bluuebunny/crossref_metadata_2025 huggingface dataset:
An evaluation of the interaction of meloxicam with frusemide in patients with compensated chronic cardiac failure
Authors: Müller F. O. , Middle M. V. , Schall R. , Terblanché J. , Hundt H. K. L. , Groenewoud G.
Published: October 2003

Aims To evaluate the interaction of meloxicam with frusemide in patients with compensated cardiac failure.

Methods Nineteen patients with Grade II or III compensated chronic cardiac failure completed this randomized, double‐blind, cross‐over study. The patients received 40 mg frusemide day−1 for 7 days. Thereafter, patients received either 15 mg meloxicam plus 40 mg frusemide day−1, or one placebo tablet plus 40 mg frusemide day−1 for 7 days. After a washout period of 7 days during which patients received 40 mg frusemide day−1 for 7 days, the patients were crossed over to the alternate treatment. The effect of concomitant ingestion of meloxicam and frusemide on frusemide‐induced diuresis, urine and serum electrolytes, urinary frusemide excretion, and plasma frusemide pharmacokinetics was also determined.

Results The estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ mean ratio of the variables Cmax, AUCss and Cmax/AUCss for plasma frusemide were 121% (101% to 145%), 106% (96.4% to 117%), and 114% (98.3% to 132%), respectively. Similarly, the estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ of the mean ratio of the variable cumulative urinary frusemide excretion after multiple doses of frusemide were 123% (101% to 150%) for the period 0–8 h, and 122% (105% to 142%) for the period 0–24 h after drug administration on day 7. The estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ mean ratio of the pharmacodynamic variables cumulative sodium excretion was 105% (95.2% to 116%) for the period 0–8 h and 108% (96.5% to 121%) for the period 0–24 h after drug administration on day 7.

Conclusions Meloxicam may lead to slightly increased maximum concentrations of frusemide in plasma, as well as to slightly increased urinary excretion of frusemide, without affecting the pharmacodynamics of frusemide. Thus there is no clinically significant pharmacokinetic or pharmacodynamic interaction of meloxicam with frusemide following repeated co‐administration of meloxicam and frusemide to patients with compensated chronic cardiac failure.
Decreased oral availability of cyclosporin A at second administration in humans
Authors: Lee Young‐Joo , Chung Suk‐Jae , Shim Chang‐Koo
Published: October 2003

Aims The objective of this study was to determine the extent of period effect on the pharmacokinetics of cyclosporin A (CsA) during consecutive dosing.

Methods Sandimmune Neoral® and Neoplanta® capsules were administered to twenty‐four healthy Korean male subjects at a single CsA dose of 175 mg in a 2×2 crossover investigation with a 2‐week wash‐out phase. Concentrations of CsA in blood were measured by a r.i.a. method for a period of 48 h.

Results The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there is a significant (P<0.01) period effect in AUC(0,last) (area under the blood concentration‐time curve above the assay limit) and Cmax (maximum blood concentration) between the administrations. A 6 and 9% decrease in the AUC(0,last) and Cmax, respectively was seen at the second administration.

Conclusions This period effect on the pharmacokinetics of CsA may be relevant for the patients who need consecutive administration of the drug.
Clinical trials and clinical practice: do doctors use the same criteria to judge outcome?
Authors: Mark Chaput de Saintonge D. , Evans S. J. W. , Crane G. J. , Kirwan J. R.
Published: October 2003

Aims The results of clinical trials often seem to have little influence on the practice of individual doctors. This could be because trial information is presented in the style of a scientific experiment which cannot often be clearly related to the context of everyday patient care. We tested the hypothesis that such framing effects would cause doctors to assess the clinical significance of treatment outcomes differently when presented as clinical trial results rather than as individual patient data.

Methods Fourteen rheumatologists independently reviewed the same 50 sets of data obtained from patients with rheumatoid arthritis. The data consisted of 10 commonly used clinical and laboratory variables measured before and after a period of treatment. The same data were presented in two formats on two separate occasions. The patient data format was a collection of typed sheets attributing each set of results to an individual patient. The clinical trial format was a professionally printed and bound booklet in which each set of results was laid out as summary results of a small uncontrolled clinical trial. Doctors judged the degree of improvement or deterioration and its clinical importance for each data set for both formats. These changes were converted into units of ‘Clinical Importance’.

Results Although some statistically significant differences emerged in the individual doctors’ judgements between the formats none of these was of a clinically important size. The median of the mean trial—patient difference between the formats for all 14 doctors was 0.035 units of clinical importance [ 95% CI −0.244 to 0.074].

