bluuebunny/crossref_metadata_2025 huggingface dataset:
P2Y‐Receptors stimulating the proliferation of human mesangial cells through the MAPK42/44 pathway
Authors: Vonend Oliver , Grote Tobias , Oberhauser Vitus , von Kügelgen Ivar , Rump Lars Christian
Published: July 2003

Mesangial cell proliferation is observed in a number of kidney diseases. The sympathetic cotransmitter ATP is suspected to play a major role in proliferative processes. Therefore, the effects of exogenous ATP on human mesangial cells in culture were studied.

Fresh human kidney cortex was processed to obtain mesangial cells in culture. Effects of nucleotides on [3H]thymidine incorporation, the activation of mitogen‐activated protein kinase and the cell number were studied. The involved P2‐receptors were characterized pharmacologically. In addition, we searched for mRNA for P2Y‐ and P2X‐receptors by RT–PCR.

ATP (0.1–300 μM) and related nucleotides induced a significant increase in [3H]thymidine incorporation up to 220% of control. The adenine nucleotides ATP and ADP were about equally effective. Also ATP‐γ‐S, UTP, ADP‐β‐S and 2‐m‐thio‐ADP induced a weaker response. UDP and α‐β‐methylene‐ATP failed to induce an effect on [3H]thymidine uptake.

ATP (100μM) induced a fast activation of the MAPK42/44 pathway. The effects of ATP on MAPK42/44 activation and [3H]thymidine incorporation were reduced by the MAPK inhibitor PD 98059. Platelet‐derived growth factor (PDGF 5 ng ml−1) increased the cell number to more than 122% of control. ATP (10 μM) on top of PDGF amplified PDGF induced cell proliferation to 136% of control.

RT–PCR products for P2Y1,2,4,6,11,12‐ and P2X1,2,4,5,6,7‐receptor subtypes were detected in human mesangial cells.

ATP has mitogenic effects on human mesangial cells. DNA synthesis is increased by the activation of the MAPK42/44 pathway. ATP amplifies PDGF‐induced cell hyperplasia.

British Journal of Pharmacology (2003) 139, 1119–1126. doi:10.1038/sj.bjp.0705358
Nicotine and nicotinic receptor antagonists potentiate the antidepressant‐like effects of imipramine and citalopram
Authors: Popik Piotr , Kozela Ewa , Krawczyk Martyna
Published: July 2003

Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect.

In the tail‐suspension test (C57/Bl male mice), nicotine (0.8–1.2 mg kg−1 s.c. or i.p.) given 15–60 min before the measurement exerted no effect on immobility.

Given 30 min before the measurement, citalopram (2 mg kg−1) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg−1, 15 but not 40 min before the test) to citalopram‐treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg−1) did not affect immobility, but given in combination with 0.8 mg kg−1 of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg−1) also produced an enhancement in the anti‐immobility effect of imipramine (20 mg kg−1).

We further investigated if nAChR antagonists would influence the antidepressant‐like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1–2.5 mg kg−1) and dihydro‐β‐erythroidine (2 mg kg−1) potentiated the antidepressant‐like effect of imipramine (4–20 mg kg−1). Mecamylamine (2.5 mg kg−1) but not dihydro‐β‐erythroidine also increased the antidepressant‐like effect produced by 2 mg kg−1 of citalopram.

The interaction between nAChR antagonists and antidepressants appeared synergistic.

Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity.

The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail‐suspension test.

British Journal of Pharmacology (2003) 139, 1196–1202. doi:10.1038/sj.bjp.0705359
Anti‐inflammatory and analgesic effects of paeonol in carrageenan‐evoked thermal hyperalgesia
Authors: Chou Tz‐Chong
Published: July 2003

Paeonol was tested for its anti‐inflammatory and analgesic effects in a rat model of carrageenan‐evoked thermal hyperalgesia. The possible mechanisms involved in these effects were also investigated.

Pre‐ and post‐treatment with paeonol (30, 50 or 100 mg kg−1, i.p.) dose‐dependently inhibited the carrageenan‐evoked thermal hyperalgesia.

Treatment with paeonol dose‐dependently inhibited tumour necrosis factor‐α (TNF‐α) and interleukin‐lβ (IL‐1β) formation, but enhanced IL‐10 production in the rat paw exudates both at the early (1.5 h) and late phase (4 h) after carrageenan injection. However, inhibition of IL‐6 formation by paeonol was only observed at the late phase.

Paeonol dose‐dependently decreased the formation of prostaglandin E2 (PGE2) in rat paw exudates with a greater inhibition at the late phase. However, inhibition of nitrate generation was observed only during the late phase (at 4 h after carrageenan injection), accompanied by an attenuation of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) protein expression in paw tissue.

Elevated myeloperoxidase activity, an indicator of neutrophil infiltration, in carrageenan‐injected paws was also dose‐dependently reduced in paeonol‐treated rats.

Our results suggest that the mechanisms by which paeonol exerts its anti‐inflammatory and analgesic effects in this inflammatory model may be associated with decreased production of proinflammatory cytokines, NO and PGE2 and increased production of IL‐10, an anti‐inflammatory cytokine, in carrageenan‐injected rat paws. In addition, attenuation of the elevated iNOS and COX‐2 protein expression as well as neutrophil infiltration in carrageenan‐injected paws may also be involved in the beneficial effects of paeonol.

