Biomedical subjects

P D James

Publications and source records attributed to P D James.

At least 19 recordsLinked to original sources

PubMed2006

Genetic linkage and association analysis in type 1 von Willebrand disease: results from the Canadian type 1 VWD study.

BACKGROUND: von Willebrand disease (VWD) is the most common bleeding disorder known in humans, with type 1 VWD representing the majority of cases. Unlike the other variant forms of VWD, type 1 disease represents a complex genetic trait, influenced by both genetic and environmental factors. AIM: To evaluate the contribution of the von Willebrand factor (VWF) and ABO blood group loci to the type 1 VWD phenotype, and to assess the potential for locus heterogeneity in this condition, we have performed genetic linkage and association studies on a large, unselected type 1 VWD population. METHOD: We initially collected samples from 194 Canadian type 1 VWD families for analysis. After the exclusion of families found to have either type 2 or type 3 VWD, and pedigrees with samples from single generations, linkage and association analysis was performed on 155 type 1 VWD families. RESULTS AND CONCLUSION: The linkage study has shown a low heterogeneity LOD score of 2.13 with the proportion of families linked to the VWF gene estimated to be 0.41. Linkage was not detected to the ABO locus in this type 1 VWD population. In the family-based association test, significant association was found between the type 1 VWD phenotype, the quantitative traits, VWF:Ag, VWF:RCo, and FVIII:C and the ABO 'O' and 'A' alleles and the VWF codon 1584 variant. There was also weak association with the -1185 promoter polymorphism and VWF:Ag, VWF:RCo, and FVIII:C plasma levels. These studies provide further evidence to support the role for genetic loci other than VWF and ABO in the pathogenesis of type 1 VWD.

ABO Blood-Group System↗

PubMed2004

Clostridium difficile associated diarrhoea in hospitalised patients: onset in the community and hospital and role of flexible sigmoidoscopy.

OBJECTIVES: Clostridium difficile associated diarrhoea (CDAD) is a hospital acquired infection in which optimal methods for diagnosis and the scale of the problem in the community remain to be determined. In hospitalised patients with CDAD, we aimed to (i) study patients in whom the onset of diarrhoea was in the community and (ii) investigate the role of bedside flexible sigmoidoscopy in diagnosis. METHODS: Patients with CDAD (onset in hospital or community) were studied prospectively. In those with diarrhoea of unknown aetiology, flexible sigmoidoscopy was compared with stool assay for C difficile cytotoxin. RESULTS: Of 136 patients with CDAD (which was associated with antibiotic exposure in 96%), diarrhoea started in the community in 38 (28%; majority in own home) and while an inpatient in 98 (72%). The majority with CDAD onset in the community had been hospitalised over the preceding 12 months (86.8% v 57.1% in the hospital onset group; p<0.001). In 56 patients with pseudomembranous colitis at sigmoidoscopy, the stool C difficile cytotoxin test was negative in 29 (52%) but toxigenic C difficile was isolated from all of nine stool samples cultured. Of patients with pseudomembranous colitis, 30.4% relapsed over the subsequent 57.7(4.2) days. CONCLUSIONS: In a significant proportion of hospitalised patients with CDAD, diarrhoea started in the community. However, the majority of these had been hospital inpatients previously when they may have acquired C difficile, with the subsequent onset of diarrhoea in the community following exposure to antibiotics. Flexible sigmoidoscopy is superior to the stool C difficile cytotoxin test in a subgroup of patients with pseudomembranous colitis. Sigmoidoscopy should therefore be considered in all hospitalised patients with diarrhoea in whom the stool test for C difficile cytotoxin and enteric pathogens is negative.

Aged↗

PubMed2004

Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrent Clostridium difficile associated diarrhoea.

BACKGROUND: In Clostridium difficile associated diarrhoea (CDAD), histological changes in the colonic mucosa range from minimal inflammation to pseudomembranous colitis (PMC). The disease also recurs in a considerable proportion of patients. AIM: To investigate mucosal immune system cells in colonic biopsies of patients with CDAD. METHODS: Colonic biopsies were obtained from 12 control patients with diarrhoea, six patients with CDAD and minimal inflammation, and 10 patients with CDAD with pseudomembranous colitis (samples obtained from areas with and without inflammatory exudate). Immunohistochemical studies were performed using antibodies to T cells (CD3), macrophages (CD68), B/plasma cells (CD79alpha), and to IgA, IgM, and IgG. Labelled cells in lamina propria were quantified. RESULTS: In contrast to T cells, there were significant reductions in B/plasma cell and macrophage counts in all biopsies from patients with CDAD compared with controls (p<0.001). Studies using anti-immunoglobulin antibodies showed significant reductions in IgA producing cells in CDAD biopsies (p<0.05), with the greatest reduction in samples from patients with PMC. In contrast, there was a significant increase (p<0.05) in IgG producing cells in CDAD biopsies. Only patients with PMC relapsed. In these patients, B/plasma cell and IgA producing cell counts (in biopsies with and without inflammatory exudates) were significantly lower (p<0.01) in mucosal samples from those who subsequently relapsed (five) than those who did not. CONCLUSIONS: A selective reduction in mucosal IgA producing cells and macrophages is associated with colonic disease in C difficile infected patients. Severe reduction in colonic IgA producing cells may predispose to recurrence of CDAD.

