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Biomedical subjects

C Booth

Publications and source records attributed to C Booth.

At least 19 recordsLinked to original sources
PubMed2006

Cyclin A activity predicts clinical outcome in oral precancer and cancer.

Accurate, predictive assessment of the behaviour of oral cancers and precancers remains elusive. Increasing dysregulation of cell proliferation is a feature of carcinogenesis, and alterations in cyclin proteins regulating cell cycle progression are involved in enhanced cell proliferation. The authors of the present study have previously demonstrated increased proliferative activity in oral dysplastic lesions and poorly differentiated carcinomas, and hypothesize that cell proliferation can be used as a predictive agent in clinical management. In this preliminary study, immunohistochemical quantification of cyclin A expression was carried out for 33 excised oral lesions (ranging from mild dysplasia to invasive squamous cell carcinoma, SCC). Clinical outcome was determined as: no disease after 2 years follow-up, persistent disease, or further disease presentation. Labelling Indices (LIs) ranged from 5.5 to 32.1%, and whilst a trend to increased labelling in increasingly dysplastic and neoplastic tissue was seen, this was not statistically significant (P=0.06). High LIs were related to poor clinical outcome (P=0.003), suggesting a definite role for cyclin A measurement as a predictive tool in clinical management.

Adult↗
PubMed2006

Sustainable use of continuous positive airway pressure in extremely preterm infants during the first week after delivery.

BACKGROUND: Early use of nasal continuous positive airway pressure (nCPAP) may reduce lung damage, but it is not clear how many extremely preterm infants can be cared for without mechanical ventilation on the first days after delivery. OBJECTIVES: To describe our experience of nCPAP in infants born at <27 weeks' gestation and to determine the chance of reintubation of this group of extremely preterm infants. METHODS: A retrospective, observational study examined the period from November 2002 to October 2003, when efforts were made to extubate infants to nCPAP at the earliest opportunity. Data were collected on all infants born at <27 weeks' and gestation admitted to The Neonatal Intensive Care Unit, Queen Charlotte's and Chelsea Hospital, London, UK. The chance of an individual infant requiring reintubation within 48 h of delivery was estimated, calculating the predictive probability using a Bayesian approach, and oxygen requirements at 36 weeks' postmenstrual age were examined. RESULTS: 60 infants, 34 inborn and 26 ex utero transfers, were admitted; 7 infants admitted 24 h after birth were excluded and 5 died within 48 h. The mean birth weight was 788 g and the gestational age was 25.3 weeks. Extubation was attempted on day 1 in 21 of 52 infants on ventilators and was successful in 14; and on day 2 in 14 of 35 and successful in 10 of infants extubated within 48 h of delivery survived to discharge. 5 of 23 infants on mechanical ventilation at 48 h of age were on air at 36 weeks postmenstrual age, and 12 of 26 of those were on nCPAP at 48 h of age. The probability of an individual baby remaining on nCPAP was 66% (95% CI 46% to 86%) on day 1 and 80% (95% CI 60% to 99%) on day 2. The smallest infant to be successfully extubated was 660 g and the youngest gestational age was 23.8 weeks. CONCLUSIONS: Extremely preterm infants can be extubated to nCPAP soon after delivery, with a reasonable probability of not requiring immediate reintubation.

Continuous Positive Airway Pressure↗
PubMed2005

Acute exposure to cyclosporine does not increase plasma homocysteine in rats.

