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Biomedical subjects

J M Braganza

Publications and source records attributed to J M Braganza.

At least 19 recordsLinked to original sources
PubMed2001

Towards a novel treatment strategy for acute pancreatitis. 1. Reappraisal of the evidence on aetiogenesis.

Despite more than a century of research endeavour, there is no specific medical treatment for acute pancreatitis and early mortality is high - 20% of fatalities by the day after admission. I do not see any realistic prospect that today's focus on immunomodulation will provide a breakthrough either. The signs are that the outcome of acute pancreatitis is determined almost at its inception, and that those unfortunate individuals in whom the seeds for a precipitous course are sewn do not declare themselves until it is too late. This reappraisal of the evidence on disease aetiogenesis has been undertaken in an effort to fathom why this might be.

Acute Disease↗
PubMed2001

Towards a novel treatment strategy for acute pancreatitis. 2. Principles and potential practice.

In part 1 it was argued that a 'free radical-mast cell' template for the aetiogenesis of acute pancreatitis accommodates the evidence, whereas the prevailing 'trypsin-cytokine' template does not. In this sequel I examine the ramifications of the new philosophy in relation to speedier diagnosis, prognostic aids and, above all, a programme of active treatment which - once validated in experimental studies - could be implemented by the first medical respondent.

Acute Disease↗
PubMed1998

Antibiotic accumulation and membrane trafficking in cystic fibrosis cells.

Cystic fibrosis (CF) results from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) which is a regulated chloride channel. The deltaF508 mutation prevents the post-translational glycosylation and membrane insertion of the protein. Severe disease follows, with the formation of a viscous mucus and subsequent chronic bacterial infection of the lungs, necessitating frequent, and often long, periods of antibiotic treatment. The pharmacokinetics of antibiotics in CF patients are abnormal, with lower blood serum levels and higher clearance rates which have never been satisfactorily explained. We found that accumulation of gentamicin in nasal polyp tissue non-CF cells was subject to regulation by the effectors and inhibitors of CFTR function; regulation was lost in deltaF508 CF cells and accumulation was more than doubled because of the inhibition of exocytosis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

A framework for the aetiogenesis of chronic pancreatitis.

The traditional ductal model for the development of chronic pancreatitis leaves many questions unanswered and it has not facilitated management. An alternate philosophy centres on the acinar cell as the site of mounting oxidant stress, usually as a result of steady exposure to xenobiotics that induce cytochrome P450 mono-oxygenases while depleting glutathione: ductal changes are regarded as secondary, disease-compounding manifestations of the oxidant environment. Within this framework each burst of oxidant stress jeopardises exocytosis, to trigger an attack of pancreatitis by interfering with the methionine-to-glutathione transsulphuration pathway, which interacts closely with ascorbate and selenium. The resulting diversion of free radical oxidation products into the pancreatic interstitium causes mast cells to degranulate, thereby provoking inflammation, the activation of nociceptive axon reflexes, and profibrotic interactions.

Chronic Disease↗
PubMed1997

A pilot study of antioxidant intake in patients with cholesterol gallstones.

Whereas macronutrient intake has been extensively investigated in an attempt to unravel the pathogenesis of human cholesterol gallstones, theoretical considerations and animal models suggest that deficits in micronutrient antioxidants may be more relevant. We report a pilot study of this aspect. The plan was to obtain 7-d weighed food inventories over a 6-mo period from equal numbers of patients who had not consciously changed their diets, patients who were on low-fat diets and age- and gender-matched controls. Food tables would be used to derive daily intakes of 16 known antioxidants, essential amino acids, and essential fatty acids. Under-reporting of food intake, a recognized drawback of this dietary method, would be sought retrospectively by reference to a key publication giving minimum cut-off limits for ratios of energy intakes to basal metabolic rates. There were 18 pairs for study. Analysis of data for the 9 pairs involving patients on their normal diets showed no differences in the intakes of energy macronutrients, and cholesterol, but the patients ingested lower amounts of 10 among 16 antioxidants (P < 0.05 for methionine, alpha-tocopherol, manganese, and vitamin D; 0.05 < P < 0.10 for cysteine, beta-carotene, vitamin C, selenium, zinc, and phosphorus). Both subsets of patients ingested lower amounts of linoleic acid (diet unchanged P = 0.009, changed P = 0.026) and several essential amino acids than did matched controls. Institution of a low-fat diet caused the expected fall in intakes of energy and saturated fatty acids such that the deficit in alpha-tocopherol was amplified, but substitution of fruit and vegetables by the patients resulted in a fortuitous increase in vitamin C, beta-carotene, and manganese intake. Retrospective analysis confirmed under-reporting of food intake by all four subsets of subjects but there was no significant difference in the mean ratio of energy intake to estimated basal metabolic rate in the subset of patients who had not consciously altered their diets and the subset of matched controls. Furthermore, the lower daily intake of alpha-tocopherol and linoleic acid by these patients persisted when results were expressed relative to total fat consumption. The results support the hypothesis that insufficiency of dietary antioxidants, particularly alpha-tocopherol, may be germane to human gallstone disease; they also suggest that low intakes of linoleic acid and essential amino acids may be relevant. Because of the small sample sizes, however, these deductions should be regarded as tentative, pending confirmation by biochemical analysis of blood and especially of hepatic bile.

Adult↗
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

Iron, ascorbate and copper status of Sowetan Blacks with calcific chronic pancreatitis.

Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low-molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.

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

A preliminary report on urinary BT-PABA/PAS excretion index, serum pancreatic isoamylase and faecal chymotrypsin tests of pancreatic dysfunction in Sowetan Africans.

The steady increase in chronic pancreatitis among black Africans at Soweto, RSA, in the past 40 years necessitates an objective and non-invasive test to detect the disease at an early stage. Given the biphasic nature of the disease--secretory hyperfunction with periodic active inflammatory episodes followed by steady exocrine impairment--we assessed three potential aids. Urinary BT-PABA/PAS excretion index (PEI), serum pancreatic isoamylase (PIA) and faecal chymotrypsin activity (FCA) were measured in the following groups: 16 outwardly healthy hospital workers, 16 consecutive patients with calcifying chronic pancreatitis and 19 with abdominal pain ascribed to other conditions (disease controls). (1) Healthy controls had lower PEI than those at Manchester, UK, or Madras, India, from subclinical acinar loss--as shown by lower PABA recovery whereas intestinal absorptive capacity was maintained, as shown by recovery of PAS. (2) Using the popular cut-off for PEI (0.75) only 9 of 14 patients with chronic pancreatitis were identified (sensitivity 64%, 2 tests unsatisfactory), while a value of less than 0.54, the mean -2 S.D. in local controls, yielded sensitivity of 50%. (3) If PEI of less than 0.75 or PIA outside the reference range was taken to indicate the disease, 5 of 9 disease controls would have been classed as chronic pancreatitis (among those with both tests satisfactory): retrospective ultrasound scans did not identify these. (4) Although FCA was less than the preselected cut-off, 5 units/g, in every patient with chronic pancreatitis (100% sensitivity) its poor predictive value was indicated by low specificity: subnormal levels in 4 of 14 and 6 of 16 healthy controls or disease controls, respectively, most of whom had near-normal values of PEI, PIA or both. (5) Collectively, these results suggest a high frequency of subclinical chronic pancreatitis at Soweto, but also that the combination of tests required to identify it may prove impractical--whether in field surveys or hospital practice.

4-Aminobenzoic Acid↗