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Biomedical subjects

D Newell

Publications and source records attributed to D Newell.

At least 19 recordsLinked to original sources
PubMed2006

Use of a systematic review to assist the development of Campylobacter control strategies in broilers.

AIMS: Produce an evidence-based ranking of the major contributing factors and sources of Campylobacter occurrence in broilers produced in England, Scotland and Wales - Great Britain (GB). METHOD AND RESULTS: Relevant data were extracted from 159 research papers and findings were grouped into 14 sources of on-farm contamination and 37 contributing factors. A relevancy score was developed to take into account various measures from each study of applicability to GB broilers and strength of findings. Results indicate that major sources of Campylobacter include a depopulation event, another house on-farm, on-farm staff, and other animals on farm. The depopulation schedule (staggered slaughter) and multiple houses on-farm were identified as contributing factors associated with increasing the risk, and those decreasing the risk were use of a hygiene barrier, parent company and certain seasons of rearing. CONCLUSIONS: Although the review was more resource intensive compared to narrative studies, the system allows an increased level of transparency and the ability to investigate patterns and trends. SIGNIFICANCE AND IMPACT OF THE STUDY: This paper provides the first evidence-based ranking of the major sources and contributing factors for Campylobacter presence in broilers in GB using a systematic review.

Animal Husbandry↗
PubMed2002

The EORTC Laboratory Research Division. European Organisation for Research and Treatment of Cancer.

The Laboratory Research Division (LRD) of the EORTC currently consists of five Groups with expertise that includes pre-clinical drug development, all aspects of cancer pharmacology, clinically-relevant receptor and biomarker studies, functional imaging and contemporary pathology. The LRD provides a Europewide resource for cancer clinical trials with particular expertise in the evolving field of translational research. In the development of therapies designed to exploit the molecular and cellular pathology of cancer, it is essential that translational research is included at all stages and the EORTC, through the LRD, has access to such expertise. In addition to providing support for drug development and clinical trials, the LRD represents a unique forum for the development of contemporary translational research expertise, the establishment of quality standards and the education of young laboratory and clinical scientists embarking on careers in oncology.

Europe↗
PubMed2001

Intra-arterial urokinase for acute ischemic stroke: factors associated with complications.

The authors abstracted the records of 43 patients treated with intra-arterial urokinase for acute ischemic stroke to identify predictors of serious complications. Sixteen (37%) had such a complication. Higher urokinase dose (>1.5 x 10(6) U), higher mean arterial blood pressure before treatment (>130 mm Hg), basilar occlusive strokes, and severe strokes were most predictive of these complications. Although urokinase is no longer manufactured, these findings identify patients at risk for complications from other intra-arterial thrombolytics.

Acute Disease↗
PubMed2001

A quantitative risk assessment for the occurrence of campylobacter in chickens at the point of slaughter.

A quantitative risk assessment model investigating the risk of human infection with campylobacter from the consumption of chicken meat/products is currently being formulated. Here such an approach is used to evaluate the probability that a random bird, selected at slaughter from Great Britain's national poultry flock, will be campylobacter-positive. This is determined from the probability that a flock chosen at random contains at least one colonized bird and the within-flock prevalence of such a flock at slaughter. The model indicates that the probability bird chosen at random being campylobacter-positive at slaughter is 0.53. This probability value has associated uncertainty, the 5th percentile being 0.51 and the 95th percentile 0.55. The model predicts that delaying the age at first exposure to campylobacter can have a significant impact on reducing the probability of a bird being campylobacter-positive at slaughter. However, implementation of current biosecurity methods makes this difficult to achieve.

Animals↗
PubMed2001

A DNA vaccine encoding MPB83 from Mycobacterium bovis reduces M. bovis dissemination to the kidneys of mice and is expressed in primary cell cultures of the European badger (Meles meles).