There is interest in the postulate that cyclosporine a (CsA) contributes to the elevated homocysteine levels seen in organ transplant recipients, as hyperhomocysteinemia is now considered an independent risk factor for cardiovascular disease (CVD) and may partially explain the increased prevalence of CVD in this population. The main purpose of this investigation was to determine the effect of CsA administration on plasma homocysteine. Eighteen female Sprague Dawley rats (4 months old) were randomly assigned to either a treatment or a control group. For 18 days the treatment group received of CsA (25 mg/kg/d) while the control group received the same volume of the vehicle. Blood samples obtained following sacrifice to measure CsA, total homocysteine, and plasma creatinine. There were no significant differences in plasma homocysteine (mean values +/- SD: treatment = 4.79 +/- 0.63 micromol/L, control = 4.46 +/- 0.75 micromol/L; P = .37). Homocysteine was not significantly correlated with final CsA concentrations (r = .17; P = .69). There was a significant difference in plasma creatinine values between the two groups (treatment = 60.44 +/- 7.68 micromol/L, control = 46.33 +/- 1.66 micromol/L; P < .001). Furthermore, plasma homocysteine and creatinine were positively correlated with the treatment group (r = .73; P < .05) but not the controls (r = -.10; P = .81). In conclusion, CsA does not influence plasma homocysteine concentrations in rats.

Animals↗
PubMed2004

Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage.

Glucagon-like peptide-2 and its dipeptidyl peptidase (DP-IV) resistant analogue teduglutide are trophic for the gastrointestinal epithelium. Exposure increases villus height and crypt size and results in increased overall intestinal weight. As these effects may be mediated through stimulation of the stem cell compartment, they may promote intestinal healing and act as potential anti-mucositis agents in patients undergoing cancer chemotherapy. A study was initiated to investigate the protective effects of teduglutide on the murine small intestinal epithelium following gamma-irradiation using the crypt microcolony assay as a measure of stem cell survival and functional competence. Teduglutide demonstrated intestinotrophic effects in both CD1 and BDF1 mouse strains. In BDF1 mice, subcutaneous injection of GLP-2 or teduglutide (0.2 mg/kg/day, b.i.d.) for 14 days increased intestinal weight by 28% and resulted in comparable increases in crypt size, villus height and area. Teduglutide given daily for 6 or 14 days prior to whole body, gamma-irradiation significantly increased crypt stem cell survival when compared with vehicle-treated controls. The mean levels of protection over a range of doses provided protection factors from 1.3 to 1.5. A protective effect was only observed when teduglutide was given before irradiation. These results suggest that teduglutide has the ability to modulate clonogenic stem cell survival in the small intestine and this may have a useful clinical application in the prevention of cancer therapy-induced mucositis.

Animals↗
PubMed2003

Acute effect of high-calcium milk with or without additional magnesium, or calcium phosphate on parathyroid hormone and biochemical markers of bone resorption.

OBJECTIVE: To assess whether there are any differences in the postprandial physiological responses to apple drink (control), calcium phosphate (tricalcium phosphate, TCP) and high-calcium skim milk (HCSM) with or without additional magnesium in postmenopausal women. DESIGN: Randomized, controlled, cross-over. Measurements after overnight fast before each drink, and subsequently every hour for 8 h postprandially. SETTING: Human Nutrition Studies Laboratory, Milk and Health Research Centre, Massey University, Palmerston North, New Zealand. SUBJECTS: Twenty-one healthy postmenopausal women. INTERVENTION: Four drinks, each 400 ml. (1) Apple drink (25% fruit juice). (2) TCP dispersed in water containing 1200 mg Ca. (3) HCSM containing 1200 mg Ca and 65.5 mg Mg. (4) HCSM containing 1200 mg Ca and 172 mg Mg. RESULTS: There was no difference in baseline serum calcium, PTH or C-telopeptide levels between drinks. There were no overall differences in serum calcium after apple or after either milk, but after TCP serum calcium increased from a baseline value of 2.12+/-0.08 to a mean peak of 2.21+/-0.12 mmol/l (s.d.) (P=0.0001) after 2 h. There were no significant differences in serum PTH after either apple or HCSM+Mg. In contrast, after TCP, serum PTH decreased from 2.76+/-0.69 to a mean nadir of 2.23+/-0.65 pmol/l (P=0.0001) after 1 h, and after HCSM, it decreased from 2.71+/-0.78 to a mean nadir of 2.51+/-0.87 pmol/l (P=0.007) after 2 h. Serum C-telopeptides decreased after each drink, reaching nadirs after 5 h. At this time the serum values for each of the high calcium drinks were not different from each other, but were significantly less than for apple (P=0.001 for each), being 0.22+/-0.09 ng/ml for apple, 0.15+/-0.08 for TCP, 0.14+/-0.07 for HCSM and 0.16+/-0.07 for HCSM+Mg. CONCLUSION: Despite differences in serum calcium and PTH responses to the three high-calcium drinks that we tested, there was no distinguishable difference in serum C-telopeptides between high calcium drinks.

