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Biomedical subjects

N Hunter

Publications and source records attributed to N Hunter.

At least 127 records · Page 7Linked to original sources
PubMed1995

The prostaglandin E1 analog, misoprostol, a normal tissue protector, does not protect four murine tumors in vivo from radiation injury.

The clinical development of radioprotectors, such as misoprostol, to protect normal tissue during cancer treatment must proceed with the assurance that tumors are not protected similarly or significantly. To provide data on this critical question, radiation-induced growth delay with or without the presence of misoprostol was measured in four murine tumors grown in the flanks of mice: the Lewis lung carcinoma, M-5076 ovarian sarcoma, FSA and NFSA. The effect of misoprostol on the tumor control dose (TCD50) of radiation was measured in FSA-bearing mice with or without prior treatment with the nonsteroidal anti-inflammatory agent, indomethacin. Misoprostol did not influence the in vivo growth of any of the four tumors, nor did it protect any of the tumors from radiation-induced growth delay. Likewise, there was no increase in the radiation TCD50 to treat the FSA in vivo in control or indomethacin-treated tumor-bearing mice. To measure any possible influence of tumor burden on the protective effect of misoprostol on normal tissue in mice, the protective effect of misoprostol on the survival of intestinal clonogenic cells was measured in M-5076-bearing mice and found to be the same as in non-tumor-bearing mice. These data suggest that misoprostol protects normal tissue in mice without protecting at least four experimental murine tumors. The data support the contention that misoprostol can achieve therapeutic gain by protecting normal tissues without protecting tumors.

Animals↗
PubMed1994

Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland.

Bovine spongiform encephalopathy (BSE) is one of a family of scrapie-like diseases which affect various mammals. Polymorphisms and mutations of the PrP gene have been associated with the incidence of experimental and natural scrapie in other animals and this study of the bovine PrP gene was undertaken to discover whether there was a similar association with PrP genotype in cattle with BSE. There are two known polymorphisms of the coding region of the bovine PrP gene, a silent HindII restriction site polymorphism and a difference in the number of an octapeptide repeated sequence (either five or six copies). An analysis of 370 cattle in Scotland revealed no difference between the frequencies of these PrP genotypes in healthy cattle and cattle with BSE.

Animals↗
PubMed1994

Fludarabine improves the therapeutic ratio of radiotherapy in mouse tumors after single-dose irradiation.

PURPOSE: Fludarabine, an adenine nucleoside analogue, and an effective inhibitor of chromosome repair, was previously shown to synergistically enhance radiation-induced regrowth delay in three murine tumors. The purpose of this study was to assess whether fludarabine can increase the therapeutic ratio of radiotherapy in murine tumors, that is, to increase local tumor control without significantly modifying the radiation-induced normal tissue response. METHODS AND MATERIALS: Mice bearing 8-mm tumors in the right thigh (SA-NH sarcoma and MCA-K mammary carcinoma) were given 800 mg/kg fludarabine IP 3 h or 24 h before single doses of photon irradiation. Local tumor control was assessed by the TCD50 assay 100 days after treatment. Acute normal tissue toxicity was assessed in the skin (degree of epilation 30 days after irradiation) and in the jejunum (crypt regeneration assay), and late normal tissue toxicity was assessed by a leg contracture assay 120 days after treatment. RESULTS: In both tumors and with both drug schedules, fludarabine enhanced radiation-induced local tumor control (dose modification factors (DMF) of 1.24 (95% confidence limits 1.19-1.31) and 1.26 (95% confidence limits 1.20-1.32) for SA-NH, and 1.38 (95% confidence limits 1.25-1.50) and 1.35 (95% confidence limits 1.22-1.16) for MCA-K tumors). When given 3 h before radiation, fludarabine offered a slight protection from skin toxicity (DMF = 0.83, 95% confidence limits 0.77-0.86) but enhanced jejunum toxicity (DMF = 1.53). When fludarabine was given 24 h before irradiation, the reverse trend was observed (DMF = 1.11 (95% confidence limits 1.07-1.16) and 0.89, respectively). No enhancement of leg contracture was observed for either fludarabine schedule. CONCLUSION: The data presented here demonstrate that fludarabine can potentiate local tumor control induced by single-dose irradiation. While jejunum sensitization limited the relative effectiveness when fludarabine was administered 3 h before irradiation, a therapeutic ratio greater than one was always achieved when fludarabine was given 24 h before irradiation.

Animals↗
PubMed1994

Is tumor cell radiation resistance correlated with metastatic ability?

