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Biomedical subjects

D Scott

Publications and source records attributed to D Scott.

At least 127 records · Page 7Linked to original sources
PubMed1998

Radiation-induced micronuclei in human fibroblasts in relation to clonogenic radiosensitivity.

As part of our programme for developing predictive tests for normal tissue response to radiotherapy, we have investigated the efficacy of the cytokinesis-block micronucleus (MN) assay as a means of detecting interindividual differences in cellular radiosensitivity. A study was made of nine fibroblast strains established from vaginal biopsies of pretreatment cervical cancer patients and an ataxia telangiectasia (A-T) cell strain. Cells were irradiated in plateau phase, replated and treated with cytochalasin B 24 h later. MN formation was examined 72 h after irradiation as the number of MN in 100 binucleate cells. The method yielded low spontaneous MN yields (<7 per 100 cells), and mean induced MN frequencies after 3.5 Gy varied between cell strains from 18 to 144 per 100 cells. However, in repeat experiments, considerable intrastrain variability was observed (CV = 32%), with up to twofold differences in MN yields, although this was less than interstrain variability (CV = 62%). An analysis was made of the relationship between MN results and previously obtained clonogenic survival data. There was a significant correlation between MN yields and clonogenic survival. However, when the A-T strain was excluded from the analysis, the correlation lost significance, mainly because of one slow-growing strain which was the most sensitive to cell killing but had almost the lowest MN frequency. With current methodology, the MN assay on human fibroblasts does not appear to have a role in predictive testing of normal tissue radiosensitivity.

Cell Survival↗
PubMed1998

Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition?

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. We previously showed that 42% of an unselected series of breast cancer patients and 9% of healthy control subjects showed elevated chromosomal radiosensitivity of lymphocytes irradiated in the G2 phase of the cell cycle. We suggested that, in addition to the highly penetrant genes BRCA1 and BRCA2, which confer a very high risk of breast cancer and are carried by about 5% of all breast cancer patients, there are also low-penetrance predisposing genes carried by a much higher proportion of breast cancer patients, a view supported by recent epidemiological studies. Ideally, testing for the presence of these putative genes should involve the use of simpler methods than the G2 assay, which requires metaphase analysis of chromosome damage. Here we report on the use of a simple, rapid micronucleus assay in G0 lymphocytes exposed to high dose rate (HDR) or low dose rate gamma-irradiation, with delayed mitogenic stimulation. Good assay reproducibility was obtained, particularly with the HDR protocol, which identified 31% (12 out of 39) of breast cancer patients compared with 5% (2 out of 42) of healthy controls as having elevated radiation sensitivity. In the long term, such cytogenetic assays may have the potential for selecting women for intensive screening for breast cancer.

Adult↗
PubMed1998

Induction of lympho-haemopoietic malignancy: impact of preconception paternal irradiation.

PURPOSE: To investigate the effects of preconception paternal irradiation (PPI) from injected 239Pu on the susceptibility to induction of lympho-haemopoietic malignancy by subsequent irradiation or exposure to a chemical carcinogen. MATERIALS AND METHODS: The male CBA/H and DBA2 mouse was injected with 0, 128 or 256 Bqg(-1) 239Pu 12 weeks before mating with the normal CBA/H and C57B1 female respectively. CBA/H offspring were exposed to 3.3 Gy gamma-rays total body irradiation: BDF1 offspring were injected with 50 mg kg(-1) methyl nitrosourea (MNU). The offspring were assayed for changes in bone marrow progenitor cell numbers and chromosome aberrations and were followed up for subsequent induction of neoplasia. RESULTS: While the untreated mouse showed a normal distribution for cellularity, spleen colony-forming units (CFU-S) and fibroblastoid colony-forming units (CFU-F), significant numbers of PPI offspring presented levels outside the normal range. There was a tendency for them also to show increased, dose-related, levels of chromosomal aberrations. Offspring treated with irradiation or MNU developed an increased incidence of lympho-haemopoietic malignancies. CONCLUSIONS: These studies have shown that PPI results in offspring that are more susceptible to the induction of lymphohaemopoietic malignancy on encountering a secondary carcinogenic insult. This may be linked to inherited chromosomal instability and abnormal kinetics of haemopoiesis. The experiments indicate a potential mechanism by which an increased incidence of leukaemia may be linked to PPI.

Animals↗
PubMed1998

Behavioral and psychiatric manifestations in dementia patients in a community: caregiver burden and outcome.