Aged↗
PubMed2002

Cell kinetic studies in the murine ventral tongue epithelium: thymidine metabolism studies and circadian rhythm determination.

The oral mucosa is a rapidly replacing body tissue that has received relatively little attention in terms of defining its cell kinetics and cellular organization. The tissue is sensitive to the effects of cytotoxic agents, the consequence of which can be stem cell death with the subsequent development of ulcers and the symptoms of oral mucositis. There is considerable interest in designing strategies to protect oral stem cells and, hence, reduce the mucositis side-effects in cancer therapy patients. Here we present details of a new histometric approach designed to investigate the changing patterns in cellularity in the ventral tongue mucosa. This initial paper in a series of four papers presents observations on the changing patterns in the labelling index following tritiated thymidine administration, which suggest a delayed uptake of tritiated thymidine from a long-term intracellular thymidine pool, a phenomenon that will complicate cell kinetic interpretations in a variety of experimental situations. We also provide data on the changing pattern of mitotic activity through a 24-h period (circadian rhythms). Using vincristine-induced stathmokinesis, the data indicate that 54% of the basal cells divide each day and that there is a high degree of synchrony in mitotic activity with a mitotic peak occurring around 13.00 h. The mitotic circadian peak occurs 9-12 h after the circadian peak in DNA synthesis. The data presented here and in the subsequent papers could be interpreted to indicate that basal cells of BDF1 mice have an average turnover time of about 26-44 h with some cells cycling once a day and others with a 2- or 3-day cell cycle time.

Animals↗
PubMed2002

Epithelial cell proliferative activity and oral cancer progression.

Accurate, predictive assessment of the behaviour and progression of oral cancers and precancers remains elusive in clinical practice. Archival tissue specimens from 10 previously treated patients with oral lesions of known clinical outcome (3 years post-treatment) were re-examined histopathologically, and proliferative cell labelling indices (LIs) determined for Ki67, cyclin A and histone mRNA cell cycle markers. While histone mRNA labelling ultimately proved unreliable, both Ki67 and cyclin A LIs demonstrated a clear trend for enhanced labelling to occur in increasingly dysplastic and neoplastic tissue, with particular emphasis on suprabasal labelling in abnormal tissue. Perhaps of greatest significance was the observation of increased LIs and suprabasal labelling in lesions with poor clinical outcome, such as patients developing recurrent disease or cervical lymph node metastasis. Measurement of cell proliferative activity in individual oral epithelial dysplastic lesions or invasive squamous cell carcinomas may thus provide unique, predictive information on clinical outcome.

Aged↗
PubMed2002

Cell kinetic studies in murine ventral tongue epithelium: cell cycle progression studies using double labelling techniques.

The dorsal and ventral epithelia on the murine tongue exhibit very pronounced circadian rhythms in terms of the cell cycle. These rhythms are such that three injections of tritiated thymidine 3 h apart spanning the circadian peak in S phase cells labelled between 40 and 50% of the basal cells. Injection of bromodeoxyuridine generally gave slightly lower labelling indices. Approximately the same proportion (54% of the basal cells) could be accumulated in metaphase over a 24-h period using vincristine as a stathmokinetic agent. The experiments reported here using mouse ventral tongue epithelium use double-labelling approaches to address the question: what proportion of the approximately 50% of the basal cells that are proliferating have a 24-h cell cycle and can therefore be labelled by a similar labelling protocol the following day? The results suggest a heterogeneity amongst the proliferating basal cells, similar to the heterogeneity proposed for the dorsal tongue epithelium. Although not all the basal component has been accounted for, the data presented here suggest that about 20% of the basal cells may have a cell cycle time of 24 h, about 30% appear to have a longer cell cycle time (48 or 72 h), while about 20% of the basal cells appear to be postmitotic maturing G1 cells, awaiting the appropriate signals for migration into the suprabasal layer.