Adolescent↗

PubMed2003

Differences in the perception of blood transfusion risk between laypeople and physicians.

BACKGROUND: There is little objective evidence to support the commonly held belief that laypeople perceive blood transfusion risk differently from physicians. Acknowledging and characterizing such differences may improve risk communication. The objective of this study was to characterize how laypeople and physicians perceive the risks of blood transfusion in comparison with a wide variety of other hazards. STUDY DESIGN AND METHODS: A total of 161 laypeople and 91 physicians and medical trainees were surveyed in Kingston, Ontario, between March and August 2000. The perceived riskiness and other qualitative characteristics of blood transfusion and 9 other hazards were measured by psychometric scaling and principal components analysis. RESULTS: The overall return rate was 100 percent, with 86 percent of surveys having no missing responses. Physicians perceived the risks of blood transfusion and most other hazards to be less dreaded and severe, but also less understood and controllable than laypeople. CONCLUSION: Laypeople and physicians perceive risk differently for blood transfusion, but this perceptual gap between the groups for blood transfusion may be representative of a more generalized phenomenon that spans different types of hazards, both medical and nonmedical. Awareness of such differences may facilitate risk communication and shared decision making between physicians and their patients.

Adult↗

PubMed2002

Expression of antimicrobial neutrophil defensins in epithelial cells of active inflammatory bowel disease mucosa.

BACKGROUND/AIMS: The normal intestinal epithelium is increasingly being recognised as an important component of the mucosal innate protection against microorganisms. Human neutrophil defensins 1-3 (HNP 1-3) and lysozyme are components of the systemic innate immunity. The aim of this study was to investigate the expression of HNP 1-3 and lysozyme in normal and active inflammatory bowel disease (IBD) mucosa. METHODS: Mucosal tissue sections were studied by immunohistochemistry using antibodies to neutrophil defensins 1-3 and lysozyme. Extracts of purified intestinal epithelial cells were used for immunoblotting studies and antimicrobial activity against the phoP negative strain of Salmonella typhimurium. RESULTS: Surface epithelial cells strongly immunoreactive for neutrophil defensins and lysozyme were seen in active ulcerative colitis and Crohn's disease (but not normal or inactive IBD) mucosal samples. Many of these cells coexpressed both of the antimicrobial proteins. Immunoblotting studies confirmed the expression of neutrophil defensins in extracts of purified ulcerative colitis epithelial cells, which also demonstrated antimicrobial activity. CONCLUSION: HNP 1-3 and lysozyme are expressed in surface enterocytes of mucosa with active IBD and they may play an important role in intestinal host defence against luminal microorganisms.

Cell Extracts↗

PubMed2001

Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology.

BACKGROUND/AIMS: The significance of abnormal liver function tests in the absence of diagnostic serology is unclear. The aim of this study was to report liver biopsy findings in a large group of patients with unexplained abnormal liver biochemistry. METHODS: Histological findings were examined in 354 patients who underwent liver biopsy to investigate abnormal liver function tests. RESULTS: Six percent of patients had a normal liver biopsy while 26% were found to have some degree of fibrosis and 6% were cirrhotic. Thirty four and 32% of biopsies suggested non-alcoholic steatohepatits or fatty liver respectively. Other diagnoses included cryptogenic hepatitis, drug toxicity, primary and secondary biliary cirrhosis, autoimmune hepatits, alcohol-related liver disease, primary sclerosing cholangitis, haemochromatosis, amyloid and glycogen storage disease. Patient management was directly altered in 18% of patients due to liver biopsy findings and three families were entered into screening programmes for inheritable liver disease. CONCLUSIONS: The finding of abnormal liver function tests in the absence of diagnostic serology may indicate significant liver disease. Liver biopsy yields a range of liver diseases of diverse nature and extent. Liver diseases may be uncovered for which specific treatment is indicated.

Biopsy, Needle↗

PubMed2000

Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine.

