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1.  Comparative mutagenicities of N6-methoxy-2,6-diaminopurine and N6-methoxyaminopurine 2'-deoxyribonucleosides and their 5'-triphosphates. 
Nucleic Acids Research  1998;26(5):1144-1149.
The structure of the deoxyribonucleoside derived from N 6-methoxy-2, 6-diaminopurine (dK) was examined by NMR. The methoxyamino residue was found predominantly in the imino rather than the amino tautomer (ratio: 9:1 in DMSO). The nucleoside proved to be a potent transition mutagen in Escherichia coli , in contrast to the closely related nucleoside derived from the analogue N6-methoxyaminopurine (dZ), which was only weakly mutagenic. The 5'-triphosphate derivatives, dKTP and dZTP, were synthesized; Taq polymerase incorporated dKTP opposite both T and, less well, opposite dC in template DNA. Both analogue triphosphates produced transition mutations when added to PCR reactions. In each case, there was a large excess of AT-->GC compared to GC-->AT mutations (ratios were 15:1 for dKTP and 10:1 for dZTP). Polymerase extension times in each cycle had to be extended, consistent with a decreased rate of DNA synthesis in the presence of the analogues. This and the mutagenic ratios are discussed in terms of syn-anti inversion of the methoxyl group.
PMCID: PMC147402  PMID: 9469819
2.  The mechanism of mutation induction by a hydrogen bond ambivalent, bicyclic N4-oxy-2'-deoxycytidine in Escherichia coli. 
Nucleic Acids Research  1997;25(8):1548-1552.
The triphosphate of the nucleoside deoxyribosyl dihydropyrimido[4,5-c][1,2]oxazin-7-one (dP) is known to be incorporated into DNA efficiently by Taq polymerase and is a useful tool for polymerase-mediated in vitro mutagenesis. It is shown here that dP is a potent mutagen in Escherichia coli and Salmonella typhimurium . In E.coli , this deoxycytidine analog induces both GC-->AT and AT-->GC transitions. No induced transversions are observed. It is highly mutagenic in wild-type E.coli, but this is much reduced in a strain lacking thymidine kinase. Mutagenesis induced by dP is efficiently inhibited by the addition of thymidine. Partially purified thymidine kinase from E.coli catalyzes phosphorylation of dP to its 5'-monophosphate. When E.coli was grown in the presence of dP, the nucleoside analog was incorporated into its DNA. The content of dP in DNA was dependent on the concentration of dP added to the medium. The incorporation characteristics of the 5'-triphosphate of dP (dPTP) were also studied using E.coli DNA polymerase I large fragment. The results confirm that this triphosphate can be incorporated opposite A and G in the template with similar efficiencies. This indicates that dP is metabolized as a thymidine analog and that the resulting triphosphate induces a high rate of mutagenesis through replicational errors.
PMCID: PMC146628  PMID: 9092660
3.  Role of CD8 T cells in primary Chlamydia infection. 
Infection and Immunity  1995;63(2):516-521.
The role of CD4 and CD8 T cells in primary Chlamydia trachomatis pneumonia was investigated by using in vivo depletion techniques to eliminate T-cell populations. Reduction of either CD4 T cells or CD8 T cells caused a significant increase in organism burden in the lungs, as measured by both quantitative culture and detection of chlamydial antigen on day 14 postinfection. Chlamydia-specific antibody levels in plasma or antigen-induced gamma interferon (IFN-gamma) production by spleen cells was dramatically reduced by depletion of CD4 cells. The reduction in IFN-gamma achieved by depletion of CD8 cells did not reach statistical significance. In the survival studies, depletion of CD4 cells led to a significant increase in mortality. Although there was a trend toward higher mortality, depletion of CD8 cells did not significantly increase mortality. The role of CD8 T cells in host defense was clarified in studies using beta 2-microglobulin-deficient (major histocompatibility class I antigen-deficient, C1D) mice which are defective in CD8 T-cell function. In this model, a significant increase in organism burden was seen during infection in C1D mice compared with that C57BL/6 controls and a significant increase in mortality was observed as well. However, surviving C1D mice were able to clear the infection by day 34. C1D mice had increased numbers of CD4 T cells in both the spleen and the lungs during infection compared with those of C57BL/6 controls. IFN-gamma in C57BL/6 mice was produced by both CD4 and CD8 cells. Thus, there is a protective role for both CD4 and CD8 cells in host defense against Chlamydia infection, but the former appear to be dominant.
