scispace - formally typeset
Search or ask a question

Showing papers by "St Bartholomew's Hospital published in 1995"


Journal ArticleDOI
TL;DR: The constitutive cyclooxygenase-1 (COX-1) can thus be considered a “housekeeping” enzyme, in contrast to cyclo oxygenogenase-2 ( COX-2) which is activated by tissue damage.
Abstract: The discovery of a second cyclooxygenase has provided fresh impetus to the search for new anti-inflammatory drugs. The second enzyme is effectively absent from healthy tissues but its levels rise dramatically during inflammation. It can be induced in migratory cells by bacterial lipopolysaccharide, cytokines and growth factors. The constitutive cyclooxygenase-1 (COX-1) can thus be considered a "housekeeping" enzyme, in contrast to cyclooxygenase-2 (COX-2) which is activated by tissue damage. Both enzymes have a molecular weight of around 70 kDa and similar Km and Vmax values for their reaction with arachidonic acid. Several non steroid anti-inflammatory drugs which have more than 1,000 fold selectivity for COX-2 over COX-1 are in the early stages of drug development.

796 citations


Journal Article
TL;DR: Aerobic exercise causes a modest loss in weight without dieting and exercise provides some conservation of FFM during weight loss by dieting, probably in part by maintaining glycogen and water.
Abstract: Objective To determine if physical training conserves fat-free mass (FFM) in overweight men or women during weight loss. Design Journals published between 1966 and 1993 were searched by MEDLINE and by handsearch to obtain all reports on human subjects in which the effect of exercise on body composition was studied in at least two concurrent treatment groups, of which at least one group did, and one group did not, undergo an exercise programme designed to promote fat loss. The relation between loss of weight, and loss of FFM, was examined by linear regression analysis among exercising and non-exercising groups of men or women. Subjects Twenty-eight publications reported results on 226 sedentary men in 13 groups, 233 exercising men in 14 groups, 199 sedentary women in 23 groups, and 258 exercising women in 28 groups. Results Aerobic exercise without dietary restriction among men caused a weight loss of 3 kg in 30 weeks compared with sedentary controls, and 1.4 kg in 12 weeks among women, but there was little effect on FFM. Resistance exercise had little effect on weight loss, but increased FFM by about 2 kg in men and 1 kg in women. Regression analysis shows that for a weight loss of 10 kg by diet alone the expected loss of FFM is 2.9 kg in men and 2.2 kg in women. When similar weight loss is achieved by exercise combined with dietary restriction the expected loss of FFM is reduced to 1.7 kg in men, and women. It is probable that the FFM conserved by exercise during weight loss contains more water and potassium than average FFM. The subjects studied were not severely obese. Conclusions Aerobic exercise causes a modest loss in weight without dieting. Exercise provides some conservation of FFM during weight loss by dieting, probably in part by maintaining glycogen and water.

446 citations


Journal ArticleDOI
TL;DR: The paper describes and gives examples of four main types of definition which make up the taxonomy: global (type I); component (type II); focused (type III); and combination definitions (type IV).
Abstract: Quality of life is of central concern in evaluative research, improved quality of life is probably the most desirable outcome of all health care policies However, definitions of quality of life are as numerous and inconsistent as the methods of assessing it Stemming from a larger piece of work looking at the definition and measurement of quality of life, this paper highlights the lack of a consensus definition of quality of life by means of a taxonomy of definitions that emerge from the literature The paper describes and gives examples of four main types of definition which make up the taxonomy global (type I), component (type II), focused (type III), and combination definitions (type IV) In addition, an outline of factors influencing the definition of quality of life is given, and an alternative strategy for both defining and measuring the concept (the use of lay definitions) is suggested

430 citations


Journal ArticleDOI
TL;DR: In this paper, the authors reported plasma levels of a specific nonenzymatic peroxidation product of arachidonic acid, esterified 8-epi-PGF2α, from healthy and NIDDM individuals as an index of oxidative stress in vivo.