Patients who experience local failure following radiation treatment of epithelial malignancies exhibit a substantially higher rate of distant metastasis than those patients who achieve permanent local control. This fact has raised concern that the local failure to control the primary/regional tumor may serve as a marker of a particularly malignant neoplasm, i.e., high metastatic activity and radiation resistance. If this were true, there would be no gains in survival by increasing the efficacy of treating the primary/regional disease because the new local controls would develop distant metastasis. To investigate this concept, the relationship between distant metastasis probability and tumor cell radiation resistance has been studied by examining laboratory and clinical data (in vitro and in vivo assays) from six collaborating centers. TCD50s (radiation dose which inactivates half of the irradiated tumors) and incidence of distant metastasis in mice with local control have been evaluated for 24 murine tumor systems. SF2s (surviving fraction after 2 Gy) were determined in vitro for cell lines from 8 human, 13 mouse, and 15 rat tumors/tumor sublines and the metastatic activity assessed after injection of the cells into syngeneic murine hosts and xenogenic hosts for the human tumors. SF2s of cells from carcinomas of the head/neck, cervix, and endometrium which were controlled locally by radiation +/- surgery from four centers were compared for those which did and those which did not metastasize. The total number of patients studied was 222. The cumulative distributions of SF2s of locally controlled tumors which did and did not metastasize were not different in each of the data sets. Similarly, there was no demonstrable relationship between TCD50s and metastatic frequency in local control mice. Furthermore, the SF2s of murine and human tumor cell lines did not track with metastatic activity. Radiation sensitivity of clinical and laboratory tumors did not correlate with metastatic activity in studies of data from six centers.

Animals↗
PubMed1994

Potentiation of radiation-induced regrowth delay in murine tumors by fludarabine.

Fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-monophosphate), an adenine nucleoside analogue, has previously been shown to inhibit the repair of radiation-induced chromosome damage. Thus fludarabine may have therapeutic utility in combination with photon irradiation. The purpose of this study was to determine whether fludarabine could enhance radiation-induced murine tumor regrowth delay and to determine the most effective dose and schedule of the combination. A significant (P < 0.05) absolute regrowth delay enhancement was observed in three murine tumor models (SA-NH, a sarcoma; and MCA-K and MCA-4, mammary carcinomas) when fludarabine (800 mg/kg) was given 1 h prior to 25 Gy gamma-irradiation. While fludarabine enhanced radiation-induced tumor regrowth delay when given between -36 h and +6 h of radiation (SA-NH tumor), the greatest enhancement was observed when fludarabine was given at -24 h prior to irradiation (radiation dose modification factor of 1.82 at -24 h compared to 1.57 at -3 h prior to radiation). The degree of fludarabine enhancement (at -3 or -24 h) was dose dependent at doses above 200 mg/kg. When fludarabine and radiation were administered on a fractionated schedule (fludarabine given 3 h prior to radiation each day for 4 days), the dose modification factor increased to 2.14 (1.63 if the effect of fludarabine alone is subtracted). These results suggest that fludarabine enhances radiation-induced tumor regrowth delay in a more than additive fashion after both single and fractionated treatments, and the degree of enhancement is dependent on the sequence and timing of administration, the fludarabine dose, and the tumor type. Thus, fludarabine may have clinical potential as a radiation enhancer in the treatment of solid tumors.

Animals↗
PubMed1994

The association of a codon 136 PrP gene variant with the occurrence of natural scrapie.

Incidence of both experimental and natural scrapie in sheep has been associated with polymorphisms of the PrP gene. In case/control studies the PrP allele which encodes valine at codon 136 (Val136) is found in 96-100% of naturally infected scrapie sheep of Shetland, Scottish Halfbred and Blue du Maine breeds. In contrast, in healthy animals from the same flocks, the most frequent allele encodes Ala136 (91-100% of sheep). However Val136 does not correlate with incidence of scrapie in two other flocks--Poll Dorsets and Suffolks--and there may therefore be breed differences in PrP genotypes affected by scrapie.

Alleles↗
PubMed1994

Dynamics of tumor cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide.

Experiments were performed to establish the extent and kinetics of tumor cell repopulation in a murine sarcoma, designated SA-NH, treated with cyclophosphamide (CY). Mice bearing 8-mm leg tumors were treated with 200 mg/kg CY which caused a transient tumor regression. Changes in the absolute clonogen content of tumors was determined by the change in TCD50 values (50% tumor control) obtained under hypoxic conditions of local tumor irradiation at different times after CY treatment until tumors regrew to the pretreatment size. For comparison, hypoxic TCD50 values were determined during the growth of tumors not treated with CY. CY greatly depleted tumors of clonogenic cells as manifested by the reduction in the control TCD50 value of 64.5 Gy to 32.8 Gy 1 day after CY treatment. The reduced TCD50 value remained unchanged for 2 weeks after treatment with CY, at which time the TCD50 began to rapidly increase, continuing until the end of the observation period of 21 days when tumors reached the pretreatment size. In contrast, there was a constant but slower increase in TCD50 values during the growth of tumors not treated with CY. The daily increase in TCD50 was more than twice as high in CY-treated than in CY-untreated tumors: 4.5 Gy/day versus 2.1 Gy/day. This implies that the rate of clonogen production in CY-treated tumors was twice as high as that of unperturbed tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie.