PMCID: PMC173025  PMID: 7822016
4.  Gamma interferon levels during Chlamydia trachomatis pneumonia in mice. 
Infection and Immunity  1993;61(8):3556-3558.
Host defense against murine Chlamydia trachomatis (mouse pneumonitis agent [MoPn]) in a murine model was investigated. Gamma interferon (IFN-gamma) was produced in the lungs by both MoPn-susceptible nude athymic (nu/nu) and MoPn-resistant heterozygous (nu/+) mice. In vivo depletion of IFN-gamma in nu/nu mice led to exacerbation of infection. Fluorescence-activated cell sorter analysis disclosed induction of GL3 antibody-positive cells (putatively gamma/delta+ T cells) in nu/nu mouse lung during infection with MoPn. Treatment of nu/nu mice in vivo with antibody to NK cells (anti-asialo GM1 antibody) or to gamma/delta cells (UC7-13D5) did not significantly decrease IFN-gamma production in the lung. However, treatment of severe combined immunodeficiency mice (which lack gamma/delta cells) with antibody to NK cells significantly reduced lung IFN-gamma levels.
PMCID: PMC281040  PMID: 8335389
5.  Chlamydia trachomatis pneumonia induces in vivo production of interleukin-1 and -6. 
Infection and Immunity  1992;60(3):1217-1220.
Cytokine induction during Chlamydia trachomatis pneumonia may alter the pathogenesis or course of disease. We examined interleukin-1 (IL-1) and IL-6 production by measuring mRNA and bioactivity in murine lungs. mRNA and bioactivity for IL-1 alpha, IL-1 beta, and IL-6 increased after Chlamydia infection. These cytokines may be important in regulating host defenses against C. trachomatis.
PMCID: PMC257615  PMID: 1541536
6.  Role for CD8+ T cells in antichlamydial immunity defined by Chlamydia-specific T-lymphocyte clones. 
Infection and Immunity  1994;62(11):5195-5197.
The role of CD8+ T cells in antichlamydial immunity was investigated in a murine model of chlamydial genital infection by using T-cell clones generated against the Chlamydia trachomatis agent of mouse pneumonitis (MoPn). Two CD8+ T-cell clones tested (2.1F and 2.14-9) were chlamydia antigen specific and MHC restricted and reacted against MoPn as well as the Chlamydia psittaci agent of guinea pig inclusion conjunctivitis and C. trachomatis serovar E, suggesting the recognition of a genus-specific antigen. Upon adoptive transfer into persistently MoPn-infected nu/nu mice, 55.6% of the recipients of clone 2.1F (15 of 27) resolved the infection but recipients of clone 2.14-9 did not. The ability to resolve the MoPn infection correlated with the capacity of clone 2.1F to elaborate a combination of gamma interferon and tumor necrosis factor alpha. The results suggested that in addition to CD4+ T cells, CD8+ T cells may also contribute to antichlamydial T-cell immunity in vivo.
PMCID: PMC303248  PMID: 7927806
7.  Production of colony-stimulating factors during pneumonia caused by Chlamydia trachomatis. 
Infection and Immunity  1991;59(7):2370-2375.