British Journal of Pharmacology (2003) 139, 1146–1152. doi:10.1038/sj.bjp.0705360
Reconstitution of gene expression from a regulatory‐protein‐deficient hepatitis B virus genome by cell‐permeable HBx protein
Authors: Hafner Angela , Brandenburg Boerries , Hildt Eberhard
Published: July 2003

Various functions are ascribed to the HBx regulatory protein of the hepatitis B virus (HBV). Due to the low expression level of HBx, it has been difficult to correlate spatial and temporal HBx expression levels with specific functions. Based on a novel cell‐permeable peptide, known as the translocation motif (TLM), cell‐permeable HBx fusion proteins were generated. The TLM–HBx fusion protein is rapidly internalized from the medium into almost all cells, whereas no significant internalization was seen with wild‐type HBx. The major fraction of internalized HBx protein moves from the cytoplasm to the nucleus. The cytosolic fraction, however, activates c‐RAF1/extracellular‐signal‐related kinase 2 signalling and causes activation of activator protein 1 (AP1) and nuclear factor‐κB. The TLM–HBx protein rescues HBV gene expression from an activator‐deficient HBV genome. These results indicate that cell‐permeable regulatory proteins provide a novel, efficient tool for a clearly defined, dose‐dependent analysis of regulatory protein function, without affecting the integrity of the cell, and can be used for the safe reconstitution of virus production from a regulatory‐protein‐deficient virus genome.
Differential effects of baclofen on lower oesophageal sphincter pressure and proximal gastric motility in humans
Authors: Lee K.‐J. , Vos R. , Janssens J. , Tack J.
Published: July 2003

Background: The γ‐aminobutyric acid receptor type B agonist, baclofen, inhibits transient lower oesophageal sphincter relaxations by influencing a vagal pathway. Although post‐prandial proximal gastric function, which is vagally mediated, is important in the occurrence of transient lower oesophageal sphincter relaxations, the effects of baclofen on post‐prandial proximal gastric motility in humans remains undetermined.

Aim: To determine the effects of baclofen on post‐prandial lower oesophageal sphincter function and proximal gastric motility in healthy subjects.

Methods: In 11 healthy volunteers, a barostat bag and an oesophageal manometric catheter with a sleeve were simultaneously positioned; 40 mg of oral baclofen or placebo was then given in a randomized, double‐blind manner. Subsequently, the intragastric bag volume, oesophageal and lower oesophageal sphincter pressure and oesophageal pH were recorded during the 90 min before and 120 min after a meal.

Results: During the post‐prandial period, unlike the fasting period, baclofen decreased the rate of transient lower oesophageal sphincter relaxations and increased the basal lower oesophageal sphincter pressure compared with placebo. However, the meal‐induced decrease in the tone and phasic contractility of the fundus was not affected by baclofen.

Conclusion: The γ‐aminobutyric acid receptor type B agonist, baclofen, has a potent effect on post‐prandial lower oesophageal sphincter motility without altering post‐prandial proximal gastric motility, suggesting differential effects of baclofen on different signals of gastrointestinal vagal afferents.
Current therapeutic options for gastric antral vascular ectasia
Authors: Sebastian S. , O'Morain C. A. , Buckley M. J. M.
Published: July 2003

Gastric antral vascular ectasia, or ‘watermelon stomach’, is a rare but important cause of gastrointestinal blood loss and anaemia, which has characteristic endoscopic and histological features. The pathogenesis of this condition remains unclear; however, many associated disorders have been documented. Various medical, surgical and endoscopic therapeutic modalities have been attempted with variable success. Leading contenders for the therapeutic modality of choice include hormonal therapy, endoscopic Nd:YAG laser and argon plasma coagulation. Randomized controlled trials to identify the ideal treatment method are lacking at present.
Studies of compliance with delayed‐release mesalazine therapy in patients with inflammatory bowel disease
Authors: Shale M. J. , Riley S. A.
Published: July 2003

Background: Non‐compliance with maintenance mesalazine therapy may be a risk factor for relapse in inflammatory bowel disease, but the prevalence and determinants of non‐compliance are unknown.

Aim: To study the prevalence and determinants of non‐compliance in patients with inflammatory bowel disease.

Methods: Out‐patients receiving delayed‐release mesalazine were studied. Compliance was determined by direct enquiry and by analysis of urine samples for 5‐aminosalicylic acid/N‐acetyl‐5‐aminosalicylic acid. Potential determinants of compliance were assessed.

Results: Ninety‐eight patients were studied. Forty‐two patients (43%) reported taking < 80% of their prescribed dose. Logistic regression revealed the independent predictors of non‐compliance to be three‐times daily dosing [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.8–8.4] and full‐time employment (OR, 2.7; 95% CI, 1.1–6.9). Urine from 12 patients (12%) contained no detectable 5‐aminosalicylic acid/N‐acetyl‐5‐aminosalicylic acid, and 18 patients (18%) had levels below those expected. Depression was the only independent predictor of complete non‐compliance (OR, 10.5; 95% CI, 1.8–79.0), and three‐times daily dosing was the only independent predictor of partial non‐compliance (OR, 3.7; 95% CI, 1.8–8.9). Self‐reporting correctly identified 66% of patients judged to be non‐compliant on urinary drug measurement.

Conclusions: Non‐compliance with maintenance mesalazine therapy is common in patients with inflammatory bowel disease. Three‐times daily dosing and full‐time employment are predictors of partial non‐compliance, whilst depression is associated with complete non‐compliance. Self‐reporting detects most non‐compliant patients.
High variation of tioguanine absorption in patients with chronic active Crohn's disease
Authors: Deibert P. , Dilger K. , Fischer C. , Hofmann U. , Nauck S. , Stoelben S. , Kreisel W.
Published: July 2003

Background : Tioguanine (thioguanine) has been suggested as a therapeutic alternative for patients with Crohn's disease resistant or intolerant to azathioprine or mercaptopurine. However, pharmacokinetic data on tioguanine in inflammatory bowel disease are missing.