412 citations


Journal ArticleDOI
TL;DR: The results demonstrate that the two bacterial wall components, PepG and LTA, work together to cause systemic inflammation and multiple systems failure associated with Gram-positive organisms.
Abstract: Although the incidence of Gram-positive sepsis has risen strongly, it is unclear how Gram-positive organisms (without endotoxin) initiate septic shock. We investigated whether two cell wall components from Staphylococcus aureus, peptidoglycan (PepG) and lipoteichoic acid (LTA), can induce the inflammatory response and multiple organ dysfunction syndrome (MODS) associated with septic shock caused by Gram-positive organisms. In cultured macrophages, LTA (10 micrograms/ml), but not PepG (100 micrograms/ml), induces the release of nitric oxide measured as nitrite. PepG, however, caused a 4-fold increase in the production of nitrite elicited by LTA. Furthermore, PepG antibodies inhibited the release of nitrite elicited by killed S. aureus. Administration of both PepG (10 mg/kg; i.v.) and LTA (3 mg/kg; i.v.) in anesthetized rats resulted in the release of tumor necrosis factor alpha and interferon gamma and MODS, as indicated by a decrease in arterial oxygen pressure (lung) and an increase in plasma concentrations of bilirubin and alanine aminotransferase (liver), creatinine and urea (kidney), lipase (pancreas), and creatine kinase (heart or skeletal muscle). There was also the expression of inducible nitric oxide synthase in these organs, circulatory failure, and 50% mortality. These effects were not observed after administration of PepG or LTA alone. Even a high dose of LTA (10 mg/kg) causes only circulatory failure but no MODS. Thus, our results demonstrate that the two bacterial wall components, PepG and LTA, work together to cause systemic inflammation and multiple systems failure associated with Gram-positive organisms.

373 citations


Journal ArticleDOI
TL;DR: Whether endogenous NO regulates the activity and/or expression of COX in vivo is investigated by measuring NOS and COX activity in the lung and kidney, as well as release of prostanoids from the perfused lung of normal and LPS‐treated rats.
Abstract: 1. Lipopolysaccharide (LPS) co-induces nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) in J774.2 macrophages. Here we have used LPS-activated J774.2 macrophages to investigate the effects of exogenous or endogenous nitric oxide (NO) on COX-2 in both intact and broken cell preparations. NOS activity was assessed by measuring the accumulation of nitrite using the Griess reaction. COX-2 activity was assessed by measuring the formation of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by radioimmunoassay. Western blot analysis was used to determine the expression of COX-2 protein. We have also investigated whether endogenous NO regulates the activity and/or expression of COX in vivo by measuring NOS and COX activity in the lung and kidney, as well as release of prostanoids from the perfused lung of normal and LPS-treated rats. 2. Incubation of cultured murine macrophages (J774.2 cells) with LPS (1 microgram ml-1) for 24 h caused a time-dependent accumulation of nitrite and 6-keto-PGF1 alpha in the cell culture medium which was first significant after 6 h. The formation of both 6-keto-PGF1 alpha and nitrite elicited by LPS was inhibited by cycloheximide (1 microM) or dexamethasone (1 microM). Western blot analysis showed that J774.2 macrophages contained COX-2 protein after LPS administration, whereas untreated cells contained no COX-2. 3. The accumulation of 6-keto-PGF1 alpha in the medium of LPS-activated J774.2 macrophages was concentration-dependently inhibited by chronic (24 h) exposure to sodium nitroprusside (SNP; 1-1000 microM). Sodium nitroprusside (1-1000 microM) also acutely (30 min) inhibited COX-2 activity in broken cell preparations of LPS-activated (12 h) J774.2 macrophages, in a similar concentration dependent manner. Addition of adrenaline (5 mM) and glutathione (0.1 mM) increased the activity of COX-2 in broken cell preparations. In the presence of these co-factors, SNP inhibited prostanoid production only at the highest concentration used (1 mM). When J774.2 cells were incubated in the presence of LPS (1 microg ml-1) and NG-monomethyl-L-arginine (L-NMMA: 1 mM) for 12 h, SNP at the highest concentration used (1 mM) acutely (30 min) inhibited the activity of COX-2 in cell homogenates with co-factors. However, when J774.2 macrophages were incubated for 24 or 12 h with LPS (1 microg ml-1)and L-NMMA (1 mM), the addition of SNP (0.001-1I000 microM) increased in a concentration-dependent manner the accumulation of 6-keto-PGF1a in intact cells (measured at 24 h) and COX-2 activity in cell homogenates in the presence of co-factors (determined at 12 h). SNP (1 mM; together with LPS for 12 h)decreased the amount of COX-2 protein induced by LPS in J774.2 macrophages.4. Indomethacin (30 1AM) abolished the formation of 6-keto-PGFa by LPS-activated macrophages, but had no effect on the release of nitrite. Conversely, L-NMMA, at the highest concentrations used (1 and 10 mM), increased the release of 6-keto-PGFIa an effect which was reversed by excess L-arginine (3 mM)but not by D-arginine. Similarly, the decrease in nitrite formation caused by L-NMMA was partially reversed by L-arginine (3 mM), but not by D-arginine. L-NMMA (10 mM; together with LPS for 12 h)increased the amount of COX-2 protein induced by LPS in J774.2 macrophages.5. In separate experiments, J774.2 macrophages were activated with LPS (1 microg ml-1), and L-NMMA(10 mM) was added for various times (0.5-24 h) before the collection of mediun at 24 h. L-NMMAenhanced the release of 6-keto-PGFI,, in a time-dependent manner, with the maximal enhancement seen when the NOS inhibitor was incubated with the cells for 24 h. 6. In experiments on male Wistar rats, we investigated the effect of L-NMMA on the release of prostanoids (6-keto-PGF1a prostaglandin E2, thromboxane B2) elicited by arachidonic acid (AA,30nmol) from ex vivo perfused kidneys and lungs. The release from the organs from normal and LPS-treated rats was unaffected by L-NMMA intraperitoneally (30 mg kg-1) for 6 h together with LPS(5 mg kg-1) or LPS vehicle. Similarly, acute (5 min) in vitro exposure to L-NMMA (1 mM) of the perfused organs from control and LPS-treated animals did not change the release of prostanoids elicited by AA (30 nmol).7. These results show that LPS causes the induction of iNOS and COX-2 in J774.2 macrophages. The co-release of NO and PGI2 induced by LPS is dependent on protein synthesis and occurs after a lag-time of 6-12 h. The formation of COX metabolites has no effect on NOS activity whereas NO inhibits both COX-2 activity and induction. These results demonstrate that NOS and COX can be co-induced in vitro and that under these conditions large amounts of NO inhibit the degree of COX expression and activity.In the absence of endogenous NO, lesser amounts of exogenous NO increase the activity of COX-2. In those situations in vivo when the level of NO induction is relatively low, NO does not regulate the increased activity of COX.