The colony-stimulating factors (CSFs) are cytokines involved in the production, differentiation, and activation of host phagocytes. During murine infection with Chlamydia trachomatis (MoPn), plasma CSF levels increased in euthymic (nu/+) and athymic (nu/nu) BALB/c mice. Levels declined later in infection, with the nu/+ mice resolving the infection but the nu/nu mice succumbing by day 16. Either live or heat-killed Chlamydia organisms could induce CSF increases on day 7 postchallenge in nu/+ mice; however, by day 14, only mice challenged with live organisms maintained high plasma levels. CSFs were also produced by spleen cells of nu/+ and nu/nu mice in response to Chlamydia antigen. Spleen cell CSF production was detectable by days 3 to 5 postinfection. In nu/+ mice, spleen cell CSF production was elevated throughout the rest of the time course but in nu/nu mice fell significantly at day 14. Like the plasma CSF activity (CSA) production, spleen cell CSA production on day 7 was seen in mice challenged with either live or heat-killed Chlamydia organisms, but on day 14 only nu/+ mice challenged with live organisms maintained significant CSA production. To further characterize the T-cell dependence of CSA production, spleen cells of nu/+ mice were depleted of T cells or T-cell subsets before producing supernatants. On day 14 postinfection, the CD4+ lymphocyte was the major producer of CSFs. Additionally, there were different types of CSFs secreted by nu/+ and nu/nu mice as determined by the ability of spleen cell supernatants to support the granulocyte-macrophage CSF/interleukin 3-dependent cell line FDCP-1. Supernatants from nu/+ mice had 4 to 8 times the level of FDCP-1 CSF activity of the supernatants from nu/nu mice. These results support the evidence that nu/+ mice were producing some CSFs by T-cell-dependent mechanisms. This is the first report of CSF production in vivo during Chlamydia infection. Furthermore, we show that CSFs are produced by both T-cell-dependent and T-cell-independent mechanisms. The capacity of the CSFs to increase the production and effector function of phagocytes may be important to host defenses.
PMCID: PMC258020  PMID: 1828791
8.  A role in vivo for tumor necrosis factor alpha in host defense against Chlamydia trachomatis. 
Infection and Immunity  1990;58(6):1572-1576.
In a mouse model of pneumonia caused by murine Chlamydia trachomatis (mouse pneumonitis agent [MoPn]), tumor necrosis factor alpha (TNF-alpha) antigen and bioactivity were demonstrated in vivo in the lung during MoPn infection in both athymic (nude) and heterozygous (nu/+) mice. Antibody to TNF-alpha that was exogenously given neutralized the TNF-alpha in the lung, significantly accelerated mortality, and caused a borderline increase in MoPn counts in the lung by culture in nu/+ mice. Lipopolysaccharide-induced TNF-alpha activity or injections of recombinant murine TNF-alpha significantly but modestly protected nu/+ mice against MoPn-induced mortality. TNF-alpha is produced in vivo during C. trachomatis infection and plays a role in host defense.
PMCID: PMC258678  PMID: 2341167
9.  Tumor necrosis factor alpha is a cytotoxin induced by murine Chlamydia trachomatis infection. 
Infection and Immunity  1989;57(5):1351-1355.
A mouse model of pneumonia caused by murine Chlamydia trachomatis (mouse pneumonitis agent) was used to demonstrate that whole spleen cells from both nude athymic mice (nu/nu) and heterozygous mice (nu/+) produced tumor necrosis factor alpha in vitro in response to mouse pneumonitis agent antigen. The tumor necrosis factor alpha measured in these supernatants by immunoassay was shown to have bioactivity in a cytotoxic assay in which uninfected target cells were used. This cytotoxicity was distinct from the gamma interferon-related cytotoxicity against C. trachomatis-infected targets that we described previously.
PMCID: PMC313281  PMID: 2707849
10.  Global Oral Health Inequalities 
Advances in Dental Research  2011;23(2):207-210.
