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Biomedical subjects

J Firth

Publications and source records attributed to J Firth.

At least 19 recordsLinked to original sources
PubMed2000

Evaluation of fecal pancreatic elastase-1 as a measure of pancreatic exocrine function in children with cystic fibrosis.

Pancreatic elastase-1 (EL-1) is a specific human protease synthesised by the acinar cells. It is stable, unaffected by exogenous pancreatic enzyme treatment, and correlates well with stimulated pancreatic function tests. We report our experience of EL-1 measurements in 142 patients from a large cystic fibrosis (CF) clinic. The median patient age was 7.7 years (range, 0.1-20.8 years), 93 were homozygous and 38 heterozygous for DeltaF508, and 11 had other or unidentified mutations. There were 85 non-CF control subjects. Seven were pancreatic sufficient (PS). The median (quartile 1-quartile 3) fecal EL-1 of the 135 pancreatic insufficient (PI) patients was 10 microg/g stool (2.5-33); of the 7 PS patients, 698 microg/g stool (400.5-824.5), and of the non-CF controls, 615 microg/g stool (420-773). Using the Mann-Whitney U test, there was a statistically significant difference for fecal EL-1 activity between the PS and PI patients (P = 0.0001) and the PI and control group (P < 0.0001), but not between the control and PS groups (P = 0.63). Median (quartile 1-quartile 3) fecal EL-1 in the pancreatic insufficient DeltaF508 homozygotes was 10 microg/g stool (2-33), and in the heterozygotes 12 microg/g stool (4-39) (not significant, P = 0.62). We now use fecal EL-1 as evidence of PI in screened CF infants (reliable over the age of 2 weeks); in older CF patients at diagnosis; for confirming the need for pancreatic enzymes in patients referred to the clinic already taking enzymes; for annual monitoring of PS patients to detect the onset of PI; and as supporting evidence when excluding the diagnosis of CF in patients attending the pediatric gastroenterology clinic. The low values in the first 2 weeks in some normal and premature infants, and the persisting normal values in PS infants, make the fecal EL-1 test unsuitable for neonatal CF screening.

Adolescent↗
PubMed2000

Management of acute pancreatitis: a comparative audit of clinical practice against the recommendations of the british society of gastroenterology

AIMS: In 1998 the British Society of Gastroenterology (BSG) published national guidelines for the management of acute pancreatitis (AP) in an attempt to improve diagnosis and reduce mortality rates. A comparative audit was undertaken of the management of AP against the BSG recommendations. METHODS: A retrospective analysis of 53 patients (median age 61 (range 24-95) years) admitted with AP during 1998 was undertaken and a comparison was made with the BSG guidelines. RESULTS: Some 70 per cent (n = 37) of the patients were admitted with mild AP and 30 per cent (n = 16) with severe AP. The BSG recommendations are shown in parentheses in the following text. The overall mortality rate was 17 per cent (less than 10 per cent), zero in mild AP and 56 per cent in patients with severe AP (less than 30 per cent). A correct diagnosis of AP was made within 48 h of admission in all patients (100 per cent). Severity stratification within 48 h using the Glasgow criteria and C-reactive protein (CRP) level, as suggested by the BSG, was done in approximately 80 per cent of patients. Table 1. CRP was measured in 51 per cent of the patients within the first 4 days (100 per cent) and at the end of the first week (100 per cent). Gallstones and alcohol counted for 72 per cent of causes of AP and the aetiology was determined in 77 per cent (75-80 per cent). All patients with severe AP were managed in a high-dependency or intensive therapy unit with central venous pressure monitoring and prophylactic intravenous antibiotics, and underwent dynamic computed tomography within 3-10 days of admission (100 per cent). Some 86 per cent of patients with suspected common bile duct (CBD) stones (jaundice, deranged liver function tests, dilated CBD) underwent endoscopic retrograde cholangiopancreatography with or without duct drainage and clearance. CONCLUSIONS: Management of AP closely mirrors the BSG guidelines, but fails to fully address severity stratification with respect to LDH, CRP and PaO2 at 48 h. A thorough analysis of patients with severe AP (i.e. extent of pancreatic necrosis, onset of infection) has been undertaken to explain the mortality rate and it is proposed to prospectively audit admissions with AP in 1999 in order to close the audit loop.

Journal Article↗
PubMed2000

Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients.

The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.

Adult↗
PubMed1999

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.

Adult↗
PubMed1999

The effect of age, diabetes, and other comorbidity on the survival of patients on dialysis: a systematic quantitative overview of the literature.

