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D Schofield

Publications and source records attributed to D Schofield.

At least 19 recordsLinked to original sources
PubMed2005

Intravenous antioxidant modulation of end-organ damage in L-arginine-induced experimental acute pancreatitis.

BACKGROUND: Oxidative stress mediates acinar injury in experimental acute pancreatitis (AP) and antioxidants are depleted in human AP. This study tests the hypothesis that exogenous antioxidant supplementation ameliorates experimental AP. METHODS: Male Sprague-Dawley rats were randomly allocated to 1 of 4 groups (n = 5/group) and sacrificed at 72 h. AP was induced by 250 mg per 100 g body weight of 20% L-arginine hydrochloride in 0.15 mol/l sodium chloride. Group allocations were: group 1 (control) no intervention; group 2 AP; group 3 early multiple antioxidant (MAOX) intervention comprising 15 microg/kg selenium, 30 microg/kg ascorbate and 300 mg/kg N-acetylcysteine given at 6 and 30 h and group 4 the MAOX combination above given at 24 and 48 h. Endpoints were: serum amylase, antioxidant levels, bronchoalveolar lavage (BAL) protein and lung myeloperoxidase (MPO) activity and histological assessment of pancreatic injury. RESULTS: L-arginine induced AP characterised by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Early MAOX reduced pulmonary MPO and BAL protein and reduced acinar swelling, degranulation and pancreatic parenchymal infiltration by inflammatory cells. These features were absent when intervention was delayed. CONCLUSION: In this model, early but not late antioxidant intervention ameliorates pancreatic and pulmonary injury.

Acetylcysteine↗
PubMed2003

Intravenous n-acetylcysteine, ascorbic acid and selenium-based anti-oxidant therapy in severe acute pancreatitis.

BACKGROUND: To observe outcome in a cohort of patients with severe acute pancreatitis receiving multiple anti-oxidant therapy. METHODS: An observational study was carried out in 46 consecutive patients with acute pancreatitis fulfilling current Atlanta consensus criteria for severe disease. All patients received multiple anti-oxidant therapy based on intravenous selenium, N-acetylcysteine and ascorbic acid plus beta-carotene and alpha-tocopherol delivered via nasogastric tube. Principal outcomes were the effect of anti-oxidant supplementation on anti-oxidant levels, morbidity and mortality in patients on anti-oxidant therapy, case-control analysis of observed survival compared to predicted survival derived from logistic organ dysfunction score (LODS), logistic regression analysis of factors influencing outcome and side effect profile of anti-oxidant therapy. RESULTS: Paired baseline and post-supplementation data were available for 25 patients and revealed that anti-oxidant supplementation restored vitamin C (P = 0.003) and selenium (P = 0.028) toward normal. In univariate survival analysis, patient survival to discharge was best predicted by admission APACHE-II score with relative risk of death increasing 12.6% for each unit increase (95% CI 6.0% to 19.6%). The mean LODS calculated on admission to hospital was 3.7 (standard error of the mean 4.1) giving a predicted mortality for the cohort of 21%. The observed in-hospital mortality was 43%. CONCLUSIONS: Case-control analyses do not appear to demonstrate any benefit from the multiple anti-oxidant combination of selenium, N-acetylcysteine and ascorbic acid in severe acute pancreatitis.

Acetylcysteine↗
PubMed2001

Low dose computed tomography in suspected acute renal colic.

AIM: To evaluate whether computed tomography (CT) of the renal tract in suspected renal colic using reduced exposure factors maintains diagnostic accuracy. METHODS: Prospective multi-centre cohort study. Patients with suspected renal colic were examined using computed tomography (CT) of the renal tract followed by intravenous urography (IVU) in four different centres with five different CT systems. RESULTS: Sixty-nine patients with suspected renal colic had CT of the renal tract followed by IVU. CT was performed with reduced exposure factors, giving a mean CT effective dose of 3.5 (range 2.8-4.5) mSv compared with 1.5 mSv for IVU. Ureteric calculi were detected in 43 patients: CT and IVU detected 40 (93%) ureteric calculi. CT identified other lesions causing symptoms in five patients and identified renal calculi in 24 patients. IVU identified renal calculi in six patients and made false positive diagnosis of renal calculi in seven patients. Mean examination time for CT was 5 minutes and for IVU was 80 minutes. CONCLUSION: CT examination at reduced exposure factors maintains the diagnostic accuracy recorded in other series.