Despite impressive worldwide improvements in oral health, inequalities in oral health status among and within countries remain a daunting public health challenge. Oral health inequalities arise from a complex web of health determinants, including social, behavioral, economic, genetic, environmental, and health system factors. Eliminating these inequalities cannot be accomplished in isolation of oral health from overall health, or without recognizing that oral health is influenced at multiple individual, family, community, and health systems levels. For several reasons, this is an opportune time for global efforts targeted at reducing oral health inequalities. Global health is increasingly viewed not just as a humanitarian obligation, but also as a vehicle for health diplomacy and part of the broader mission to reduce poverty, build stronger economies, and strengthen global security. Despite the global economic recession, there are trends that portend well for support of global health efforts: increased globalization of research and development, growing investment from private philanthropy, an absolute growth of spending in research and innovation, and an enhanced interest in global health among young people. More systematic and far-reaching efforts will be required to address oral health inequalities through the engagement of oral health funders and sponsors of research, with partners from multiple public and private sectors. The oral health community must be “at the table” with other health disciplines and create opportunities for eliminating inequalities through collaborations that can harness both the intellectual and financial resources of multiple sectors and institutions.
PMCID: PMC3144034  PMID: 21490232
global; oral health; inequalities; disparities; research; funding
11.  Global Oral Health Inequalities 
Advances in Dental Research  2011;23(2):211-220.
The IADR Global Oral Health Inequalities Task Group on Dental Caries has synthesized current evidence and opinion to identify a five-year implementation and research agenda which should lead to improvements in global oral health, with particular reference to the implementation of current best evidence as well as integrated action to reduce caries and health inequalities between and within countries. The Group determined that research should: integrate health and oral health wherever possible, using common risk factors; be able to respond to and influence international developments in health, healthcare, and health payment systems as well as dental prevention and materials; and exploit the potential for novel funding partnerships with industry and foundations. More effective communication between and among the basic science, clinical science, and health promotion/public health research communities is needed. Translation of research into policy and practice should be a priority for all. Both community and individual interventions need tailoring to achieve a more equal and person-centered preventive focus and reduce any social gradient in health. Recommendations are made for both clinical and public health implementation of existing research and for caries-related research agendas in clinical science, health promotion/public health, and basic science.
PMCID: PMC3144035  PMID: 21490233
Dental caries; health inequalities; health disparities; implementation research; translational research
12.  Initiating and maintaining resistance training in older adults: a social cognitive theory-based approach 
Numerous research studies performed in “lab-gyms” with supervised training have demonstrated that simple, brief (20–30 min) resistance training protocols performed 2–3/week following the American College of Sports Medicine’s guidelines positively affect risk factors associated with heart disease, cancers, diabetes, sarcopenia and other disabilities. For more than a decade, resistance training has been recommended for adults, particularly older adults, as a prime preventive intervention, and increasing the prevalence of resistance training is an objective of Healthy People 2010. However, the prevalence rate for resistance training is only estimated at 10–15% for older adults, despite the leisure time of older adults and access to facilities in developed countries. The reasons that the prevalence rate remains low include public health policy not emphasising resistance training, misinformation, and the lack of theoretically driven approaches demonstrating effective transfer and maintenance of training to minimally supervised settings once initial, generally successful, supervised training is completed. Social cognitive theory (SCT) has been applied to physical activity and aerobic training with some success, but there are aspects of resistance training that are unique including its intensity, progression, precision, and time and place specificity. Social cognitive theory, particularly with a focus on self-regulation and response expectancy and affect within an ecological context, can be directly applied to these unique aspects of resistance training for long-term maintenance.
PMCID: PMC2709760  PMID: 18628361
13.  Monitoring liver disorders in vinyl chloride monomer workers using greyscale ultrasonography. 
Recognition that vinyl chloride could be hepatotoxic led to a survey of workers to determine whether changes had been induced by past exposure, and to evaluate standard liver function tests as monitors of early liver abnormalities. Standard liver function tests were found to be unsuitable for the detection of such abnormalities in the population at risk. Of 487 workers examined, 102 (20-9%) had abnormalities on initial testing but only two were finally shown to have portal hypertension; in both cases, thrombocytopaenia provided the first diagnostic evidence since liver function tests were normal. Furthermore, 40 (35-7%) of 112 control subjects had initial test abnormalities. A sample of 19 workers with various exposures to vinyl chloride monomer were examined blind by greyscale ultrasonography. Five with minimal or no exposure were confirmed as normal but 12 of the remainder had abnormalities. These consisted of an enlarged portal vein (seven instances), splenomegaly (eight), and changes in hepatic texture (seven). Five of these 12 cases had previously been considered normal. It was concluded that greyscale ultrasonography had many advantages over standard methods for screening workers exposed to hepatotoxic chemicals, and should be the subject of a large scale evaluation.