347 citations


Journal ArticleDOI
TL;DR: Age and previous and continuing responsiveness of follicular lymphoma to therapy are the principal determinants of survival following recurrence, with improvement in survival with new treatments most readily in older patients, while more intensive approaches should be tested in younger patients in whom remission is achieved with difficulty.
Abstract: PURPOSETo examine outcome of treatment for patients with recurrent follicular lymphoma.PATIENTS AND METHODSTwo hundred twelve newly diagnosed follicular lymphoma patients were studied. One hundred seventy-nine were initially treated successfully. Recurrent or progressive lymphoma developed in 116. Treatment was given according to disease stage and current protocols, mostly with single alkylating agents. A policy of repeated lymph node and bone marrow biopsy was pursued.RESULTSThe overall median survival duration was 9 years, with a median follow-up duration of 12 years. Following recurrence, the median survival duration was 4 1/2 years. Only eight of 116 patients with recurrent disease died of causes unrelated to lymphoma. The overall response rate to first re-treatment was 78% and showed slight decline with successive recurrences, reaching 48% after the fourth treatment. The median duration of second remission was 13 months, (v 31 months for first remission), with the only significant predictive factor b...

333 citations


Journal ArticleDOI
TL;DR: Meta-analysis of the published results from 54 randomised controlled trials of adjuvant chemotherapy in head and neck cancer suggests that chemotherapy might increase absolute survival by 6.5% and the investigation of optimal agents and scheduling for synchronous radiotherapy and chemotherapy might still be important in clinical trials in head or neck cancer.
Abstract: Meta-analysis of the published results from 54 randomised controlled trials of adjuvant chemotherapy in head and neck cancer suggests that chemotherapy might increase absolute survival by 6.5% (95% confidence interval 3.1-9.9%). The odds ratio in favour of chemotherapy is 1.37 (95% confidence interval 1.24-1.5). Single-agent chemotherapy given synchronously with radiotherapy increased survival by 12.1% (95% confidence interval 5-19%). The benefit from neoadjuvant chemotherapy was less: a rate difference of 3.7% (95% confidence interval 0.9-6.5%). The results suggest that the investigation of optimal agents and scheduling for synchronous radiotherapy and chemotherapy might still be important in clinical trials in head and neck cancer.

330 citations


Journal ArticleDOI
TL;DR: Prostacyclin is the main product of arachidonic acid in all vascular tissues tested to date and strongly vasodilates all vascular beds studied, and is the most potent endogenous inhibitor of platelet aggregation yet discovered.
Abstract: Since the 1930s and the discovery by von Euler of a vasoactive, lipid-soluble substance that he erroneously assumed was generated by the prostate gland and therefore should be called "prostaglandin," the family of prostaglandins has grown to some 90 substances. These lipid mediators are derived from arachidonic acid in the "arachidonic acid cascade." In 1976, while looking for the enzyme that generates the unstable prostanoid thromboxane A2 from arachidonic acid, Moncada and Vane discovered prostaglandin I2 and renamed it "prostacyclin." Prostacyclin is the main product of arachidonic acid in all vascular tissues tested to date and strongly vasodilates all vascular beds studied. It is also the most potent endogenous inhibitor of platelet aggregation yet discovered, both inhibiting aggregation and dispersing existing aggregates. It acts through activation of adenylate cyclase, leading to increased levels of cyclic adenosine monophosphate. It also appears to have a "cytoprotective" activity, as yet not completely understood. Its effects are short-lasting, disappearing within 30 minutes of cessation of infusion. A stable, freeze-dried preparation of prostacyclin (epoprostenol) is available for administration to humans, and several analogs with therapeutically desirable characteristics are currently being clinically tested and should become commercially available soon. Clinical application of prostacyclin is bedeviled by 2 characteristics: it is pharmacologically unstable, so care must be taken in its use, and the correct dosage regimens have not yet been established.