Aim: To determine the disposition of three different 40 mg tablet preparations of tioguanine in patients with Crohn's disease.

Methods : Six patients with chronic active Crohn's disease were included in a randomized, cross‐over, single‐dose study. Pharmacokinetic analysis was based on plasma concentrations of tioguanine during 6 h after dosing. Tioguanine was measured by a validated high‐pressure liquid chromatographic method.

Results : The areas under the curve (AUC) varied 4–7‐fold between patients. In two patients, tioguanine was not detected in plasma following the intake of one of the three tablets; another patient did not absorb tioguanine in two of the three different preparations. No significant differences were found in the AUC and Cmax values between the three tablets. In all patients, there was a second peak in plasma concentration following a meal 3 h after drug administration.

Conclusions : The absorption of tioguanine is highly variable in patients with Crohn's disease, which may be responsible for treatment failure. Therapy with tioguanine may be improved by monitoring tioguanine nucleotides as a surrogate parameter of efficacy.
Does gall‐bladder ejection fraction on cholecystokinin cholescintigraphy predict outcome after cholecystectomy in suspected functional biliary pain?
Authors: Delgado‐Aros S. , Cremonini F. , Bredenoord A. J. , Camilleri M.
Published: July 2003

Background : Patients with suspected functional biliary pain often undergo cholecystectomy if a decreased gall‐bladder ejection fraction (GBEF < 35%) is demonstrated by cholecystokinin cholescintigraphy. However, the validity of GBEF in predicting which patients will have symptomatic relief following cholecystectomy is unclear.

Aim : To determine whether patients with suspected functional biliary pain with decreased GBEF have a better symptomatic outcome after cholecystectomy than those with normal GBEF.

Methods : Systematic review and meta‐analysis of the published literature through MEDLINE and EMBASE databases.

Results : We included nine studies with a total of 974 patients with suspected functional biliary pain; 362 patients underwent cholecystectomy. Most studies assessed outcome by direct patient interview. Mean ages across the studies ranged from 35 to 47 years; 78% of all patients were female. Mean duration of follow‐up after surgery ranged from 1 to 2.5 years. After cholecystectomy, 94% of the patients with reduced GBEF had a positive outcome compared to 85% among those with normal GBEF. The pooled Mantel–Haenszel odds ratio for positive outcome was 1.37 (95% confidence interval 0.56–3.34), P = 0.56.

Conclusion : These data do not support the use of GBEF to select patients with suspected functional biliary pain for cholecystectomy. Prospective randomized trials are required if this practice is to be evidence‐based.
Coeliac disease presenting with symptoms of irritable bowel syndrome
Authors: Shahbazkhani B. , Forootan M. , Merat S. , Akbari M. R. , Nasserimoghadam S. , Vahedi H. , Malekzadeh R.
Published: July 2003

Background : Coeliac disease may easily mimic symptoms which are parts of the criteria used for diagnosing irritable bowel syndrome.

Aim : To find the frequency of coeliac disease among patients diagnosed as irritable bowel syndrome.

Methods : During a period of one year, irritable bowel syndrome patients referred to a university clinic in Tehran were studied. For each patient, an asymptomatic sibling was enrolled as control. Serological tests for coeliac disease were performed in all patients and controls. If positive, duodenal biopsy was performed to confirm the diagnosis. Patients subsequently diagnosed as coeliac disease were placed on a gluten free diet and re‐evaluated after 6 months.

Results : One hundred and five cases of irritable bowel syndrome and 105 controls were enrolled. Coeliac disease was diagnosed in 12 of the irritable bowel syndrome patients and none of the controls. Eleven coeliac disease patients adhered to a gluten free diet. After 6 months, all 11 patients had significant improvement in symptoms and three were totally asymptomatic. Six allowed repeated endoscopy after 6 months of gluten free diet, of which five showed improvement in histological findings.

Conclusions : Coeliac disease is a common finding among patients labelled as irritable bowel syndrome. In this sub‐group, a gluten free diet may lead to a significant improvement in symptoms. Routine testing for coeliac disease may be indicated in all patients being evaluated for irritable bowel syndrome.
Preliminary evaluation of an injectable anal sphincter bulking agent (Durasphere) in the management of faecal incontinence
Authors: Davis K. , Kumar D. , Poloniecki J.
Published: July 2003

Background : It has been previously shown that ‘bulking’ of internal anal sphincter defects may provide an effective method to treat patients with faecal incontinence, but the benefit wears off with time.

Aim : To assess the efficacy of a larger molecule, bulking agent (Durasphere) over the short‐ and long‐term in patients with an internal anal sphincter defect refractory to conservative management.

Patients : Eighteen patients (nine male, nine female) with a mean age of 60 years were recruited. All patients had persistent faecal leakage/soiling.

Methods : Durasphere was injected in the submucosal plane to restore anal canal symmetry. All patients had anorectal physiology, endoanal ultrasound, continence grading, patient satisfaction and quality of life scores assessed at 1, 3, 6 and 12 months.

Results : The mean follow‐up is 28.5 months. Changes from baseline were not statistically significant up to 6 months. At 12 months there was significant improvement in the continence grading (P = 0.003), patient satisfaction (P = 0.053) and all quality of life subscales: lifestyle (P = 0.004), coping (P = 0.011), depression (P = 0.024) and embarrassment (P = 0.059). Anorectal physiological parameters apart from the maximum tolerable rectal volume at 12 months (P = 0.036) showed no significant improvement.