Animals↗
PubMed2002

Cell kinetic studies in the murine ventral tongue epithelium: the effects of repeated exposure to keratinocyte growth factor.

Keratinocyte growth factor (KGF) stimulates proliferation and differentiation in various epithelial systems. Three daily subcutaneous injections of 125 microg of this protein into mice induce dramatic changes in the histology and histometric measurements of the ventral tongue epithelium. The thickness of the epithelium is increased two-fold and the number of cells beneath a 1-mm length of the surface is increased 1.6-fold. KGF also induces a four-fold increase in the number of S phase cells labelled with tritiated thymidine in the basal layer on the third day after KGF administration. The increase in thickness and cellularity persist for at least 4 days after the end of the KGF injections. However, there is a dramatic fall in the number of S phase cells detected by 3HTdR pulse labelling 2 days after the end of the KGF treatment. There are indications that by 7 days after the 3-day regimen of KGF treatment, both thickness and cellularity have fallen back to near control levels. Continued exposure to KGF over a period of 7 days does not result in any further increases in thickness, cellularity or proliferation. In fact, the proliferation decreases on the fifth, sixth and seventh days of KGF injection to control values on day 7. These changes in the epithelium following KGF treatment suggest that the thicker and more cellular epithelium may be more able to cope with an exposure to a cytotoxic agent and hence be protected in comparison with normal or vehicle-treated epithelium.

Animals↗
PubMed2002

Cell kinetic studies in the murine ventral tongue epithelium: mucositis induced by radiation and its protection by pretreatment with keratinocyte growth factor (KGF).

Radiation kills or reduces reproductive capacity of proliferating cells, including stem cells. In the oral mucosae this can result in a decline in the number of cells in the tissue which, if severe enough, will result in the formation of an ulcer when the cellularity essentially reaches zero. We have used histometric measurements of cellularity following exposure to radiation in mouse ventral tongue epithelium as a model for oral mucositis (ulcer development). Here we provide further measurements of cellularity changes in the basal layer and in the epithelium as a whole at various times following 15, 20 or 25 Gy doses. The protective effects of prior treatment with keratinocyte growth factor (KGF) are also investigated. 20 Gy of 300 kV X-rays has become our standard reference dose and the changes in cellularity seen following this dose are highly reproducible, with minimum values being observed 6 days following irradiation. A higher dose results in a greater reduction of cellularity, although the minimum value also occurs at 6 days. A lower dose (15 Gy) results in a much shallower curve, with a minimum value being observed about 1 day earlier. These changes in cellularity can be related to the less sensitive index of mucositis, namely epithelial thickness. There is also a sharp peak in proliferation about 1 day after the minimum in cellularity, i.e. on day 7. The peak following a lower dose of radiation occurs a little earlier and, following the higher dose, the peak tends to be broader. Previous work and data presented in the preceding paper in this series has shown that KGF, given over a period of 3 days, results in a dramatic increase in epithelial thickness in oral mucosa, including the ventral tongue. As a result of the increased cellularity induced by KGF given before radiation, a delay in the fall in cellularity results, which is the consequence of the increased number of cells in the epithelium at the beginning of the study.

Animals↗
PubMed2001

Quantitative amplification of single-stranded DNA (QAOS) demonstrates that cdc13-1 mutants generate ssDNA in a telomere to centromere direction.

We have developed a method that allows quantitative amplification of single-stranded DNA (QAOS) in a sample that is primarily double-stranded DNA (dsDNA). Single-stranded DNA (ssDNA) is first captured by annealing a tagging primer at low temperature. Primer extension follows to create a novel, ssDNA-dependent, tagged molecule that can be detected by PCR. Using QAOS levels of between 0.2 and 100% ssDNA can be accurately quantified. We have used QAOS to characterise ssDNA levels at three loci near the right telomere of chromosome V in budding yeast cdc13-1 mutants. Our results confirm and extend previous studies which demonstrate that when Cdc13p, a telomere-binding protein, is disabled, loci close to the telomere become single stranded whereas centromere proximal sequences do not. In contrast to an earlier model, our new results are consistent with a model in which a RAD24-dependent, 5' to 3' exonuclease moves from the telomere toward the centromere in cdc13-1 mutants. QAOS has been adapted, using degenerate tagging primers, to preferentially amplify all ssDNA sequences within samples that are primarily dsDNA. This approach may be useful for identifying ssDNA sequences associated with physiological or pathological states in other organisms.

