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Biomedical subjects

K Taylor

Publications and source records attributed to K Taylor.

At least 109 records · Page 6Linked to original sources
PubMed1999

Long-term interferon-alpha 2A does not induce sustained hematologic remission in younger patients with essential thrombocythemia.

The ability of Interferon alpha (alpha-IFN) to alter the natural history of essential thrombocythemia (ET) and induce sustained hematologic remission would provide further impetus to consider this agent in younger patients with this disease and may influence the decision to commence treatment in asymptomatic patients. This study has failed to demonstrate any sustained hematologic remissions after cessation of long-term (2 years) alpha-IFN administration in a group of 34 female patients with a median age of 41 years (range 14-68) who were considered at intermediate to high risk of thrombotic complications. In the twenty-one patients completing two years of therapy, 13 (62%) had complete hematological responses (CHR; platelet count <400 x 10(9)/L), 7 (33%) partial hematological responses (PHR; platelet count 400-600 x 10(9)/L) and no thrombotic or hemorrhagic complications occurred. In all patients who discontinued alpha-IFN at 2 years, platelet counts rose above the normal range within 1-4 months and the majority required reinstitution of some form of therapy. The inability of long-term alpha-IFN to induce sustained, unmaintained hematologic remission argues strongly against any significant effect on the neoplastic clone at the doses used in this study. This study does, however, confirm the efficacy of long-term alpha-IFN in younger female patients with ET, a group not previously well represented in clinical trials of the agent.

Adolescent↗
PubMed1998

DnaA-mediated regulation of phage lambda-derived replicons in the absence of pR and Cro function.

Bacteriophage lambda-derived replicons can replicate in Escherichia coli cells as plasmids. In the control of replication of these plasmids, an important role was ascribed to the lambda Cro repressor autoregulatory loop. However, the oR/pR-cro-tR-cII' region could be replaced by the ptetA promoter under the control of the TetR repressor, producing plasmid pTClambda. Here, we demonstrate that stable maintenance of pTClambda depends on the host DnaA function because deletion of one of DnaA-binding sequences present in pTClambda resulted in a decrease in the plasmid (pTClambda) copy number and poor maintenance of pTClambda in E. coli. Moreover, in contrast to the replication of the wild-type lambda plasmid, previously found to be positively regulated by DnaA (acting on a relaxed DnaA box situated immediately downstream of the pR promoter), the replication of pTC plasmids (devoid of pR) was found to be negatively regulated by DnaA. Contrary to wild-type lambda plasmids, in cells harboring lambda cro[temperature-sensitive (ts)] or pTClambda (but not pTClambda) plasmid, the lambda replication complex was heat shock resistant; this complex, however, disassembled after inactivation of DnaA function. This disassembly was blocked by DNA gyrase inhibitors. According to our model outlined previously, we propose that the heat shock resistance of the replication complex of lambdacro- plasmids depends on the interaction of the DNA-bound DnaA protein with the DNA-bound lambda replication complex. The replication complex-DnaA-lambda DNA structure may be directly related to the role of DnaA as the Cro-replacing negative regulator of lambdacro- plasmid replication.

Bacterial Proteins↗
PubMed1998

Evolution of an enzyme active site: the structure of a new crystal form of muconate lactonizing enzyme compared with mandelate racemase and enolase.

Muconate lactonizing enzyme (MLE), a component of the beta-ketoadipate pathway of Pseudomonas putida, is a member of a family of related enzymes (the "enolase superfamily") that catalyze the abstraction of the alpha-proton of a carboxylic acid in the context of different overall reactions. New untwinned crystal forms of MLE were obtained, one of which diffracts to better than 2.0-A resolution. The packing of the octameric enzyme in this crystal form is unusual, because the asymmetric unit contains three subunits. The structure of MLE presented here contains no bound metal ion, but is very similar to a recently determined Mn2+-bound structure. Thus, absence of the metal ion does not perturb the structure of the active site. The structures of enolase, mandelate racemase, and MLE were superimposed. A comparison of metal ligands suggests that enolase may retain some characteristics of the ancestor of this enzyme family. Comparison of other residues involved in catalysis indicates two unusual patterns of conservation: (i) that the position of catalytic atoms remains constant, although the residues that contain them are located at different points in the protein fold; and (ii) that the positions of catalytic residues in the protein scaffold are conserved, whereas their identities and roles in catalysis vary.