Conclusions : Anal sphincter bulking with Durasphere is safe and effective in the short term as well as the longer term. More importantly, there is no evidence of attenuation of effect over time.
The long‐term effect of Helicobacter pylori eradication therapy on symptoms in dyspeptic patients with fundic atrophic gastritis
Authors: Kamada T. , Haruma K. , Hata J. , Kusunoki H. , Sasaki A. , Ito M. , Tanaka S. , Yoshihara M.
Published: July 2003

Aim : To investigate whether curing Helicobacter pylori infection improves symptoms over the long‐term in Japanese patients with nonulcer dyspepsia and fundic atrophic gastritis.

Methods : Ninety H. pylori‐positive dyspeptic patients with fundic atrophic gastritis were enrolled in this study. We performed a randomized double‐blind placebo‐controlled trial comparing triple therapy (n = 45) with that of placebo alone (n = 45). Inflammation and mucosal atrophy were scored according to the Updated Sydney System. Symptoms were scored on a scale of 0 to 3 for six items. Fasting samples of gastric juice were taken before endoscopy, and gastric pH was determined. Serum gastrin and pepsinogen levels were measured, and body mass index was determined. These patients were followed up for 3 years, and all measures were evaluated both before and after therapy.

Results : Significant improvement in dyspeptic symptoms and gastritis scores, significant decrease in gastric pH, and significant increase in body mass index were found after 3 years eradication in nonulcer dyspepsia patients treated successfully for H. pylori infection. There were no significant changes in the placebo group.

Conclusion : Our study shows that eradicating of H. pylori results in significant long‐term reduction in symptoms of nonulcer dyspepsia with fundic atrophic gastritis.
Economic analysis of celecoxib versus diclofenac plus omeprazole for the treatment of arthritis in patients at risk of ulcer disease
Authors: Lee K. K. C. , You J. H. S. , Ho J. T. S. , Suen B. Y. , Yung M. Y. , Lau W. H. , Lee V. W. Y. , Sung J. Y. , Chan F. K. L.
Published: July 2003

Aim : To evaluate the economic impact of celecoxib therapy vs. diclofenac plus omeprazole therapy for the treatment of arthritis in Chinese patients with a high risk of bleeding, from the perspective of a public health organization in Hong Kong.

Methods : The medical records of 287 Chinese arthritic patients with a history of bleeding ulcers who had previously participated in a randomised study of celecoxib 200 mg twice daily and extended‐release diclofenac 75 mg twice daily plus 20 mg of omeprazole daily for 6 months were reviewed.

Results : Compared to the diclofenac plus omeprazole group, the average total direct cost per patient in the celecoxib group showed a significant reduction of 11%, from $HK 10 915 (range $HK 10 915–57 899) to $HK 9714 (range $HK 9714–89 770) (P < 0.0001) (1 $US = 7.8 $HK). The median direct medical cost for routine management in the celecoxib group was significantly lower (11%) than that for the diclofenac plus omeprazole group [$HK 10 915 (range 10 915–28 048) vs. $HK 9714 (range $HK 6946–26 179) (P < 0.0001)]. In patients who experienced recurrent bleeding, the celecoxib group showed a significantly higher median cost of management of recurrent bleeding than the diclofenac plus omeprazole group [$HK 8466 (range 572–29 851) vs. $HK 23 210 (range $HK 12 318–65 823)] (P = 0.036).

Conclusions : Celecoxib therapy appears to cost less compared with diclofenac plus omeprazole for treatment of arthritis in Chinese patients with a high risk of bleeding.
Antibiotic prophylaxis for percutaneous endoscopic gastrostomy — a prospective, randomised, double‐blind trial
Authors: Ahmad I. , Mouncher A. , Abdoolah A. , Stenson R. , Wright J. , Daniels A. , Tillett J. , Hawthorne A. B. , Thomas G.
Published: July 2003

Background : Peristomal infection can sometimes complicate percutaneous endoscopic gastrostomy (PEG) placement. Antibiotic prophylaxis has, in some studies, been shown to reduce the incidence. However, the use of prophylaxis varies widely, possibly because the design and findings of the studies have differed, making their relevance to clinical practice difficult to interpret.

Aim : To determine the efficacy of antibiotics, either prophylaxis or concurrent antibiotics at the time of the procedure, in reducing peristomal infection after PEG insertion in the context of a study designed to reflect current practice.

Methods : One hundred and forty‐one patients undergoing PEG placement were randomised to group one to receive either a single dose of 750 mg of intravenous cefuroxime (n = 50) or placebo (n = 51) 30 min before PEG insertion. Forty patients who, for various reasons, were already receiving antibiotics were allocated to group two. The peristomal site was evaluated on day 3, 5 and 7 following insertion. Erythema and exudate were scored on a scale from 0 to 4; induration was scored on a scale of 0–3. A maximum combined score of 8 or higher or the presence of pus was criteria for infection. The primary outcome measure was the occurrence of a peristomal wound infection at any time within one week of PEG insertion.

Results : Peristomal wound infection was significantly reduced in patients who received antibiotics either as a single dose of cefuroxime [one of 33 (3%)], or in those on antibiotics for prior indications [one of 36 (3%)], compared with placebo [six of 33 (18%)], P = 0.04 and 0.03, respectively.

Conclusion : Antibiotics, either prophylaxis or concurrent, reduce the incidence of peristomal wound infection after PEG placement.
What is the long‐term outcome of the different subgroups of functional dyspepsia?
Authors: Heikkinen M. , Färkkilä M.
Published: July 2003

Background : Functional dyspepsia is often a long‐lasting disorder that accounts for substantial healthcare costs. It has been classified into subgroups assuming that it can guide management of dyspepsia.

Aim : To evaluate the clinical significance of subgrouping functional dyspepsia in a long‐term perspective study.