Acute Disease↗
PubMed1999

Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations.

The hSNF5/INI1 gene which encodes a member of the SWI/SNF chromatin ATP-dependent remodeling complex, is a new tumor suppressor gene localized on chromosome 22q11.2 and recently shown to be mutated in malignant rhabdoid tumors. We have searched for hSNF5/INI1 mutations in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography. A total of 31 homozygous deletions and 36 point alterations were identified. Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and one editing mutations. Mutations were retrieved in most rhabdoid tumors, whatever their sites of occurrence, indicating the common pathogenetic origin of these tumors. Recurrent hSNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas. In contrast, hSNF5/INI1 point mutations were not detected in breast cancers, Wilms' tumors, gliomas, ependymomas, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.2 loci. These results suggest that rhabdoid tumors, choroid plexus carcinomas and a subset of medulloblastomas and cPNETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype.

Chromatography, High Pressure Liquid↗
PubMed1998

Hypoplastic dysplastic kidney with a vaginal ectopic ureter identified by technetium-99m-DMSA scintigraphy.

Ectopic insertion of a ureter draining a hypoplastic dysplastic kidney is a significant cause of urinary incontinence in girls. In this case, such a kidney was detected with 99mTc-DMSA scintigraphy but not by intravenous pyelography. Scintigraphy facilitated further delineation of the anatomy with CT prior to nephrectomy. Based on this case and a literature review, we suggest that 99mTc-DMSA scintigraphy be performed early when evaluating girls with urinary incontinence.

Child↗
PubMed1996

A pilot study of blood antioxidant and free radical marker profiles in patients awaiting coronary artery bypass grafting.

Coronary artery bypass grafting (CABG) carries a high risk of acute pancreatitis. We report a pilot study to investigate whether pre-existing oxidative stress might underlie this susceptibility, in that a burst of free radical activity not only accompanies the reperfusion stage of CABG but seems to be a pivotal step in the pathogenesis of pancreatitis. Samples of peripheral venous blood were obtained on the morning of surgery from 8 consecutive patients (age, median and range, 62, 35-70 years) with > 75% stenosis in at least three coronary vessels and a further 8 (64, 49-70 years) who had received 1200 mg allopurinol in divided doses in the previous 48 h: the results were compared with profiles of 8 healthy controls (56, 50-60 years) with normal exercise ECG. None of the patients or controls currently smoked cigarettes and the majority drank alcohol on a social basis. Compared with controls, untreated patients had lower levels of glutathione (P < 0.001) and ascorbate (P < 0.05) in plasma, alpha-tocopherol (vitamin E as molar ratio of cholesterol, P < 0.025 and beta-carotene (P < 0.05) in serum. There was no difference in serum selenium levels, but values in patients and controls were lower than in younger controls from this area (P < 0.02). Samples from the patients contained higher concentrations of lipid peroxides than control samples (P < 0.25) but there was no evidence of excessive isomerisation of linoleic acid or oxidation of ascorbate and erythrocytes showed normal ATP and energy charge with no increase in membrane lipid peroxidisability. Treatment with allopurinol did not alter this pattern, such that the ratio of oxidised to total glutathione in plasma was higher among the 16 patients than 8 controls (P < 0.025). Habitually inadequate intakes are the best explanation for the patients' deficits in aqueous phase antioxidants; prescribed low cholesterol diets would exacerbate any prior insufficiency of lipid-phase antioxidants. Correction of these deficits during the months leading up to surgery should reduce the risk of CABG-induced acute pancreatitis.

Adult↗
PubMed1996

Dietary intake of micronutrient antioxidants in relation to blood levels in patients with systemic sclerosis.