Nucleic acid (DNA) vaccination against tuberculosis in the European badger (Meles meles) is one approach to addressing the escalating problem of bovine tuberculosis in Great Britain. The aim of vaccination is to reduce the burden of tuberculosis within the badger population and the shedding of Mycobacterium bovis to levels that would break the transmission of infection to cattle. To this end, the vaccine would be required to limit the amount of disseminated tuberculosis in the badger, especially dissemination to the kidney from where M. bovis can be shed in the urine. A promising candidate DNA vaccine encoding a 26 kDa major antigen (MPB83) of M. bovis was evaluated in a mouse model of disseminated M. bovis infection. Using the DNA vaccine, protection against infection of the kidney was found to be greater than that achieved with the current live vaccine, Bacille Calmette-Guerin (BCG). Kidney tissue and skeletal muscle from the badger was used to derive primary cell cultures in which to examine the expression of MPB83 following transfection with the DNA vaccine. Kidney cortex gave rise to a monotypic culture of epithelial cells whilst the muscle gave rise to a mixed culture of fibroblasts and myoblasts. During culture the myoblasts differentiated into multinucleated myotubes, verified by immunofluorescent detection of mammalian desmin. Successful expression of MPB83 by transfected epithelial and myotube cells was confirmed by immunofluorescence using a monoclonal antibody specific to the protein. These observations fulfil the early requirements for the development of a DNA vaccine for badger tuberculosis.

Animals↗
PubMed2001

A test of processing efficiency theory in a team sport context.

In this study, we tested some key postulates of Eysenck and Calvo's processing efficiency theory in a team sport. The participants were 12 elite male volleyball players who were followed throughout the course of a competitive season. Self-report measures of pre-match and in-game cognitive anxiety and mental effort were collected in groups of players high and low in dispositional anxiety. Player performance was determined from the statistical analysis of match-play. Sets were classified according to the point spread separating the two teams into one of three levels of criticality. Game momentum was also analysed to determine its influence on in-game state anxiety. Significant differences in in-game cognitive anxiety were apparent between high and low trait anxiety groups. An interaction between anxiety grouping and momentum condition was also evident in cognitive anxiety. Differences in set criticality were reflected in significant elevations in mental effort, an effect more pronounced in dispositionally high anxious performers. Consistent with the predictions of processing efficiency theory, mental effort ratings were higher in high trait-anxious players in settings where their performance was equivalent to that of low trait-anxious performers. The usefulness of processing efficiency theory as an explanatory framework in sport anxiety research is discussed in the light of these findings.

Adult↗
PubMed1999

Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Injury Consortium Study Group.

A phase II prospective, randomized, double blind clinical trial of Bradycor, a bradykinin antagonist, was conducted at 31 centers within North America in severely brain injured patients. Patients of Glasgow Coma Score (GCS) 3-8 (n = 139) with at least one reactive pupil were randomized to receive either Bradycor, 3 microg/kg/min or placebo as a continuous intravenous infusion for 5 days, with the infusion beginning within 12 h of the injury. The primary objective was to assess the efficacy of a continuous infusion of Bradycor (3.0 mc/kg/min) in preventing elevation of intracranial pressure (ICP). Other efficacy measures included the effect of Bradycor on the Therapy Intensity Level (TIL), mortality, and functional outcome. A secondary objective was to evaluate the safety of Bradycor in patients with severe brain injury. Randomization was carried out according to a computer generated randomization list. Patients were followed for the first 14 days of hospitalization with long-term outcome assessed at 3 and 6 months after injury. During the infusion and while the ICP monitor was in place, ICP measurements were recorded hourly along with blood pressure and heart rate. A modified version of the TIL was used to record therapeutic interventions hourly, while the ICP was being monitored. Outcome was assessed at 3 and 6 months after injury using the Glasgow Outcome Score (GOS). Bradycor was well tolerated in this patient population, and no adverse events were attributable to the compound. Although positive trends were seen for both ICP and TIL in the Bradycor group, these differences analyzed on a daily basis were not significant. However, a mixed model of variance which included treatment, day, treatment by day interaction, age and GCS revealed that the percentage time ICP of >15 mm Hg on days 4 and 5 was significantly lower in the Bradycor group compared to placebo (p = 0.035). There were fewer deaths in the Bradycor group, which had a 28-day all cause mortality of 20% versus 27% on placebo. Patients treated with Bradycor showed a 10.3% improvement in favorable outcome at 3 months and a 12% improvement in dichotomized GOS at 6 months (p = 0.26). The consistent positive trends seen in ICP, TIL, neuropsychological tests, and, most importantly, 3- and 6-month GOS provide supportive evidence that a bradykinin antagonist may play a neuroprotective role in severe brain injury.