Methods : Consecutive patients with dyspepsia identified by general practitioners were investigated. Those patients with functional dyspepsia (n = 201) were enrolled in this study. Initially, patients were divided into five subgroups (ulcer‐like, dysmotility‐like, reflux‐like, unspecified, and irritable bowel syndrome‐like). Patients' medical histories were reviewed after 6–7 years, and the number and outcome of repeated investigations were analysed. At the end of follow‐up, patients filled in a questionnaire similar to that at baseline, and were invited for gastroscopy.

Results : Only 2% of patients developed peptic ulcer during follow‐up, none of them were in the ulcer‐like subgroup. When referrals to hospital and examinations during follow‐up were registered, no statistically significant differences existed between subgroups. Patients with reflux‐like dyspepsia made fewer revisits than others (P = 0.02), but had used antidyspepsia drugs during the previous year more often (P = 0.036). Stability of the subgroups over time was poor.

Conclusions : Functional dyspepsia is a long‐lasting disorder with a very good prognosis. Subgroups of functional dyspepsia play only a minor role in prediction of the long‐term outcome, and their usefulness in clinical practice is also hampered by subgroup instability over time.
Infliximab for refractory ulcerative colitis or indeterminate colitis: an open‐label multicentre study
Authors: Gornet J.‐M. , Couve S. , Hassani Z. , Delchier J.‐C. , Marteau P. , Cosnes J. , Bouhnik Y. , Dupas J.‐L. , Modigliani R. , Taillard F. , Lemann M.
Published: July 2003

Background : The efficacy of infliximab in ulcerative colitis (UC) and indeterminate colitis has been poorly assessed and preliminary results are conflicting.

Methods : The records of 30 patients treated with infliximab for ulcerative colitis (n = 19) or indeterminate colitis (n = 11) were reviewed. Infliximab was given because of steroid resistance (n = 18), dependence (n = 5) or intolerance (n = 7); five patients had failed on cyclosporin; 19 patients had a severe flare‐up.

Results : Median duration of follow‐up was 10 months. In 28 patients with active disease, the response rate was 75% at day 7, with 43% having a complete remission, and 50% at month 1, with 32% having a complete remission. Among the 22 responders, the probability of relapse was 73% at month 6. The probability of complete remission without steroids, taking into account the re‐treatment for relapse (n = 11), was 57% (95% confidence interval (CI): 45% to 69%) at month 6. The probability of colectomy was 33% (95% CI: 23% to 43%) at month 12. In indeterminate colitis, response rate was only 50% at day 7 and 30% at month 1. Concomitant use of antimetabolite agents was associated with better results.

Conclusions : Infliximab was able to induce a rapid response in some patients with UC or indeterminate colitis refractory to conventional treatment. Long‐term results were less favourable, with frequent relapses, and about one‐third of the patients required a colectomy.
Consent for anaesthesia
Authors: White S. M. , Baldwin T. J.
Published: July 2003

Summary Current professional guidelines concerning information and consent for anaesthesia are a fair representation of English law. However, they reject the need for specific, written consent for anaesthesia, a position which is in accordance with other Western jurisdictions. This is understandable, as there would be a number of problems inherent in such an approach: the consent process would be unnecessarily labour and time intensive, the generic nature of the information to be disclosed would not allow for operator‐dependent variables, and many of the disclosable risks continue to be of uncertain incidence. Moreover, written consent is not needed in order to defend cases of assault by anaesthetists. However, for the very reason that there are a large number of risks associated with anaesthesia (risks that are unknown to the majority of surgeons), together with the possibility of the courts moving towards a reasonable patient standard of information disclosure (as a result of the introduction of human rights legislation into English law), it is our view that the Association of Anaesthetists of Great Britain and Ireland should change their guidelines and advise anaesthetists to obtain separate, written affirmation from patients that certain risks and consequences of anaesthesia have been explained to them. In addition, a standardised consent form for anaesthesia may prove invaluable in retrospectively defending a claim of negligence founded around information disclosure, by recording exactly the risks and consequences of interventions discussed by the anaesthetist and the patient.
Food allergy to wheat: identification of immunogloglin E and immunoglobulin G‐binding proteins with sequential extracts and purified proteins from wheat flour
Authors: Battais F. , Pineau F. , Popineau Y. , Aparicio C. , Kanny G. , Guerin L. , Moneret‐Vautrin D. A. , Denery‐Papini S.
Published: July 2003

Background Cereal‐associated allergy is particularly considered a serious problem, because cereals are essential in our daily diet. Wheat proteins are classified into albumins, globulins and prolamins (insoluble gliadins and glutenins).

Objectives Our objectives were to study the involvement in food allergy to wheat of these different protein types by using purified fractions and to identify those binding IgE and IgG antibodies.

Methods Sera were obtained from 28 patients with food allergy to wheat. Albumins/globulins, gliadins and glutenins were obtained by sequential extraction based on differential solubility; α‐, β‐, γ‐ and ω‐gliadins and low molecular weight (LMW) and high molecular weight (HMW) glutenin subunits were purified by chromatography. IgE binding to these extracts and fractions were analysed by radioallergosorbent test (RAST), and immunoblotting; IgG binding was detected by enzyme‐linked immunosorbent assay (ELISA).

Results In RAST, 60% of sera were shown to have specific IgE antibodies against α‐, β‐gliadins and LMW glutenin subunits, 55% to γ‐gliadins, 48% to ω‐gliadins and 26% to HMW glutenins. Immunoblotting analysis confirmed results obtained in RAST concerning LMW and HMW glutenin subunits and showed that 67% of patients have IgE antibodies to the albumin/globulin fraction.