Binding Sites↗
PubMed1998

Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence.

Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.

Chromosome Mapping↗
PubMed1998

DnaA-stimulated transcriptional activation of orilambda: Escherichia coli RNA polymerase beta subunit as a transcriptional activator contact site.

We present evidence that Escherichia coli RNA polymerase beta subunit may be a transcriptional activator contact site. Stimulation of the activity of the pR promoter by DnaA protein is necessary for replication of plasmids derived from bacteriophage lambda. We found that DnaA activates the pR promoter in vitro. Particular mutations in the rpoB gene were able to suppress negative effects that certain dnaA mutations had on the replication of lambda plasmids; this suppression was allele-specific. When a potential DnaA-binding sequence located several base pairs downstream of the pR promoter was scrambled by in vitro mutagenesis, the pR promoter was no longer activated by DnaA both in vivo and in vitro. Therefore, we conclude that DnaA may contact the beta subunit of RNA polymerase during activation of the pR promoter. A new classification of prokaryotic transcriptional activators is proposed.

Bacterial Proteins↗
PubMed1998

Dendritic cells stimulate the expansion of bcr-abl specific CD8+ T cells with cytotoxic activity against leukemic cells from patients with chronic myeloid leukemia.

The role of T lymphocytes in the control of chronic myeloid leukemia (CML) after bone marrow transplantations has been clearly shown. This effect closely correlates with graft-versus-host disease (GVHD). A specific graft-versus-leukemia (GVL) effect separate from GVHD has been postulated but has been difficult to show. One possible target for specific GVL activity is the bcr-abl fusion protein characteristic of CML. We have investigated the use of normal peptide-pulsed dendritic cells for the generation of cytotoxic, bcr-abl-specific T cells from normal donors. T cells (CD3+, CD8+, TCR alpha beta+, and NK receptor-negative) generated from a normal donor (HLA A24, B52, B59, Cw1) after stimulation with autologous dendritic cells, primed with a 16 mer peptide spanning the b3a2 breakpoint of bcr-abl, lysed CML cells from the peripheral blood of seven patients with CML with the b3a2 breakpoint. CML cells from four patients with only the b2a2 breakpoint were not lysed. Phytohemagglutinin (PHA) blasts derived from peripheral blood of patients with CML were not lysed, suggesting that cytotoxicity was not due to alloreactivity. Blocking experiments with anti-HLA-A,B,C indicated that cytotoxicity was dependent on recognition of major histocompatibility complex (MHC) class I molecules, although cytotoxicity was not MHC-restricted because not all patients shared HLA types with the T-cell donor. Specificity for bcr-abl and absence of alloreactivity was confirmed by the presence of lytic activity against autologous and allogeneic class I HLA-A matched monocytes pulsed with the 16 mer bcr-abl fusion peptide, but not against unpulsed monocytes or monocytes pulsed with other peptides. These results show that bcr-abl-specific T cells with marked cytotoxic activity against CML cells can be generated and amplified from normal donor peripheral blood. Recognition of HLA molecules is essential for cytotoxicity but strict HLA identity is not required.

Antigens↗
PubMed1998

Replication and maintenance of lambda plasmids devoid of the Cro repressor autoregulatory loop in Escherichia coli.