PMCID: PMC1008128  PMID: 962999
14.  Coudé Catheter 
British Medical Journal  1958;2(5097):693.
PMCID: PMC2026430
15.  Expression of the matrix metalloproteinase 9 in Hodgkin's disease is independent of EBV status 
Molecular Pathology  2000;53(3):145-149.
Background—In vitro the Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP-1) has been shown to upregulate expression of matrix metalloproteinase 9 (MMP-9), a member of a family of zinc dependent endopeptidases that is believed to facilitate tumour invasion and metastasis by degradation of the extracellular matrix.
Aim—To test whether the expression of MMP-9 in Hodgkin's disease correlates with EBV status and survival and to investigate whether LMP-1 expression affects MMP-9 concentrations in the Hodgkin's disease cell line, L428.
Methods—MMP-9 expression was measured by means of immunohistochemistry in a series of Hodgkin's disease tumours and this expression was correlated with EBV status and survival. The influence of LMP-1 on MMP-9 expression was also investigated in the Hodgkin's disease cell line, L428.
Results—MMP-9 expression was demonstrated in the malignant Hodgkin and Reed-Sternberg cells of all (n = 86) formalin fixed, paraffin wax embedded Hodgkin's disease tumours examined. Although the intensity of MMP-9 immunostaining varied between cases, there was no correlation between MMP-9 expression and EBV status or survival. MMP-9 expression was also detected in a variety of non-malignant cells, including fibroblasts. MMP-9 was detected by zymography in the L428 and KMH2 Hodgkin's disease cell lines, whereas low or undetectable amounts of MMP-9 were found in the L591 Hodgkin's disease cell line. Induction of LMP-1 expression in the Hodgkin's disease cell line L428 did not result in a detectable increase in the values of MMP-9 as measured by zymography.
Conclusions—These results demonstrate that MMP-9 is consistently expressed by the Hodgkin and Reed-Sternberg cells of Hodgkin's disease tumours and by the Hodgkin's disease cell lines, L428 and KMH2. However, this expression does not appear to be related either to LMP-1 values or to survival.
PMCID: PMC1186921  PMID: 10897334
matrix metalloproteinase 9; Hodgkin's disease; Epstein-Barr virus; latent membrane protein 1
16.  Targeted Disruption of Fibronectin-Integrin Interactions in Human Gingival Fibroblasts by the RI Protease of Porphyromonas gingivalis W50 
Infection and Immunity  1999;67(4):1837-1843.