Conclusions This evidence does not support the hypothesis that framing effects are a major cause of the failure of clinical trials to influence clinical practice.
Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients
Authors: Akhlaghi Fatemeh , McLachlan Andrew J. , Keogh Anne M. , Brown Kenneth F.
Published: October 2003

Aims To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients.

Methods Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate‐concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P‐PHARM software) the ratio of dose rate to trough concentration at steady state (DR/Csstrough ), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/Csstrough was calculated for each patient before and after simvastatin administration.

Results The mean fu increased by 29%, from 1.40±0.1% (mean±s.d.) to 1.82±0.22% after simvastatin administration (P<0.01). Mean trough concentrations of cyclosporine in whole blood were 349 μg l−1 before and 242 μg l−1 after simvastatin administration (P<0.0001). The mean cyclosporine daily dosage was 2.87 mg kg−1 and 2.33 mg kg−1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/Csstrough was significantly increased from 24.5 l h−1 before to 28.9 l h−1 after simvastatin administration (P<0.05). Furthermore the median increase in cyclosporine DR/Csstrough was 18 l h−1 (−3.1 to 42.1 l h−1, interquartile range).

Conclusions Cyclosporine fraction unbound and clearance are increased following co‐administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.
Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients
Authors: Simon Nicolas , Brunet Philippe , Roumenov Dimitri , Dussol Bertrand , Barre Jerome , Duche Jean‐Claude , Albengres Edith , D’Athis Philippe , Chauvet‐Monges Anne‐Marie , Berland Yvon , Tillement Jean‐Paul
Published: October 2003

Aims In renal allograft recipients, trimetazidine (Vastarel® ) was proposed to be associated with the classic immunosuppressant treatments because it displays anti‐ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun®, and trimetazidine.

Methods Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40 mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin‐2 and soluble interleukin‐2 receptor levels were measured.

Results The data showed that neither cyclosporin A blood pharmacokinetic parameters, Cmax, tmax, AUC, nor the concentrations of interleukin‐2 and soluble interleukin‐2 receptors were significantly modified.

Conclusions Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.
The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90)
Authors: Peck Richard W. , Seaber Emma J. , Dixon* Ruth , Gillotin† Catherine G. , Weatherley Barry C. , Layton** Gary , Posner‡ John
Published: October 2003

Aims Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan.

Methods A double‐blind, randomized, crossover study of the effects of pre‐treatment with propranolol 160 mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10 mg dose of zolmitriptan in 12 healthy volunteers.

Results Propranolol increased mean zolmitriptan Cmax and AUC by 56% and 37% respectively; mean t1/2 was prolonged from 3.1 to 4.0 h. Mean Cmax and AUC of the pharmacologically active N‐desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUCm/AUCp ) fell from 0.46 to 0.26. Mean Cmax and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUCm/AUCp from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11 mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response.

Conclusions The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.
Adult T‐cell leukaemia/lymphoma with multiple integrations of human T‐cell lymphotropic virus type I proviral DNA: differing clinical features are linked to varied proviral integration
Authors: Shimamoto Yoshinori , Miyahara Masaharu , Yamada Hiroko , Shibata Keisuke , Matsuzaki Miwako , Ono Kazutoshi
Published: October 2003

Multiple integrations of human T‐cell lymphotropic virus type I (HTLV‐I) proviral DNA are occasionally found in tumour cells from patients with adult T‐cell leukaemia/lymphoma (ATL). However, the clinical implications of multiple integrations of HTLV‐I in ATL have not been well established. We studied 95 patients with ATL to elucidate the relationship between the multiple integrations of HTLV‐I and the clinical characteristics. The proviral DNA of HTLV‐I was examined by standard Southern blot analysis using the probe of an entire HTLV‐I genome and the endonucleases with or without cleavage sites within the provirus. Multiple integrations of HTLV‐I were detected in eight patients as extraordinary multiple bands; five patients showed multiple bands of the same intensity, and the remaining three showed multiple bands of differing intensities. The patients were divided into two groups based on these band patterns. One group was considered to exhibit one tumour cell clone carrying multiple copies of the provirus, whereas the other was considered to exhibit multiple tumour cell clones, each carrying one copy of the provirus. The former group of patients manifested a highly aggressive clinical course with frequent peculiar organ infiltrations, including the retina, uvea and muscle, along with the presence of large peripheral leukaemic T cells having flower‐like nuclei. The latter group demonstrated an indolent clinical course with skin lesions or small leukaemic T cells having cleaved or lobulated nuclei. These findings suggest that the pattern of multiple HTLV‐I integrations into the tumour cell(s) has clinical implications in ATL. This may help to explain the heterogeneity of this disease.
Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies
Authors: Zhang Yanming , Poetsch Micaela , Weber‐Matthiesen Klaus , Rohde Kirsten , Winkemann Martin , Haferlach Torsten , Gassmann Winfried , Ludwig Wolf‐Dieter , Grote Werner , LÖffler Helmut , Schlegelberger Brigitte
Published: October 2003