OBJECTIVE: To document habitual intakes of micronutrient antioxidants in patients with systemic sclerosis (SSc) in light of studies reporting subnormal levels of ascorbate and selenium in this patient group. METHODS: Dietary intakes of vitamin C, selenium, alpha-tocopherol, beta-carotene, and sulfur amino acid precursors of glutathione were assessed using the 7 day weighed record in 12 patients with SSc and in 12 healthy control subjects. The intakes of the first 4 substances were examined in relation to plasma/serum levels, while intakes of sulfur amino acids were examined in relation to urinary inorganic sulfate. RESULTS: Antioxidant and sulfur amino acid intakes were similar in patients and controls, although the patients had lower levels of selenium (median 74 compared to 87 milligrams in controls; p = 0.014) and of vitamin C in plasma (median 6.0 compared to 11.1 milligrams/l in controls; p = 0.08). Inorganic sulfate concentration in urine was similar in patients and controls. CONCLUSION: Our results suggest that reduced blood levels of the water soluble antioxidants selenium and ascorbic acid in patients with SSc are not due to dietary deficiency. Other explanations must therefore be sought.

Adult↗
PubMed1995

Micronutrient antioxidant status in black South Africans with chronic pancreatitis: opportunity for prophylaxis.

Biochemical assessments of micronutrient antioxidant status were done in 14 consecutive black patients with calcific chronic pancreatitis and 15 controls at Soweto, near Johannesburg in southern Africa. The patients showed subnormal levels of vitamin C in plasma; selenium, beta-carotene and alpha-tocopherol in serum; and inorganic sulphate (as an index of long-term sulphur amino acid intake) in urine (P < 0.001 for each): furthermore, among the patients ascorbate constituted a lower fraction of vitamin C (P < 0.002), indicating heightened oxidation of the bioactive form. By comparing the results in Sowetan controls with reference ranges from Manchester, UK, the markedly lower vitamin C and, hence, ascorbate levels in the Sowetans was underlined (P < 0.001) and their selenium levels were also lower (P < 0.001), but beta-carotene, alpha-tocopherol and inorganic sulphate levels were comparable. The very low bioavailability of ascorbate among Sowetan controls is reminiscent of our previous finding in outwardly healthy people at Madras in southern India: in both these areas chronic pancreatitis is currently endemic, has a propensity to pancreatic calculi and runs a virulent course towards premature death from diabetes, malnutrition or pancreatic cancer. Considering that low ascorbate levels are a feature in patients with chronic pancreatitis who develop pancreatic calculi at Manchester and that antioxidant supplements ameliorate painful symptoms, we suggest that poor antioxidant intake may predispose underprivileged tropical communities to the disease. If so, there could be an opportunity for prophylaxis through a daily tablet containing vitamin C, perhaps along with selenium at Soweto and beta-carotene at Madras.

Adult↗
PubMed1995

Evidence of toxic metabolite stress in black South Africans with chronic pancreatitis.

We report the results of a further study to test our hypothesis that toxic metabolite stress is germane to heightened free radical activity and hence to the genesis of chronic pancreatitis. Consecutive black South African patients with clinically quiescent chronic pancreatitis were studied, provided that the diagnosis had been made within the previous 2 years and that they did not have overt liver disease. All of them had been advised to stop drinking alcohol. Analysis of an early morning sample of urine showed a lower ratio of inorganic to ester sulphate (P < 0.001) and a higher ratio of D-glucaric acid to creatinine (P < 0.02) in the group of 14 patients than in 15 local controls, while plasma analysis showed a lower concentration of glutathione (GSH) in the patients (P < 0.001). This evidence of increased utilisation of phase II conjugative pathways of xenobiotic disposal was in keeping with on-going toxic metabolite stress from heightened phase I oxidative metabolism in the group of patients. Parallel studies of theophylline pharmacokinetics showed heightened drug clearance compatible with induced cytochrome P-4501A2 in two patients, whereas increased activity of gamma-glutamyl transferase in serum suggested persisting induction of P-4502E1, as by ethanol, in several others. The contemporaneous increases in free radical activity and utilisation of xenobiotic disposal pathways in Sowetan Africans with chronic pancreatitis is in line with the toxic metabolite concept of disease pathogenesis.