Cell Cycle Proteins↗
PubMed2001

Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction.

The Jagged/Notch signaling pathways control cell fate determination and differentiation, and their dysfunction is associated with human pathologies involving cardiovascular abnormalities. To determine the presence of these genes during vascular response to injury, we analyzed expression of Jagged1, Jagged2, and Notch1 through 4 after balloon catheter denudation of the rat carotid artery. Although low levels of Jagged1, Jagged2, and constitutive expression of Notch1 were seen in uninjured endothelium, expression of all was significantly increased in injured vascular cells. High Jagged1 expression was restricted to the regenerating endothelial wound edge, whereas Notch transcripts were abundant in endothelial and smooth muscle cells. To understand the basis for Jagged/Notch control of cellular phenotype, we studied an in vitro model of NIH3T3 cells transfected with a secreted form of the extracellular domain of Jagged1. We report that the soluble Jagged1 protein caused decreased cell-matrix adhesion and cell migration defects. Cadherin-mediated intercellular junctions as well as focal adhesions were modified in soluble Jagged1 transfectants, demonstrating that cell-cell contacts and adhesion plaques may be targets of Jagged/Notch activity. We suggest that Jagged regulation of cell-cell and cell-matrix interactions may contribute to the control of cell migration in situations of tissue remodeling in vivo.

3T3 Cells↗
PubMed2001

The effects of repeated doses of keratinocyte growth factor on cell proliferation in the cellular hierarchy of the crypts of the murine small intestine.

Keratinocyte growth factor (KGF) administered on a daily basis for 3 or more days can result in dramatic changes in tissue architecture, particularly the thickness in oral epithelia, and can afford protection against the cytotoxic effects of radiation on the clonogenic stem cells in the crypts. This protection of intestinal stem cells (increased numbers of surviving crypts) is reflected in an increased survival of animals exposed to a lethal dose of irradiation. The mechanisms underlying these effects are not clear. The present experiments were designed to investigate the nature of any proliferative changes induced in the crypts of the small intestine by protracted exposure to KGF. Tritiated thymidine or bromodeoxyuridine labeling showed statistically significant increases in labeling in the stem cell zone of the crypt, with a concomitant reduction in labeling in the upper regions of the crypt corresponding to the late-dividing transit population. The increase in labeling in the lower regions of the crypt was also observed with Ki-67 staining, but the reduction in the upper regions of the crypt seen with tritiated thymidine was not observed with Ki-67. Metaphase arrest data suggest that the rate of progression through the cell cycle is essentially the same in KGF-treated animals as in controls, but there is a statistically significant increase in the number of mitotic events per crypt. Double labeling studies suggest that, at certain times of the day, there is a greater influx into S phase than efflux. The data overall indicate that KGF induces some complex proliferative changes in the intestinal crypts and are consistent with the hypothesis that the radioprotection may be afforded, at least in part, by a KGF-induced increase in stem cell numbers and/or increases in the number of stem cells in the S phase of the cell cycle. This alteration in the homeostasis of the crypt is compensated for by a foreshortening of the dividing transit lineage.

Animals↗
PubMed2000

Adsorption of Diblock Copolymers of Poly(ethylene oxide) and Poly(lactide) at Hydrophilic Silica from Aqueous Solution.