Plasmids derived from bacteriophage lambda are known as lambda plasmids. These plasmids contain the ori lambda region and lambda replication genes O and P. Typical lambda plasmids also contain the cro gene, the product of which is a repressor of the pR promoter when present at relatively high concentrations. These genes stably maintain the plasmid in Escherichia coli at copy numbers of 20 to 50 per cell. According to a generally accepted model, stable maintenance of lambda plasmids is possible due to the Cro repressor autoregulatory loop (the cro gene is under control of pR). Here we demonstrate that lambda plasmids devoid of the Cro autoregulatory loop can also be stably maintained in E. coli strains. We present data for two such plasmids: pTC lambda 1 in which the pR-cro region has been replaced by the ptetA promoter and the tetR gene (coding for the TetR repressor), and a standard lambda plasmid with inactivated cro gene (lambda cro-null plasmid). Thus, the presence of the Cro repressor autoregulatory loop does not appear to be essential to the maintenance of lambda plasmids in vivo.

Bacteriophage lambda↗
PubMed1998

Simian Y chromosomes: species-specific rearrangements of DAZ, RBM, and TSPY versus contiguity of PAR and SRY.

The three human male specific expressed gene families DAZ, RBM, and TSPY are known to be repetitively clustered in the Y-specific region of the human Y Chromosome (Chr). RBM and TSPY are Y-specifically conserved in simians, whereas DAZ cannot be detected on the Y chromosomes of New World monkeys. The proximity of SRY to the pseudoautosomal region (PAR) is highly conserved and thus most effectively stabilizes the pseudoautosomal boundary on the Y (PABY) in simians. In contrast, the non-recombining part of the Y Chrs, including DAZ, RBM, and TSPY, was exposed to species-specific amplifications, diversifications, and rearrangements. Evolutionary fast fixation of any of these variations was possible as long as they did not interfere with male fertility.

Animals↗
PubMed1998

Interaction of the Escherichia coli DnaA protein with bacteriophage lambda DNA.

Interaction of the Escherichia coli DnaA (replication initiator) protein with restriction fragments of phage lambda DNA demonstrated differential binding of DnaA along the whole lambda DNA. Interaction of DnaA with the lambda replication region (from the promoter pR to the origin of replication, orilambda) demonstrated a strong binding of DnaA to the region around the p(o) promoter where synthesis of a short antisense oop RNA is initiated. The four sequences protected by DnaA (two 9mers and two 5mers) are not related even to a relaxed DnaA box. The pattern of protection of these four sequences and the location of three DNase I hypersensitive sites in the lambda DNA r strand, together with results of mobility shift assays and electron microscopy studies, may indicate an interaction involving DnaA monomers bound to different DNA positions on one side of the helix and the formation of higher-order nucleoprotein structures. Therefore, it is tempting to suggest that DnaA, in addition to its activity in regulation of replication and transcription, could be considered as a factor which structures certain chromosomal regions.

Bacterial Proteins↗
PubMed1998

ORBIS--training nurses worldwide in ophthalmic care.

The unique nature of the ORBIS teaching mission is reflected in many arenas. The ORBIS organization recognizes that the nurse's role is critical to achieving their mission of preventing blindness through education, hence the emphasis on nurse education. The roles of the head nurse, nurse educator, staff nurses, and the biomedical engineering department are discussed briefly with emphasis on the needs assessment and the different programs offered to meet the identified needs.

Aircraft↗
PubMed1998

Collection of Ph-negative progenitor cells with granulocyte-colony stimulating factor in patients with chronic myeloid leukaemia who respond to recombinant alpha-interferon.