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML), FAB M5a, one had pro‐B‐acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19–20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL‐1 gene on 11q23 confirmed that in each case the ALL‐1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topoisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. ALL with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL‐1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL‐1 rearrangement expressed CD34. Moreover, the pro‐B‐ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.
Spontaneous remission in a patient with therapy‐related myelodysplastic syndrome (t‐MDS) with monosomy 7
Authors: Renneboog B. , Hansen V. , Heimann P. , De Mulder A. , Janssen F. , Ferster A.
Published: October 2003

We describe a case of spontaneously reversible refractory anaemia, a subtype of myelodysplastic syndrome (MDS), with monosomy 7 secondary to chronic treatment with azathioprine (AZA) in a young renal transplant recipient. AZA was stopped after that conventional cytogenetics and fluorescence in situ hybridization (FISH) had demonstrated the existence of a monosomy 7 clone. 4 months later, haematological values had considerably improved and the karyotypic examination as well as the FISH analysis were normal. The spontaneous remission of this MDS with monosomy 7, which is usually associated with a particularly poor prognosis, could be due to the recovery of a better immunosurveillance following the withdrawal of AZA.
Measurement of health‐related quality of life in multiple myeloma
Authors: Wisløff Finn , Eika Sverre , Hippe Erik , Hjorth Martin , Holmberg Erik , Kaasa Stein , Palva Ilmari , Westin Jan
Published: October 2003

When a randomized trial (NMSG 4/90) comparing treatment with melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma was inititated in 1990, a quality‐of‐life assessment was integrated into the study. We used the questionnaire (QLQ‐C30) developed by the European Organization of Research and Treatment of Cancer (EORTC) Study Group on Quality of Life. The QLQ‐C30 incorporates five functional scales, three symptom scales, a global health and quality‐of‐life scale and some single symptom measures. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 524 (90.2%) of 581 patients enrolled in the NMSG 4/90 completed the first questionnaire, and 484 (83.3%) completed all questionnaires given to them. All but one of the scales met the minimum criteria of reliability (Cronbach’s alpha ≥0.70). Validity was shown by (1) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pre‐treatment W.H.O. performance index and Durie & Salmon stage, and (2) the sensitivity to changes in objective disease status (response and relapse). This is the first report of the measurement of health‐related quality of life in a prospective clinical trial in multiple myeloma. The results demonstrate that the QLQ‐C30 is a reliable and valid instrument for the measurement of quality of life in these patients. The data will be used for a cost–utility analysis of the results of the NMSG 4/90 trial.
Clinical relevance of residual disease monitoring by polymerase chain reaction in patients with ALL‐1/AF‐4 positive‐acute lymphoblastic leukaemia
Authors: Cimino Giuseppe , Elia Loredana , Rivolta Anna , Rapanotti Maria Cristina , Rossi Vincenzo , Alimena Giuliana , Annino Luciana , Canaani Eli , Lo Coco Francesco , Biondi Andrea
Published: October 2003

In this study we used reverse transcriptase‐polymerase chain reaction (RT‐PCR) for the longitudinal monitoring of minimal residual disease in 12 patients with ALL‐1/AF‐4 positive ALL. Of these, seven also showed at presentation a typical t(4;11) cytogenetic translocation. Seven patients were infants <18 months of age and five were adults.

Eleven patients were treated with high‐dose intensive induction and consolidation chemotherapy without bone marrow transplantation and one received conservative treatment due to poor performance status. Three had resistant disease, four relapsed within 12 months after achieving complete remission, and five are in continuous complete remission (CCR) at 32, 39, 52, 53 and 61 months from diagnosis, respectively. The sequential analysis of the ALL‐1/AF‐4 hybrid transcript showed a persistently negative RT‐PCR in the five CCR long‐term survivors. The PCR analysis resulted persistently positive in the remaining seven cases, including the four cases who relapsed after the achievement of clinical CR.