BACKGROUND/AIM: Azathioprine is standard therapy for maintenance of remission in patients with autoimmune hepatitis. However, approximately 15% of patients are intolerant of therapy and 10% do not respond to it. There is a need for alternative therapies. We describe here the results of mycophenolate mofetil therapy in patients with autoimmune hepatitis. PATIENTS: We studied seven patients with type 1 AIH (six female). Three were intolerant of azathioprine and had elevated transaminases and liver histology showing active disease despite prednisolone therapy. Four had been on a dose of 2 mg per kg of azathioprine without complete normalisation of ALT, and had liver biopsies showing active disease. All were treated with mycophenolate 1 g bd and were followed for a median of 46 months (21-59). End points were improvement in histological inflammation, ALT and prednisolone dose. RESULTS: Five of the seven (71%) patients had normal transaminases after 3 months of treatment. The steroid dose fell from a median of 20 mg per day to 2 mg per day at 9 months (p=0.0001) and the hepatic activity index fell from median 11 to 3 (p=0.001) after 7 months of therapy. One patient required dose reduction because of a fall in white cell count. No other adverse effects were seen. CONCLUSIONS: Mycophenolate mofetil is effective and well tolerated in patients with type 1 AIH who are intolerant of, or do not respond to, azathioprine.

Adolescent↗

PubMed1996

Randomised controlled trial of faecal-occult-blood screening for colorectal cancer.

BACKGROUND: There is growing evidence that faecal-occult-blood (FOB) screening may reduce colorectal cancer (CRC) mortality, but this reduction in CRC mortality has not been shown in an unselected population-based randomised controlled trial. The aim of this study was to assess the effect of FOB screening on CRC mortality in such a setting. METHODS: Between February, 1981, and January, 1991, 152,850 people aged 45-74 years who lived in the Nottingham area of the UK were recruited to our study. Participants were randomly allocated FOB screening (76,466) or no screening (controls; 76,384). Controls were not told about the study and received no intervention. Screening-group participants were sent a Haemoccult FOB test kit with instructions from their family doctor. FOB tests were not rehydrated and dietary restrictions were imposed only for retesting borderline results. Individuals with negative FOB tests at the first screening, together with those who tested positive but in whom no neoplasia was found on colonoscopy, were invited to take part in further screening every 2 years. Screening was stopped in February, 1995, by which time screening-group participants had been offered FOB tests between three and six times. Screening-group participants who had a positive test were offered full colonoscopy. All participants were followed up until June, 1995. The primary outcome measure was CRC mortality. FINDINGS: Of the 152,850 individuals recruited to the study, 2599 could not be traced or had emigrated and were excluded from the analysis. Thus, there were 75,253 participants in the screening group and 74,998 controls. 44,838 (59.6%) screening-group participants completed at least one screening. 28,720 (38.2%) of these individuals completed all the FOB tests they were offered and 16,118 (21.4%) completed at least one screening but not all the tests they were offered. 30,415 (40.4%) did not complete any test. Of 893 cancers (20% stage A) diagnosed in screening-group participants (CRC incidence of 1.49 per 1000 person-years), 236 (26.4%) were detected by FOB screening, 249 (27.9%) presented after a negative FOB test or investigation, and 400 (44.8%) presented in non-responders. The incidence of cancer in the control group (856 cases, 11% stage A) was 1.44 per 1000 person-years. Median follow-up was 7.8 years (range 4.5-14.5). 360 people died from CRC in the screening group compared with 420 in the control group-a 15% reduction in cumulative CRC mortality in the screening group (odds ratio=0.85 [95%; CI 0.74-0.98], p = 0.026). INTERPRETATION: Our findings together with evidence from other trials suggest that consideration should be given to a national programme of FOB screening to reduce CRC mortality in the general population.

Adenoma↗

PubMed1994

Analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection.

To study the cellular infiltrate that occurs within the airways of infants with respiratory syncytial virus bronchiolitis, samples of airways secretions were obtained by bronchial lavage from the lower respiratory tract of infants ventilated for this condition and from the upper airway of non-intubated infants with this disorder using nasopharyngeal aspirates. Cytospin samples were prepared so that differential cell counts could be performed on the cells obtained and alkaline phosphatase-antialkaline phosphatase immunocytochemical analysis of lymphocyte subsets was carried out using a panel of monoclonal antibodies, which included anti-CD3, anti-CD4, anti-CD8, anti-CD19, and anti-TcR gamma delta. Results from the lower and upper airways were similar. Large numbers of inflammatory cells were obtained, of which neutrophils accounted for a median of 93% in the upper airway and 76% in the lower airway. The numbers of CD8 positive cells detected were small and consistently less than CD4 positive cells, median CD4:CD8 ratios being 22.5:1 and 15:1 for the lower and upper airways. CD19 positive cells were rarely observed and no gamma delta positive lymphocytes were detected. These results indicate that neutrophils probably play a major part in causing symptoms in these infants. They do not support the concept that excessive lymphocyte mediated cytotoxic activity is principally responsible for the pathology in respiratory syncytial virus bronchiolitis.