Adolescent↗
PubMed1995

Evidence for early oxidative stress in acute pancreatitis. Clues for correction.

Pancreatic oxidative stress with depletion of pancreatic glutathione is an early feature in all tested models of acute pancreatitis, and sooner or later the problem extends to the lung, irrespective of disease severity, whether toward spontaneous recovery or death from multisystem organ failure. We, therefore, sought evidence of oxidative stress in the human disease by analyzing admission blood samples. We found it from high concentrations of oxidatively altered linoleic acid in serum and vitamin C in plasma (p < 0.001 vs controls or a group of other acute abdominal crises where the proportion of patients with admission Apache II scores < or > 8 was similar). These changes were accompanied by subnormal levels of ascorbic acid in plasma (p < 0.001); selenium (p < 0.001), beta-carotene (p < 0.001), and alpha-tocopherol in serum (p = 0.005 for its molar ratio to cholesterol). Paradoxically, the plasma concentration of S-adenosylmethionine was elevated (p = 0.02), suggesting that this proximate bioactive metabolite of the essential amino acid had backtracked because its intracellular metabolism down the methionine trans-sulfuration pathway toward glutathione synthesis was disrupted. The aberrations transcended putative etiological factor, duration of symptoms, or disease severity. We conclude: (1) that oxidative stress has pervaded the vascular compartment by the time of admission in patients with acute pancreatitis, and, (2) that blood micronutrient antioxidant profiles at this stage are consistent not only with compromised intracellular capacity to synthesize/refurbish glutathione, but also vulnerability of intra- and extracellular lipid targets.

Acetylcysteine↗
PubMed1995

Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas.

Patients with the nevoid basal cell carcinoma syndrome (NBCCS) are at increased risk for medulloblastomas as well as for basal cell carcinomas. The gene for NBCCS has been mapped to chromosome 9q22.3-q31 by linkage analysis, and loss of heterozygosity (LOH) in this region has been demonstrated in approximately one-half of sporadic basal cell carcinomas. In the present study, LOH for chromosome 9q22.3-q31 microsatellite markers was investigated in medulloblastomas occurring among children with NBCCS and in sporadic medulloblastomas. Histologically, all 3 NBCCS medulloblastomas were noted to have a desmoplastic phenotype, and LOH was detected in both of the 2 cases for which microsatellite markers were heterozygous in normal tissues. LOH was also detected in a subset of sporadic medulloblastomas, each of which were found to display the desmoplastic phenotype. In all, 3 of the 6 sporadic desmoplastic tumors showed LOH, whereas LOH was not seen in any of the 11 sporadic, non-desmoplastic medulloblastomas studied. Additionally, desmoplastic tumors lacking detectable LOH each showed histological features of so-called cerebellar neuroblastoma, a subgroup of desmoplastic medulloblastoma with extensive neuroblastomatous differentiation. The data are consistent with a role for inactivation of a tumor suppressor gene at chromosome 9q in the development of medulloblastomas in patients with NBCCS and of sporadic medulloblastomas characterized by a desmoplastic phenotype similar to that found in patients with NBCCS. Restriction of chromosome 9q loss to non-neuroblastomatous desmoplastic tumors suggests that this variant of medulloblastoma maybe pathogenetically distinct from tumors having other histological phenotypes.

Adolescent↗
PubMed1994

Identification of the neurotrophin receptors p75 and trk in a series of Wilms' tumors.