Cell surface integrins mediate interactions between cells and their extracellular matrix and are frequently exploited by a range of bacterial pathogens to facilitate adherence and/or invasion. In this study we examined the effects of Porphyromonas gingivalis proteases on human gingival fibroblast (HGF) integrins and their fibronectin matrix. Culture supernatant from the virulent strain W50 caused considerably greater loss of the β1 integrin subunit from HGF in vitro than did that of the beige-pigmented strain W50/BE1. Prior treatment of the W50 culture supernatant with the protease inhibitor Nα-p-tosyl-l-lysine chloromethyl ketone (TLCK) blocked its effects on cultured cells, indicating that this process is proteolytically mediated. Purified arginine-specific proteases from P. gingivalis W50 were able to mimic the effects of the whole-culture supernatant on loss of β1 integrin expression. However purified RI, an α/β heterodimer in which the catalytic chain is associated with an adhesin chain, was 12 times more active than RIA, the catalytic monomer, in causing loss of the α5β1 integrin (fibronectin receptor) from HGF. No effect was observed on the αVβ3 integrin (vitronectin receptor). The sites of action of RI and RIA were investigated in cells exposed to proteases pretreated with TLCK to inactivate the catalytic component. Use of both monoclonal antibody 1A1, which recognizes only the adhesin chain of RI, and a rabbit antibody against P. gingivalis whole cells indicated localization of RI on the fibroblasts in a clear, linear pattern typical of that seen with fibronectin and α5β1 integrin. Exact colocalization of RI with fibronectin and its α5β1 receptor was confirmed by double labeling and multiple-exposure photomicroscopy. In contrast, RIA bound to fibroblasts in a weak, patchy manner, showing only fine linear or granular staining. It is concluded that the adhesin component of RI targets the P. gingivalis arginine-protease to sites of fibronectin deposition on HGF, contributing to the rapid loss of both fibronectin and its main α5β1 integrin receptor. Given the importance of integrin-ligand interactions in fibroblast function, their targeted disruption by RI may represent a novel mechanism of damage in periodontal disease.
PMCID: PMC96535  PMID: 10085025
17.  Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis. 
Infection and Immunity  1997;65(7):2876-2882.
A murine model of pneumonia due to the mouse pneumonitis agent (MoPn [murine Chlamydia trachomatis]) in mice deficient in CD4+ T-cell function (major histocompatibility complex [MHC] class II function [class II-/-], CD8+ T-cell function (beta2-microglobulin deficient, MHC class I deficient [Beta2m-/-]), B-cell function (C57BL/10J-Igh(tm1Cgn) [Igh-/-]), and gamma interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [Ifg-/-]) or interleukin-4 (C57BL/6J(tm1Cgn29) [IL4-/-]) production was employed to determine if each of these mechanisms was critical to resistance against reinfection by C. trachomatis or if alternate compensatory mechanisms existed in their absence which could potentially be exploited in vaccine development. Resistance to reinfection with MoPn was heavily dependent on CD4+ T cells. CD4 T-cell-deficient MHC class II-/- mice were very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked antibody production but did produce IFN-gamma, apparently by mechanisms involving NK and CD8+ T cells. Neutralization of IFN-gamma in these mice led to a borderline increase in susceptibility, showing a possible role (albeit small) of this cytokine in this setting. Tumor necrosis factor alpha (TNF-alpha) was also present at increased levels in these mice. Igh-/- B-cell-deficient mice which produce no antibody to MoPn were only modestly more susceptible to reinfection than immunized B-cell-intact controls, showing that antibody, including lung immunoglobulin A, is not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were elevated in Igh-/- mice compared to those in controls. IL-4-/- mice (deficient in Th2 function) could develop normal resistance to reinfection with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impaired in their ability to develop acquired immunity to MoPn, again indicating a role for this cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg-/- mice (which have elevated levels of other cytokines, including TNF-alpha and granulocyte-macrophage colony-stimulating factor) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma is not an absolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depletion of TNF-alpha significantly increased MoPn levels in the lungs in these mice. Thus, resistance to reinfection in this model is flexible and multifactorial and is heavily dependent on CD4+ T cells, with a probable role for IFN-gamma and TNF-alpha and a possible modest role for Th1-dependent antibody. Since IFN-gamma was dispensable in host defense, the highly effective mechanism or mechanisms which can compensate for its absence (which include TNF-alpha) deserve further study.
PMCID: PMC175404  PMID: 9199462
18.  Role of gamma-delta T cells in murine Chlamydia trachomatis infection. 
Infection and Immunity  1996;64(9):3916-3919.