This study aimed to demonstrate that sufficient Ph-negative blood progenitors could be collected following administration of glycosylated rhG-CSF (lenograstim) to patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) who responded to recombinant alpha-interferon (alpha-IFN) (Ph-positive marrow metaphases < 35%). 23 patients received lenograstim (150 microg/m2) once daily for a median of 9 d. Peak circulating numbers of white blood cells (36.4 x 10(9)/l), CD34+ cells (24/ microl) and colony-forming unit-granulocyte-macrophage (CFU-GM; 1346.5/ml) occurred at a median of day 8, day 8 and day 7, respectively. Two to six (median three) leukaphereses (LK) were performed from days 5 to 12. The median number of mononuclear cells (MNC), CD34+ cells and CFU-GM collected per patient was 7.35 x 10(8/)kg, 2.72 x 10(6)/kg and 10.23 x 10(4)/kg, respectively. 22/23 patients had LK which contained either 10(4) CFU-GM/kg and/or 10(6) CD34+ cells/kg; 47LK (from 20/22 patients) were evaluable for cytogenetics. The median percentage of Ph-positive cells was 0, and 43/47 LK (91%) contained <35% Ph-positive cells; 25 (53%) were entirely negative. Sixteen of 20 evaluable patients had one or more LK with <35% Ph-positive cells, and 12 had at least one 100% Ph-negative LK. Mobilization and collection of Ph-negative cells were not influenced by the dose or duration of alpha-IFN administration before (or during) lenograstim administration or by the quality of cytogenetic response (complete v major) during lenograstim administration. No significant side-effects were observed. Thus, lenograstim administration can result in satisfactory Ph-negative blood progenitor cell collection. Autologous transplantation of such cells may be used when indicated.

Adjuvants, Immunologic↗
PubMed1998

Polycystic ovaries and associated metabolic abnormalities in Indian subcontinent Asian women.

OBJECTIVES: To determine the prevalence of polycystic ovaries (PCO) in Asian women living in England who are of Indian subcontinent origin or ancestry and to investigate the relationship between the presence of PCO and/or non-insulin dependent diabetes mellitus (NIDDM) and insulin sensitivity and other metabolic parameters. DESIGN: A random sample of Indian subcontinent Asian women was obtained from the lists of local General Practitioners and a translating service. These women were invited to attend for a medical history questionnaire, examination, venous blood sample for hormonal assessment and transvaginal ovarian ultrasonography. Groups of women without PCO or NIDDM, with NIDDM but not PCO, with PCO but not NIDDM and with both NIDDM and PCO were drawn at random from this population and from Indian subcontinent Asian women attending the Diabetes Unit. They underwent further studies, including measurement of insulin sensitivity using a short intravenous insulin tolerance test. SUBJECTS: 212 Indian subcontinent Asian women aged 18-40 took part in the initial study. Insulin sensitivity was measured in 13 women without PCO or NIDDM, 13 women with NIDDM but not PCO, 15 women with PCO but not NIDDM and 12 women with both NIDDM and PCO. MEASUREMENTS: The main outcome measures were prevalence of polycystic ovaries, clinical features of hyperandrogenism, fertility, blood pressure, serum gonadotrophins, testosterone and sex hormone binding globulin, fasting blood lipids, glucose and insulin, and insulin sensitivity. RESULTS: The prevalence of PCO in Indian subcontinent Asian women was 52% (110/212). There were significant associations between PCO and menstrual irregularity; infertility; the Ferriman and Gallwey score for body hair distribution; the presence of acanthosis nigricans and the fasting blood glucose concentration. There were no differences between women with PCO and those with normal ovarian morphology with respect to systolic and diastolic blood pressure, fasting total, HDL and LDL cholesterol and triglyceride concentrations. The subgroup of women without PCO or NIDDM had the highest insulin sensitivity (189.1 +/- 46.4 mumol glucose/l/min, mean +/- SD) and the women with both PCO and NIDDM had the lowest insulin sensitivity (80.5 +/- 30.9 mumol glucose/l/min). There was no significant difference in insulin sensitivity between those with PCO but not NIDDM (125.0 +/- 59.5 mumol glucose/l/min) and those with NIDDM but not PCO (120.8 + 38.0 mumol glucose/l/min). The effects of NIDDM and PCO on insulin sensitivity were independent; the effect of PCO on insulin sensitivity was -60 mumol glucose/l/min (95% confidence interval -100 to -21, P = 0.004) and the effect of NIDDM was -68 mumol glucose/l/min (95% confidence interval -105 to -31, P < 0.001). There were no significant relationships between insulin sensitivity and fasting plasma insulin, systolic or diastolic blood pressure, fasting serum cholesterol or triglyceride. CONCLUSIONS: The prevalence of polycystic ovaries in Indian subcontinent Asian women is very high and it has significant clinical associations. Polycystic ovaries and non-insulin dependent diabetes mellitus are associated with similar degrees of reduced insulin sensitivity in this population. Their effects are independent suggesting that these changes in insulin sensitivity involve different mechanisms. Polycystic ovaries unlike non-insulin dependent diabetes mellitus, are not associated with a defect in the secretion of insulin.

