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Biomedical subjects

Peter Taylor

Publications and source records attributed to Peter Taylor.

At least 19 recordsLinked to original sources
PubMed2006

Novel candidate genes in unstable areas of human atherosclerotic plaques.

OBJECTIVE: Comparison of gene expression in stable versus unstable atherosclerotic plaque may be confounded by interpatient variability. The aim of this study was to identify differences in gene expression between stable and unstable segments of plaque obtained from the same patient. METHODS AND RESULTS: Human carotid endarterectomy specimens were segmented and macroscopically classified using a morphological classification system. Two analytical methods, an intraplaque and an interplaque analysis, revealed 170 and 1916 differentially expressed genes, respectively using Affymetrix gene chip analysis. A total of 115 genes were identified from both analyses. The differential expression of 27 genes was also confirmed using quantitative-polymerase chain reaction on a larger panel of samples. Eighteen of these genes have not been associated previously with plaque instability, including the metalloproteinase, ADAMDEC1 (approximately 37-fold), retinoic acid receptor responder-1 (approximately 5-fold), and cysteine protease legumain (approximately 3-fold). Matrix metalloproteinase-9 (MMP-9), cathepsin B, and a novel gene, legumain, a potential activator of MMPs and cathepsins, were also confirmed at the protein level. CONCLUSIONS: The differential expression of 18 genes not previously associated with plaque rupture has been confirmed in stable and unstable regions of the same atherosclerotic plaque. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability.

Atherosclerosis↗
PubMed2006

Expression of human soluble complement receptor 1 by a pig endothelial cell line inhibits lysis by human serum.

The importance of complement activation and naturally occurring anti-pig antibodies in the hyperacute rejection (HAR) observed in models of pig-to-human xenotransplantation is well established. To overcome this, much effort has been dedicated to preparing transgenic pigs by knocking out Galalpha(1-3)Gal expression in these animals, or knocking in the expression of human complement regulatory proteins (CRPs), such as CD59 or decay accelerating factor. A soluble form of another membrane CRP, complement receptor type 1 (CR1), has also been shown to inhibit complement activation. Here, we show that transfection of a pig endothelial cell line with a truncated form of human soluble complement receptor 1 (sCR1) almost completely protected these cells from complement-mediated lysis by human AB serum. Pigs genetically manipulated to express human sCR1 may represent an additional strategy to inhibit HAR of pig-to-human transplanted organs.

Animals↗
PubMed2005

Synthesis and characterization of new palladium-clotrimazole and palladium-chloroquine complexes showing cytotoxicity for tumor cell lines in vitro.

New palladium complexes of chloroquine (CQ) and clotrimazole (CTZ) have been prepared, characterized, and evaluated against four tumor cell lines in vitro. [Pd (CQ)2Cl2] (1) was synthesized by the reaction of PdCl2(CH3CN)2 with CQ, and the [Pd (CTZ)2Cl2] (2) complex by a similar reaction. The new compounds were characterized by a combination of FAB-MS (fast atom bombardment-mass spectrum), elemental analysis, molar conductivity, IR, and NMR spectroscopy. The solid-state structure of 2 has been determined by X-ray crystallography. 2 crystallizes in the monoclinic space group P(2(1)/c), with a = 21.100(4) A, b = 13.408(3) A, c = 22.642(5) A. The structure refinement converged at R1 = 0.0728, wR2 = 0.1918. The cytotoxicity of these two complexes for the tumor cell lines, PANC-1, SKBR-3, MDA-MB231 and HT-29, was compared with that of the original ligands. Ligation of palladium to CTZ led to an increase in the IC50, although a three-fold reduction in the IC50 of CQ was observed on ligation to the metal when tested against the MDA-MB231 cell line.

Antineoplastic Agents↗
PubMed2005

The relationship between persistent organic pollutants in maternal and neonatal tissues and immune responses to allergens: A novel exploratory study.