Adolescent↗
PubMed1997

Phase II study of 21 day schedule oral etoposide in children. New Agents Group of the United Kingdom Children's Cancer Study Group (UKCCSG).

We report a multicentre phase II study of orally administered prolonged schedule etoposide in children with refractory or relapsed malignancy. 83 children were entered into the study. The largest diagnostic groups were neuroblastoma (n = 20), rhabdomyosarcoma/soft tissue sarcoma (n = 16) and brain tumours (n = 16). Etoposide was administered twice daily at a dose of 50 mg/m2/day for 21 days using the intravenous preparation given orally. Disease reassessment was performed after the second course. Etoposide plasma concentrations were measured by HPLC, 2 and 6 h after administration of therapy on days 7 and 14 in 15 patients. 61 patients completed two courses and were evaluable for response. There was 1 complete response (CR), 5 partial responses (PR) 22 stable disease (SD) and 33 progressive disease (PD). Of the 6 with responses, 3 had a diagnosis of medulloblastoma/cerebral primitive neuroectodermal tumour. 24 of 26 patients with SD/PR/CR received further courses with excellent palliative effect. The main toxicity observed was myelosuppression, with 8% and 7% of evaluable courses complicated by grade III-IV neutropenia and thrombocytopenia, respectively. Severe infection (grade III-IV) was rare, complicating only 2/94 evaluable courses. Plasma etoposide median concentrations at 2 h after administration on day 7 of course 1 were 1.5 (range 0.6-2.4) micrograms/ml. Total course 1 area under the etoposide plasma concentration versus time curve (AUC) values were estimated using a limited sampling model. Grade > or = 2 leucopenia was only observed in patients with a day 72 h etoposide concentration of > 2 micrograms/ml or a course 1 AUC of > 35 mg/ml.min. It is concluded that given at a dose of 50 mg/m2/day in two doses for 21 day courses, oral etoposide is well tolerated in children. A correlation between drug concentrations and toxicity was observed. Overall, a low response rate was seen (approximately 10%), but disease stabilisation appears to occur, and useful palliative effect was frequently noted. The response in brain tumours was more encouraging (3/14 PR) and this group requires further evaluation.

Administration, Oral↗
PubMed1997

The quiet revolution: reporting of health outcomes in general medical journals.

This study reviews the extent of evaluation of health outcomes in three general medical journals over the past decade by examining papers published in the original research section of the New England Journal of Medicine (NEJM), The Lancet, and the Medical Journal of Australia (MJA) in 1982 and 1992. Evaluations were identified and classified according to the type of comparison group and the type of outcome measures employed. They were divided into three categories: those employing a comparison group; those employing a before-and-after study design (or own comparison group); and those with no comparison group. The categories of outcome measures were mortality, clinical or intermediate measures of health state, and final outcome measures (quality of life). Results show that the proportion of papers evaluating a health services intervention remained stable over the period. However, the MJA published considerably fewer evaluations than the other journals. In the NEJM and The Lancet, 75 per cent of evaluations incorporated comparison groups, in the MJA, less than 40 per cent. Overall, the proportion of papers reporting final outcome measures increased significantly between 1982 and 1992 (p = 0.04) but the change in each journal individually did not reach statistical significance. This study indicates that the reporting of health outcomes evaluations has remained constant but there has been some change in the use of comparison groups and final outcome measures over time.

