the study were to characterize the expression patterns of EGF and TGF-alpha and their receptor, EGF receptor (EGF-R), and to analyze regional patterns of cell proliferation during primary palate morphogenesis when facial primordia outgrow and fuse to form the premaxillary and upper lip regions. The expression of all molecules was studied with indirect immunohistochemistry with conventional and/or confocal microscopes in normal days 10 and 11 CD1 mice. 5-Bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA) were used as markers of cell proliferation. EGF, TGF-alpha, and EGF-R were found to have similar distribution patterns at all stages examined. In the anterior region of the face, the molecules were intensely localized at the tips and peripheral regions of the medial and lateral nasal prominences. Upon fusion of the facial prominences, all three molecules were present mainly at the fusion area and the tips and peripheral areas of the maxillary and nasal prominences. BrdU and PCNA were found to have distribution patterns similar to those of EGF, TGF-alpha, and EGF-R, with intense staining at the tips and peripheral regions of the facial prominences. These results show that EGF, TGF-alpha, and their receptor were expressed more intensely in regions of the developing primary palate where cell proliferation was most pronounced, and suggest that EGF, TGF-alpha, and EGF-R may play a role in cell proliferation during morphogenesis of the primary palate.

Animals↗

Competitive inhibition of HIV-1 protease by biphenyl carboxylic acids.

A novel series of nonpeptidic compounds that contain a biphenyl carboxylic acid group have been shown to inhibit HIV-1 protease. The active compounds, most of which are highly soluble, have IC50 values in the range of 3.4-74 microM. The structure-inhibitory activity relationship demonstrates the necessity of the biphenyl carboxylic acid group for inhibition, which is enhanced by the presence of a sulfone group and by halogenation of an adjacent phenyl group. A double reciprocal plot of inhibition data on two of the compounds clearly shows that the inhibition occurs in a competitive manner, with Ki values of 1.1 and 3.4 microM. Inhibition by several of the compounds was found to be reversible and fast-binding, while one of the biphenyl carboxylic acids inhibits in a reversible slow-binding manner. Time-dependent inhibition studies were conducted on this compound, and it was determined to have the kinetic values of kon = 0.18 microM-1min-1, koff = 9.7 x 10(-2)min-1, and Ki = 0.14 microM. Thus, the slow-binding inhibitor is the most potent in the series. Molecular modeling has provided information on a possible binding mode for two different biphenyl carboxylic acid inhibitors of HIV-1 protease.

Amino Acid Sequence↗