These data emphasize the clinical relevance of PCR monitoring analysis in t(4;11) ALL patients and should be considered in order to better determine variable post‐remission treatment according to risk prediction.
Stem cell factor receptor (c‐kit, CD117) is expressed on blast cells from most immature types of acute myeloid malignancies but is also a characteristic of a subset of acute promyelocytic leukaemia
Authors: Di Noto R. , Lo Pardo C. , Schiavone E. M. , Manzo C. , Vacca C. , Ferrara F. , Del Vecchio L.
Published: October 2003

Investigating 208 patients with acute haematological malignancies, we found that stem cell factor receptor (SCFR) was expressed on high numbers of blast cells from the vast majority of patients (93%) with refractory anaemia with excess of blasts in transformation. SCFR was also detected in 62% of AMLs, in which it was directly associated to the expression of CD7, interleukin 6 receptor and CD34, and inversely to that of CD11b and CD14. SCFR‐positive cases were preferentially represented in AML‐M1 (70%) and in AML‐M2 (83%) subsets, whereas only 45% of the remaining samples (M3–M4–M5) exhibited SCFR positivity. Interestingly, 50% of cases with acute promyelocytic leukaemia expressed SCFR and this molecule was heterogenously regulated by in vitro treatment with all‐trans retinoic acid.
Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all‐trans‐retinoic acid
Authors: Federici Augusto B. , Falanga Anna , Lattuada Antonella , Rocco Nicola Di , Barbui Tiziano , Mannucci Pier Mannuccio
Published: October 2003

Plasma von Willebrand factor (VWF) was investigated in five patients with acute promyelocytic leukaemia (APL) before and after administration of the differentiating agent all‐trans‐retinoic acid (ATRA). The purpose of the study was to see how the proteolytic state associated with APL affects VWF structure and function and whether ATRA reverses any abnormality. At the onset of APL, multimeric analysis of plasma VWF revealed a lack of the largest multimers. After ATRA, there was a progressive correction of the multimeric pattern in all cases, with transient appearance of ultralarge multimers in two cases. Proteolysis was investigated with immunopurified and reduced VWF from each patient’s plasma. This was electrophoresed and probed with two monoclonal antibodies that identify the 225 kD native subunit and the three native fragments of 189, 176 and 140 kD and differentiate novel proteolytic fragments produced by different proteinases. At the onset of APL, the 225 kD native subunit was relatively decreased, with the appearance of an array of novel VWF proteolytic fragments, ranging in size from <140 to <225 kD. These novel fragments observed in patients were similar to those produced in vitro by digestion of purified VWF with plasmin or elastase. After ATRA therapy, proteolysis diminished progressively in parallel with the improvement of other haemostatic measurements, but persisted to some extent. We conclude that VWF proteolysis in APL is produced by plasmin and elastase. Changes of VWF structure and function might adversely affect haemostasis in APL. Therefore, improvement of VWF after ATRA administration might explain in part the effectiveness of this drug in reducing haemorrhagic complications.
N‐acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis
Authors: Sevillano S. , De Dios I. , De La Mano A. M. , Manso M. A.
Published: October 2003

Abstract.  Oxygen free radicals (OFR) are produced in the course of acute pancreatitis (AP). In addition to injurious oxidative effects, they are also involved in the regulation of cell growth. The aim of the present study was to examine the relationship between the effectiveness of N‐acetyl‐l‐cysteine (NAC) to prevent the generation of OFR and the changes in the cell‐cycle pattern of acinar cells in the course of AP induced in rats by pancreatic duct obstruction (PDO). NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Flow‐cytometric measurement of OFR generation in acinar cells was carried out using dihydrorhodamine as fluorescent dye. Plasma amylase activity, pancreatic glutathione (GSH) content and TNF‐α plasma levels were also measured. The distribution of acinar cells throughout the different cell‐cycle phases was analysed at different AP stages by flow cytometry using propidium iodide staining. NAC administration reduced the depletion of pancreatic GSH content and prevented OFR generation in acinar cells of rats with PDO‐induced acute pancreatitis. As a result, AP became less severe as reflected by the significant improvement of hyper‐amylasaemia and maintenance of plasma TNF‐α levels at values not significantly different from controls were found. NAC administration inhibited progression of cell‐cycle phases, maintaining acinar cells in quiescent state at early PDO times. The protection from oxidative damage by NAC treatment during early AP, allows the pancreatic cell to enter S‐phase actively at later stages, thereby allowing acinar cells to proliferate and preventing the pancreatic atrophy provoked by PDO‐induced AP. The results provide evidence that OFR play a critical role in the progression of acinar cell‐cycle phases. Prevention of OFR generation of acinar cells in rats with PDO‐induced AP through NAC treatment, not only protects pancreas from oxidative damage but also promotes beneficial changes in the cell cycle progression which reduce the risk of pancreatic atrophy.
‘Entopy’: localized mucosal allergic disease in the absence of systemic responses for atopy
Authors: Powe D. G. , Jagger C. , Kleinjan A. , Carney A. S. , Jenkins D. , Jones N. S.
Published: October 2003

Background
The Th2 immune response in the nasal mucosa of subjects with allergic rhinitis is mediated by allergen‐specific IgE. Moreover, these subjects show positive responses for markers of systemic atopy, including allergen‐specific skin sensitivity and raised serum IgE titres. In contrast, idiopathic rhinitis (IR) subjects with similar histological nasal mucosal features differ in being defined as non‐allergic because they have negative atopic responses.