293 citations


Journal ArticleDOI
TL;DR: The identification of a cDNA clone for the adrenomedullin receptor that was originally isolated as an orphan receptor from rat lung is reported, which encodes a polypeptide of 395 residues that contains seven transmembrane domains and has a general structural resemblance to other members of the G protein-linked receptor superfamily.

290 citations


Journal ArticleDOI
TL;DR: Isothioureas represent a new class of NOS inhibitors which includes the most potent inhibitors of iNOS activity reported to date.
Abstract: 1. The induction of a calcium-independent isoform of nitric oxide (NO) synthase (iNOS) and a subsequent enhanced formation of NO has been implicated in the pathophysiology of a variety of diseases including inflammation and circulatory shock. Here we demonstrate that the S-substituted isothioureas, S-methylisothiourea (SMT), S-(2-aminoethyl)isothiourea (aminoethyl-TU), S-ethylisothiourea (ethyl-TU) and S-isopropylisothiourea (isopropyl-TU) potently inhibit iNOS activity in J774.2 macrophages activated with bacterial endotoxin with EC50 values 8-24 times lower than that of NG-methyl-L-arginine (MeArg) and 200-times lower than that of NG-nitro-L-arginine (L-NO2Arg). 2. The inhibition of iNOS activity by these S-substituted isothioureas is dose-dependently prevented by excess of L-arginine suggesting that these isothioureas are competitive inhibitors of iNOS at the L-arginine binding site. 3. Ethyl-TU and isopropyl-TU are 4-6 times more potent than MeArg in inhibiting the constitutive NOS activity in homogenates of bovine aortic endothelial cells (eNOS) and are more potent pressor agents than MeArg in the anaesthetized rat. SMT is equipotent with MeArg, whereas aminoethyl-TU is 6-times less potent in inhibiting eNOS activity in vitro. Both SMT and aminoethyl-TU, however, elicit only weak pressor responses (approximately 15 mmHg at 10 mg kg-1, i.v.) in vivo. 4. A comparison of the potencies of ethyl-, iso-propyl-, n-propyl-, t-butyl- and n-butyl-isothioureas on iNOS activity shows that the inhibitory activity of S-substituted isothioureas declines sharply if the side chain exceeds 2 carbon atoms in length. Similarly, substitution of the ethylene side chain of ethyl-TU also results in a diminished potency. Substitution of either one or both nitrogens of SMT with either amino or alkyl groups also substantially reduces its NOS inhibitory potency.5. In conclusion, isothioureas represent a new class of NOS inhibitors which includes the most potent inhibitors of iNOS activity reported to date. Some members of this class (ethyl-TU and isopropyl-TU)are potent inhibitors of eNOS and iNOS with little selectivity towards either isoform, while others (SMT and aminoethyl-TU) are relatively selective inhibitors of iNOS activity. These latter agents may become useful tools for studying the role of iNOS in various disease models and may be useful in the therapy of diseases that are associated with an enhanced formation of NO due to iNOS induction, such as inflammation, circulatory shock or cancer.

Journal ArticleDOI
01 Mar 1995-Gut
TL;DR: There is an increase in IFN gamma secreting cells but not in IL 4 secrebing cells in H pylori positive and negative gastritis, and it is not known if this TH1 type reaction has a pathogenetic or protective role.
Abstract: Little is known of the function of the T cells in the inflammatory infiltrate in Helicobacter pylori associated gastritis. This study thus measured T cell in vivo activation by enumerating the frequency of interferon gamma (IFN gamma) and interleukin 4 (IL 4) secreting cells isolated from the gastric antral mucosa in patients with or without gastritis and in H pylori positive and negative gastritis. Fifty four samples were examined for cytokine secretion. Four antral biopsy specimens from each patient (n = 51) were taken during diagnostic endoscopy. One was used to estimate histological gastritis and the presence of H pylori, and three of the samples were used to isolate T cells by enzymatic digestion. IFN gamma and IL 4 secreting cells were enumerated by ELISPOT. Thirty four samples had gastritis and 79% of those were H pylori positive. None of the samples from non-inflamed mucosa had H pylori. The numbers of IFN gamma secreting cells per 10(5) T cells were higher in gastritis than in normal mucosa (145 v 20 IFN gamma spots, p < 0.01), and higher in H pylori negative than H pylori positive gastritis (371 v 110 IFN gamma spots, p < 0.05). The frequencies of IL 4 secreting cells did not differ between gastritis and non-inflamed mucosa. In conclusion, there is an increase in IFN gamma secreting cells but not in IL 4 secreting cells in H pylori positive and negative gastritis. It is not known if this TH1 type reaction has a pathogenetic or protective role.