BACKGROUND: The UK Renal Registry quotes a 1-year death rate for patients established on dialysis of 19.4 per 100 patient years. Clinical experience, reflected in the UK Renal Association Standards Document (RASD), recognizes qualitatively that age, diabetes, and other comorbidities increase the risk of death. The aim of this paper is to provide quantitative estimates of the relative risk of death associated with particular patient characteristics. METHODS: Quantitative techniques were used to estimate relative risk of death in the seven studies quoted in the RASD document and 17 other papers identified in a systematic literature search. Relative risk data from each study were pooled using a fixed effects model (f). A random effects model (r) was applied to pool relative risks if heterogeneity was found to exist between studies. A meta-regression analysis was also carried out to investigate whether study covariates substantially explained the heterogeneity between studies. RESULTS: Pooling the papers identified in the systematic literature search with those from the RASD gave rise to a relative risk of death of 1.029 (95% CI 1.013-1.045) (r) associated with each year's increase in age. The relative risk associated with the presence of diabetes was 1.91 (95% CI 1.67-2.17) (r), whilst that associated with heart disease was 1.59 (95% CI 1.49-1.69) (f), and with peripheral vascular disease 1.58 (95% CI 1.29-1.93) (r). Heterogeneity was found in the estimates of risk associated with age, diabetes, and peripheral vascular disease. Important study covariates included the use of incident or prevalent cases, the use of routine data sources or data collected specifically for a particular study, the country in which the study was located, the use of a P value to infer the standard error of a relative risk estimate in a particular study, and the method of classifying diabetes. CONCLUSIONS: Published studies can be used to quantify the relative risk of death for dialysis patients with various comorbidities. This information is important if attempts are to be made to set standards for the performance of dialysis units, and to compare the performance of one dialysis unit with that of another.

Aging↗
PubMed1996

Pressure-induced myogenic responses in human isolated cerebral resistance arteries.

BACKGROUND AND PURPOSE: Pressure-induced myogenic responses have been demonstrated in cerebral resistance arteries isolated from a number of species. In the present study, we determined the response of human isolated cerebral resistance arteries to a pressure stimulus. METHODS: Arteries were set up in a pressure myograph and exposed to alterations in intravascular pressure. RESULTS: Human isolated cerebral resistance arteries developed spontaneous intrinsic tone in response to a pressure stimulus over the pressure range of 20 to 90 mm Hg that was not apparent in the absence of extracellular calcium. This intrinsic tone may be an inherent property of the vascular smooth muscle, since it remained after functional removal of the endothelium. CONCLUSIONS: Human isolated cerebral resistance arteries spontaneously contract when exposed to raised intravascular pressure. This pressure-induced myogenic response may contribute to cerebral autoregulation of blood flow.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Modulation of host matrix metalloproteinases by bacterial virulence factors relevant in human periodontal diseases.

OBJECTIVE: Bacterial pathogens involved in periodontal diseases exert a part of their destructive effect by triggering and inducing host cells to elevate their secretion of matrix metalloproteinases (MMPs). Pathogen-secreted phospholipase (PLC) is one bacterial product that may trigger this host response. The roles of exogenous PLC leading to the release, secretion and expression of MMPs by peripheral blood neutrophils (PMNs), cultured epithelial cells of human gingiva and porcine periodontal ligament were investigated. Also the activities of PLC in the diseased and healthy gingival sulcular fluid (crevicular fluid, GCF) and molecular forms of gelatinases present in dental plaque were investigated. MATERIALS AND METHODS: GCF, salivary and dental plaque samples were analyzed for PLC and proteinase activities. The abilities of PLC to induce PMNs and oral epithelial cells to release and express their MMPs were examined by specific functional, immunological and molecular biology means. RESULTS: PMN-derived MMPs were found to predominate in periodontitis GCF and plaque, and PLC activities were higher in GCF of adult periodontitis patients than in healthy controls. Purified bacterial PLC (1 mU ml(-1)) efficiently induced PMN degranulation. PLC also induced MMP expression in the cultured epithelial cells. The strongest response was seen in MMP-9 and less in MMP-2. The induction was dose-dependent in the range of 0.0-1.0 U ml(-1) PI-PLC, and quiescent cultures were more responsive than proliferating ones. PLC induction of MMPs was polar, with increased levels of MMP-9 in the apical region and increased MMP-2 levels secreted in the basal direction. Northern analysis showed a strong increase in mRNA levels of MMP-9 and a smaller increase for MMP-2 and MMP-1. In the second part of the study we investigated the molecular forms of the released MMPs during periodontitis. In bacterial plaque of periodontitis patients the MMP-9 were found to be converted into lower molecular weight forms. Isolated proteinase from Porphyromonas gingivalis (ATCC 33277) was able to convert human proMMPs to their active forms. CONCLUSION: Bacterial PLC may induce degranulation of PMN MMPs and increase MMP expression in oral epithelial cells. The released proteases can be converted into active form by the proteases of plaque bacteria. Thereby, the pathogenic oral bacteria may indirectly participate in the destruction of periodontal tissues.