The adsorption of a series of amphiphilic poly(ethylene oxide)-poly(DL-lactide) (PEO-PL) diblock copolymers at the water/silica interface was investigated by ellipsometry and reflectometry. For all copolymers, a much higher saturation adsorption is found compared to that of the PEO homopolymers, indicating the importance of the PL block for the adsorption. The copolymers display a saturation adsorption that increases with increasing hydrophobic content of the polymer, and decreases with increasing hydrophilic content of the polymer. Despite this, however, the layer thickness observed is rather similar for all polymers, regardless of the length and composition of the copolymers. Moreover, the layer thicknesses were significantly higher than what would be expected for the unperturbered copolymer dimensions. The initial adsorption kinetics of the different copolymers are comparable. The initial adsorption rate increases cooperatively with concentration and is slower than that expected for diffusion-controlled adsorption. Moreover, the adsorption increases only slightly over a concentration the range from 20 to 50 degrees C. Furthermore, pH titrations show that all polymers exhibit a critical desorption pH of 8-9, which is lower than the corresponding value of pH 10.5 observed for the PEO homopolymer. These results are discussed in terms of the adsorption mechanism and the adsorbed layer structure and formation. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

Adsorption of Diblock Copolymers of Poly(ethylene oxide) and Polylactide at Hydrophobized Silica from Aqueous Solution.

The adsorption of a series of amphiphilic diblock copolymers of poly(ethylene oxide) (PEO) and poly(DL-lactide) (PL) at hydrophobized silica from aqueous solution was studied using time-resolved ellipsometry and reflectometry. The adsorbed amounts only display a weak dependence on the copolymer composition in both water and phosphate-buffered solution. For the short copolymers, the layer thickness decreases slightly with increasing length of the hydrophobic block. Furthermore, in comparison with the short copolymers, the layer thickness of the long copolymers is substantially higher. Upon degradation of the PL block, the adsorbed amount is found to decrease and approach that of the corresponding PEO homopolymer. Protein rejection studies indicate that the adsorption of fibrinogen is inhibited by copolymer preadsorption. The protein rejection is enhanced with increasing surface coverage of the preadsorbed copolymer, but largely independent of the length of the PL block and the PEO block. For all polymers investigated, essentially complete protein rejection is obtained above a critical surface coverage that is significantly lower than the saturation coverage of the copolymers. Removing the copolymer from bulk solution after preadsorption causes a partial desorption, resulting in reduced protein rejection. However, the protein rejection capacity with and without copolymer in the bulk solution is found to be similar at a given surface coverage. Contrary to the behavior of the intact copolymers, fibrinogen adsorption is found to be significant at surfaces pretreated with an extensively degraded copolymer and, in fact, quantitatively comparable to that at the hydrophobic surface in the absence of preadsorption. This finding, together with that of the effect of the copolymer composition on protein rejection, suggests that an efficient protein rejection is maintained until only a few L units remain in the copolymer, i.e., until nearly completed degradation. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

A non-transmembrane form of Jagged-1 regulates the formation of matrix-dependent chord-like structures.

Jagged-Notch interactions regulate a transmembrane ligand-receptor signaling pathway involved in the regulation of cell fate determination as well as myoblast and endothelial cell differentiation. To further examine the role of the transmembrane ligand, Jagged-1, in the regulation of cell differentiation, we stably transfected NIH 3T3 cells with a truncated form of Jagged(J)-1, which results in the secretion of a soluble(s) form of the protein. Comparison of gene expression by serial analysis demonstrated that among the 227 transcripts differentially regulated in the sJ-1 transfectants, the expression of the pro-alpha-2(I) collagen transcript and pro-alpha-1(I) collagen translation product was predominantly repressed in sJ-1 transfectants. When plated on extracellular matrices, sJ-1 transfectants formed prominent chord-like structures on type I collagen but not on fibrin, fibronectin, or vitronectin. While the sJ-1 transfectants exhibited growth kinetics similar to control cells and were unable to grow in soft agar, the cells were less sensitive to contact inhibition of growth in vitro and sJ-1 allografts formed tissue masses in nude mice after a prolonged latency period and exhibited an abundance of host-derived microvascular endothelial cells. These data suggest that J-1 may be able to modulate, in a matrix-dependent manner, the organization of cell to cell interactions including its ability to promote the development of chord-like structures.

3T3 Cells↗