The aim of the present study was to document behavioral disturbances in dementia patients in a sample not specifically referred to a clinic. Ninety patients with dementia in a community were studied in relation to the behavioral and psychiatric manifestations as perceived by their caregivers. They were categorized into two subgroups based on severity of the illness, namely mild and moderate-severe, for the purpose of comparison. There were 68 patients with Alzheimer disease, 10 with vascular dementia, and the remaining 12 formed a miscellaneous group.The frequency of the following behaviors in relation to the severity of the dementia were assessed: aggression, physical violence, wandering, incontinence, disinhibition, binge-eating, hallucinations, delusions, and depression. The most common behavioral change was aggression (59%), followed by wandering (27%), delusions (22%), and incontinence (18%). Aggression caused the most distress to the caregiver. There was a higher incidence of wandering, incontinence (p= 0.009), and persecutory delusions (p=0.02) in the moderate severe group. A significantly higher proportion of the moderate-severe group required further care and intervention (p=0.04). This study is probably one of the rare nonclinical surveys on this subject.

Aged↗
PubMed1998

The Na(+)-K(+)-ATPase beta 1 subunit is associated with the HK alpha 2 protein in the rat kidney.

The Na-K-ATPase beta 1 subunit acts as the beta subunit for the HK alpha 2 protein in the rat kidney. The colonic H(+)-K(+)-ATPase is a member of the P-type ATPases, and has been shown to contribute to potassium transport by the mammalian kidney and colon. The P-type ATPases often consist of an alpha subunit that contains the catalytic site and a beta subunit that participates in regulation of enzyme activity and targeting of the enzyme to the plasma membrane. The cDNA of the alpha subunit (HK alpha 2) has been cloned and the HK alpha 2 protein has been isolated from the rat kidney and colon. However, a unique beta subunit for the colonic H(+)-K(+)-ATPase has not been described. To determine if one of the known beta subunits present in the kidney might act as the beta subunit for the colonic H(+)-K(+)-ATPase, microsomes enriched in the colonic H(+)-K(+)-ATPase were isolated using an HK alpha 2-specific antibody (AS 31.7) and the Minimac magnetic separation system. Immunoblots of rat kidney microsomal protein isolated with antibody AS 31.7 were probed with antibodies directed against the gastric HK beta subunit, Na(+)-K(+)-ATPase alpha 1, and Na(+)-K(+)-ATPase beta 1 subunits. A band of the appropriate size was detected with Na(+)-K(+)-ATPase beta 1-specific antibodies, but not those directed against HK beta 1. These data suggest that Na(+)-K(+)-ATPase beta 1 could be the beta subunit for the colonic H(+)-K(+)-ATPase in the kidney.

Animals↗
PubMed1998

Effects of variations in dietary calcium and phosphorus supply on plasma and bone osteocalcin concentrations and bone mineralization in growing pigs.

Growing pigs were fed diets supplying 45% (low), 70% (intermediate) and 100% (high) recommended dietary allowances of calcium (the Ca:P ratio was kept constant), but otherwise adequate in nutrients. The effects of varying calcium and phosphorus intakes on bone and plasma osteocalcin were monitored. Mineral content of the diet did not affect feed conversion and live weight gain. Plasma phosphorus concentrations decreased significantly in pigs fed a low mineral diet compared with those fed the high mineral diet, but there were no changes in plasma calcium and osteocalcin concentrations. Bones from the low mineral group had marked reductions in dry matter, calcium and phosphorus contents, as well as increased collagen, pyridinoline and deoxypyridinoline concentrations: osteocalcin concentrations in bone were unaffected by treatment. The results showed no direct link between osteocalcin and the degree of bone mineralization.

Animals↗
PubMed1998

The life and death of Helicobacter pylori.

The ability of Helicobacter pylori to survive in the varying acidity of the stomach is considered to be linked to its ability to maintain a tolerable pH in its periplasmic space by acid dependent activation of internal urease activity. Whereas survival of H pylori can occur between a periplasmic pH of 4.0 to 8.0, growth can only occur between a periplasmic pH of 6.0 to 8.0. When urease activity is only able to elevate periplasmic pH to between 4.0 and 6.0, the organisms will survive but not divide. In the absence of division, antibiotics such as clarithromycin and amoxycillin are ineffective. Proton pump inhibitors, by elevating gastric pH, would increase the population of dividing organisms and hence synergise with these antibiotics.

Adenosine Triphosphate↗
PubMed1998

Intestinal permeability and inflammation in patients on NSAIDs.