Adult↗
PubMed1994

Observer variation and discriminatory value of biopsy features in inflammatory bowel disease.

If skilled histopathologists disagree over the same biopsy specimen, at least one must have an incorrect interpretation. Thus, disagreement is associated with, although not the cause of, diagnostic error. The present study aimed to determine the magnitude of variation among 10 observers with a special interest in gastrointestinal histopathology. They independently interpreted the same biopsy specimens for morphological features which may discriminate between patients with Crohn's disease and ulcerative colitis and normal subjects. Thirty of 41 features had agreement measures significantly better than expected by chance (p < 0.05). The range of agreement in the 45 observer pairs over the final diagnosis was 65-76%. There was good agreement in discriminating between normal slides and those showing confirmed inflammatory bowel disease. For normal slides, however, the term nonspecific inflammation was often applied and without any consistency. In addition, true Crohn's disease slides were often and consistently thought to be ulcerative colitis. Having identified 11 important discriminatory morphological features, two multiple regression analyses were then carried out to produce a scoring system for inflammatory bowel disease. These results suggest there is considerable room for improvement in the reliability of colonic biopsy specimen interpretation and that this could probably be achieved using more exact definitions of morphological features and diseases.

Colitis, Ulcerative↗
PubMed1994

Benign intracranial hypertension: a cause of CSF rhinorrhoea.

Four patients undergoing treatment for benign intracranial hypertension presented with spontaneous CSF rhinorrhoea. The four patients, all women, were aged between 33 and 44 years. They had been receiving treatment for benign intracranial hypertension for a period ranging from eight months to 11 years, before developing the CSF leak. There was no history of previous head injury and there were no congenital anomalies of the floor of the anterior fossa. The site of the CSF fistula was localised to the cribriform plate in all four cases. The pathophysiology of the CSF rhinorrhoea and the surgical management of this group of patients are discussed. The authors propose that benign intracranial hypertension should be included in the classification of high pressure CSF leaks.

Adult↗
PubMed1992

Home accidents in older people: role of primary health care team.

OBJECTIVES: To determine the incidence and nature of unreported and reported home accidents in older people and to investigate associated environmental factors. DESIGN: Postal questionnaire requesting information on home accidents in the preceding month. SETTING: Inner London general practice. SUBJECTS: All registered patients aged over 65 years (n = 1662), of whom 120 were inappropriately registered and 1293 responded. MAIN OUTCOME MEASURE: Circumstances and consequences of accidents in the home. RESULTS: 108 accidents were recorded in 100 patients, giving a home accident rate of 84/1000 patients, equivalent to an annual rate of 1002/1000. 73 accidents were falls, and 83 were unreported. Of the 25 reported accidents, 19 were reported to general practice and six to accident and emergency departments (5.6% of all events). Rates of home accidents increased with age and were higher in women than men (79/819 upsilon 29/474; chi 2 = 4.5, df = 1, p less than 0.05). CONCLUSIONS: The incidence of home accidents in people aged over 65 years was high but few events were reported to medical services. General practice provided the main contact for patients who reported home accidents, and primary care workers have important opportunities for advising elderly patients on home accident prevention. Improved publicity on home safety targeted at older people and their carers would support the primary health care team in this role.

Accident Prevention↗
PubMed1992

Dynamic studies of gadolinium uptake in brain tumors using inversion-recovery echo-planar imaging.

Echo-planar imaging has been used to observe the dynamics of Gd-DTPA uptake in brain tumors. It has been possible to examine both vascular uptake and diffusion across the blood-brain barrier in a single experiment, by using the IR-MBEST echo-planar sequence which combines a high temporal resolution (approximately 3 s) with strong T1 weighting. To model the uptake it is necessary to know the arterial concentration of Gd-DTPA; in this study the signal in the sagittal sinus was measured to avoid the need to take repeated blood samples. The time constant for transfer across the blood-brain barrier was measured to be between 20 and 1050 s for different tumors. The results of the modeling correlated with the results of other assessments of tumor vascularity.

Adult↗
PubMed1992

Using changes in attributable risk to predict long-term efficacy of simvastatin treatment.

It is a common perception that coronary heart disease (CHD) deaths will decline by 2% for every 1% decrease in serum total cholesterol (TC). We investigated the changes in serum TC concentrations obtained with simvastatin, an inhibitor of hydroxymethylglutaryl-CoA reductase, in 70 hypercholesterolemic subjects. Although simvastatin reduced serum TC concentrations by 30% after 6 months, calculations from age- and risk-related TC quintiles show that the absolute difference in attributable CHD deaths would be just > 1%. These results are reminiscent of the experience from several large prospective primary drug trials that demonstrated impressive relative benefit ratios but much smaller absolute differences (< 2%) in CHD endpoints between the treated and untreated groups. This epidemiologically based approach of assessing efficacy and potential long-term benefit of a lipid-lowering drug may be more appropriate and potentially less misleading than just the percentage change of TC (or other lipoproteins) so frequently reported in short-term drug trials.