Adolescent↗
PubMed1998

Trypanosoma congolense infection of trypanotolerant N'Dama (Bos taurus) cattle is associated with decreased secretion of nitric oxide by interferon-gamma-activated monocytes and increased transcription of interleukin-10.

The mechanisms whereby trypanotolerant N'Dama cattle control infection with Trypanosoma congolense are unknown. Previous studies have suggested that the monocytes of N'Dama cattle are more highly activated during infection than those of trypanosusceptible Boran cattle. However, we have recently reported that the monocytes of Boran cattle have a reduced capacity to secrete nitric oxide during trypanosome infection. We therefore evaluated the production of nitric oxide by monocytes of trypanotolerant N'Dama cattle infected with T. congolense in response to interferon-gamma, bacterial lipopolysaccharide or trypanosome antigens. Interferon-gamma-induced nitric oxide production was decreased between days 25 and 76 of infection, while lipopolysaccharide-induced secretion of nitric oxide was increased at days 13 and again at day 76 post-infection. Trypanosome antigens did not elicit nitric oxide production. Analysis of interleukin-10 mRNA transcription in peripheral blood leucocytes revealed an increase at time points that coincided with decreased interferon-gamma-induced nitric oxide synthesis. In contrast, interferon-gamma mRNA expression was not changed during infection while tumour necrosis factor-alpha was slightly reduced at day 32 post-infection. Recombinant interleukin-10 suppressed interferon-gamma-induced nitric oxide and tumour necrosis factor-alpha secretion, but not lipopolysaccharide-induced nitric oxide secretion in cultures of peripheral blood mononuclear cells and monocytes of uninfected cattle. These results suggest that the nitric oxide response of monocytes to IFN-gamma but not lipopolysaccharide, is suppressed during infection. The kinetics of the upregulation of interleukin-10 and its biological activity indicate a possible association with the depression of nitric oxide production and control of tumour necrosis factor-alpha.

Animals↗
PubMed1998

Cytogenetic and molecular investigations of Y chromosome sequences and their role in Turner syndrome.

It has been proposed that all live born females with Turner syndrome carry a cell line containing two sex chromosomes, which may be present at a low level of mosaicism (Hook & Warburton, 1983; Hassold et al. 1985; 1988; Connor & Loughlin, 1989). If the second sex chromosome is a Y, these patients are at risk of developing gonadoblastoma. In this study, 50 patients found to have a 45,X karyotype by conventional cytogenetic analysis, were screened by the polymerase chain reaction (PCR), for the presence of Y chromosome sequences. Two patients were positive for six of the eight Y chromosome loci tested and additional cytogenetic analysis confirmed the presence of a marker chromosome, in 8% and 3% of cells respectively. Fluorescence in situ hybridization (FISH) was used to confirm that the markers were of Y chromosome origin and helped to elucidate their structure. In addition, four other patients were found to have a Y chromosome by initial routine cytogenetic analysis. FISH, in conjunction with PCR, elucidated the structure of the Y chromosomes. This study illustrates the value of using a combination of cytogenetic and molecular techniques, to identify Y chromosome sequences in Turner syndrome.

Cytogenetics↗
PubMed1998

Exploring the barriers to cervical screening in an urban Canadian setting.