Australia↗
PubMed1996

Helicobacter pylori gastritis and serum pepsinogen levels in a healthy population: development of a biomarker strategy for gastric atrophy in high risk groups.

This study aimed to estimate the prevalence and type of chronic gastritis in an asymptomatic working population and to determine whether a combination of serum pepsinogen levels and Helicobacter pylori serology could be used to identify a subgroup with atrophic gastritis at elevated risk of gastric carcinoma. A 10% subsample of 544 male volunteer factory workers aged 18-63 years and participating in a larger study underwent endoscopy and biopsy. Of these men, 29 were seropositive for Helicobacter pylori; all but three (89.7%) had chronic gastritis. Serum pepsinogen A levels increased with progression from a corpus predominant pattern of gastritis through pangastritis to an antral predominant pattern. Nine subjects had corpus atrophy, which was in most cases accompanied by fasting hypochlorhydria and hypergastrinaemia. A combination of pepsinogen A below 80 ng ml-1 and Helicobaceter pylori seropositivity detected corpus atrophy with sensitivity 88.9% and specificity 92.3%. A second screening stage, using a pepsinogen A/C ratio of below 2.5 as a cut-off, resulted in a reduction in numbers requiring further investigation but with some loss of sensitivity (77.8%). Application of this two-stage screening programme to the original sample of 544 workers would have resulted in 11 (2.2%) men being selected for follow-up, excluding 25 (5.1%) false negatives. Our results suggest that a combination of serum pepsinogen levels and Helicobacter pylori serology could be useful as a biomarker strategy for detection of individuals at increased risk of gastric carcinoma and for non-invasive investigation of the natural history of Helicobacter pylori gastritis.

Adolescent↗
PubMed1996

Etoposide phosphate infusion with therapeutic drug monitoring in combination with carboplatin dosed by area under the curve: a cancer research campaign phase I/II committee study.

The area under the plasma concentration-time curve (AUC) following an intravenous dose of etoposide varies considerably among patients, which in part contributes to the unpredictability of toxicity and response seen in individual patients. This study evaluated the utility of therapeutic drug monitoring of etoposide in reducing the interpatient variability of etoposide steady-state concentrations during prolonged infusion. The etoposide prodrug etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ) was administered by infusion using an adaptive dosing strategy. It was given in combination with carboplatin, which was dosed on an AUC basis. Patients with histologically or cytologically proven small cell lung cancer were treated with etoposide phosphate by continuous 120-hour infusion and carboplatin at a dose calculated by the Calvert formula to give an AUC of 5 mg/ mL.min. Blood samples were taken on days 2 through 5 of each treatment cycle, and high-performance liquid chromatography was used to measure the plasma etoposide concentration. The resultant concentrations were compared with target concentrations of 1 or 2 micrograms/mL and these data were used to calculate the rate of infusion for the following 24 hours. In the first cohort, the target etoposide concentration was 1 microgram/mL, and this was achieved (mean +/- SD = 1.05 +/- 0.24 micrograms/mL) by infusing etoposide phosphate doses of 21 to 109 mg (15 to 68 mg/m2) per day. In the second cohort, the target concentration of 2.0 micrograms/mL was achieved (mean +/- SD = 2.05 +/- 0.31 micrograms/mL) with infused etoposide phosphate doses of 69 to 193 mg (41 to 114 mg/m2) per day. This technique reduced the variation in plasma levels and resulted in predictable hematologic toxicity. Cumulative hematologic toxicity necessitated an extension of the treatment cycle from 3 to 4 weeks, however. Of six evaluable patients, two had a complete response and one had a partial response. Therapeutic drug monitoring was shown to reduce the interpatient variation in the plasma etoposide concentration by half and shows promise for individualizing treatment with combination chemotherapy. Exploiting the known relationships between the pharmacokinetics and pharmacodynamics of these two drugs by using therapeutic drug monitoring may lead to better therapeutic safety and efficacy.