BACKGROUND: Modern persistent organic pollutants (POPs) contamination are logical candidates in the investigation of the, as yet, unexplained association between allergic disease and progressive industrialisation. POPs have been detected in human cord blood, placental tissues and breast milk, and the reported association between cord blood IgE levels and cord/placental POP levels has raised concerns about potential immunological effects in early life. METHODS: The initial aim of this study was to determine if POPs were detectable in maternal blood, cord blood, placental tissues, adipose tissue and breast milk samples from randomly selected Western Australian women (n = 31), where allergic disease is epidemic. Gas chromatography was used to detect polychlorinated biphenyl compounds [PCBs] (as Aroclor 1232, 1254, 1260) and organochlorine (OC) pesticides, including p,p'-DDT, p,p'-DDE, hexachlorobenzene (HCB), lindane, heptachlor epoxide, dieldrin and chlordane. Secondly, we assessed the relationship between POP levels detected in vivo and maternal and neonatal responses (cytokine and lymphoproliferation) to allergens and mitogens. RESULTS: Low level POP contamination was detected in adipose tissue and breast milk (but not in cord blood, maternal blood or placental tissues). The most ubiquitous compound found in over 90% of adipose tissues samples was a OC metabolite of DDT, p,p'-DDE (median 0.07 mg/kg; interquartile range [IQR] 0.05-0.12). However, the majority of other OC compounds were not detectable and PCB were not detectable in any samples. The three main residues detected in breast milk were p,p'-DDE (0.003 mg/l; 0.001-0.009), dieldrin (0.001 mg/l; 0.001-0.046) and HCB (0.001 mg/l; 0.001-0.001). These levels are significantly lower than reported over 20 years ago. There were no consistent relationships between POP levels in vivo and maternal or infant responses, with the exception of a significant inverse association (Spearman rank correlation: r = -0.406, p = 0.049) between maternal adipose tissue levels of OC p,p'-DDE and maternal T helper cell Type 1 interferon [IFN] gamma to mitogens. CONCLUSION: This study provides the first evidence (in Australia) since the early 1990's that adipose OC levels have continued to fall. The negligible levels in this randomly selected group are significantly lower than those previously recorded, suggesting that POP contamination (at biologically relevant levels) is not likely to be a major contributing factor in the increasing rates of allergy in Western Australia. However, the relationship between Th1 immune function and OC contamination is consistent with other reports and is worth investigating as a relevant factor in populations where OC contamination is greater.

Adipose Tissue↗
PubMed2005

Ajoene inhibits both primary tumor growth and metastasis of B16/BL6 melanoma cells in C57BL/6 mice.

Ajoene is an organosulphur compound derived from garlic with important effects on several membrane-associated processes such as platelet aggregation, as well as being cytotoxic for tumor cell lines in vitro. In the present study, we investigated the effect of ajoene on different cell types in vitro, as well as its inhibitory effects on both primary tumors and metastasis in a mouse model. We found ajoene to inhibit tumor cell growth in vitro, but also to inhibit strongly metastasis to lung in the B16/BL6 melanoma tumor model in C57BL/6 mice. As far as we are aware, this is the first report of the anti-metastatic effect of ajoene. Ajoene also inhibited tumor-endothelial cell adhesion, as well as the in vivo TNF-alpha response to lipopolysaccharide. Possible mechanisms of its antitumoral activity are discussed in the light of these results.

3T3 Cells↗
PubMed2005

Molecular therapeutic targets in rheumatoid arthritis.

In an attempt to combat the pain and damage generated by rheumatoid arthritis (ra), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned.

Animals↗
PubMed2005

Proinflammatory factors present in sera from patients with acute dengue infection induce activation and apoptosis of human microvascular endothelial cells: possible role of TNF-alpha in endothelial cell damage in dengue.

There is evidence that severe dengue disease is associated with alterations of the microvascular endothelium. We examined the hypothesis that activation and damage of microvascular endothelial cells (EC) could be induced by inflammatory mediators present in dengue patient's sera. We cultured human microvascular EC (HMEC-1) in vitro with sera from patients with acute dengue infection. Sera from patients with acute dengue induced an increase in ICAM-1 expression on HMEC-1. This effect was greater with samples from the acute febrile phase than with samples from the convalescent phase of the disease. Acute dengue sera had elevated levels of TNF-alpha and the endothelial activating effect of acute dengue sera was inhibited up to 80% by pre-treatment with monoclonal antibodies against TNF-alpha. Furthermore, acute dengue sera induced apoptosis in HMEC-1. These findings support the pathophysiologic significance of microvascular EC and serum inflammatory mediators in dengue.