Objective
We hypothesized that it is possible to have an allergic Th2 disease pathway localized in the nasal mucosa of ‘non‐allergic’ rhinitis subjects despite an absence of atopic responses.

Methods
The presence of house dust mite and grass pollen‐specific IgE antibodies was investigated in non‐atopic (n=10) and atopic (n=11) subjects with persistent rhinitis and compared to normal (n=12) control subjects. Biotin‐labelled allergen was used to localize specific allergen‐binding antibodies in situ in sections of nasal mucosa.

Results
Grass pollen allergen binding was detected in the nasal mucosa of 3/10 non‐atopic IR subjects but, in contrast, dust mite‐specific antibodies were not detected. Specific antibodies were present in a total of 8/11 mucosal samples from the allergic group, but none was detected in normal control tissues.

Conclusion
These findings support the concept of localized nasal allergy in ‘non‐atopic’ rhinitis subjects. We propose the term ‘entopy’ to define this phenomenon and believe that this concept has a wider implication for localized allergic responses in other mucosal sites.
CpG DNA and immunotherapy of allergic airway diseases
Authors: Jain V. V. , Kitagaki K. , Kline J. N.
Published: October 2003

Atopic asthma is a highly prevalent and serious health problem for which no therapy currently offers the hope of a cure. Preindustrialized and rural populations appear relatively protected from the asthma epidemic; the hygiene hypothesis ascribes this protection to the effects of microbes and microbial products. An important immunostimulant component of microbes is DNA; bacterial DNA contains sequence motifs centred on the CpG dinucleotide, which are suppressed in mammalian DNA. Oligonucleotides containing these motifs (CpG ODN), like bacterial DNA, promote Th1 and regulatory‐type immune responses. Using CpG ODN, we and others have demonstrated in murine studies that CpG ODN are effective in preventing the development of atopic airways disease. Moreover, when administered in conjunction with experimental allergen, they promote the reversal of established eosinophilic inflammation. These data suggest that CpG ODN may be a novel therapeutic tool for the treatment of atopic asthma.
Interleukin‐1β and interleukin‐1ra levels in nasal lavages during experimental rhinovirus infection in asthmatic and non‐asthmatic subjects
Authors: De Kluijver J. , Grünberg K. , Pons D. , De Klerk E. P. A. , Dick C. R. , Sterk P. J. , Hiemstra P. S.
Published: October 2003

Background
Exacerbations of asthma are often associated with rhinovirus (RV)‐induced common colds. During experimental RV‐infection in healthy subjects, increased levels of the pro‐inflammatory mediator IL‐1β and the anti‐inflammatory IL‐1 receptor antagonist (IL‐1ra) have been found in nasal lavage.

Objective
We postulated that the balance between nasal pro‐ and anti‐inflammatory mediator expression is disturbed in asthma, resulting in more extensive inflammation following RV‐exposure in asthma.

Methods
We determined IL‐1ra, IL‐1β, and IL‐8 in nasal lavages (days −2, 3, and 6) of non‐asthmatics and asthmatics (with and without pre‐treatment with the inhaled steroid budesonide) before and after experimental RV16‐infection (days 0 and 1).

Results
Following RV16‐infection, a significant increase in IL‐8 was observed in the placebo‐ and budesonide‐treated asthmatics (P=0.033 and 0.037, respectively), whereas IL‐1β only increased in the two asthma groups combined (P=0.035). A small, but significant, increase in IL‐1ra was only observed in the budesonide‐treated asthmatics (P=0.047). At baseline, IL‐1ra levels were significantly higher in the non‐asthmatics than in the placebo‐treated asthmatics (P=0.017).