The role of gamma-delta T cells in host resistance to Chlamydia trachomatis was characterized by using a murine model of pneumonia caused by the mouse pneumonitis agent (MoPn), murine C. trachomatis. At days 3 and 7 after infection, gamma-delta T-cell-deficient knockout mice had significantly higher levels of MoPn in the lungs than did immunologically intact controls. At day 20, paradoxically, gamma-delta T-cell-deficient mice were more resistant to MoPn than were controls. This increased resistance was not due to an increased production of toxic cytokines or interleukin-10 in controls on that day. Gamma-delta T cells play a role in protection early in MoPn infection, but they may be deleterious later in infection, as has been observed in models of salmonella and trypanosome infection.
PMCID: PMC174314  PMID: 8751950
19.  Occupationally related angiosarcoma of the liver in the United Kingdom 1972-1994. 
Gut  1996;39(2):312-318.
BACKGROUND: Angiosarcoma of the liver (ASL) has been described in vinyl chloride workers worldwide. AIM: To describe the UK experience of occupationally related ASL. PATIENTS: Twenty patients who died from ASL after exposure to vinyl chloride. METHODS: The case records and pathological findings of these 20 patients were reviewed. RESULTS: Twenty men in the United Kingdom aged 37 to 71 years have developed ASL in association with occupational exposure to vinyl chloride monomer VCM in two factories. All had been exposed to VCM for three to 29 years, the tumour developing nine to 35 years after first exposure. Presenting clinical features included abdominal pain, malaise, jaundice, ascites, and massive hepatomegaly. In most cases the disease progressed rapidly, death occurring within a few weeks from hepatic coma. In 17 cases there was no spread outside the liver. In four cases there had been haemorrhage from oesophageal varices due to non-cirrhotic portal fibrosis diagnosed six to 18 years previously. At necropsy the livers of these men showed considerable, often massive, replacement by tumour, apparently multifocal, with necrosis and haemorrhage. CONCLUSIONS: In view of the long latency between exposure and development of the tumour the full extent of ASL occurrence may not be known until 35 years after the introduction of the Code of Practice in 1975.
PMCID: PMC1383317  PMID: 8977349
20.  Pharmacokinetics of vancomycin in adult cystic fibrosis patients. 
Although the depositions of many antibiotics are altered in cystic fibrosis patients, that of vancomycin has not been studied. To assess vancomycin pharmacokinetics, 10 adult cystic fibrosis patients were given a parenteral dose of vancomycin (15 mg/kg) during the first 72 h of hospitalization for acute bronchopulmonary exacerbation. Blood samples were obtained at 0, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 15, and 24 h. The mean (standard deviation) weight, measured creatinine clearance, and Taussig clinical score were 51 (13) kg, 130 (39) ml/min/1.73 m2, and 64 (13), respectively. Multicompartmental pharmacokinetic parameters were best described by a two-compartment model. The mean (standard deviation) volume of distribution, total body clearance, and terminal elimination rate constant were 0.58 (0.15) liter/kg, 91 (19) ml/min/1.73 m2, and 0.123 (0.05) h-1, respectively. These values were consistent with vancomycin pharmacokinetic parameters obtained in previous studies of healthy adult volunteers. Vancomycin dosages predicted by using a two-compartment Bayesian model were approximately 15 mg/kg every 8 to 12 h. There were poor correlations between clinical score or creatinine clearance and any pharmacokinetic parameter (r values of < 0.32). The coefficient of correlation between urine flow rate and total body clearance was 0.7 (P < 0.05). Adult cystic fibrosis patients exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus cystic fibrosis does not alter vancomycin pharmacokinetics.
PMCID: PMC163080  PMID: 8787903
21.  Rapid diagnosis of malignancy using flow cytometry. 
Archives of Disease in Childhood  1993;68(3):393-398.
The rapid and accurate diagnosis of childhood malignancy is important both in the planning of appropriate treatment and in relieving the inevitable family anxiety. The use of flow cytometry to analyse monoclonal antibody coated single cell suspensions is widely accepted as having increased the speed and accuracy of diagnosis in leukaemias, though its use in solid tumour diagnosis is not widely reported. Ten cases of childhood malignancy in whom the diagnosis was initially made by flow cytometry and subsequently confirmed histologically are described. The technique has a number of advantages. Only a small sample is required as the analysis is carried out on a single cell suspension, the method is rapid, a diagnosis being reached within three hours of receipt of the sample, and information is obtained on cell lineage and stage of differentiation. Diagnostic accuracy is good when compared with histological results.