Man and sheep are the two species in which spongiform encephalopathies occur naturally, and in which there are recognized genetic components that predispose an individual person or sheep to clinical disease. In both species mutations/polymorphisms in the PrP gene have been linked to the incidence of natural disease, but only in sheep is it possible to investigate by deliberate exposure to infection whether these polymorphisms are directly correlated with survival time. Cheviot sheep of different PrP genotypes were challenged with one of two isolates of scrapie or an isolate of bovine spongiform encephalopathy and the survival time and incidence of disease were monitored. Genotype analysis showed that dimorphisms in codons 136 and 171 of the ovine PrP gene correlated with control of disease incidence and modulation of incubation time. Crucially, the functional effects of these domains of PrP were shown to alternate depending on the isolate of infecting agent.

Alleles↗
PubMed1994

An appraisal of the virulence factors associated with streptococcal endocarditis.

Platelet aggregation is believed to be a virulence factor in infective endocarditis. Other factors may be adhesion to components of thrombotic vegetations, particularly platelets, fibronectin and fibrinogen. Two strains from the Streptococcus sanguis group (SSG) were chosen for comparative study on the basis that one aggregated both human and rat platelets and the other lacked this capacity. Both strains caused endocarditis in the rat model but the aggregating strain was found in higher numbers in the excised vegetations. The nonaggregating strain was unable to bind to human or rat platelets but could bind insoluble fibronectin, insoluble fibrinogen and platelet-fibrin clots from both sources, albeit to a lesser extent than the aggregating strain. These results suggest that whereas adhesion to, and aggregation of, platelets are not essential events in the initiation of the pathogenesis of experimental endocarditis, they may be factors contributing to virulence.

Animals↗
PubMed1994

Association of amyloid P protein with pathology in periodontal tissues.

The lesion of chronic periodontitis is characterized by the persistence of perivascular collections of degenerate plasma cells. In this study, immunohistochemical demonstration of amyloid P (AP) component was used to define the distribution of this protein in established periodontitis lesions and in biopsies of non-destructive marginal gingivitis. Quantitative assessment of AP indicated significantly higher levels in periodontitis than in gingivitis for all regions of the tissue. This was associated with pathology as determined by the intensity of plasma cell accumulation and the extent of connective tissue matrix degradation. AP was concentrated in the deep connective tissue areas but perivascular accumulation was also noted, as was deposition associated with nerve bundles and, occasionally, in the extracellular matrix of the lining epithelium. These findings have potential significance in relation to the pathology of chronic periodontitis as AP has been shown to interact in a calcium-dependent manner with a number of ligands including fibronectin, elastic fibres, C-4 binding protein and amyloid fibrils.

Adult↗
PubMed1994

Extraction of amyloid-like fibrils from chronically inflamed periodontal tissues.

Immunohistological studies have established an association between the deposition of the amyloid P protein and disease status in chronically inflamed periodontal tissues. The aim of this study was to determine if amyloid-like fibrils could be extracted from these tissues. Biopsies were homogenised and extracted exhaustively in saline before serial extraction in distilled water. Electrophoretic analysis revealed the presence of previously undetected protein bands in the fifth water extraction. These were probed and were found to react with antisera to kappa and lambda immunoglobulin light chains but not with antisera to mu, gamma or alpha heavy chains. Electron microscopic study indicated fibrils of 9.7 nm diameter. These bound Congo Red and exhibited green birefringence under polarised light. The results supported the presence of an amyloid-like matrix composed of immunoglobulin light chains in the lesions of chronic periodontitis. This could explain the persistence of foci of degenerate plasma cells and the paucity of granulation tissue formation in the disease process.

Amyloid↗
PubMed1994

The vascular response in chronic periodontitis.

