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P Gill

Publications and source records attributed to P Gill.

At least 91 records · Page 5Linked to original sources
PubMed1997

Development of guidelines to designate alleles using an STR multiplex system.

We have carried out extensive validation of a multiplex system of 6 STR loci and the Amelogenin sex test to investigate the following characteristics: relative peak areas of heterozygote peaks; non-specific artefacts; stutters caused by slippage of the Taq enzyme; pull-up (an electronic artefact often associated with software). The purpose of this paper is to demonstrate how interpretation guidelines can be formulated by experimentation and analysis using casework samples. Automation allows data relating to band position (in base pairs), peak area and peak height to be easily collected and manipulated in spreadsheets or computer programs. This paves the way to designing expert systems to carry out the interpretative process.

Alleles↗
PubMed1997

Report of the European DNA profiling group (EDNAP): an investigation of the complex STR loci D21S11 and HUMFIBRA (FGA).

This paper describes a collaborative exercise which was intended to demonstrate whether uniformity of DNA profiling results could be achieved between European laboratories using two complex short tandem repeat (STR) loci. The loci D21S11 and HUMFIBRA (FGA) were chosen because they are commonly used by different European laboratories. D21S11 has approximately 14 common alleles (f > 0.001), whereas HUMFIBRA has 19 common alleles. Laboratories were asked to test seven blood stains, one of which was a known control, and to report the results to the coordinating laboratory. The exercise demonstrated that complex STRs were amenable to standardisation.

Alleles↗
PubMed1997

Human P50 suppression is not affected by variations in wakeful alertness.

The amplitude and suppression of the auditory P50 event-related potential may be useful for studying schizophrenia and drug abuse; however, the low reliability of the P50 suppression measure limits its value for correlation with clinical measures. Reliability can be increased either by improving measurement methods or by reducing or eliminating sources of variance in the recordings. In this paper, the effect on P50 amplitude and suppression of variation in wakeful alertness within an experimental session was examined in 20 normal subjects. The percentage of beta power in the interval immediately prior to the P50 stimuli was used as an index of alertness. P50 amplitudes or C-T ratios were estimated using peak-picking and using the singular value decomposition (SVD) method. No effects of variation of wakeful alertness were observed on any P50 amplitude or suppression measure. Comparing the peak-picking vs SVD estimates replicated our prior results showing markedly higher reliabilities with SVD. We conclude: 1) that variation within an experimental session in wakeful alertness level as indexed by the percentage of beta power does not affect P50 amplitude or suppression, and 2) the SVD method brings the reliability of the C-T ratio up to levels where its usefulness in clinical studies can be examined.

Acoustic Stimulation↗
PubMed1997

Cytokine signaling through the novel tyrosine kinase RAFTK in Kaposi's sarcoma cells.

A number of cytokines, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), oncostatin M (OSM), IL-6, and tumor necrosis factor alpha (TNF-alpha), have been postulated to have a role in the pathogenesis of Kaposi's sarcoma (KS). The proliferative effects of bFGF and OSM may be via their reported activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway in KS cells. We now report that KS cells express a recently identified focal adhesion kinase termed RAFTK which appears in other cell systems to coordinate surface signals between cytokine and integrin receptors and the cytoskeleton as well as act downstream to modulate JNK activation. We also report that the tyrosine kinase receptor FLT-4, present on normal lymphatic endothelium, is robustly expressed in KS cells. Treatment of KS cells with VEGF-related protein (VRP), the ligand for the FLT-4 receptor, as well as with the cytokines bFGF, OSM, IL-6, VEGF, or TNF-alpha resulted in phosphorylation and activation of RAFTK. Following its activation, there was an enhanced association of RAFTK with the cytoskeletal protein paxillin. This association was mediated by the hydrophobic COOH-terminal domain of the kinase. Furthermore, JNK activity was increased in KS cells after VEGF or VRP stimulation. We postulate that in these tumor cells RAFTK may be activated by a diverse group of stimulatory cytokines and facilitate signal transduction to the cytoskeleton and downstream to the growth promoting JNK pathway.

Animals↗
PubMed1997

Glucocorticoids induce Kaposi's sarcoma cell proliferation through the regulation of transforming growth factor-beta.

