bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical, subclinical and potential autoimmune diseases in an Italian population of children with coeliac disease
Authors: GUARISO G. , CONTE S. , PRESOTTO F. , BASSO D. , BROTTO F. , POZZA L. VISONÀ DALLA , PEDINI B. , BETTERLE C.
Published: October 2008

Background Several studies have suggested a link between coeliac disease and other autoimmune diseases.

Aim To compare the presence of autoimmune disease in children with coeliac disease and in controls.

Methods When coeliac disease was diagnosed, 267 children were evaluated for clinical autoimmune disease (with signs/symptoms), subclinical autoimmune disease (with autoantibodies and subclinical impairment of the target organ) or potential autoimmune disease (with autoantibodies only) and compared with 220 healthy controls. 170 coeliac disease patients were followed up for a mean 47 ± 31 months, in complete remission on a gluten‐free diet. Ninety‐nine controls were followed up for 45 ± 33 months.

Results When coeliac disease was diagnosed, 71 (27%) children had autoimmune disease vs. 1% among the controls (P < 0.001): 31 had clinical autoimmune disease and 40 had subclinical or potential autoimmune disease.

During the follow‐up, the clinical autoimmune disease cases slightly decreased from 12% to 11%, while the potential autoimmune disease cases increased from 14% to 21%. Of the 99 controls, none had any variation in their autoantibody profile.

Conclusions Gluten‐free diet does not modify the natural history of autoimmunity in patients with coeliac disease. However, gluten‐free diet seems to produce a favourable effect on the previously present clinical autoimmune disease and to prevent the development of new clinical autoimmune disease, but does not affect the onset of potential autoimmunity, which tends to increase with time.
Clinical trial: persistent gastro‐oesophageal reflux symptoms despite standard therapy with proton pump inhibitors – a follow‐up study of intraluminal‐impedance guided therapy
Authors: BECKER V. , BAJBOUJ M. , WALLER K. , SCHMID R. M. , MEINING A.
Published: October 2008

Background  Persistent gastro‐oesophageal reflux disease (GERD), despite proton pump inhibitor (PPI) therapy, is a common problem. Combined pH/impedance monitoring (pH/MII) enables detection of reflux episodes.

Aim  To identify patients with objective episodes of persistent reflux and second, to evaluate the effect of modified therapy based on the results of pH/MII.

Methods  In all, 143 patients were examined with pH/MII because of GERD‐symptoms resistant to PPI‐therapy. Patients with pathological pH/MII (group 1) and with normal results (group 2) were identified. Therapy modifications were evaluated after a minimum follow‐up of 3 months.

Results  In 56 of 143 (39.1%) patients, pathological findings in pH/MII were identified. Therapy was escalated in 33/52 patients (group 1) and in 30/71 patients (group 2). Escalating therapy led to symptomatic relief in 90.9% of the patients in group 1 and 43.3% of the patients in group 2 (P < 0.001).

Conclusions  GERD symptoms refractory to PPI‐therapy could be objectively identified with pH/MII in almost 40% of all patients. Furthermore, escalating anti‐reflux therapy if pH/MII was pathological is associated with a significantly higher rate of successful treatment compared to the patients with normal findings. Therefore, pH/MII facilitates a more focussed therapeutical approach to patients with PPI‐resistant GERD.
The epidemiology and virology of hepatitis C virus genotype 5 in central France
Authors: ABERGEL A. , UGHETTO S. , DUBOST S. , BONNY C. , AUBLET‐CUVELIER B. , DELAROCQUE‐ASTAGNEAU E. , BAILLY J. L. , BOMMELAER G. , CASANOVA S. , DELTEIL J. , DENY P. , LAURICHESSE H. , ODENT‐MALAURE H. , ROUSSEL J. , PEIGUE‐LAFEUILLE H. , HENQUELL C.
Published: October 2008

Background  We previously reported high prevalence of hepatitis C virus genotype 5a (HCV 5) (14%) in Central France.

Aim  To identify the risk factors associated with HCV5 infection and to characterize local HCV5 lineages.