Acute Disease↗

PubMed1992

The early diagnosis of oesophageal adenocarcinoma by endoscopic screening.

Oesophageal carcinoma has a very poor prognosis unless detected at a pre-symptomatic stage. This can only be done by screening and patients with Barrett's columnar lined epithelium of the oesophagus (CLO) are high risk candidates for an endoscopic screening programme. Surveillance studies in CLO patients, when reviewed, showed that the incidence of adenocarcinoma was between 1 in 52 and 1 in 81 patient years, with a mean of 1 in 76. This paper describes the Nottingham experience with an endoscopic screening programme that was established in 1976. To date it has detected four adenocarcinomas at a mean cost similar to that of detecting breast cancer by screening.

Adenocarcinoma↗

PubMed1992

Assessment of proliferation of squamous, Barrett's and gastric mucosa in patients with columnar lined Barrett's oesophagus.

There is no satisfactory biomarker yet available for predicting the likelihood of premalignant changes or carcinoma developing in Barrett's or columnar lined oesophagus. In this study we have evaluated the proliferation of squamous epithelium, columnar epithelium from columnar lined oesophagus and gastric columnar epithelium from 23 Barrett's patients using positive immunoreactivity with the mouse monoclonal antibody Ki67 (which recognises an antigen associated with proliferative cells) with a view to using this parameter as a biomarker. Squamous epithelium had significantly higher Ki67 immunostaining as compared with columnar epithelium from columnar lined oesophagus (when examining the tissue with greater than 15% cells staining positive for Ki67, Fisher's exact test p = 0.004) but there was no difference found between the epithelium from the columnar lined oesophagus and gastric columnar epithelium. There was no correlation between histological inflammation and Ki67 immunoreactivity of Barrett's mucosa, and the Ki67 immunostaining of two patients with dysplasia was no different from the rest of the group. There was, however, a significant correlation between the Ki67 immunoreactivity of columnar epithelium from columnar lined oesophagus and columnar epithelium from the stomach (correlation coefficient = 0.44, p = 0.03) suggesting that epithelium from columnar lined oesophagus behaves in a similar fashion to gastric epithelium.

Adult↗

PubMed1992

Length of Barrett's oesophagus: an important factor in the development of dysplasia and adenocarcinoma.

In a 15 year prospective study of endoscopic surveillance of columnar lined oesophagus, 102 patients with a mean follow up of 54 (12.5) months and total follow up of 462 years have been evaluated. Of all the sets of biopsies taken, 59 in 21 patients were found to exhibit dysplasia or carcinoma. Four male patients had carcinoma of the oesophagus, indicating a 30 times increased risk of development of adenocarcinoma in columnar lined oesophagus. The length of columnar lined oesophagus in subjects with dysplasia was significantly longer as compared with the whole group (p = 0.01) and when compared with the patients without dysplasia (p = 0.005). None of the patients with dysplasia had a columnar lined oesophagus of less than 8 cm. Length of columnar lined oesophagus therefore seems to be a significant risk factor in the development of dysplasia and subsequent carcinoma and intensive follow up of patients with columnar lined oesophagus greater than 8 cm in length is recommended.

Adenocarcinoma↗

PubMed1992

Chronic giardiasis of the stomach.

Two cases of chronic giardiasis of the stomach diagnosed from gastric mucosal biopsy specimens are reported. The first case was associated with an acute-on-chronic gastritis and Helicobacter-like organisms, and the second with an adenocarcinoma of the stomach. In both cases the trophozoites had been missed in earlier biopsy specimens. As far as is known this is the first report of giardiasis of the stomach.

Aged↗

PubMed1991

The effects of temperature, pH and growth rate on secondary metabolism in Streptomyces thermoviolaceus grown in a chemostat.

Streptomyces thermoviolaceus was grown in a chemostat under conditions of glutamate limitation. The effects of growth rate on production of the antibiotic granaticin, extracellular protein and protease activity as components of secondary metabolism were studied at 37, 45 and 50 degrees C. The amount of each secondary metabolite synthesized was highly dependent on growth rate and temperature. Granaticin yields were highest at growth rates of 0.1 to 0.15 h-1 at 37 degrees C, 0.175 h-1 at 45 degrees C and 0.045 h-1 at 50 degrees C. Protease activity of culture supernatants responded to low nutrient concentration and/or low growth rate. Measurements of extracellular protein revealed complex changes in amount which were dependent on growth rate and temperature. At 45 degrees C and a growth rate of 0.15 h-1, biomass yield was highest between pH 5.5 to 6.5 whereas granaticin synthesis was low at pH 5.5 and rose to highest values at between pH 6.5 and 7.5.