The role of vascular endothelial cells (EC) in periodontitis was investigated in a series of histological studies. Expansion of the vasculature was found to occur with development of gingivitis and periodontitis. This was thought to contribute to the characteristic tissue degradation in the developing disease. Vascular expansion could also play a role in the formation of a previously unreported perivascular hyaline material (PHyM). Polymorphonuclear leukocytes (PMN) are known to be protective in periodontitis, and the location, incidence and extent of PHyM suggested a role for PHyM in periodontitis by inhibiting PMN emigration. PMN emigration was found to occur from specialized high EC (HEC) lined post capillary venules. This was unexpected, as such vessels have previously been found to exchange lymphocytes almost exclusively. Detailed histochemical, ultrastructural and biosynthetic studies of these specialized blood vessels led to the suggestion that HEC may be specially adapted for the synthesis of cytokines in periodontitis. A negative association between expression of the membrane bound ectoenzyme, alkaline phosphatase, and HEC suggested a role for this enzyme in leukocyte emigration. These observations compel re-evaluation of the role of EC in chronic inflammation, and in periodontitis in particular. The direction of current and future work is discussed.

Chronic Disease↗
PubMed1994

Changes in the radiation sensitivity of mouse skin during fractionated and prolonged treatments.

Reactions of the skin of the right thigh of mice were used as an experimental model to test possible changes in the radiosensitivity of mouse skin, as represented by changes in the linear-quadratic (LQ) model parameters alpha and beta, as a function of fractionation interval and overall treatment time. In the first series of experiments, variable numbers of 3-Gy fractions with intervals of 6, 24 or 48 h were applied, followed by top-up doses to increase the skin damage to a level that could be scored. The results showed that mouse skin is more sensitive to 3-Gy fractions applied with 48-h intervals than to 3-Gy fractions applied with 6- or 24-h intervals. In the second series of experiments we used single-dose or fractionated test treatments for previously unirradiated mice and mice treated with priming doses of 10, 20 or 30 Gy given 1-18 days before the test treatment. The sensitivity appeared to be higher after intervals of 14-18 days than after 1-10 days after priming treatments of 20 and 30 Gy. The increased sensitivity 18 days after 20 Gy was mainly the result of an increase in the beta component of the LQ model; higher values of alpha were also determined. We conclude that the radiosensitivity of mouse skin is higher during a radiation-induced proliferative response.

Animals↗
PubMed1993

Intraocular pressure and retinal vascular changes during transient exposure to microgravity.

We measured intraocular pressures and retinal vascular diameters from 11 subjects during 20 seconds of microgravity produced by parabolic flight on board a KC-135 aircraft. Intraocular pressures increased 58% during parabolic flight compared to baseline values (19 +/- 1 mm Hg vs 12 +/- 1 mm Hg, respectively; P < .001). A 4% reduction in the caliber of retinal arteries was also noted during microgravity, but this change did not achieve statistical significance (7.8 +/- 0.3 pixels at zerogravity vs 8.1 +/- 0.3 pixels at 1g; P = .07). The increase in intraocular pressure and trend of arteries to constrict are thought to result from cephalad shifts in intravascular and extravascular body fluids as a result of the absence of the 1g hydrostatic gradient. The results of our study confirm that this fluid shift and its effects on the eye occur rapidly, within 20 seconds of exposure to microgravity.

Adult↗
PubMed1993

Rescue of a single yeast artificial chromosome from a cotransformation event utilizing segregation at meiosis.

During the construction of yeast artificial chromosome (YAC) libraries to facilitate mapping of the human genome, two YACs may be cotransformed into the same yeast cell, making further analysis very difficult. We present a simple method to rescue the required YAC that utilizes the segregation of chromosomes at meiosis. In brief, we crossed the cotransformed yeast cell with a non-YAC-containing strain and induced the resulting diploid to sporulate and undergo meiosis. The new haploid generation included some yeast cells that contained only the desired YAC. These YACs were analyzed by conventional methods. To exclude the possibility that major rearrangement occurred during the procedure, we analyzed the YACs with restriction enzymes that cut only rarely. We conclude that this is a useful technique to rescue cotransformed YACs.

Chromosomes, Artificial, Yeast↗
PubMed1993

Swaledale sheep affected by natural scrapie differ significantly in PrP genotype frequencies from healthy sheep and those selected for reduced incidence of scrapie.

PrP glycoprotein gene polymorphisms were examined in Swaledale sheep affected by natural scrapie, in healthy sheep and in Swaledales selected for low susceptibility to scrapie. The three groups differed significantly in frequencies of PrP genotypes detected by the restriction enzymes EcoRI, HindIII and BspHI, the latter being indicative of a PrP protein amino acid difference at codon 136. These frequency differences were confirmed in a single-flock study and present good evidence that scrapie susceptibility and resistance are associated with PrP gene variants in Swaledale sheep.

Age Factors↗