Adult↗
PubMed1991

Determination of 4-hydroxyandrost-4-ene-3,17-dione metabolism in breast cancer patients using high-performance liquid chromatography-mass spectrometry.

A sensitive procedure for studying the metabolism of the steroidal aromatase inhibitor 4-hydroxy-androst-4-ene-3,17-dione (4OHA) was developed based on enzyme hydrolysis, liquid-liquid extraction and reversed-phase liquid chromatography coupled with a mass spectrometer (LC-MS) using a thermospray interface. Seven metabolites were identified from the hydrolysed urine samples together with the parent drug. The major routes of metabolism were via dehydrogenation, reduction of the ketone functional groups, reduction at the C-4-C-5 double bond and hydroxylation at the C-5 position. Confirmation of the identity of 4OHA and its metabolites isolated from female patients' urine samples was accomplished by comparison of the retention times of their corresponding synthetic standards on LC-MS. We have demonstrated that this technique is particularly suitable for studying the metabolism of steroidal drugs.

Administration, Oral↗
PubMed1991

Primary non-Hodgkin's lymphoma of the central nervous system: phase II study of chemotherapy (BVAM) prior to radiotherapy.

Ten patients were diagnosed as having primary non-Hodgkin's lymphoma of the central nervous system at University Hospital, Nottingham, between September 1986 and April 1989. None had clinical evidence of HIV-1 infection. All the patients started treatment with chemotherapy (BVAM), designed to cross the blood-brain barrier, followed by radiotherapy. Seven patients completed both chemotherapy and radiotherapy. Dose reduction during chemotherapy was necessary in three patients because of neutropenia. In two of the six patients with solitary tumours, complete resection was achieved surgically prior to treatment. Five of the remaining eight patients (63%) had radiological evidence of a complete response with chemotherapy. The other three patients had no response to chemotherapy but one had a complete response after radiotherapy. The two-year cause-specific survival of the 10 patients was 37%. Two of the three patients who had a postoperative performance status of 0 or 1 (ECOG/WHO) are alive and disease-free at 26 and 46 months from diagnosis. The median survival of the seven patients with a performance status of 2-4 was 10 months with two patients alive and disease-free at 19 and 26 months. The two-year cause-specific survival of these seven patients was 22%.

Adult↗
PubMed1987

Prescriptive v. exploratory psychotherapy. Outcomes of the Sheffield Psychotherapy Project.

Prior research suggests that psychotherapeutic techniques which differ in their contents are quite similar in their outcomes. Outcome data are reported from a study designed to maximise sensitivity to technique effects on outcome in a clinically realistic setting, and to permit detailed analysis of the relations between content, immediate impact, and outcome of therapy. Forty professional and managerial workers with depression or anxiety received eight sessions of Prescriptive (cognitive/behavioural) and eight sessions of Exploratory (relationship-oriented) therapy in a crossover design, with each client seeing the same therapist throughout. Outcome was assessed by standard interview and questionnaire methods. The results favoured Prescriptive therapy, although this difference was of moderate extent. The outcome was largely unaffected by the order in which the two methods were offered.

Anxiety Disorders↗
PubMed1987

Disposition of 3H-enisoprost, a gastric antisecretory prostaglandin, in healthy humans.

1. After oral administration of 3H-enisoprost (450 micrograms) to five healthy men, as a solution in capsules, peak 3H levels of 5624 +/- 566 pg equiv./ml (mean +/- S.E.M.) were reached within one hour. No unchanged drug was detected in plasma. 2. Enisoprost was rapidly de-esterified to SC-36067 [(+/-)11 alpha, 16 zeta-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651 +/- 200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of beta-oxidation, omega-oxidation and 9-keto-reduction. 3. After nine days 59.0 +/- 2.98% and 17.4 +/- 1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days. 4. Five urinary metabolites were identified by GC-MS. These were (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (+/-)3-[3 alpha,5-dihydroxy-2 beta-(4-hydroxy-4-methyl-1E-octenyl)-1 alpha-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (+/-)3-[2 beta-(8-carboxy-4-hydroxy- 4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (+/-)3-[2 beta-(8-carboxy-4- hydroxy-4-methyl-1E-octenyl)-3 alpha,5-dihydroxy-1 alpha-cyclopentanyl] propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its gamma lactone (2.6% dose). 5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1 alpha- cyclopent-3-enyl]propanoic acid and (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1- propanoic acid. 6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11 alpha-hydroxy group in SC-36067 or its metabolites also occurred.

Adult↗