Adult↗
PubMed1995

Variability in serum pepsinogen levels in an asymptomatic population.

OBJECTIVE: To investigate the variability in serum pepsinogen levels in an asymptomatic population. DESIGN: Cross-sectional survey of 420 men aged 18-63 years, without symptoms or a history of gastric disease, recruited from four factories in Stoke-on-Trent. METHODS: During an interview, data on history of gastric health, 'lifestyle' and occupation were collected, blood samples were taken for measurement of serum pepsinogen and anti-Helicobacter pylori antibody levels and height and weight were measured. RESULTS: Extreme (low/high) levels of pepsinogens A and C, indicative of chronic gastritis, were found in 24 (5.7%) and 61 (14.5%) of the participants, respectively. Low A-C ratios, indicative of moderate or severe gastric atrophy, were found in 13 (3.1%) participants. Of the variables examined, Helicobacter pylori serology had the strongest influence on serum pepsinogen levels. Serum pepsinogen A and C levels were significantly higher in the 33.6% of participants who were seropositive. The effect was more marked for pepsinogen C; thus, A-C ratios were lower in seropositive individuals. In seronegative participants, both pepsinogen A and pepsinogen C levels increased with increasing age; pepsinogen A levels increased with increasing height and were higher in smokers, but decreased with increasing weight. The effect of smoking on pepsinogen A levels was also detectable in seropositive individuals, but was considerably less marked. Among seronegative participants, those employed on the 'shop-floor' in manual jobs had higher serum pepsinogen C levels and lower A-C ratios than office-based workers. CONCLUSION: H. pylori serology was a major source of variation in serum pepsinogen levels, but causes of gastritis other than H. pylori were indicated. Independent of these effects, serum pepsinogen levels may also vary with age, height and weight. Screening of serum pepsinogen levels in the general population may identify 5-15% who require further investigation. Other 'filters' may be required in conjunction with serum pepsinogen levels to identify those needing investigation for significant gastric pathology.

Adult↗
PubMed1993

mRNA structure, in situ, as assessed by microscopic techniques.

The secondary and tertiary structure of RNA, in situ, is thought to be involved in distinct functions such as directing association of the RNA with the cytoskeleton, enzymatic activity of some RNAs, and the control of translation. In situ transcription (IST), a procedure by which cDNA is synthesized in situ, has been used to assess mRNA structure in situ using fixed cells or tissues. Distinct banding patterns were noted for mouse and rat POMC. Unique IST banding patterns were observed when an oligonucleotide complementary to a putative POMC stem-loop structure was used to prime IST. Indeed local changes in banding patterns could be elicited by pharmacological agents which modulate POMC translation. Inhibition of POMC synthesis with NaF or dexamethasone decreased the number of POMC mRNAs in the polysome fractions and increased the intensity of high molecular weight IST-derived bands. Forskolin, a stimulator of POMC synthesis, had the opposite effect. One mechanism by which translational control is thought to occur is by regulation of ribosome movement down the mRNA by specific binding of cytosolic proteins to RNA structure. Cytosolic protein fractions from AtT20 pituitary cells have been shown to specifically bind to the IST-predicted RNA structure. These findings suggest that 1) mRNA structure can be assessed in situ, 2) translation may be altered by the secondary and tertiary structure of mRNAs, and 3) a predicted stem-loop structure exists in situ in the 5'-end of POMC mRNA.

Animals↗
PubMed1993

Treatment of steroid-dependent asthma with recombinant interferon-gamma.