Glucocorticoid (GC) use is known to induce or enhance the growth of Kaposi's sarcoma (KS) in many clinical settings including human immunodeficiency virus infection, collagen vascular disease, lymphoproliferative disorders, and renal transplantation. Because GCs may induce immune suppression and thus tumor growth, we determined whether GCs had a direct effect on KS growth. We found that GCs directly induce the growth of KS cell lines. In examining the mechanism of action of GCs, we did not observe induction of known autocrine growth factors for KS including interleukin-1 (IL-1), IL-6, oncostatin-M, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). We thus examined factor(s) that inhibit KS growth. Transforming growth factor-beta (TGF-beta) is produced by KS cells and has pleiotropic effects, including inhibiting the growth of hematopoietic and endothelial cells. We show that TGF-beta is produced by KS cells in both the latent and active forms, and that TGF-beta is an autocrine growth inhibitory factor. We then studied the effects of GCs on the regulation of TGF-beta and found that GCs do not inhibit TGF-beta transcription, but significantly inhibit TGF-beta activation. This effect is mediated through regulation of the TGF-beta activation pathway. TGF-beta is activated by plasmin which is positively regulated by plasminogen activator (PA) and PA receptor (PAR), and negatively regulated by plasminogen activator inhibitor (PAI). GCs downregulated PAR and upregulated PAI. Thus, glucocorticoids enhance KS cell growth through the regulation of TGF-beta activation.

Cell Division↗
PubMed1997

A high observed substitution rate in the human mitochondrial DNA control region.

The rate and pattern of sequence substitutions in the mitochondrial DNA (mtDNA) control region (CR) is of central importance to studies of human evolution and to forensic identity testing. Here, we report a direct measurement of the intergenerational substitution rate in the human CR. We compared DNA sequences of two CR hypervariable segments from close maternal relatives, from 134 independent mtDNA lineages spanning 327 generational events. Ten substitutions were observed, resulting in an empirical rate of 1/33 generations, or 2.5/site/Myr. This is roughly twenty-fold higher than estimates derived from phylogenetic analyses. This disparity cannot be accounted for simply by substitutions at mutational hot spots, suggesting additional factors that produce the discrepancy between very near-term and long-term apparent rates of sequence divergence. The data also indicate that extremely rapid segregation of CR sequence variants between generations is common in humans, with a very small mtDNA bottleneck. These results have implications for forensic applications and studies of human evolution.

Animals↗
PubMed1997

Neonatal welfare and placental transfer of fentanyl and bupivacaine during ambulatory combined spinal epidural analgesia for labour.

To investigate current concerns that potent opioid drugs, such as fentanyl, used for labour regional analgesia may affect neonatal status, maternal and umbilical plasma concentrations of fentanyl and bupivacaine at delivery were measured in 40 nulliparous patients receiving low-dose combined spinal epidural analgesia. Neonatal assessments included Apgar scores, umbilical blood gases and neurobehavioural tests. All maternal and umbilical venous plasma concentrations were low. Maternal and umbilical vein total fentanyl concentrations increased with increasing doses of epidural fentanyl (r = 0.46 and 0.30, respectively, p < 0.01). There were no significant differences between maternal and umbilical venous plasma total or free concentrations of fentanyl. Mean umbilical vein/maternal fentanyl ratios were 1.12 for total drug and 1.20 for free drug and values were unrelated to the last epidural bolus to delivery interval (r = 0.12, p = 0.49). There were no correlations between Apgar scores, umbilical blood gases or neurobehavioural scores and umbilical venous concentrations of either fentanyl or bupivacaine. The dose of fentanyl used for ambulatory combined spinal epidural analgesia would appear to have a negligible effect on neonatal condition.

Ambulatory Care↗
PubMed1997

The Romanovs.

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DNA Fingerprinting↗
PubMed1997

Interleukin-4 receptor expression on AIDS-associated Kaposi's sarcoma cells and their targeting by a chimeric protein comprised of circularly permuted interleukin-4 and Pseudomonas exotoxin.