Cervical cancer is potentially one of the most preventable cancers. The benefits of cervical screening come to those who are actually screened. Despite the known value of cervical screening, a significant number of women do not avail themselves of the procedure. This study examined the barriers to cervical screening in an urban Canadian setting. Focus group methodology was used to explore the perspectives of socioeconomically disadvantaged women regarding their access to health care. The sessions were tape-recorded, and subsequent content analysis revealed four broad themes: being able to talk with doctors is important; being treated as a person is important; finding answers to many questions about cancer is important; and having a Pap test is uncomfortable. Implications for practice and program design were highlighted.

Adult↗
PubMed1998

Divergent effects of angiotensin-converting enzyme inhibition and angiotensin II-receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats.

There is mechanistic rationale to suggest differential effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1)-receptor antagonism on ventricular remodeling after myocardial infarction (MI). We compared the effects of ACE inhibition, AT1-receptor antagonism, and their combination on post-MI ventricular remodeling in rats. We induced MI in 62 rats, which then received one of four treatments: (a) placebo; (b) the ACE inhibitor, enalapril; (c) the AT1-receptor antagonist, losartan; and (d) enalapril and losartan in combination. Two weeks after MI, we examined: (a) heart weight (HW)/body weight (BW) ratio; (b) nonmyocyte cellular proliferation in the noninfarct zone by using proliferating cell nuclear antigen staining; and (c) collagen content within the noninfarct zone. Placebo-treated, infarcted rats developed significant increases in HW/BW ratio (p < 0.001), left ventricular (LV) volume (p < 0.01), nonmyocyte cellular proliferation (p < 0.04), and collagen content (p < 0.01) compared with noninfarcted controls. Enalapril, losartan, and combination therapy limited the increase in HW/BW ratio (all p values <0.01 vs. placebo). Enalapril inhibited nonmyocyte proliferation (p < 0.01 vs. placebo), whereas losartan had a smaller effect (p = NS vs. placebo; p < 0.03 vs. enalapril); combined treatment also reduced nonmyocyte cellular proliferation but did not reach statistical significance (p = 0.08 vs. placebo). Enalapril and combination treatment significantly diminished collagen content (both p values <0.01 vs. placebo), whereas losartan did not. Thus, ACE inhibition and AT1-receptor antagonism equally limited myocardial hypertrophy after MI in rats, but ACE inhibition more effectively prevented nonmyocyte cellular proliferation and collagen deposition in the noninfarcted myocardium. Combination therapy was no more effective than was ACE inhibition alone. These data suggest that the myocyte hypertrophic response after MI is strongly influenced by activation of the AT1 receptor, whereas nonmyocyte cellular proliferation and collagen deposition result, in part, from mechanisms separate from AT1-receptor activation.

Angiotensin Receptor Antagonists↗
PubMed1998

Prospective comparison of temperature guided microwave and radiofrequency catheter ablation in the swine heart.

Microwave energy has been proposed as an alternative to radiofrequency energy for use during catheter ablation procedures. The purpose of this study was to prospectively compare, in an animal model, the lesion size associated with temperature guided catheter ablation using either microwave or radiofrequency energy. Eleven swine underwent catheter ablation with either radiofrequency (N = 4) or microwave energy (N = 7). In each animal catheter ablation was performed at 7-15 sites. At each site energy was delivered for 60 seconds using closed loop feedback temperature control to achieve a target temperature of 70 degrees C. Cardiac catheterization was performed before and after ablation. Animals were sacrificed approximately one month following the ablation procedure. Analysis of lesion size demonstrated that overall lesions created using radiofrequency energy were larger than those created using microwave energy. In the ventricle, lesions created using microwave energy were longer, but had a similar width and depth as those created using radiofrequency energy. An important relation was observed between the depth of lesions created using microwave energy and catheter stability, as evidenced by the temperature profile. Overall, lesions created using microwave energy are smaller than those created using radiofrequency energy. Catheter stability has an important impact on lesion size.

Animals↗