Method  A case‐control study and phylogenetic analysis were conducted.

Results  In all, 131 HCV5 and 343 HCV non 5 infected patients were enrolled. No HCV5 patient was born in sub‐Saharan Africa and only two were injection drug user. HCV5 contamination was associated with living in a rural area called Vic le Comte (VLC) in non‐transfused patients (OR = 17.7), with transfusion in patients living outside VLC (OR = 3.8) and with receiving injections in patients from VLC (OR = 3.1). More than 80% of the patients from outside VLC were contaminated by transfusion and those from VLC mainly by an iatrogenic factor – injections performed before 1972 by the local physician. Phylogenetic analysis of HCV5 isolates evidenced no distinct genetic cluster, but close relationships between the isolates of spouse pairs and between blood donors and recipients.

Conclusions  Our results suggest that HCV5 spread in our district by iatrogenic route before 1972 and then via transfusion to the whole district. Collaborative studies are underway to study viral sequences from different parts of Africa and Europe to estimate the origin of our HCV 5a strains.
Psychiatric symptoms during interferon treatment for hepatitis C:experiences from a tertiary care hepatology centre
Authors: EVON D. M. , VERMA A. , SIMPSON K. , GALANKO J. A. , DOUGHERTY K. A. , FRIED M. W.
Published: October 2008

Background Most research on the psychiatric symptoms of peginterferon/ribavirin for the treatment of hepatitis C comes from VA centres and clinical trials with rigid entry criteria that often excluded patients with markers of mental health and substance use disturbance (MH/SUD). The findings from these lines of research may not be generalizable to patients treated under standard of care in a tertiary care setting.

Aim To investigate the incidence and outcomes of psychiatric symptoms in patients treated under standard of care protocol, not enrolled in clinical trials.

Methods This is a retrospective analysis of 215 patients who underwent therapy from 2002 to 2006 at a university‐based tertiary care centre. Survival curves explored the relationship between history of MH/SUD and the development of psychiatric symptoms on treatment.

Results The cumulative history of MH/SUD was 67%. Of these, 39% had taken psychotropic medications previously, and 80% continued on them during therapy. On therapy, 46% developed depressive symptoms, 19% and 46% endorsed anxiety and irritability respectively. Cumulatively, 64% of patients indicated mood disturbance on therapy. Most symptoms developed between weeks 2 and 18, and rarely after week 20. Of those who developed mood symptoms, 66% required an intervention. Treatment discontinuation was infrequent.

Conclusions This large observational study provides important insights into the incidence and course of psychiatric symptoms in an unselected sample of patients treated in a tertiary care setting. Patients had higher rates of MH/SUD comorbidity, psychotropic medication use and exhibit higher rates of mood disturbance on therapy compared with previous reports, although a majority completed the prescribed treatment regimen.
Vitamin B12 deficiency in hypersecretors during long‐term acid suppression with proton pump inhibitors
Authors: HIRSCHOWITZ B. I. , WORTHINGTON J. , MOHNEN J.
Published: October 2008

Background  Proton pump inhibitors (PPIs) may cause cyanocobalamin (vitamin B12) malabsorption, but measuring serum B12 alone may underestimate the prevalence. However, B12 deficiency elevates methylmalonic acid and homocysteine, both additional markers of B12 deficiency.

Aim  To determine the true prevalence of B12 deficiency and whether acid suppression by PPI caused it.

Methods  Sixty‐one acid hypersecretors (basal acid output >15 mmol/h), 46 with gastrinoma [Zollinger–Ellison (ZE) syndrome] and 15 without [acid hypersecretor without gastrinoma (pseudo‐ZE)], were treated with lansoprazole to determine its long‐term (up to 18 years) pharmacological and clinical efficacy and safety, particularly as regards malabsorption of B12.

Results  Of 61 patients, six (10%) had low serum B12. Additional tests uncovered B12 deficiency in 13 (31%) of 41 still‐available patients, despite normal serum B12. B12 replacement reduced elevated homocysteine and methylmalonic acid, supporting the diagnosis. Also, measuring both basal and stimulated gastric secretion, we found that acid suppression was neither prolonged nor profound enough to explain the B12 deficiency.