Antibiotics, Antineoplastic↗

PubMed1991

Comparison of the diagnostic yields of disposable and reusable cytology brushes in fibreoptic bronchoscopy.

Disposable rake and reusable bristle type cytology brushes have been compared in 50 patients undergoing fibreoptic bronchoscopy for suspected malignancy. Forty seven patients were eventually found to have carcinoma of the bronchus. A diagnosis of malignancy was made from the specimens taken with one or other brush in 34 patients, from the reusable brush in 28, and from the disposable brush in 31. The specimens taken with the two types of brush were of similar quality. The reusable brush is about five times less expensive per procedure but carries a risk of cross contamination and cross infection, and time is needed to clean the brush after each bronchoscopy. The diagnostic yield appears to be at least as good with the disposable brush.

Adult↗

PubMed1989

Randomised, controlled trial of faecal occult blood screening for colorectal cancer. Results for first 107,349 subjects.

To assess the effectiveness of screening by faecal occult blood tests, 107,349 people without symptoms of colorectal disease identified from general practitioner records have been randomly allocated to test and control groups. 53,464 test subjects were invited to carry out the screening test; 27,651 (53%) of the 52,258 who received the tests did so. Further investigation of the 618 (2.3%) with positive tests showed 63 cancers (52% stage A) and 367 adenomas (266 subjects). Rescreening of subjects with negative results every 2 years (9510 first rescreen, 3639 second) has shown a significant fall in the rate of positive results (1.7% of 7344; 0.3% of 2906). Cancers have also been diagnosed in 20 subjects presenting in the interval between a negative test and rescreening, and in 83 non-responders. The incidence of cancer in the control group (123 subjects; 10.6% stage A) was 0.72 per 1000 person-years. Cancers detected by screening were at a less advanced pathological stage, but it is too early to show any effect of screening on mortality from colorectal cancer.

Adenocarcinoma↗

PubMed1989

Clinical evaluation of the augmented delta quotient monitor for intraoperative electroencephalographic monitoring of children during surgery and cardiopulmonary bypass for repair of congenital cardiac defects.

To assess the augmented delta quotient (ADQ) monitor as a monitor of cerebral function during cardiac surgery, we monitored during operation the electroencephalograms of 48 young subjects (aged 2 weeks to 19 yr). We found ADQ patterns produced by cardiopulmonary bypass, hypothermia and general anaesthetic agents correlated with those obtained from a compressed spectral array (CSA) monitor and could be differentiated from changes caused by cerebral ischaemia, except in the youngest group of patients (less than or equal to 18 months) undergoing deep hypothermia (19.4 (SD 0.8) degrees C nasopharyngeal). In all other age groups the ADQ proved to be a simple monitor of the adequacy of cerebral perfusion. Neurological deficit occurred only if the ADQ was abnormal during hypotension for a period exceeding 7 min. ADQ evaluation of cerebral function was limited by events which produced artificially normal ADQ readings such as low amplitude EEG activity and the described isoflurane effect that was demonstrated to occur in some cardiac patients. The results obtained by the ADQ were comparable to those obtained by compressed spectral array and the ADQ was easier to use and interpret.

Adolescent↗

PubMed1989

The effects of temperature on growth and production of the antibiotic granaticin by a thermotolerant streptomycete.

The synthesis of granaticin, a polyketide-derived antibiotic synthesized as a secondary metabolite by Streptomyces thermoviolaceus strain NCIB 10076, was studied at different growth temperatures. Quantitative measurements of the antibiotic made during batch fermentations showed that the yield was greatest at 45 degrees C, whereas the rate of synthesis was most rapid at 37 degrees C. The timing of the appearance of granaticin in culture could not be assigned to any particular phase of growth or to de-repression due to depletion of any particular nutrient. However, at all temperatures, appearance of the antibiotic coincided with a rise in ammoniacal nitrogen presumably due to deamination of glutamate, the carbon source for growth. We have previously shown that production of the antibiotic is pH sensitive and that some carbon sources result in higher titres than others. This paper examines the effect of temperature on the physiology of growth and on antibiotic production in more detail under conditions that also allow an exact measurement of granaticin yield.

Anti-Bacterial Agents↗