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E J Hall

Publications and source records attributed to E J Hall.

At least 19 recordsLinked to original sources
PubMed2006

A microbeam study of DNA double-strand breaks in bystander primary human fibroblasts.

Radiation-induced bystander effect has been well documented. However, the mechanisms are poorly understood. How we incorporate this effect into the classical models of risk assessment remains an open question. Here, the induction of bystander effect was studied by assessing DNA double-strand break (DSB) formation in situ with the rapid and sensitive gamma-H2AX focus formation assay. Utilising the Columbia University single-cell microbeam system to deliver 2 or 20 individual alpha particles to selected cell nuclei in a precisely known proportion of cells in a population, the induced DNA DSB incidences were quantified 30 min and 18 h post-IR. The increase in DNA DSB incidence in bystander cells lacked of a linear dose response indicating that neither the dose of irradiation nor proportion of irradiated cells in a population, is a critical parameter. This study confirms a binary all-or-nothing model of triggering the bystander response. The delay and persistence of the bystander response suggests a different mechanism of DSB induction in bystander cells than in directly irradiated cells.

Alpha Particles↗
PubMed2006

The inaugural Frank Ellis Lecture--latrogenic cancer: the impact of intensity-modulated radiotherapy.

It is an honour and personal pleasure to give the inaugural Frank Ellis Lecture to celebrate his 100th birthday, and to acknowledge his enormous contributions to radiation oncology. Intensity-modulated radiotherapy (IMRT) allows dose to be concentrated in the tumour volume while sparing normal tissues. However, the downside to IMRT is the potential to increase the number of radiation-induced second cancers because more fields are used which involves a bigger volume of normal tissue exposed to lower doses. It has been estimated that IMRT may double the incidence of solid cancers in long-term survivors. This may be acceptable in older patients if balanced by an improvement in local tumour control and reduced toxicity. On the other hand, the incidence of second cancers is higher in children, so that doubling it may not be acceptable. IMRT represents a special case for children. First, they are more sensitive to radiation-induced cancer than adults. Second, radiation scattered from the treatment volume is more important in the small body of the child. Third, there is the question of genetic susceptibility, as many childhood cancers involve a germline mutation. The levels of leakage radiation in current Linacs can be reduced, but the cost would be substantial. An alternative strategy is to replace X-rays with protons. This is an advantage only if the proton machine uses a pencil scanning beam, as passive modulation of a scattering foil produces neutrons, which results in an effective dose to the patient higher than that characteristic of IMRT.

Child↗
PubMed2006

Bacterial cholangitis/cholangiohepatitis with or without concurrent cholecystitis in four dogs.

OBJECTIVES: To evaluate the clinical, clinical pathology, diagnostic imaging, microbiological and pathological features of cholangitis/cholangiohepatitis in the dog. METHODS: The study design was a retrospective review of cases of bacterial cholangitis/cholangiohepatitis presented to the University of Bristol during the period 1995 to 2000. The diagnosis was made based on hepatic histopathological findings and positive bile culture results. RESULTS: Four dogs met the inclusion criteria. Common presenting signs included anorexia (n=4), jaundice (n=4), vomiting (n=4) and pyrexia (n=2). All four dogs had a leucocytosis or neutrophilia reported at some time in their history along with serum bilirubin elevation. In addition, serum alkaline phosphatase and alanine transaminase activity was increased in all of the dogs in which it was measured both before and at the time of referral. In general, the diagnostic imaging findings were non-specific. Organisms cultured from bile aspirates were Escherichia coli (n=3), Clostridium species (n=2) and a faecal Streptococcus species (n=1). Two cases resolved with medical treatment alone; two with concurrent cholecystitis required cholecystectomy. Following surgery, both of these cases showed a resolution of clinical signs. CLINICAL SIGNIFICANCE: This report highlights the fact that bacterial cholangitis/cholangiohepatitis with or without concurrent cholecystitis should be considered as a potential differential in dogs presenting with signs referable to biliary tract disease.

Alkaline Phosphatase↗
PubMed2005

Cytokine mRNA quantification in histologically normal canine duodenal mucosa by real-time RT-PCR.