Conclusion Results obtained in the different tests showed common features and in agreement with other studies indicated the presence of numerous allergens in food allergy to wheat; α‐, β‐, γ‐ and ω‐gliadins, LMW glutenin subunits and some water/salt‐soluble proteins appeared as major IgE binding allergens, whereas HMW glutenins were only minor allergens. The same type of antigenic profile against gliadins and glutenins was observed with IgG antibodies. Important sequence or structural homologies between the various gliadins and LMW glutenin subunits could certainly explain similarity of IgE binding to these proteins.
Lectins interact differentially with purified human eosinophils, cultured cord blood‐derived mast cells and the myeloid leukaemic cell line AML14.3D10: induction of interleukin‐4 secretion is conserved among granulocytes, but is not proportional to agglutination or lectin–glycoprotein interaction
Authors: Hoffmann H. J. , Dahl C. , Schiøtz P. O. , Berglund L. , Dahl R.
Published: July 2003

Background Atopy is closely associated with the cellular T helper type‐2 (Th2) phenotype, that is dominated by the pleiotrophic cytokine IL‐4. The cellular source of IL‐4 has yet to be determined, although basophils have been proposed. Eosinophils and mast cells are likely contenders investigated here, and the eosinophil‐like leukaemia line AML14.3D10 is compared to eosinophils as an in vitro culturable model for eosinophils. Lectins can cross‐link‐specific surface glycoproteins and are found in the ingested (processed foods) and inhaled (airborne pollen grains) human environment. Therefore it is of interest to determine whether lectins can elicit the release of IL‐4 from Th2‐associated granulocytes other than basophils.

Method This study investigated the ability of eosinophils, AML14.3D10 and mast cells to secrete preformed IL‐4 in response to stimulation with lectins, and explored molecular mechanisms underlying the interaction.

Results Purified eosinophils and basophils, and cultured mast cells and AML14.3D10 cells were incubated with 1 µm lectin. Agglutination was scored by microscopy. IL‐4 secretion was measured by enayme‐linked immunosorbent assay. Biotinylated lectins were used to determine binding to cells by flow cytometry and in lectin blots of sodium dodecyl sulphate (SDS) gels.

Discussion Purified human eosinophils, AML14.3D10 cells and cultured mast cells secrete IL‐4 with a pattern similar to that found in basophils when stimulated with a panel of reactive and unreactive lectins. The lectin SNA induces IL‐4 secretion from mast cells and basophils, but not from eosinophils or AML14.3D10. Eosinophils appear to secrete only pre‐formed IL‐4, whereas mast cells may synthesize IL‐4 on ligation with the lectin LCA. Lectins that agglutinate the granulocytes investigated do not necessarily induce secretion of IL‐4. Lectins that elicit secretion of IL‐4 bind more to eosinophils than unreactive lectins as determined by flow cytometry and lectin blotting of SDS gels.

Conclusion As granulocytes with functions related to that of basophils, eosinophils, AML14.3D10 and cultured mast cells respond to stimulation with lectins similarly to basophils. This emphasizes the possibility that eosinophils and mast cells may be linked in their cellular heritage as the cellular partners, and lectins as ligands, may contribute to the maintenance of a Th2‐favoured microenvironment that is thought to underlie the allergic march.
Monitoring of seasonal variability in bronchial hyper‐responsiveness and sputum cell counts in non‐asthmatic subjects with rhinitis and effect of specific immunotherapy
Authors: Polosa R. , Li Gotti F. , Mangano G. , Mastruzzo C. , Pistorio M. P. , Crimi N.
Published: July 2003

Bronchial hyper‐responsiveness (BHR) is documented in a proportion of non‐asthmatic individuals with allergic rhinitis (NAAR) and reflects inflammatory events in the lower airways. Natural exposure to allergens is known to modulate BHR and the level of airway inflammation in asthma, but less consistently in NAAR. Specific immunotherapy (SIT) attenuates symptoms possibly by reducing BHR and airway inflammation. The influence of natural exposure to Parietaria pollen on BHR and sputum cell counts of NAAR was investigated and the effect of Parietaria SIT examined. Thirty NAAR, monosensitized to Parietaria judaica, participated in a randomized, double‐blind, placebo‐controlled, parallel group study of the effects of a Parietaria pollen vaccine on symptoms/medication score, BHR to inhaled methacholine and adenosine 5′‐monophosphate (AMP), and cell counts in the sputum collected out of and during the pollen seasons for 36 months. Seasonal variation in BHR to inhaled methacholine and AMP and changes in sputum cell counts were documented. Changes were consistent for AMP, but not methacholine, and invariably associated with modifications in sputum eosinophils and epithelial cells. The clinical efficacy of Parietaria SIT was associated with a decline in the seasonal deterioration of BHR to AMP, whereas no significant effect was observed on BHR to methacholine or sputum cell differentials. Between‐groups comparison of the seasonal changes in PC15 methacholine values and sputum cell differentials calculated as the AUC were not statistically significant, whereas a significant difference in PC15 AMP was demonstrated throughout the study (P=0.029), the median (inter‐quartile range) AUC values being 2478.5 (1153.3–3600.0) and 1545.5 (755.3–1797.9) for the SIT‐ and placebo‐treated group, respectively. Bronchial airways of NAAR exhibit features of active inflammation that deteriorate during natural allergen exposure, particularly with regard to BHR to AMP. The clinical efficacy of Parietaria SIT was exclusively associated with attenuation in seasonal worsening of PC15 AMP, suggesting that AMP may be useful in monitoring changes in allergic inflammation of the airways.
Proliferation and inflammation in bronchial epithelium after allergen in atopic asthmatics
Authors: Ricciardolo F. L. M. , Stefano A. Di , Krieken J. H. J. M. van , Sont J. K. , Schadewijk A. van , Rabe K. F. , Donner C. F. , Hiemstra P. S. , Sterk P. J. , Mauad T.
Published: July 2003

Background
The mechanisms that regulate epithelial integrity and repair in asthma are poorly understood. We hypothesized that allergen exposure could alter epithelial inflammation, damage and proliferation in atopic asthma.