Journal ArticleDOI
05 Aug 1995-BMJ
TL;DR: The results confirm the findings of an earlier report that when chiropractic or hospital therapists treat patients with low back pain as they would in day to day practice those treated by chiropractor derive more benefit and long term satisfaction than those treating by hospitals.
Abstract: Objective : To compare the effectiveness over three years of chiropractic and hospital outpatient management for low back pain. Design : Randomised allocation of patients to chiropractic or hospital outpatient management. Setting : Chiropractic clinics and hospital outpatient departments within reasonable travelling distance of each other in 11 centres. Subjects : 741 men and women aged 18-64 years with low back pain in whom manipulation was not contraindicated. Outcome measures : Change in total Oswestry questionnaire score and in score for pain and patient satisfaction with allocated treatment. Results : According to total Oswestry scores improvement in all patients at three years was about 29% more in those treated by chiropractors than in those treated by the hospitals. The beneficial effect of chiropractic on pain was particularly clear. Those treated by chiropractors had more further treatments for back pain after the completion of trial treatment. Among both those initially referred from chiropractors and from hospitals more rated chiropractic helpful at three years than hospital management. Conclusions : At three years the results confirm the findings of an earlier report that when chiropractic or hospital therapists treat patients with low back pain as they would in day to day practice those treated by chiropractic derive more benefit and long term satisfaction than those treated by hospitals.

Journal ArticleDOI
TL;DR: The sensitivity in the diagnosis of Cushing's syndrome of a single in-patient sleeping midnight cortisol to a standard 48‐hour in‐patient low‐dose dexamethasone suppression test (LDDST) during the same admission is compared.
Abstract: OBJECTIVE The diagnosis of Cushing's syndrome remains a major challenge in clinical endocrinology. Various screening tests are commonly used to support a biochemical diagnosis in the context of clinical suspicion. The aim of this study was to compare the sensitivity in the diagnosis of Cushing's syndrome of a single in-patient sleeping midnight cortisol to a standard 48-hour in-patient low-dose dexamethasone suppression test (LDDST) during the same admission. DESIGN A retrospective analysis was performed on 150 patients investigated in our department between the years 1970 and 1994 with a confirmed diagnosis of Cushing's syndrome. PATIENTS One hundred and fifty patients with a diagnosis of Cushing's syndrome were analysed : 110 with Cushing's disease ; 12 with tumours with ectopic ACTH secretion ; 8 with ACTH dependent Cushing's syndrome of so far undetermined origin ; 17 with cortisol secreting adrenal tumours ; 3 with adrenocortical nodular hyperplasia. Twenty normal volunteers and nine patients with non-endocrine conditions were also investigated as controls. MEASUREMENTS Plasma cortisol was measured by radioimmunoassay (RIA) in the 122 patients presenting after 1980, and by fluorimetry prior to this date. RESULTS In all the control subjects the sleeping midnight cortisol was < 50 nmol/l, below the lowest standard of the routine in-house RIA. In every patient with Cushing's syndrome the sleeping midnight cortisol was detectable with a value greater than 50 nmol/l, with a range of 70-2000 nmol/l. In contrast, in three cases, all of whom had proven Cushing's disease on histology, there was uncharacteristic complete suppression of plasma cortisol to < 50 nmol/l following the LDDST. CONCLUSION In this series of 150 cases, a single in-patient sleeping midnight cortisol above 50 nmol/l had a 100% sensitivity for the diagnosis of Cushing's syndrome, clearly different from normal subjects. In contrast, the low-dose dexamethasone suppression test had a sensitivity of 98% even when the drug was administered as an in-patient. We recommend that a low-dose dexamethasone suppression test should not be used alone for confirmation of Cushing's syndrome since it may miss 2% of cases.

Journal ArticleDOI
TL;DR: This study elucidates the beneficial and adverse effects of aminoethyl‐isothiourea (AE‐ITU), a relatively selective inhibitor of iNOS activity, and NG‐methyl‐l‐arginine (l‐NMMA), a non‐selective inhibitor of NOS activity on the MODS caused by endotoxaemia.
Abstract: 1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.