CD4(+) T helper cells are important for the regulation of immune responses in the intestinal mucosa and they exert their effects through the secretion of pro-inflammatory and immunomodulatory cytokines. Human patients with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis have alterations in the normal intestinal cytokine profile. These cytokine abnormalities have been shown at both the protein and messenger RNA (mRNA) level. The role that mucosal cytokines play in the pathogenesis of canine IBD has only been investigated using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of gut tissue, as cytokine antisera are not available for this species. Real-time RT-PCR has been recognised to be a more accurate and sensitive method of quantifying mRNA transcripts, so in this study TaqMan real-time RT-PCR assays for the quantification of mRNA encoding IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IFN-gamma, TNF-alpha and TGF-beta in canine intestinal mucosa were developed. The amount of these templates was quantified in normal canine duodenal mucosa (n = 8). IL-18, TGF-beta and TNF-alpha were found to be the most abundant transcripts, with IL-10 and IFN-gamma present at levels approximately 10-fold less. IL-2, IL-4, IL-5, IL-6 and IL-12 were the least abundant templates, with some RNA samples having no detectable mRNA copies. The methods developed in this study will form the basis of further work investigating the expression of mRNA encoding cytokines in mucosa from dogs with chronic enteropathies. In addition, these real-time PCR assays can also be used for the quantification of canine cytokine mRNA in other diseases.

Animals↗
PubMed2005

Genetic susceptibility to radiation.

In the context of space radiation, it is important to know whether the human population includes genetically predisposed radiosensitive subsets. One possibility is that haploinsufficiency for ATM confers radiosensitivity, and this defect involves 1-3% of the population. Using knock-out mice we chose to study cataractogenesis in the lens and oncogenic transformation in mouse embryo fibroblasts to assay for effects of ATM deficiency. Radiation induced cataracts appeared earlier in the heterozygous versus wild-type animals following exposure to either gamma rays or 1 GeV/nucleon iron ions. In addition, it was found that embryo fibroblasts of Atm heterozygotes showed an increased incidence of oncogenic transformation compared with their normal litter-matched counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally significant radio sensitive subpopulation. Knock-out mice are now available for other genes including BRCA1 and 2, and Mrad9. An exciting possibility is the creation of double heterozygotes for pairs of mutated genes that function in the same signal transduction pathway, and consequently confer even greater radiosensitivity.

Aerospace Medicine↗
PubMed2005

Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes.

Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

Animals↗
PubMed2005

Detection of allelic variants of the canine IGHA gene by fluorescence resonance energy transfer melting temperature examination.

The fluorescence resonance energy transfer (FRET) dual hybridisation probe system has been used for the detection of the accumulation of target DNA during real-time PCR and for the identification of nucleotide polymorphisms through examination of melt curves. This system involves the use of two oligonucleotide probes which are located close to each other and are complementary to an internal segment of a target DNA of interest. Four allelic variants of the gene encoding the hinge region of the immunoglobulin A (IgA) heavy chain (IGHA) have been so far identified in the dog and this variability is due to a combination of single nucleotide polymorphisms and insertion/deletion of nucleic acid motifs. An individual dog may be homozygous or heterozygous for these allelic variants. The purpose of this study was to develop a FRET-based dual probe melting temperature assay to identify the alleles present within an individual dog and to use this assay to determine the frequency of the four allelic variants in different breeds within the canine population. A single pair of oligonucleotide probes were designed that were able to discriminate between the four allelic variants in both homozygous and heterozygous individuals. The genotype of 96 DNA samples obtained from various purebreeds of dogs was determined using this FRET assay. The frequency of each allele differed between the breed groups. The results of this study indicate that it is possible to distinguish relatively complex gene polymorphisms using a single set of oligonucleotide probes. Furthermore, any future comparison of IGHA genotypes between normal and diseased dog populations must take into account the breed variation in allelic frequency.

Alleles↗
PubMed2005

Ultrasonographic evaluation of the thickness of the small intestinal wall in dogs with inflammatory bowel disease.

OBJECTIVES: To establish whether the intestinal wall thickness, as measured ultrasonographically, is significantly increased in dogs with inflammatory bowel disease (IBD). The results would provide the information necessary to decide whether measurement of ultrasonographic wall thickness can predict IBD in dogs. METHODS: The intestinal wall thickness of 75 dogs with idiopathic IBD, as measured by ultrasonography, was compared with recently published normal values. IBD was either confirmed histologically (n = 54) or suspected (n = 21). In all cases there was a positive response to immunosuppressive treatment. RESULTS: A positive association between intestinal wall thickness in dogs and either the histological diagnosis or the response to treatment was not found. Ultrasonographic intestinal wall measurements do not appear to be able to establish a diagnosis of intestinal inflammation and may result in a false negative diagnosis in cases of IBD. CLINICAL SIGNIFICANCE: The same 'grey zone' of between 4 and 6 mm used in humans can be used in the canine duodenum to distinguish the normal range, reserving the term 'abnormal' for an intestinal measurement greater than 6 mm in the duodenum and greater than 4.7 mm in the jejunum.