Objective
We studied epithelial cell infiltration, shedding, expression of the proliferation marker Ki‐67 and the epithelial cell–cell adhesion molecules Ep‐CAM and E‐cadherin in bronchial biopsies of 10 atopic mild asthmatics 48 h after experimental diluent (D) and allergen (A) challenge in a cross‐over design.

Methods
Epithelial shedding, expressed as percentage of not intact epithelium, Ki‐67+, eosinophil/EG‐2+, CD4+ and CD8+ cells were quantified by image analysis in bronchial epithelium, and adhesion molecules were analysed semi‐quantitatively.

Results
Epithelial shedding was not altered by A (D: 88.1±3.1% vs. A: 89.2±3.7%; P=0.63). The numbers of Ki‐67+ epithelial (D: 10.2±0.2 vs. A: 19.9±0.3 cells/mm; P=0.03), EG‐2+ (D: 4.3±0.5 vs. A: 27±0.3 cells/mm; P=0.04) and CD4+ cells (D: 1.7±1.2 vs. A: 12.3±0.6 cells/mm; P=0.04) were significantly increased after A, whilst CD8+ numbers were not significantly changed (P>0.05). E‐cadherin and Ep‐CAM epithelial staining showed a similar intensity after D and A (P>0.05). We found a positive correlation between EG‐2+ and Ki‐67+ cells in the epithelium (Rs: 0.63; P=0.02).

Conclusion
Our study indicates that allergen challenge increases epithelial proliferation in conjunction with inflammation at 2 days after exposure. This favours the hypothesis that long‐lasting epithelial restitution is involved in the pathogenesis of asthma.
Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites
Authors: Mechiche H. , Naline E. , Candenas L. , Pinto F. M. , Birembault P. , Advenier C. , Devillier P.
Published: July 2003

Background  Evidence suggests that small airways contribute to clinically significant processes in asthma. Cysteinyl leukotrienes (CysLTs) are considered to be pivotal mediators in the pathogenesis of asthma. Montelukast (MK), a specific CysLT1 receptor antagonist, is metabolized in two main hydroxylated metabolites (termed M5 and M6, respectively).

Objectives  The aims of this study were to compare the responsiveness of small and large human bronchi to the three CysLTs, to evaluate the antagonist activity of MK, M5 and M6 in these preparations of human bronchi, and to characterize the CysLT receptors involved in the contractile response.

Methods and results  In isolated small bronchus (i.d. 0.5–2 mm), the potencies (−log molar EC50) of LTC4, LTD4 and LTE4 were 9.3 (n=11), 9.1 (n=30) and 8.4 (n=14), respectively. The three CysLTs were about 30‐fold more potent in small bronchi than in larger bronchi (i.d. 4–6 mm). In small bronchi, MK significantly shifted to the right the CysLT concentration–effect curves with pA2 values against LTC4, LTD4 and LTE4 of 9.1 (n=3), 9.0 (n=11) and 8.7 (n=5), respectively. The antagonist potencies of M6 and M5 were similar to MK and fivefold lower, respectively. A similar activity of MK against the three CysLTs suggested that CysLT1 receptors are involved in the contraction of human bronchus. Analysis by RT‐PCR also indicated that human bronchus mainly expressed CysLT1 receptors.

Conclusion  MK exerts a potent antagonist activity against the particularly potent constricting effects of CysLTs in isolated human small bronchi, which only expressed the CysLT1 receptor subtype. The metabolites of MK are also potent in vitro antagonists, but may not participate in the therapeutic activity of MK due to their low plasma concentrations in patients treated with the recommended dose of MK.
Eosinophils from patients with asthma express higher levels of the pan‐leucocyte receptor CD45 and the isoform CD45RO
Authors: Blaylock M. G. , Lipworth B. J. , Dempsey O. J. , Duncan C. J. A. , Lee D. K. C. , Lawrie A. , Douglas J. G. , Walsh G. M.
Published: July 2003

Background
Eosinophils and their secreted mediators are heavily implicated as effector cells in asthma and other allergic diseases. Comparisons were made between expression of CD45, CD45RA, CD45RB and CD45RO by eosinophils from asthmatic patients and non‐asthmatic atopic and non‐atopic, non‐asthmatic control subjects.

Methods
Twenty‐seven patients with asthma and 33 control subjects were recruited for the study. Eosinophil expression of CD45, CD45RA, CD45RB and CD45RO was established by immunostaining and flow cytometry was performed on whole leucocyte samples. Eosinophil apoptosis in response to CD45 and CD45 isoform monoclonal antibody (mAb)‐dependent receptor ligation was assessed by binding of annexin V and flow cytometry.

Results
Eosinophils from patients with asthma expressed significantly (P<0.05) higher levels of pan‐CD45 and CD45RO compared with eosinophils from non‐asthmatic, non‐atopic subjects. No significant correlations were found between expression of either pan‐CD45 or CD45RO and the degree of symptoms in the asthmatic patients as defined by lung function (FEV1 and FEF25–75) and methacholine PD20. Increased expression of pan‐CD45 or CD45RO did not appear to be a consequence of the atopic phenotype. Higher expression of pan‐CD45 or CD45RO by eosinophils from asthmatic patients was not associated with greater sensitivity to CD45 and CD45RO mAb receptor ligation‐induced eosinophil apoptosis.