The molecular mechanisms underlying the pathogenesis of Wilms' tumor (WT) are poorly understood, although a variety of growth factors including platelet-derived growth factor and insulin-like growth factor are expressed and are thought to contribute to tumor development. In earlier studies, WT cells in culture were found to express the low affinity nerve growth factor receptor, p75. These WT cells were capable of responding to the neurotrophin (NT) NGF, suggesting that NT may be involved in WT pathogenesis. We have examined a group of WT immunohistochemically with antibodies recognizing known trk receptor proteins, the p75 receptor, and the NTs, NGF and NT-3. Confirmatory immunoprecipitation and Western blots were then performed on representative WT samples from the study group. The p75 receptor was found predominantly in the epithelial and blastemal components where high levels of NT were also identified. The trk A and B receptors were primarily within stromal components, whereas the trk C and C' receptors were present within epithelial structures. Western blot analyses confirmed the presence of the respective receptor proteins with variations correlating in some cases with histological type. The selective presence of NT receptors and growth factors in this series of WT implies autocrine/paracrine mechanisms for tumor development.

Blotting, Western↗
PubMed1994

Micronutrient antioxidant status in patients with primary Raynaud's phenomenon and systemic sclerosis.

OBJECTIVE: To investigate the possibility that micronutrient antioxidant status is an important factor in determining the severity of Raynaud's phenomenon (RP) and in differentiating between patients with primary Raynaud's phenomenon (PRP) and those in whom Raynaud's is secondary to systemic sclerosis (SSc). METHODS: Four micronutrient antioxidants (selenium, vitamin E, beta-carotene and ascorbic acid) and 2 "markers" of free radical associated activity were assayed in peripheral blood from 10 patients with PRP, 9 with limited cutaneous SSc (ISSc), 9 with diffuse SSc (dSSc) and 15 healthy control subjects. RESULTS: Plasma ascorbic acid was reduced in all 3 groups of patients: median level 10.6 mg/l in controls, 4.8 mg/l in PRP (p < 0.01), 2.5 mg/l in ISSc (p < 0.01) and 6.8 mg/l in dSSc (p < 0.05). A reduction in serum selenium was especially found in dSSc (median 75 micrograms/l compared to 100 micrograms/l in controls, p < 0.05). In keeping with these deficiencies, the serum concentration of 9, 11, linoleic acid was elevated in RP patients: median values for the molar ratio of the isomer to the parent fatty acid were 1.91% in controls, 3.70% in ISSc (p < 0.05) and 3.85% in dSSc (p < 0.01). Smoking patients showed lower levels of ascorbic acid and higher levels of the linoleic isomer than nonsmokers. CONCLUSION: Deficiencies of ascorbic acid and selenium may predispose towards irreversible tissue injury in RP patients and cigarette smoke may be an independent risk factor. Micronutrient antioxidant supplements may be of therapeutic value.

Aging↗
PubMed1993

Vitamin C status in patients with acute pancreatitis.

Vitamin C is a key antioxidant in human blood plasma and hence could influence the outcome of conditions such as acute pancreatitis in which oxidative stress apparently plays a pivotal role. The concentrations of vitamin C and its immediately bioavailable form, ascorbic acid, in fasting plasma samples from 30 healthy volunteers were compared with those in admission samples from 29 consecutive patients with acute pancreatitis and 27 patients with other acute abdominal crises. Median (range) levels of vitamin C and ascorbic acid, respectively, were 15 (6.3-19) and 12 (4.5-18) micrograms/ml in the control group, 2.8 (0.3-10) and < 0.5 (< 0.5-6.0) micrograms/ml in patients with acute pancreatitis, and 3.7 (0.6-15) and 2.3 (< 0.5-15) micrograms/ml in those with other acute abdominal problems. Admission plasma samples showed equally low vitamin C levels in both groups of patients (P < 0.001 versus controls), but those from patients with acute pancreatitis were further characterized by a disproportionate reduction in ascorbic acid, such that the concentration of ascorbic acid and its ratio to vitamin C were both significantly lower than in samples from patients with an acute abdomen (P < 0.005 and P < 0.001 respectively). It is concluded that the stress of an acute intra-abdominal crisis is accompanied by a non-specific decrease in the plasma level of vitamin C. In acute pancreatitis early and profound oxidative stress compounds this problem by denaturing the available vitamin. There may be a case for the judicious parenteral administration of ascorbic acid to patients with acute pancreatitis to boost plasma antioxidant defence.

Abdomen, Acute↗