PMCID: PMC1793878  PMID: 8466243
22.  Normal postnatal androgen production and action in isolated micropenis and isolated hypospadias. 
Archives of Disease in Childhood  1991;66(9):1033-1036.
To try and find out if a defect in androgen biosynthesis or action could be responsible for the incomplete virilisation seen in boys with isolated hypospadias and isolated micropenis, androgen receptor binding was studied in genital skin fibroblasts established from 18 boys with isolated micropenis and 19 boys with isolated hypospadias. The production of gonadotrophins and testosterone was also measured in the boys with micropenis. There was no evidence of gonadotrophin deficiency, or of a defect in testosterone biosynthesis in the boys with micropenis, and there was no evidence of a quantitative or qualitative defect of androgen binding in either group. These isolated abnormalities may be the result of transient defects in androgen synthesis or action, or both, during a critical phase of embryogenesis.
PMCID: PMC1793041  PMID: 1929508
23.  Hyperinsulinaemic hypoglycaemia in small for dates babies. 
Archives of Disease in Childhood  1990;65(10):1118-1120.
Blood glucose concentrations were measured prospectively in 27 small for dates infants in the first 48 hours after birth: 10 infants became hypoglycaemic. Of these, five had inappropriately raised plasma insulin concentrations. Plasma free fatty acids were lower and carbohydrate intake higher in these five infants, further supporting the diagnosis of hyperinsulinism. The hypoglycaemia recurred in four of the five hyperinsulinaemic infants, but in none of those who were not hyperinsulinaemic. Hyperinsulinism is common in small for dates babies. It is important to recognise this because hypoglycaemia is likely to recur and appropriate treatment is needed to prevent long term sequelae.
PMCID: PMC1792359  PMID: 2248501
24.  Delayed auditory brainstem responses in diabetes mellitus 
Diabetic patients have longer interpeak latencies in the brainstem auditory evoked responses than age-matched controls. The delay is not related to clinical hearing loss or blood glucose level at time of testing. Since waves I and II are normal in latency, the conduction velocity of the eighth nerve is not involved. The delay occurs between waves II and V, which would reflect altered transmission times in auditory brainstem and midbrain structures, and suggests the presence of a central neuropathy in patients with diabetes.
PMCID: PMC491071  PMID: 7288453
25.  Genetic control of murine resistance to Toxoplasma gondii. 
Infection and Immunity  1978;19(2):416-420.
The genetics of murine susceptibility to Toxoplasma gondii was investigated in inbred mice and their F1 and F2 offspring. Among four strains of congenic mice of the B10 background, those with H-2a/a and H-2b/b genotypes were more susceptible than were those with H-2d/d and H-2k/k genotypes. Breeding studies utilizing three of these strains demonstrated linkage between the H-2a allele and greater susceptibility. These data suggest the existence of an H-2-linked gene affecting susceptibility to T. gondii. In challenge of recombinant inbred mice derived from C57Bl/6J (high susceptibility) and BALB/c (low susceptibility) strains, lines BE, BJ, and BK were more susceptible than lines BD, BG, BH, and BI. These data are consistent with the existence of a second disease susceptibility gene linked to the H-13 locus. F1 offspring of the C57B1/6J X B10.D2 mice were significantly less susceptible than either parent. This phenotypic complementary suggests the presence of more than one genetic mechanism of resistance to T. gondii. From these combined data, we conclude that (i) susceptibility to T. gondii in mice is affected by at least two genes, (ii) one of the genes is linked to the H-2 and one to the H-13 locus, and (iii) more than a single mechanism of resistance must be considered to explain the observed genetic controls of susceptibility.
PMCID: PMC414099  PMID: 631881

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