Journal ArticleDOI
TL;DR: The effects of aminoguanidine, a relatively selective inhibitor of the cytokine‐ inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin is investigated.
Abstract: 1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 +/- 4 mmHg (time 0, control) to 79 +/- 9 mmHg at 180 min (P 0.05). In contrast,aminoguanidine was a less potent inhibitor than L-NAME of the constitutive nitric oxide synthase in rat brain homogenates (n = 3-6, IC50 is 140 +/- 10 and 0.6 +/- 0.1 I1M, respectively, P<0.05). In addition, the inhibitory effect of aminoguanidine on iNOS activity showed a slower onset than that of L-NAME(maximal inhibition at 90 min and 30 min, respectively).5. Treatment of conscious Swiss albino (T/O) mice with a high dose of endotoxin (60 mg kg-1, i.p.)resulted in a survival rate of only 8% at 24 h (n = 12). However, therapeutic application of aminoguanidine (15 mg kg-1, i.p. at 2 h and 6 h after LPS) increased the 24 h survival rate to 75%(n = 8), whereas L-NAME (3 mg kg-1, i.p. at 2 h and 6 h after LPS) did not affect the survival rate(11%, n=9).6 Thus, aminoguanidine inhibits iNOS activity and attenuates the delayed circulatory failure caused by endotoxic shock in the rat and improves survival in a murine model of endotoxaemia. Aminoguanidine,or novel, more potent selective inhibitors of iNOS may be useful in the therapy of septic shock.

Journal ArticleDOI
TL;DR: Support is provided for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and some similarities in the genetic basis of essential hypertension in populations of different ethnicity are suggested.
Abstract: The renin-angiotensin system regulates blood pressure and sodium balance. The angiotensinogen gene which encodes the key substrate within this system has been linked to essential hypertension in White Europeans. It has been suggested that people of West African ancestry may have a different genetic basis for hypertension. In this study we have tested whether there is linkage of the angiotensinogen gene to essential hypertension in African Caribbeans from St. Vincent and the Grenadines. DNA from 63 affected sibling pairs with hypertension was tested for linkage by analyzing whether there was excess allele sharing among siblings genotyped using an angiotensinogen dinucleotide repeat sequence. There was significant support for linkage (T = 3.07, P = 0.001) and association of this locus to hypertension (chi 2 = 50.2, 12 degrees of freedom, P << 0.001). A DNA polymorphism which alters methionine to threonine at position 235 (M235T) within the angiotensinogen peptide has been associated previously with hypertension. However, we found no association of this variant with hypertension in this study. These findings provide support for linkage and association of the angiotensinogen locus to hypertension in African Caribbeans and suggest some similarities in the genetic basis of essential hypertension in populations of different ethnicity.

Journal Article
TL;DR: Erythromycin attenuated neutrophil chemotaxis and adhesion to human endothelial cells, mediated by incubation with conditioned medium obtained from HIE-exposed epithelial cell cultures, in vitro, and suggest that influenzae-induced release of inflammatory mediators from airway epithelial cells could contribute to chronic airway inflammation.
Abstract: Although several studies have demonstrated that low-dose, long-term erythromycin treatment is effective in the management of patients with chronic lower respiratory tract infections, such as chronic bronchitis, bronchiolitis and bronchiectasis, the mechanisms underlying the action of erythromycin are not clear. We have cultured human bronchial epithelial cells (HBEC) as explant cultures from surgical tissue, and have investigated the effect of erythromycin on H. influenzae endotoxin (HIE)-induced release of inflammatory mediators in these cultures. Confluent epithelial cell cultures were incubated with 100 micrograms.mL-1 HIE +/- 0.1-10 micrograms.mL-1 erythromycin and were investigated for interleukin-6 (IL-6), interleukin-8 (IL-8) and soluble intercellular adhesion molecule-1 (sICAM-1) released into the culture medium after 24 h. HIE significantly increased the release of IL-6 from 3.9 +/- 1.5 pg.micrograms-1 cellular protein (in control untreated cultures) to 12.1 +/- 1.5 pg.micrograms-1 cellular protein, and IL-8 from 83.7 +/- 8.2 pg.micrograms-1 cellular protein (in control cultures) to 225.7 +/- 44.8 pg.micrograms-1 cellular protein. Similarly, HIE led to a significantly greater release of sICAM-1 from 0.04 +/- 0.01 ng.microgram-1 cellular protein, in control cultures, to 3.8 +/- 0.9 ng.microgram-1 cellular protein. Incubation of the epithelial cultures in the presence of 0.1-10 micrograms.mL-1 erythromycin significantly blocked the HIE-induced release of IL-6, IL-8, and sICAM-1, at all concentrations of erythromycin investigated. Erythromycin also attenuated neutrophil chemotaxis and adhesion to human endothelial cells, mediated by incubation with conditioned medium obtained from HIE-exposed epithelial cell cultures, in vitro. These results suggest that H. influenzae-induced release of inflammatory mediators from airway epithelial cells could contribute to chronic airway inflammation, and that this effect may be modulated by treatment with erythromycin.