Conclusions  In long‐term recipients of PPIs, B12 deficiency was more frequent (29%) than detected by measuring only serum B12, and there was not enough acid suppression to explain this deficiency.
Clinical trial: normal diet vs. partial replacement with oral E028 formula for the prevention of gastrointestinal toxicity in cancer patients undergoing pelvic radiotherapy
Authors: MCGOUGH C. , WEDLAKE L. , BALDWIN C. , HACKETT C. , NORMAN A. R. , BLAKE P. , HARRINGTON K. , TAIT D. , KHOO V. , FROST G. , ANDREYEV H. J. N.
Published: October 2008

Background  Acute gastrointestinal symptoms affect 90% of patients during pelvic radiotherapy. Elemental diet is protective in animal models. A nonrandomized study suggested benefit from a partial elemental diet. A pilot study suggested that radiotherapy patients only tolerate oral elemental diet comprising one‐third of total calories for 3 weeks.

Aim  To assess the feasibility and efficacy of replacing one‐third of normal diet with elemental diet during the first 3 weeks of pelvic radiotherapy in reducing acute gastrointestinal toxicity.

Methods  Patients were randomized to elemental diet or no intervention. Toxicity was assessed using the Inflammatory Bowel Disease Questionnaire, Vaizey Incontinence scale and Radiation Therapy Oncology Group tool. Faecal calprotectin measured intestinal mucosal inflammation.

Results  Twenty‐nine women and 21 men, median age 61.5 years were randomized. Patients taking elemental diet did not have lower gastrointestinal toxicity ratings or inflammatory markers (P > 0.2). The mean dose taken was 21% (2–36%) of total caloric requirements.

Conclusions  Patients cannot tolerate large volumes of oral elemental diet. The quantities consumed in this study produced no therapeutic benefit. Future studies should aim to replace a higher proportion of nutritional intake for a longer duration of radiotherapy treatment.
Functional heartburn vs. non‐erosive reflux disease: similarities and differences
Authors: HERSHCOVICI T. , ZIMMERMAN J.
Published: October 2008

Background  Bowel symptoms have been associated with non‐erosive reflux disease (NERD). However, their role in functional heartburn (FH) has not been established.

Aims  To characterize bowel symptoms in FH and NERD patients, and investigate their role as predictors of severity of reflux symptoms.

Methods  A prospective study of patients with normal upper endoscopy undergoing a 24‐h oesophageal pH monitoring for the evaluation of reflux symptoms. Patients with oesophageal acid exposure <3.1% and a symptom index <50% were classified as FH (n = 60), while those with oesophageal acid exposure >4% were defined as NERD (n = 160). Symptom severity was scored on validated scales.

Results  In FH, a female predominance was noted (P < 0.001). Reflux symptoms were scored higher in NERD patients (P < 0.001) while bowel symptoms were similarly scored in the two groups. In both groups, severity of reflux symptoms was independently associated with a composite score on the bowel scales (P < 0.001) and was not predicted by oesophageal acid exposure. In FH, reflux symptom severity was inversely related to age (P = 0.03), while in NERD, the opposite was true (P = 0.01).

Conclusions  In both FH and NERD, bowel symptoms were the strongest predictors of reflux symptoms severity. A female preponderance, and an opposite relationship between reflux symptom severity and age, indicate that FH and NERD may be distinct entities.
Review article: future research on coeliac disease – a position report from the European multistakeholder platform on coeliac disease (CDEUSSA)
Authors: TRONCONE R. , IVARSSON A. , SZAJEWSKA H. , MEARIN M. L. ,   ALSO ON BEHALF OF THE MEMBERS OF THE EUROPEAN MULTISTAKEHOLDER PLATFORM ON CD (CDEUSSA)
Published: October 2008

Background  CDEUSSA is a Specific Support Action project from the Sixth Framework Programme Priority of the European Union (EU). Its aim is to bring together basic and applied research in the area of coeliac disease (CD). This paper reviews the main issues that are a result of the CDEUSSA initiative.