Animals↗
PubMed2005

Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie.

An eight-month-old Border collie was presented with anorexia, cachexia, failure to thrive and stupor. Laboratory tests demonstrated a mild anaemia, neutropenia, proteinuria and hyperammonaemia. Serum bile acid concentrations were normal, but an ammonia tolerance test (ATT) was abnormal. The dog responded to symptomatic therapy for hepatoencephalopathy. When a low serum cobalamin (vitamin B12) concentration and methylmalonic aciduria were noted, the dog was given a supplement of parenteral cobalamin. Two weeks later, a repeat ATT was normal. Cobalamin supplementation was continued every two weeks, and all clinical signs, except for proteinuria, resolved despite withdrawing all therapy for hepatoencephalopathy. A presumptive diagnosis of hereditary selective cobalamin malabsorption was made, based on the young age, Border collie breed, low serum cobalamin concentration and methylmalonic aciduria. Although hereditary selective cobalamin malabsorption in Border collies, giant schnauzers, Australian shepherd dogs and beagles has previously been reported in North America, to the authors' knowledge this is the first report of the condition in the UK and the first to document an abnormal ATT in a cobalamin-deficient dog.

Animals↗
PubMed2005

Effect of intestinal inflammation on fecal elastase concentration in dogs.

BACKGROUND: A commercially available ELISA kit for fecal elastase measurement can be used in the diagnosis of exocrine pancreatic insufficiency (EPI) in dogs. However, other causes of diarrhea also may affect fecal elastase concentration. OBJECTIVE: This study was undertaken to determine whether intestinal inflammation alters fecal elastase concentration in dogs. METHODS: Fecal elastase concentration was measured with an ELISA kit in the following groups of dogs: group 1 (n=16), control dogs, without gastrointestinal disease; group 2 (n=14), dogs with diarrhea and no histopathologic evidence of intestinal inflammation; and group 3 (n=12), dogs with diarrhea and histopathologic evidence of intestinal inflammation. Serum trypsin-like immunoreactivity (TLI) was determined in dogs with diarrhea to rule out EPI. RESULTS: All dogs in groups 2 and 3 had serum TLI concentrations >5 microg/L, ruling out EPI. No statistically significant difference was found in fecal elastase concentration among the 3 groups of dogs (P=.969). CONCLUSIONS: The results indicate that intestinal inflammation does not affect fecal elastase concentration, such that test results may be used to exclude a diagnosis of EPI even in animals with inflammatory bowel disease.

Animals↗
PubMed2004

Real-time RT-PCR: considerations for efficient and sensitive assay design.

Real-time RT-PCR has been recognised as an accurate and sensitive method of quantifying mRNA transcripts. Absence of post amplification procedures allows rapid analysis with a greater sample throughput, yet with less risk of amplicon carry-over as reaction tubes are not opened. In order to maximise sensitivity, careful reaction design and optimisation is essential. Several aspects of assay design for real-time RT-PCR are discussed in this paper. We demonstrate the effect of amplicon secondary structure on reaction efficiency and its importance for primer design. Taq-man probes with a deoxyguanosine base at the 5' end fluoresce weakly when labelled with FAM, although weak fluorescence is not a problem when probes are labelled with Texas Red. DNA contamination of RNA samples purified using silica membrane columns is a significant problem but DNase digestion can be used to reduce this, particularly in-solution. MMLV and AMV enzyme systems using a variety of RT priming methods are compared and the problem of primer-dimer formation associated with RT enzymes is described.

Animals↗
PubMed2004

Henry S. Kaplan Distinguished Scientist Award 2003. The crooked shall be made straight; dose-response relationships for carcinogenesis.

Estimates of radiation-induced malignancies come principally from the atomic (A)-bomb survivors and show an excess incidence of carcinomas that is linearly related to dose from about 5 cGy to 2.5 Gy. Above and below this dose range there is considerable uncertainty about the shape of the dose-response relationship. Both the International Commission of Radiation Protected (ICRP) and the National Council of Radiation Protection (NCRP) suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. The demonstrated bystander effect for irradiation exaggerates the consequences of small doses of radiation and implies that a linear extrapolation from high doses would underestimate low dose risks. It is possible to make estimates of the cancer risk of diagnostic radiological procedures. Helical computed tomography in children is of particular interest since it is rapidly increasing in use and the doses involved are close to the lower limit of significance in the A-bomb survivors. For example, an abdominal computed tomographic scan in a 1-year-old child can be estimated to result in a lifetime cancer risk of about 1:1000. In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. Data are available for the risk of radiation-induced malignancies for patients who received radiotherapy, e.g. for prostate or cervical cancer. New technologies such as intensity modulated radiation therapy could result in a doubling of radiation-induced second cancers since the technique involves a larger total-body dose due to leakage radiation and the dose distribution obtained involves a larger volume of normal tissue exposed to lower radiation doses.