Journal ArticleDOI
TL;DR: The DD genotype is a linkage marker for an etiologic mutation at or near the ACE gene that may confer risk of CAD detectable in subjects previously unidentifiable with "classic" risk factors, however, this risk may be quantitatively small among the general male population.
Abstract: Background We analyzed an insertion/deletion (I/D) polymorphism of the angiotensin I–converting enzyme (ACE) gene in 1226 subjects from the Caerphilly Prospective Heart Disease Study. Amplification...

Journal ArticleDOI
TL;DR: This study emphasises the difficulties in treating mantle cell lymphoma and the high frequency and prognostic importance of histological transformation.

Journal ArticleDOI
15 Mar 1995-Blood
TL;DR: A novel class of conserved transcription factors has been identified from the molecular cloning of AF10, the gene involved in the t(10;11)(p12;q23) translocation of acute myeloid leukemias.

Journal ArticleDOI
TL;DR: The RDC-1 gene was expressed in COS-7 cells and showed a dose dependant increase of cAMP in response to CGRP and adrenomedullin but there was no cAMP response to amylin or [Cys(acm)2,7]a-hCGRP.

Journal ArticleDOI
TL;DR: It is suggested that none of the single antibody specificities are as sensitive as islet cell antibodies, but that a combination of GAD65 antibodies and antibodies to 37,000/40,000 Mr islet tryptic fragments has the potential to identify more than 90 % of future cases of IDDM.
Abstract: Identification of islet autoantigens offers the possibility that antibody tests other than islet cell antibodies may be used for assessing risk of insulin-dependent diabetes mellitus (IDDM). The aim of this study was to determine the combination of islet autoantibody markers that could identify most future cases of IDDM. Islet cell antibodies, antibodies to glutamic acid decarboxylase (GAD)65, 37,000/ 40,000 Mr islet tryptic fragments, carboxypeptidase-H, and islet cell autoantigen (ICA)69 were measured in sera from 100 newly-diagnosed IDDM patients, 27 individuals prior to onset of IDDM, and 83 control subjects. Islet cell antibodies were detected in 88 % of IDDM patients and 81 % with pre-IDDM, GAD65 antibodies in 70 % of IDDM patients and 89 % with pre-IDDM, and antibodies to 37,000/40,000 Mr islet tryptic fragments in 54 % of IDDM patients and in 48 % with pre-IDDM. The latter were found only in conjunction with islet cell antibodies and were more frequent in young onset cases. All 20 IDDM patients and the 3 pre-IDDM subjects who had islet cell antibodies without GAD65 antibodies had antibodies to 37,000/40,000 Mr islet tryptic fragments, and all but one had disease onset before age 15 years. No sera strongly immunoprecipitated in vitro translated ICA69 or carboxypeptidase-H; 4 % of patients had anti-ICA69 and 11 % anti-carboxypeptidase-H levels above those of the control subjects. The findings suggest that none of the single antibody specificities are as sensitive as islet cell antibodies, but that a combination of GAD65 antibodies and antibodies to 37,000/40,000 Mr islet tryptic fragments has the potential to identify more than 90 % of future cases of IDDM. Such a strategy could eventually replace islet cell antibodies in population screening for IDDM risk assessment.

Journal ArticleDOI
TL;DR: Squinavir was well tolerated in this group of previously untreated patients with few or no symptoms; this study shows that an HIV-proteinase inhibitor is active in HIV-infected patients.

Journal ArticleDOI
TL;DR: To determine if somatic mutations similar to those seen in the germline in MEN 2 or VHL disease play a role in the pathogenesis of sporadic or familial phaeochromocytomas, 48 sporadic tumours and tumours were analysed for mutations in RET exons 9, 10, 11, 13, 14, 15, and 16, and the entire coding sequence of VHL.
Abstract: Phaeochromocytomas may occur sporadically, or as part of the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2, von Hippel-Lindau disease (VHL), and, rarely, in type 1 neurofibromatosis. In MEN 2, germline missense mutations have been found in one of eight codons within exons 10, 11, 13, 14, and 16 of the RET proto-oncogene. In VHL, germline mutations within one of the three exons are responsible for the majority of cases. To determine if somatic mutations similar to those seen in the germline in MEN 2 or VHL disease play a role in the pathogenesis of sporadic or familial phaeochromocytomas, we analysed 48 sporadic tumours and tumours from 17 MEN 2 and five VHL patients for mutations in RET exons 9, 10, 11, 13, 14, 15, and 16, and the entire coding sequence of VHL. Five of 48 sporadic phaeochromocytomas had RET mutations within exons 10, 11, and 16. Of these, one was proven to be germline and two were proven to be somatic mutations. Four of 48 had VHL mutations; these included both the bilateral cases in the series (one was proven to be a germline mutation) and two others, of which one was proven somatic.