Conclusion
These results demonstrate differences between non‐asthmatic and asthmatic subjects in the basal levels of nasal cytokines and their inhibitors, and in the effect of experimental RV‐infection on these levels. The results indicate that RV may enhance inflammation more markedly in asthmatics, and suggest that this may in part be explained by lower IL‐1ra levels. In addition, the observation that budesonide‐treatment may result in higher nasal IL‐1ra levels supports the hypothesis that steroids act in part by increasing the endogenous anti‐inflammatory screen.
Role of carbohydrates in repair of human respiratory epithelium using an in vitro model
Authors: Adam E. C. , Holgate S. T. , Fildew C. J. , Lackie P. M.
Published: October 2003

Background
The epithelial layer in the conducting airway provides a primary protective barrier. Repair of this barrier normally occurs rapidly after damage, but is compromised in diseases such as asthma.

Objective
We have developed a human in vitro model system to test our hypothesis that cell surface glycoconjugate‐based interactions are required for the normal repair of damaged epithelium.

Methods
Lectins having narrow carbohydrate specificities were used to identify and block specific carbohydrate moieties on human airway‐derived epithelial cells in culture.

Results
The lectin wheat germ agglutinin bound to N‐acetyl glucosamine and inhibited the repair of epithelial damage while having little effect on cell viability. In contrast, other N‐acetyl glucosamine binding lectins had no effect even when bound to the cell surface. The involvement of glycoconjugates was confirmed by pre‐incubating the lectin with its specific sugar, preventing the inhibition of repair.

Conclusion
These results indicate that lectin‐binding sites are involved in epithelial repair and may be important in the repetitive cycles of injury and repair seen in asthma. This model system provides an insight into the role of glycoconjugates and will help to determine the function of specific carbohydrate groups in epithelial repair. These may present a target for therapeutic intervention in respiratory and other diseases.
Fagales pollen sensitization in a birch‐free area: a respiratory cohort survey using Fagales pollen extracts and birch recombinant allergens (rBet v 1, rBet v 2, rBet v 4)
Authors: Mari A. , Wallner M. , Ferreira F.
Published: October 2003

Background
Birch allergy is one of the most common pollinosis in areas where exposure to high levels of birch pollen is common. Little is known about birch sensitivity in areas without birch pollen exposure and reactivity to birch‐related species within the Fagales order.

Objective
the aim was to evaluate Fagales reactivity within a population not exposed to birch pollen using epidemiological, diagnostic, and laboratory approaches by means of extracts and allergenic molecules.

Methods
A cohort of 5335 respiratory allergic patients was screened by means of skin testing birch, hazel, and oak pollen extracts. Patients were from a birch‐free area, but exposed to other Fagales pollen species. A subset of patients was from an intensively cultivated hazel area. A sample of the Fagales allergic population was tested with other Fagales pollen extract (alder, hornbeam, beech, chestnut) and with apple and hazelnut. IgE detection was performed with birch, hazel, oak, apple, and hazelnut extracts, and with Bet v 1, Bet v 2, Bet v 4, and bromelain. IgE immunoblots were performed using birch and hazel extracts. Epidemiological, clinical, and laboratory data were analysed by stratifying the allergic population.

Results
Twenty‐five percent of the pollen allergic cohort was skin test positive to at least one of the three Fagales species. Combined reactivity to the three species was recorded in 80% of this cohort. Isolated hazel pollen reactivity was recorded in 13.5% of the Fagales allergic patients. Sixty‐six percent of these subjects were from the intensively cultivated hazel area. Reactivity to apple and hazelnut was detected by skin test (40%) and IgE reactivity (60%), but only 19% of the positive patients reported symptoms related to at least one of the two foods. Reactivity to Bet v 1 was recorded in 84% of the birch/hazel/oak co‐reactivity group, and in 28% of the subjects with the same co‐reactivity, but associating a multiple pollen sensitization. IgE to Bet v 2 (50%) and Bet v 4 (23%) panallergens were recorded positive in the latter subset. Bet v 1 prevalence ranged between 48% and 21% among subgroups of patients coming from different areas. Furthermore, an IgE reactivity to hazel‐restricted allergenic components was detected among subjects coming from the same area and having a hazel isolated reactivity.

Conclusion
Fagales allergy can be found in birch‐free areas caused by the exposure to other Fagales species. Birch allergens can be useful for mimicking the allergenic extract, but are also the exclusive tools for a fine diagnostic and epidemiological approach to Fagales pollen allergy. Allergenic molecules from the hazel family will increase the panel of available reagents for the molecule‐based approach to allergy diagnosis and therapy.
Allergic sensitization among adults in Tallinn, Estonia
Authors: Raukas‐Kivioja A. , Raukas E. , Loit H.‐M. , Kiviloog J. , Rönmark E. , Larsson K. , Lundbäck B.
Published: October 2003

Background
The prevalence of allergic sensitization has increased worldwide during recent years.