We have recently reported that treatment of patients with severe atopic dermatitis with recombinant interferon-gamma (rIFN-gamma) resulted in clinical improvement as well as a reduction of circulating eosinophils. Since IgE-dependent late phase allergic reactions and eosinophilic infiltration are thought to play an important role in the pathogenesis of asthma, we conducted a two centre randomized double-blind placebo-controlled trial of rIFN-gamma in the treatment of steroid-dependent asthma. Patients were treated with daily subcutaneous injections of either 0.05 mg/m2 rIFN-gamma (n = 9) or placebo (n = 11) for 90 days. All patients completed the study without significant drug toxicity noted. Oral prednisone dose, forced expiratory volume in 1 second (FEV1), peak expiratory flow rates (PEFR) and circulating eosinophil counts were monitored throughout the trial. There was no significant difference between the two treatment groups in per cent reduction from baseline of daily prednisone (P = 0.51). There was also no significant difference between the two treatment groups in per cent change from baseline in FEV1 (P = 0.54) or in PEFR (P = 0.75). Total circulating eosinophil counts decreased by 31% in the rIFN-gamma group and increased by 8.5% in the placebo group (P = 0.09). We conclude that this treatment regimen was not effective in patients with steroid-dependent asthma.

Adolescent↗
PubMed1991

Simplified single sample 13Carbon urea breath test for Helicobacter pylori: comparison with histology, culture, and ELISA serology.

There is no ideal method for detecting Helicobacter pylori. The 'standard' 13Carbon urea breath test (13C-UBT), which involves collecting eight to 15 breath samples and subsequent costly analysis, was modified by pooling 21 samples of expired breath taken at five minute intervals for 40 minutes into a collecting bag, from which a single 20 ml aliquot was taken and analysed by mass spectrometry. This test was evaluated on 50 patients after routine upper gastrointestinal endoscopy, and results were compared with those from the standard 13C-UBT, bacteriology, ELISA serology, and histology--the latter being taken as the gold standard. H pylori were seen in 34 of 50 (68%) patients (in three it was detected in biopsy specimens from the corpus alone). The modified 13C-UBT was positive (pooled excretion delta 13CO2 greater than 5 per mil) in 31 patients and negative in 19 (three false negative results), specificity was 100% (standard 13C-UBT 94%) and sensitivity 92% (standard 13C-UBT 93%). The modified 13C-UBT had a coefficient of variation within subjects of 3.7%. For the ELISA serology and culture the specificities were both 100%, but the sensitivities were 82% and 68% respectively. The 13C-UBT results correlated with the grade of histological gastritis. The modified 13C-UBT is simpler, cheaper, more reproducible, and provides an easy non-invasive method for the detection of H pylori.

Adult↗
PubMed1987

N-methyl antitumour agents. A distinct class of anticancer drugs?

This article reviews the structure-activity characteristics, mode of action, pharmacokinetics and clinical utility of a group of chemically dissimilar antitumour agents which have as a common structural feature the N-methyl moiety. The importance of this feature is shown by the fact that molecules without a substituent on the nitrogen or compounds with N-alkyl groups other than methyl are usually inactive in experimental systems. This observation is supported by structure-activity studies with N-alkyl derivatives of s-triazines, triazenes, formamides, hydrazines and nitrosoureas. Representatives of these structural types which have found clinical application are, respectively, hexamethylmelamine, dacarbazine, N-methylformamide, procarbazine and streptozotocin. Mode of action studies have shown that dacarbazine, procarbazine and streptozotocin can give rise to species capable of methylating nucleic acid. This may be the lesion which produces antitumour activity. The mechanism of action of N-methylmelamines and N-methylformamide remains unclear. There is good evidence that, with the exception of N-methylnitrosoureas, host metabolism is prerequisite for activity with these agents. Although not pronounced, the clinical activity of N-methyl antitumour agents is useful, particularly as activity is not associated with severe haematological toxicity. Furthermore, responses may be observed in patients resistant to bifunctional alkylating agents. It is concluded that the drugs reviewed herein show a degree of coincidence in terms of their biological properties which may warrant a common classification. The term N-methyl antitumour agent is proposed.

Alkylating Agents↗