BACKGROUND: The frequency with which non-steroidal anti-inflammatory drugs (NSAIDs) increase small intestinal permeability and cause inflammation is uncertain. AIMS: To examine small intestinal permeability and inflammation in a large number of patients on long term NSAIDs. METHODS: Sixty eight patients receiving six different NSAIDs for over six months underwent combined absorption-permeability tests at three different test dose osmolarities (iso-, hypo-, and hyperosmolar). Two hundred and eighty six patients on 12 different NSAIDs underwent indium-111 white cell faecal excretion studies to assess the prevalence and severity of intestinal inflammation. RESULTS: The iso- and hyperosmolar tests showed significant malabsorption of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar as opposed to the iso-osmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant difference (p>0.1) in the prevalence (54-72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion. CONCLUSIONS: Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.

Adult↗
PubMed1998

Giant cell arteritis presenting as renal vasculitis.

Giant cell arteritis commonly presents with headache, polymyalgia, and visual signs and symptoms. Other neurological, respiratory or vascular symptoms occur in 10-30% of patients. It is extremely rare for giant cell arteritis to present initially with haematuria. Here we describe a case which presented with fever and haematuria, which emphasise the need to be vigilant about the diagnosis of giant cell arteritis as an underlying cause.

Aged↗
PubMed1998

Training anticipation for intermediate tennis players.

The purpose of this study was to examine the trainability of anticipation in intermediate tennis players. In particular, the study examined whether video presentations could improve on-court tennis serve returns. A series of separate A-B designs across 6 participants was implemented, with baseline and intervention scores for on-court serve-return performance being recorded. Intervention consisted of 2 phases: a training phase and an on-court testing phase. The training phase, which employed a changing criterion design, consisted of a series of tennis-serve video presentations that were replayed with gradually increasing speed. All serves were occluded on racquet/ball contact, and participants were asked to predict the type, depth, and width of the serve. Following completion of the training phase, participants were again tested on their ability to return tennis serves on the tennis court. On-court results suggested that anticipation ability and performance did improve as a result of the intervention.

Adult↗
PubMed1998

Lung abscess complicating chondromas in Carney's syndrome.

Carney's syndrome consists of a combination of three rare tumours: gastric leiomyosarcoma, pulmonary chondroma and catecholamine-secreting paraganglioma. We describe a young woman with Carney's syndrome, who developed a lung abscess, due to obstruction of a bronchus by a chondroma, 11 yrs after having had a partial gastrectomy for a leiomyosarcoma.

Adult↗
PubMed1998

Increasing attendance at sport training sessions.

A lottery incentive system was shown to be effective in increasing attendance at athletic training sessions. 20 players on one team were awarded a playing card for each training session attended, with a cash prize being presented at the end of the week to the player accumulating the best poker hand. Attendance was shown to increase during intervention and decrease when it was withdrawn.

Absenteeism↗
PubMed1997

Hyaluronan secretion into the synovial cavity of rabbit knees and comparison with albumin turnover.

1. Hyaluronan is not only a lubricant but also enhances the synovial lining's resistance to fluid outflow. This finding led to the proposal that hyaluronan (> 2 x 10(6) Da, approximately 210 nm radius) may escape across the synovial lining less freely than smaller solutes (e.g. albumin, 6.7 x 10(4) Da, 3.6 nm radius) or water. Here multiple washouts were used to measure intraarticular hyaluronan mass and secretion rate in rabbit knees, leading to an estimate of hyaluronan turnover time. Plasma albumin permeation into the joint cavity was also measured to enable comparison of turnover times between molecules of very disparate size. 2. Endogenous hyaluronan mass in the joint cavity, analysed by high performance liquid chromatography of joint washes, was 182 +/- 9.9 micrograms (mean +/- S.E.M; n = 21). Since hyaluronan concentration in synovial fluid averages 3.62 +/- 0.19 micrograms microliters-1, the endogenous synovial fluid volume was calculated to be 50 microliters (mass/concentration), about double the aspiratable volume. 3. The hyaluronan secretion rate over 4 h was 4.80 +/- 0.77 micrograms h-1 (n = 5). The rate was significantly higher in contralateral joints expanded by 2 ml Ringer solution (5.80 +/- 0.84 micrograms h-1, n = 5, P = 0.01, Student's paired t test), indicating a stretch/hydration sensitive secretory mechanism. The newly secreted chains ((2.05-2.48) x 10(6) Da) were not significantly different in length from the endogenous chains (2.95 x 10(6) Da). 4. Hyaluronan turnover time, calculated as mass/secretion rate, was 31.4-37.9 h. This is more than an order of magnitude longer than turnover time for intra-articular albumin. The latter, determined from the intra-articular albumin mass and plasma-to-cavity permeation rate was 1.8 h (95% confidence intervals 1.2-3.5 h, n = 9). The big difference in turnover times support the view that, relative to albumin and water, hyaluronan is partially sieved out and retained in the joint cavity by the synovial lining. The lining cell layer is discontinuous, so it appears that interstitial matrix itself acts as a leaky size-selective molecular filter.