Objective
The aim of the study was to estimate the prevalence of allergic sensitization and to evaluate the influence of age, gender, number of siblings, pet keeping in childhood, and residential area before the age of five on allergic sensitization among adolescents and adults aged 17–66 years in the capital of Estonia, Tallinn. A cross‐sectional study was carried out between March 1997 and December 1998.

Methods
The sensitization to 15 inhalant allergens was assessed. The associations between sensitization based on skin prick tests (SPTs), symptoms based on a structured interview, and possible risk factors were estimated. A random sample of 516 subjects was included in the study analysis.

Results
The prevalence of allergic sensitization was 34.5%, while it was 39.3% in subjects aged 20–44 years. The most prevalent sensitization was against the German cockroach, 15.5%, and it was particularly high among adolescents. It was followed by mugwort, dog, two storage mites species, and cat dander. Subjects with wheezing during the last 12 months, attacks of shortness of breath, wheezing due to furred animals, and allergic rhinitis or conjunctivitis had a significantly higher prevalence of positive SPT.

Conclusion
We found a surprisingly high prevalence of allergic sensitization among adults in Tallinn. Our results suggest that the cockroach allergen should be included in the investigation panel in order to reach a true prevalence of allergic sensitization in Estonia. Further, the pattern of allergic sensitization in Estonia appears to be different from published data about allergic sensitization in Scandinavia.
Allergen microarray: comparison of microarray using recombinant allergens with conventional diagnostic methods to detect allergen‐specific serum immunoglobulin E
Authors: Jahn‐Schmid B. , Harwanegg C. , Hiller R. , Bohle B. , Ebner C. , Scheiner O. , Mueller M. W.
Published: October 2003

Background
The availability of recombinant allergens and recent advances in biochip technology led to the development of a novel test system for the detection of allergen‐specific IgE.

Objective
To test the performance of this allergen microarray in a serological analytical study.

Methods
Standard allergens contained in grass pollen (Phl p 1, Phl p 2, Phl p 5 and Phl p 6) and tree pollen (Bet v 1 and Bet v 2) were used as a model system. The detection of allergen‐specific serum IgE using microarrays was compared with standard test systems: CAP/RAST and an in‐house ELISA. In order to test the analytical sensitivity of the assays, geometric dilutions of a serum pool containing high levels of pollen‐specific IgE from allergic individuals were tested in each system. To assess the analytical specificity, the sera of 51 patients with presumptive allergic symptoms were collected before diagnosis. Thereafter, the results for grass/tree‐pollen‐specific IgE were compared.

Results
The microarray has a good dynamic range similar to the CAP/RAST system. Microarray and ELISA showed comparable analytical sensitivity exceeding the CAP/RAST system. With respect to the analytical specificity, no significant cross‐reactivity of the allergens was observed. For two of the allergens tested, weak positive signals were detected in the microarray test system, whereas they were not detectable by CAP/RAST.

Conclusion
A good correlation of presently used methods to detect serum IgE and the novel microarray test system was observed. As a next step, a careful validation of this method for a multitude of allergens and a thorough clinical evaluation has to be provided.

Microarray testing of allergen‐specific IgE can be presumed to be the method of choice for a prospective component‐resolved diagnosis of Type I allergy, and the basis for the design and monitoring of a patient‐tailored specific immunotherapy in the future.
Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis
Authors: Figueroa D. J. , Borish L. , Baramki D. , Philip G. , Austin C. P. , Evans J. F.
Published: October 2003

Background
Cysteinyl leukotrienes (CysLTs) are bioactive lipids that have been shown to contribute to allergic and inflammatory diseases. Eosinophils and mast cells have the capacity to produce large amounts of CysLTs after allergic or non‐allergic stimulation. Molecular identification of both the synthetic and signalling proteins in the CysLT pathway allows the investigation of expression of the CysLT enzymes and receptors in active allergic rhinitis.

Objective
We examined the expression of the proteins involved in the synthesis of CysLTs and the cysteinyl leukotriene‐1 (CysLT1) and cysteinyl leukotriene‐2 (CysLT2) receptors in inflammatory cells from patients with active seasonal allergic rhinitis.

Methods
Nasal lavage samples were obtained from patients during active seasonal allergic rhinitis. Specific cellular immunocytochemical techniques were used to detect the cysteinyl leukotriene synthetic proteins, namely 5‐lipoxygenase (5‐LO), 5‐lipoxygenase‐activating protein (FLAP) and leukotriene C4 synthase (LTC4S). In situ hybridization and immunocytochemical techniques were used to identify the mRNA and proteins for the CysLT1 and CysLT2 receptors.