Conclusion
Higher expression of CD45 and CD45RO by eosinophils from asthmatic patients appeared to be a consequence of asthma rather than atopy and further supports a role for activated eosinophils in asthma.
ELISpot: a new tool for the detection of nickel sensitization
Authors: Lindemann M. , Böhmer J. , Zabel M. , Grosse‐Wilde H.
Published: July 2003

Background
The standard assay for the clinical detection of contact allergy against nickel is the patch test. For research purposes, the in vitro lymphocyte transformation test (LTT) is mostly applied. However, the in vivo application of allergens includes the potential of sensitization, whereas the LTT demands 6 days of cell culture and radioactive labelling procedures.

Objective
The purpose of this study was to validate an enzyme‐linked immunospot (ELISpot) assay to specifically detect cellular response against nickel sulphate in correlation with patch test, anamnestic data, and LTT results.

Methods
In probands with positive (n=60) and negative patch test results (n=19), cytokine ELISpot and LTT were performed in parallel using various concentrations of nickel sulphate, various numbers of responding peripheral blood mononuclear cells (PBMC), and various durations of cell cultures.

Results
Concentrations of 50 and 75 μM nickel sulphate were found to be optimal to stimulate in the ELISpot 4×105 and in the LTT 2×105 PBMC, respectively. An increase in ELISpot sensitivity was reached by pre‐incubation with nickel sulphate for 24 h prior to transfer to ELISpot plates. In nickel‐sensitive probands, an average precursor cell frequency of 19×105, 1.7×105, and 0.7×105 could be defined for IFN‐γ, IL‐2, and IL‐4 producing PBMC, respectively. In non‐sensitive probands IFN‐γ producing cells were detectable, but with significantly lower frequency (2×105; P=0.004). The prior performance of patch tests had no significant effect on cytokine production or lymphocyte proliferation. Overall, the parameters patch test, anamnestic nickel allergy, ELISpot, and LTT results were positively correlated (P<0.05).

Conclusions
Based on these experiments, the quantitative in vitro detection of cell‐mediated reactions towards nickel as well as other heavy metal ions should be possible utilizing the above‐described ELISpot assay.
Adenoviral interleukin‐12 gene transduction into human bronchial epithelial cells: up‐regulation of pro‐inflammatory cytokines and its prevention by corticosteroids
Authors: Ogawa H. , Nishimura N. , Nishioka Y. , Azuma M. , Yanagawa H. , Sone S.
Published: July 2003

Background
One of the potential effects of IL‐12 is to restore Th1/Th2 balance. Therefore, we investigated the possibility of developing a system for local delivery of IL‐12 into the airways by examining protein expression in a human bronchial epithelial cell line (BEAS‐2B) after adenoviral IL‐12 gene transduction. The effects of dexamethasone on the gene‐modified cells were also examined.

Mehods
Adenoviral vectors AxCAegfp and Ax1CIhp40ip35 were used to transduce enhanced green fluorescence protein and IL‐12 genes, respectively, into BEAS‐2B cells. Wild‐type and IL‐12 gene‐transduced BEAS‐2B cells were then incubated with or without dexamethasone, and concentrations of IL‐12, IFN‐γ, IL‐6, IL‐8, granulocyte macrophage‐colony stimulating factor and chemokines (TARC and RANTES) in the supernatant were measured by ELISA. IL‐12 receptor expression was analysed by flow cytometry and RT‐PCR.

Results
The efficiency of transgene expression in BEAS‐2B cells at a multiplicity of infection of 30 was approximately 80%. Gene‐modified BEAS‐2B cells produced biologically active IL‐12, regardless of dexamethasone treatment. While IL‐12 gene transduction led to increased production of IL‐6 and IL‐8 by BEAS‐2B cells, expressions of these proteins were suppressed by dexamethasone. Addition of exogenous IL‐12 failed to augment BEAS‐2B cell IL‐6 and IL‐8 production, and IL‐12 receptor expression by BEAS‐2B cells was not detected.

Conclusions
Our findings suggest that adenoviral IL‐12 gene transduction may be effective in inducing IL‐12 expression in the airways, and could be a potential approach in the management of bronchial asthma.
No evidence for association between the −112G/A polymorphism of UGRP1 and childhood atopic asthma
Authors: Jian Z. , Nakayama J. , Noguchi E. , Shibasaki M. , Arinami T.
Published: July 2003

Background
Susceptibility to asthma is known to involve genetic factors. Genome‐wide screens have indicated that the chromosome 5q31–q34 region is linked to and/or associated with asthma. A new gene, named UGRP1 and reported by Niimi et al., encodes uteroglobin‐related protein and is expressed in the lung and trachea. Niimi et al. showed the −112G/A polymorphism of the UGRP1 gene to be associated with asthma in a case–control study.

Objective
The objective of the present study was to replicate this association and confirm the possible role of the UGRP1−112G/A polymorphism in the aetiology of childhood asthma in a Japanese population.

Methods and results
We conducted a transmission disequilibrium test (TDT) in 131 families identified through paediatric patients being treated for asthma. A case–control study was also carried out by comparing the probands and 137 unrelated non‐atopic non‐asthmatic Japanese children and 211 unrelated healthy Japanese adults. The −112G/A polymorphism was genotyped by the PCR‐RFLP method. The TDT revealed that the −112A allele was not preferentially transmitted to asthma‐affected children (P=0.85). Neither the presence of at least one A allele in an individual's genotype (sum of the G/A and A/A genotypes) nor the −112A allele was more prevalent among the asthma subjects than among the control subjects.

Conclusion
Our findings indicate that the UGRP1−112G/A polymorphism does not play a substantial role in genetic predisposition to childhood asthma in this Japanese population.