Apoptosis↗
PubMed2005

Interferon gamma bound to extracellular matrix changes the hyporesponsiveness to LPS in crypt but not villous intestinal epithelial cells.

Intestinal epithelial cells (IEC) are hyporesponsive to LPS. Responsiveness to luminal bacteria has been implicated in the pathogenesis of inflammatory bowel diseases (IBD). In support of this, previous studies have demonstrated that some intestinal epithelial cell lines are induced by IFN-gamma to respond to LPS. However, both the responsiveness to LPS and the effect of IFN-gamma in intestinal cell lines are heterogeneous. In addition, IFN-gamma may be sequestered in the extracellular matrix (ECM) compartment. The ECM-bound form is more effective than soluble IFN-gamma in producing its biological effects in several experimental models. We investigated the effect of ECM-bound and soluble IFN-gamma treatment on interleukin-8 (IL-8) secretion in response to LPS in freshly isolated villous and crypt cells. We demonstrate that ECM-bound, but not soluble IFN-gamma, induced an increase in IL-8 secretion in response to LPS in undifferentiated crypt cells. This effect was associated with an increase in TLR4 expression. In contrast, mature villous cells did not modify their response to LPS when treated with IFN-gamma (ECM-bound or soluble). These results suggest that selective changes in immature crypt cells induced by IFN-gamma bound to extracellular matrix could contribute to inappropriate responsiveness to commensal bacteria in IBD.

Animals↗
PubMed2005

Developing an education and assessment framework for the Foundation Programme.

AIM: To develop an education and assessment framework for the second year of the Foundation Programme (F2). METHODS: A total of 23 PRHOs were recruited to the F2 pilot in August 2003. The training posts included a variety of specialties at 2 hospital trusts plus primary care. Trainee expectations and satisfaction were evaluated using questionnaires administered before and at the end of the pilot. At the end of the pilot, 10 trainees participated in a focus group and 19 trainers participated in a semistructured telephone interview. RESULTS: The majority of trainees (78%) felt that their expectations of the F2 pilot were met and all felt that they had improved their generic skills. Attendance at the generic education programme was 95%. The majority of trainees found the assessment framework useful. The percentage of undecided trainees in terms of career aspirations dropped from 48% to 13%. Trainees valued the breadth of experience provide by the year and the support provided by the programme directors and each other. A need for better communication, administrative support and time for assessment was highlighted by the trainers. CONCLUSIONS: Early, focused education on generic skills will benefit both doctors and their patients. More varied career experience will help to ensure that doctors make appropriate and timely career decisions. Pilots are identifying good practice and areas that need improvement.

Attitude↗
PubMed2005

Six-year review of Acanthamoeba keratitis in New South Wales, Australia: 1997-2002.

AIM: To assess the incidence and risk factors for Acanthamoeba keratitis (AK), the diagnostic interval, and the efficacy and outcome of current treatment among the population of New South Wales, Australia. METHODS: A retrospective review was carried out of all cases of AK treated at the Sydney Eye Hospital between January 1997 and December 2002. RESULTS: Twenty patients were identified with a mean follow up of 24.8 +/- 21.5 months. Acanthamoeba keratitis constitutes 4.7% of severe infective keratitis treated at Sydney Eye Hospital. The mean interval from first presentation to diagnosis was 26.6 +/- 35.1 days overall; 17.2 +/- 33.1 days for those presenting directly to our unit (69% being diagnosed within 72 h of presentation), and 44.1 +/- 34.0 days for those first presenting elsewhere. Of those with a diagnostic delay >1 month, 57% had been mistakenly diagnosed with Herpes simplex keratitis. Sixteen (80%) wore contact lenses, and eight (40%) had additional risk factors including poor lens hygiene. Complications occurred in 16 (80%), with seven (35%) requiring surgical intervention. Visual acuity improved in 18 (90%), worsened in two patients (10%), and 75% achieved 6/12 or better at last follow up. CONCLUSIONS: Acanthamoeba keratitis is a rare infection, and contact lens wear remains the commonest association, with poor hygiene constituting significant additional risk. The visual outcome has improved with the availability of effective amoebicidal agents, but patients with a diagnostic delay and non-contact lens wearers are at increased risk of recurrent disease. A high index of clinical suspicion remains the most effective strategy in implementing early treatment, and enabling a favourable outcome.