Results
5‐LO, FLAP and LTC4S, and the CysLT1 and CysLT2 receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells. 5‐LO, FLAP and the CysLT1 receptor, but not LTC4S or the CysLT2 receptor, were expressed in a subset of nasal neutrophils.

Conclusions
Our study demonstrates the presence of CysLT pathway proteins in key allergic and inflammatory cells from the upper airway of patients with active seasonal allergic rhinitis. Our expression data highlight the potential of CysLT‐modifying agents to treat both upper and lower airway symptoms in patients suffering from allergic rhinitis and asthma.
Praiseworthy pragmatism? Validity and action research
Authors: Hope Kevin W. , Waterman Heather A.
Published: October 2003

Background. Action research has been promoted as a suitable methodology for nursing, but is located in a discourse that challenges its claims of validity. This discourse, influenced by positivism, is similar to that which qualitative researchers have faced.

Aim. This article contributes to theoretical discussion of the validity of action research.

Findings. Because of similarities, the emergent debates around the reconceptualization of validity in qualitative research are outlined, prior to a consideration of the relative arguments in relation to action research. Three avenues of thought are discerned: that no criteria are required; that parallels with other schools are appropriate; and that new concepts specific to one school of thought should be developed.

Conclusions. Because of its ethical and action‐oriented principles, action research offers the potential to address validity issues that remain problematic to ‘pure’ qualitative researchers, and it can be claimed that its pragmatic approach is validity‐enhancing. We argue for the rejection of naïve rule‐based formulae and for recognition of the impact of contextual and pragmatic concerns, so that the potential for the added value of action research might be realized.
Pressure ulcer risk assessment: application of logistic analysis
Authors: Papanikolaou Panos , Lyne Patricia A. , Lycett Emma J.
Published: October 2003

Aim. The aim of this study was to investigate the relative importance of key factors affecting the likelihood of hospital acquired pressure ulcers, thus offering the groundwork for the development of an empirically‐based risk assessment scale. It also evaluated the predictive performance of the underlying empirical model and compared its classification ability with the empirically observed ability of the Waterlow risk assessment scale.

Background. Pressure ulcers impose a significant burden on patients and carers and demand substantial resources from the health care system. There is, however, a lack of systematic empirical research on which to base the development of risk assessment measurement tools.

Methods. Multivariate statistical methods were applied to data derived from the records of a cross‐sectional sample of around 500 randomly selected inpatient episodes drawn from the population of admissions to a single unit in a large acute hospital during a 2‐year period (October 1996 to September 1998). Double‐checking of a randomly selected 25% sample of the original records and careful screening out of records with incomplete information or inconsistent values was carried out to ensure a high quality sample. Logit analysis was used to investigate the relative contribution of risk factors, such as continence, skin condition, mobility and inter‐hospital transfer to the risk of hospital‐acquired pressure ulcer occurrence, whilst cross‐validation techniques were employed to check the predictive performance of the model.

Results. The results suggest that a simplified version of the Waterlow risk assessment tool has satisfactory predictive ability and the potential for further development.

Conclusions. Two main conclusions emerged from this study. First, it is both feasible and worthwhile to pursue improvement in the development of risk assessment tools using statistical methods. Second, locally‐determined risk factors will need to be incorporated into the construction of future risk assessment scales.
‘Economy’ line foods from four supermarkets and brand name equivalents: a comparison of their nutrient contents and costs
Authors: Cooper S. , Nelson M.
Published: October 2003

Background  Achieving healthy eating targets for low income households can be difficult because of economic barriers. Several UK supermarkets have introduced ‘value line’ or ‘economy line’ foods to improve their attractiveness to low income consumers.

Materials and methods  The costs and nutrient contents of five ‘economy’ line products of four major English supermarkets – Asda, KwikSave, Sainsbury and Tesco – were compared with branded (but not ‘own label’) equivalents. Single samples of tinned tomatoes, long‐life orange juice, potatoes, sausages and white bread were purchased in each supermarket. They represented items of potential importance in relation to ‘healthy’ choices in the shopping baskets of low income households. Nutrients analysed were fat, sodium, potassium, iron, calcium, vitamin C, and energy.

Results  Economy line foods had a nutrient composition similar to and often better than the branded goods. The economy line products frequently had nutrient contents more in line with the Balance of Good Health (e.g. lower fat and sodium) compared with the branded goods. In terms of nutrients per pence, the economy line products were far better value for money compared with the branded lines.

Conclusion  Economy line foods represent excellent value for money and are not nutritionally inferior to the branded products. They have a potentially important role to play in the promotion of healthy eating, especially amongst low income households.