Animals↗
PubMed1997

xid affects events leading to B cell cycle entry.

X-linked agammaglobulinemia patients and X-linked immunodeficient (xid) mice possess mutations in the Bruton's tyrosine kinase (Btk kinase) gene and display defects in B cell development and activation by sIg cross-linking. Btk is an early activation kinase in sIg-cross-linked B cells. xid does not ablate Btk protein kinase activity, and immediate signal transduction events, such as tyrosine phosphorylation, occur in sIg-activated xid B cells. These cells do not subsequently progress into cell division and have a high rate of apoptosis, which has been shown to correlate with an absence of sIg-mediated induction of the bcl-xL protein. To establish the point where Btk activity is critical for progression beyond immediate signaling, we examined early and late events in sIg-cross-linked xid B cells. Induction of proto-oncogenes and nuclear factors occurred normally in xid cells. However, induction of cyclins and increased GAPDH mRNA was not observed in xid cells. Degradation of the cyclin inhibitor p27Kip1 occurred normally in xid cells. After 24 h of culture with anti-mu, the remaining live, nonapoptotic xid cells were enlarged, viable, and primed for subsequent stimulation by LPS. Our data suggest that the Btk kinase is not essential for several G1 events and that the failure of sIg-activated xid B cells to enter cell cycle correlates with a defect of cyclin induction. Moreover, these data suggest that Btk is important not only for immediate events following B cell activation and control of apoptosis but also for subsequent events leading to cyclin activation.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1997

A cyclic hexapeptide is a potent antagonist of alpha 4 integrins.

The alpha 4 integrins mediate leukocyte adhesion to specific counter-receptors, including vascular cell adhesion molecule-1 (VCAM-1), the fibronectin splice variant containing connecting segment 1 (CS1), and mucosal addressin cell adhesion molecule-1. A series of cyclized peptides based on the LDV sequence of CS1 were synthesized and assayed for inhibition of alpha 4 integrin binding. The most potent peptide, C*WLDVC* (where * indicates disulfide-linked residues), inhibited alpha 4 beta 1-dependent binding of lymphocytes to VCAM-1 and CS1 with half-maximal inhibition achieved at 1 to 3 microM of peptide. The peptide proved more potent when the lymphocytes were activated with 1 mM MnCl2; half-maximal inhibition was reached at 0.4 and 0.05 microM for VCAM-1 and CS1, respectively. This represents a 100- to 800-fold increase in potency over a linear CS1 peptide in these same assays. C*WLDVC* also inhibited alpha 4 beta 7-dependent lymphocyte binding to the ligands mucosal addressin cell adhesion molecule-1, VCAM-1 and CS1. Immunoprecipitation of radiolabeled integrin indicated that the peptide could bind alpha 4 beta 1 and alpha 4 beta 7 directly and elute alpha 4 beta 1 from a CS1-conjugated agarose resin. The peptide showed selectivity for alpha 4 integrins in that it effectively inhibited alpha 4 beta 1-dependent, but not alpha 5 beta 1-dependent, binding of cells to intact fibronectin. Due to its small size and potency, C*WLDVC* may serve as a useful tool for the study of alpha 4 integrin biology and the development of small molecule therapeutics.

Amino Acid Sequence↗
PubMed1997

Cell cycle arrest defect in Li-Fraumeni Syndrome: a mechanism of cancer predisposition?

Cancer predisposition in approximately 60% of Li-Fraumeni Syndrome (LFS) families is associated with germline mutation of the TP53 gene. The p53 protein has been shown to mediate G1 arrest following DNA damage. We have investigated gamma-irradiation-induced transient and permanent G1 arrest in normal and LFS fibroblasts. The duration of transient G1 arrest varied between strains, but there was no difference in the range between normal (2-12 h) and LFS (1-13 h) cells. However, the extent of permanent G1 arrest was greatly reduced in LFS fibroblasts (mean 33+/-8% of the cell population) compared with normals (mean 67+/-9%) and correlated with their increased radiation survival (r=0.97, P<0.001). This phenotype was observed in LFS fibroblasts both with (seven cases) and without (two cases) TP53 mutation. Parallel studies with fibroblasts derived from cancer-prone, p53-deficient mice revealed no radiation-induced G1 cell cycle arrest in p53 null (-/-) cells. The p53 +/- cells were comparable to the wt p53 cells in transient G1 arrest capacity, but showed a diminished permanent G1 arrest. These data clearly implicate p53 function in permanent G1 arrest. The reduced capacity for DNA damage-induced, permanent G1 arrest in LFS may contribute significantly to cancer predisposition in this familial syndrome.

Animals↗