Animals↗
PubMed2004

Bystander effect and adaptive response in C3H 10T(1/2) cells.

PURPOSE: To address the relationship between the bystander effect and the adaptive response that can compete to impact on the dose-response curve at low doses. MATERIALS AND METHODS: A novel radiation apparatus, where targeted and non-targeted cells were grown in close proximity, was used to investigate these phenomena in C3H 10T(1/2) cells. It was further examined whether a bystander effect or an adaptive response could be induced by a factor(s) present in the supernatants of cells exposed to a high or low dose of X-rays, respectively. RESULTS: When non-hit cells were co-cultured for 24 h with cells irradiated with 5 Gy alpha-particles, a significant increase in both cell killing and oncogenic transformation frequency was observed. If these cells were treated with 2 cGy X-rays 5 h before co-culture with irradiated cells, approximately 95% of the bystander effect was cancelled out. A 2.5-fold decrease in the oncogenic transformation frequency was also observed. When cells were cultured in medium donated from cells exposed to 5 Gy X-rays, a significant bystander effect was observed for clonogenic survival. When cells were cultured for 5 h with supernatant from donor cells exposed to 2 cGy and were then irradiated with 4 Gy X-rays, they failed to show an increase in survival compared with cells directly irradiated with 4 Gy. However, a twofold reduction in the oncogenic transformation frequency was seen. CONCLUSIONS: An adaptive dose of X-rays cancelled out the majority of the bystander effect produced by alpha-particles. For oncogenic transformation, but not cell survival, radioadaption can occur in unirradiated cells via a transmissible factor(s).

Adaptation, Physiological↗
PubMed2004

Measurement of immunoglobulin concentrations in the feces of healthy dogs.

Selective immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency in humans and may be associated with chronic gastrointestinal disease. This observation has led to the suggestion that the high susceptibility of German shepherd dogs (GSD) to chronic enteropathies is related to a deficiency in mucosal IgA production. Relative deficiencies of IgA has been reported in the serum, saliva, tears, and feces of GSD both with and without alimentary disease; however, the findings of different studies are not consistent. The aim of this study was to confirm whether a relative deficiency of IgA exists in the feces of GSD. Feces were collected from healthy GSD (n = 209), Labrador retrievers (n = 96), beagles (n = 19), and miniature schnauzers (n = 32). Fecal IgA, IgM, and IgG were measured by capture enzyme-linked immunosorbent assays. Fecal IgG concentrations in the four breed groups were not significantly different. IgA concentrations were significantly greater in miniature schnauzers than in GSD (P = 0.0003) and Labradors (P = 0.0004) but not significantly different from those in beagles. IgM concentrations were significantly greater in miniature schnauzers than in GSD (P < 0.0001), Labradors (P < 0.0001), and beagles (P = 0.0098). These findings do not support the hypothesis that GSD have a relative deficiency in fecal IgA. The differences in immunoglobulin concentrations measured from a single defecation, between individuals of the same breed and between breeds, as well as the lack of an internal control molecule, make the determination of a normal reference range for all dogs impossible. Therefore, the usefulness of fecal immunoglobulin quantification for the assessment of intestinal immunoglobulin secretion in dogs is limited.

Animals↗
PubMed2004

Analgesia for patients with advanced disease: I.

This series of two articles explores the challenge of managing pain in patients with advanced malignant and non-malignant disease. Pain is a common symptom in advanced disease. Despite guidance from organisations such as the World Health Organisation, cancer pain is often inadequately managed. Managing pain in non-malignant conditions, such as end stage cardiac failure, presents an even greater challenge to healthcare professionals. This first article discusses epidemiology, definitions, pathophysiology, assessment, non-pharmacological approaches, the analgesic "ladder", and opioids. The second article will examine the use of non-opioids, anaesthetic techniques, and analgesia in dying patients as well as discussing future directions.

Analgesia↗
PubMed2004

Analgesia for patients with advanced disease: 2.

The first article in this series explored epidemiology and patterns of pain in advanced disease, non-pharmacological treatments, and the use of opioids to manage pain. This second article examines the use of non-opioid drugs and anaesthetic interventions for pain relief in advanced disease. It also discusses an approach to managing analgesia in dying patients and finally looks at future developments.

Adrenal Cortex Hormones↗