Acanthamoeba Keratitis↗
PubMed2004

Extracorporeal photopheresis differentially regulates the expression of phosphorylated STAT-1 and STAT-5 in treated monocytes and T cells, respectively.

BACKGROUND: Extracorporeal photopheresis (ECP) is effective in conditions with opposing immune etiology. ECP induces an immunomodulatory response through simultaneous monocyte activation and apoptosis induction of lymphocytes. However, ECP is also immunosuppressive, downregulating proinflammatory cytokines. Signal transducers and activators of transcription (STATs) are important mediators of cell-signaling systems, including cytokines. Ultraviolet (UV) immunosuppression is linked to reductions in cytokine-induced STAT phosphorylation. OBJECTIVE: The aim of this study was to find whether ECP downregulates STAT phosphorylation. METHODS: Pre- and post-ECP mononuclear cells from cutaneous T-cell lymphoma and chronic graft-versus-host disease patients were stimulated with either IFNbeta, IL2, or IL15. The percentage of IFNbeta-stimulated monocytes positive for phosphorylated STAT-1 (pSTAT-1) and the number of IL2- and IL15-stimulated T cells expressing phosphorylated STAT-5 (pSTAT-5) were determined at 0 and 24 h. RESULTS: Post-ECP, pSTAT-1 levels in monocytes remained unchanged; however, at 24 h post-ECP the number of T cells expressing pSTAT-5 was reduced. CONCLUSION: Following ECP, monocytes retain their ability to phosphorylate STAT-1, while pSTAT-5 expression is lost in lymphocytes. This differential effect of ECP may account for the diverse population of diseases that benefit.

DNA-Binding Proteins↗
PubMed2004

Molecular systematics and origin of sociality in mongooses (Herpestidae, Carnivora).

The Herpestidae are small terrestrial carnivores comprising 18 African and Asian genera, currently split into two subfamilies, the Herpestinae and the Galidiinae. The aim of this work was to resolve intra-familial relationships and to test the origin of sociality in the group. For this purpose we analysed sequences of the complete cytochrome b gene for 18 species of Herpestidae. The results showed that the mongooses were split into three clades: (1) the Malagasy taxa (Galidiinae and Cryptoprocta), (2) the true social mongooses and (3) the solitary mongooses, each group being also supported by morphological and chromosomal data. Our results suggested unexpected phylogenetic relationships: (1) the genus Cynictis is included in the solitary mongoose clade, (2) the genera Liberiictis and Mungos are sister-group, and (3) the genus Herpestes is polyphyletic. We examined the evolution of the sociality in mongooses by combining behavioural traits with the cytochrome b data. Some of the behavioural traits provided good synapomorphies for characterizing the social species clade, showing the potential benefit of using such characters in phylogeny. The mapping of ecological and behavioural features resulted in hypothesizing solitary behavior and life in forest as the conditions at the base of the mongoose clade.

Animals↗
PubMed2004

Priapism secondary to leukemia: effective management with prompt leukapheresis.

Priapism is a urological emergency; without prompt treatment the corpora cavernosa undergoes necrosis and fibrosis that may result in erectile dysfunction. Treatment initially involves conservative measures, such as corporeal aspiration and irrigation with saline or dilute phenylephrine. If this fails, embolization or surgical shunting is usually required. Hyperviscosity resulting from leukemia is a rare cause of priapism. We report a case of a 19-year-old man with an 18-hour history of priapism secondary to undiagnosed chronic myeloid leukaemia. We discuss the method of leukapheresis (mechanical white cell depletion) to reduce viscosity and achieve detumescence after failed aspiration.