BACKGROUND: AIDS-associated Kaposi's sarcoma (AIDS-KS) represents one of the most common malignancies associated with human immunodeficiency virus infection. To target effective therapeutic agents to AIDS-KS, we have identified a new target in the form of interleukin-4 receptors (IL-4R). MATERIALS AND METHODS: The expression of IL-4R on AIDS-KS cells and their subunit structure was determined by radioligand receptor binding, cross-linking and Northern and RT-PCR analyses. The in vitro effect of IL-4 and recombinant fusion protein made up of circularly permuted IL-4 and a mutated form of Pseudomonas exotoxin, IL-4(38-37)-PE38KDEL, was examined by clonogenic and protein synthesis inhibition assays. RESULTS: Five AIDS-KS cell lines expressed high-affinity IL-4R with a Kd of 23.5-219 pM. IL-4 appeared to cross-link to one major protein corresponding to 140 kDa and a broad band corresponding to 60-70 kDa. Both cross-linked proteins were immunoprecipitated with an antibody to human IL-4R beta chain. AIDS-KS cells exhibited IL-4R beta-specific mRNA. IL-4 caused a modest inhibition (31-34%) of colony formation in two AIDS-KS cell lines tested. IL-4(38-37)-PE38KDEL was found to be highly effective in inhibiting the protein synthesis in all five AIDS-KS examined. The IC50 ranged from 32 to 1225 pM. The cytotoxic action of IL-4 toxin was blocked by an excess of IL-4, exhibiting the specificity of IL-4(38-37)-PE38KDEL. The cytotoxicity of IL-4 toxin observed by a clonogenic assay corroborated well with the IC50 obtained by protein synthesis inhibition assay. Normal human endothelial cells expressed a negligible number of IL-4R (< 50 sites/cell) and were less sensitive or not sensitive to IL-4(38-37)-PE38KDEL. CONCLUSION: The presence of a new plasma membrane protein in the form of IL-4R on AIDS-KS cells may be targeted by IL-4(38-37)-PE38KDEL for its potential implication in the treatment of AIDS-KS.

AIDS-Related Opportunistic Infections↗
PubMed1997

Interleukin-4 receptor expression in vivo on human AIDS-related Kaposi's sarcoma.

We have investigated the expression of interleukin-4 receptors (IL-4R) in acquired immunodeficiency syndrome (AIDS)-related Kaposi's Sarcoma (KS) in situ by immunohistochemistry. Frozen and fixed sections from five patch stage and two nodular stage KS lesions were stained with anti-IL-4R monoclonal antibody with similar results. Skin biopsies from the clinically apparent lesions and adjacent clinically uninvolved skin were also examined. We observed that individual KS cells lining the irregular vascular spaces were stained with anti-IL-4R antibody, although the degree of staining was variable. The epithelioid and oval cells appear to stain more than the spindle cells in plaque stages or nodular lesions. The sections from nonclinically involved skin also contained a few cells with features of KS, singly or in clusters that also stained for IL-4R. Skin sections from four normal donors did not stain with IL-4R antibody except for hair follicles, sweat glands, and faint staining of blood vessels. KS sections were also stained with antibodies to basic fibroblast growth factor (FGF), S100, fibronectin, and von Willebrand factor. KS lesions from clinically involved and uninvolved skin sections were positive for all four antibodies. Thus, the differences between KS lesion and clinically uninvolved skin adjacent to a KS lesion may be more quantitative than qualitative. The IL-4 receptors on KS cells were functional as IL-4 modulated intercellular adhesion molecule 1 (ICAM-1) on these cells. Taken together, our results suggest that AIDS-KS cells express elevated levels of IL-4R compared to normal endothelial and skin cells and, thus, the receptors for IL-4 on KS may serve as an attractive target for anticancer therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Receptor for interleukin 13 on AIDS-associated Kaposi's sarcoma cells serves as a new target for a potent Pseudomonas exotoxin-based chimeric toxin protein.

AIDS-associated Kaposi's sarcoma (AIDS-KS), the most common malignant complication of human immunodeficiency virus infection, is characterized by neoplastic proliferation of mesenchymal cells. AIDS-KS cells release and respond to an array of cytokines through specific plasma membrane receptors. Specific targeting of potent cytotoxic agents to cell surface receptors/antigens on Kaposi's sarcoma cells may provide effective therapy for this malignancy. We have identified a new target in the form of an interleukin 13 (IL-13) receptor that is overexpressed in the five AIDS-KS cell lines examined. Radiolabeled IL-13 cross-linked to a single protein of about Mr 70,000 in AIDS-KS cells. We utilized a chimeric cytotoxic protein composed of IL-13 and a truncated Pseudomonas exotoxin (IL13-PE38QQR), which was found to be specifically and highly cytotoxic to AIDS-KS cells, as determined by protein synthesis inhibition and clonogenic assays. IL13-PE38QQR demonstrated significant antitumor activity in a human epidermoid carcinoma xenograft model. Normal human umbilical vein-derived endothelial, lymphoid, and bone marrow precursor cells expressed low levels of IL-13 receptors, and IL-13 toxin was not cytotoxic to them. Thus, IL-13 receptor on AIDS-KS cells may represent a novel plasma membrane protein(s) that could be utilized to target therapeutic agents.

ADP Ribose Transferases↗
PubMed1996

The serotonin transporter is a potential susceptibility factor for bipolar affective disorder.

The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

Alleles↗