Journal Article
E C Huskisson1, H Berry, P Gishen, R W Jubb, John Whitehead 
TL;DR: Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid did not.
Abstract: Objective. To compare the rate of radiographic progression in knee osteoarthritis (OA) comparing indomethacin with placebo and tiaprofenic acid with placebo. Methods. Rate of radiographic progression of OA of the knees was studied in 812 patients in a randomized double blind parallel group study at 20 rheumatology clinics in the United Kingdom and analyzed sequentially. Patients received either indomethacin 25 mg three times daily, tiaprofenic acid 300 mg twice daily, or matched placebo. All had access to paracetamol as a rescue analgesic. Joint space narrowing was measured by a 6 point grading scale, using radiographs taken with a standardized technique at recruitment and annually thereafter. Results. Three hundred and seventy six patients completed at least one year of study medication and therefore contributed evaluable results. More than twice as many patients showed deterioration in the indomethacin group as in the placebo group ; of 170 available patients at the 3rd interim analysis, 40 of 85 receiving indomethacin had deteriorated compared to 19 of 85 receiving placebo, a statistically significant difference (p = 0.009). No statistically significant difference (p = 0.308) was found between tiaprofenic acid and placebo at the 7th interim analysis, the conclusion of the study. Conclusion. Indomethacin increased the rate of radiological deterioration ofjoint space in patients with OA of the knee ; tiaprofenic acid did not.

Journal ArticleDOI
TL;DR: Substrate availability appears to be a stronger influence on fasting IGF‐1 levels than does insulin, and the close correlation of IGFBP‐3 with liver function indicates a dominant regulatory role of the hepatocyte.

Journal ArticleDOI
TL;DR: The evidence that this motif binds zinc, is the important DNA-binding domain in this group of regulatory proteins, and may be involved in leukemogenesis is reviewed.
Abstract: We have identified and further characterized a Caenorhabditis elegans gene, CEZF, that encodes a protein with substantial homology to the zinc finger and leucine zipper motifs of the human gene products AF10, MLLT6, and BR140. The first part of the zinc finger region of CEZF has strong similarity to the corresponding regions of AF10 (66%) and MLLT6 (64%) at the cDNA level. As this region is structurally different from previously described zinc finger motifs, sequence homology searches were done. Twenty-five other proteins with a similar motif were identified. Because the functional domain of this motif is potentially disrupted in leukemia-associated chromosomal translocations, we propose the name of leukemia-associated protein (LAP) finger. On the basis of these comparisons, the LAP domain consensus sequence is Cys1-Xaa1-2-Cys2-Xaa9-21-Cys3-Xaa2-4 -Cys4-Xaa4-5-His5-Xaa2-Cys6-Xaa12-46 - Cys7-Xaa2-Cys8, where subscripted numbers represent the number of amino acid residues. We review the evidence that this motif binds zinc, is the important DNA-binding domain in this group of regulatory proteins, and may be involved in leukemogenesis.

Journal ArticleDOI
04 Nov 1995-BMJ
TL;DR: Two view mammography is medically more effective than one view; it detects more cancers and reduces recall rates; it is also similarly cost effective financially.
Abstract: Objective: To compare one view (oblique) and two view (oblique and craniocaudal) mammography in breast cancer screening. Design: Randomised controlled trial. Setting: Nine breast screening centres in England. Subjects: 40163 women aged 50-64 attending their first breast screening examination. Interventions: Women were randomised to have one view mammography, two view mammography, or two view mammography in which one view was read by one reader and both views were read by another. Main outcome measures: Prevalence of cancer detected, recall rates, cost per cancer detected, and marginal cost per extra cancer detected. Results: Two view mammography detected 24% more women with breast cancer (95% confidence interval 16% to 31%) than one view mammography. Prevalence of detected cancer was 6.84 with two view mammography and 5.52 per 1000 women with one view. The proportion of women recalled for assessment was 15% lower (95% confidence interval 6% to 23%) with two view (6.97%) than with one view (8.16%) mammography. The cost of two view screening was higher (pounds sterling26.46 compared with pounds sterling22.00 per examination) but the average cost per cancer detected was similar (pounds sterling5330 compared with pounds sterling5310) and the marginal cost per extra cancer detected with two views was similar to the average cost (pounds sterling5400). Conclusion: Two view mammography is medically more effective than one view; it detects more cancers and reduces recall rates; it is also similarly cost effective financially.

Journal ArticleDOI
TL;DR: An improved method for analysing F2-isoprostanes in biological fluids with main advantages in the improved recovery, gas chromatographic separation and speed compared to existing techniques is described.