Adult↗
PubMed2004

Anti-TNFalpha therapy of rheumatoid arthritis: what can we learn about chronic disease?

The importance of tumour necrosis factor (TNF)alpha in rheumatoid arthritis (RA) was initially proposed on the basis of analysis of cytokine gene regulation at the local site of the disease, the synovium. This was then verified in animal models and established in an extensive series of clinical trials, culminating in now 250000 treated patients with either of two approved TNF inhibitors, antibody or fusion protein. The degree and magnitude of clinical benefit has enabled analyses of the mechanism by which anti-TNF benefits, and hence insights into important steps in the disease process. It was found that essentially all aspects of RA were ameliorated, and important mechanisms of benefit involved diminution of multiple pro-inflammatory cytokines, adhesion molecules and chemokines, leading to reduced cell trafficking, reduced angiogenesis and most importantly halting of joint destruction. What of the problems? Safety is better than prior drugs, but there is a small increase in severe infections, smaller than might have been anticipated. Cost is the major drawback limiting greater use. In view of the central pathological processes down-regulated, and their role in many diseases, the early clinical success of anti-TNF in RA led to subsequent successful trials and registration in Crohn's disease and juvenile rheumatoid arthritis, and successful trials in ankylosing spondylitis, psoriasis and psoriatic arthritis. The era of anti-cytokine therapeutics is just dawning.

Animals↗
PubMed2003

Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome.

OBJECTIVES: We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5 in patients with an atrial septal defect (ASD), patent foramen ovale (PFO), or hypoplastic left heart syndrome (HLHS). BACKGROUND: Mutations in NKX2-5 have been found in families showing secundum ASD and atrioventricular (AV) conduction block and in some individuals with tetralogy of Fallot. The prevalence of NKX2-5 mutations in sporadic cases of ASD/PFO and other forms of congenital heart disease is unknown. METHODS: A cohort of 146 individuals with secundum ASD, PFO complicated by paradoxical embolism, or HLHS were evaluated. Patients with ASD or PFO were ascertained irrespective of family history or associated cardiac abnormalities. The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and sequenced. RESULTS: Among 102 ASD and 25 PFO patients screened, 13 patients (10%) had a positive family history and 5 patients (4%) had AV conduction block. We found one previously documented NKX2-5 missense mutation, T178M, in members of a family with ASD without AV conduction block. One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were subsequently found in 18 patients with sporadic or familial HLHS. In a second ASD family without AV conduction block, we found a missense change, E21Q, previously reported as pathogenic. Because this change did not segregate with disease status, we propose that it is a non-disease-causing polymorphism. CONCLUSIONS: Our findings suggest that NKX2-5 mutations are a relatively infrequent cause of sporadic ASD and HLHS. Screening for NKX2-5 mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block.

Adolescent↗
PubMed2003

A comparison between pre- and posthibernation morphometry, hematology, and blood chemistry in viperid snakes.

Snakes from temperate climates are often made to hibernate in zoos to stimulate reproduction. Unfortunately, deaths have occurred during and after hibernation. This study evaluated the health status, pre- and posthibernation, of 31 adult viperid snakes. It included morphometric measurements, hematology, and blood chemistry. No differences were seen in body weights and weight to length ratios between pre- and posthibernation examinations, suggesting that the overall condition of the snakes did not change. No differences were seen in hematologic and blood chemistry parameters, except that bile acids (3alpha-hydroxybile acids) decreased, the implications of which are unknown. Three individuals had markedly high plasma uric acid levels posthibernation; of these, two individuals died from extensive visceral gout and one recovered with fluid therapy. Viperid snakes should be clinically healthy, well hydrated, and in good body condition when they are put into hibernation. They should be maintained in an environment with sufficient humidity and should have access to water. Blood samples should be collected on arousal for measuring plasma uric acid levels. Changes in morphometry, hematology, and blood chemistry appear to be abnormal and should be investigated thoroughly.

Animals↗