Aim  To identify the major issues in need of investigation in the areas of clinical aspects, treatment, prevention and public health.

Methods  Key stakeholders, representing a wide range of knowledge with crucial importance for CD research and practice, have participated in two workshops aimed at identifying and proposing to the EU, as high priority research, topics in the areas of clinical aspects, treatment, prevention and public health.

Results  In public health, the overall goal should be to improve quality of life of the European population by implementing primary prevention strategies, early diagnosis and improved treatments for CD. New treatment strategies need to be developed. The option of primary prevention should be fully explored, which requires combined epidemiological, clinical and basic scientific research efforts. Such studies should also consider the importance of gene–environment interactions in the development of CD. Increased knowledge is needed on the natural history of CD. Diagnostic criteria need to be revised.

Conclusions  To achieve these goals, a collaboration of the stakeholders is fundamental, including research and patient organizations, as well as industries within both diagnostics and food production.
Review article: blood platelet number and function in chronic liver disease and cirrhosis
Authors: WITTERS P. , FRESON K. , VERSLYPE C. , PEERLINCK K. , HOYLAERTS M. , NEVENS F. , VAN GEET C. , CASSIMAN D.
Published: October 2008

Background  The liver plays a central role in coagulation and fibrinolysis but is also closely intertwined with the function and number of blood platelets.

Aim  To describe and integrate all literature concerning blood platelets and liver disease by performing a thorough literature research.

Methods  A thorough literature research on ‘blood platelets’ and ‘liver disease’ was performed.

Results  Thrombocytopenia is a marked feature of chronic liver disease and cirrhosis. Traditionally, this thrombocytopenia was attributed to passive platelet sequestration in the spleen. More recent insights suggest an increased platelet breakdown and to a lesser extent decreased platelet production plays a more important role. Besides the reduction in number, other studies suggest functional platelet defects. This platelet dysfunction is probably both intrinsic to the platelets and secondary to soluble plasma factors. It reflects not only a decrease in aggregability, but also an activation of the intrinsic inhibitory pathways. The net effect, finally, is a decreased platelet function in the various types of chronic liver diseases and cirrhosis. Finally, recent data suggest that platelets are not only affected by but can also contribute to the liver disease process, as for instance, in viral hepatitis and cholestatic liver disease.

Conclusion  Platelet research in liver disease is a growing area of investigation and could provide new pathophysiological insights.
Asimadoline, a kappa‐opioid agonist, and satiation in functional dyspepsia
Authors: TALLEY N. J. , CHOUNG R. S. , CAMILLERI M. , DIERKHISING R. A. , ZINSMEISTER A. R.
Published: October 2008

Background Asimadoline, a kappa‐opioid agonist, reduces visceral sensitivity in experimental animal models and may decrease satiation and postprandial fullness in healthy individuals. However, its effect on satiation in functional dyspepsia is unclear, and any symptom benefit has not been explored.

Aim To evaluate the effects of asimadoline on satiation volume and postchallenge symptoms in functional dyspepsia.

Methods A randomized, double‐blind trial evaluated gastric satiation and symptoms before and after 8 weeks of asimadoline 0.5 mg (n = 13) or 1.0 mg (n = 13) or placebo (n = 14) b.d. in patients with functional dyspepsia (Rome II). Gastrointestinal Symptom Rating Scale and Nepean Dyspepsia Index were used to assess symptoms during the 8‐week treatment.

Results Over 8 weeks of treatment, asimadoline had no significant effect on maximum‐tolerated volume or aggregate symptom score with nutrient drink challenge, and on the mean of the total daily symptom severity score compared to placebo. In apost hocanalysis, asimadoline 0.5 mg significantly increased the maximum‐tolerated volume (1217 mL ± 90.2) compared to placebo (807 mL ± 111.8) in patients with higher postprandial fullness scores (P = 0.01).

Conclusion Asimadoline overall did not significantly alter maximum‐tolerated volume, symptoms postnutrient challenge or symptoms over 8 weeks in functional dyspepsia.
Longitudinal effects of hepatitis C virus treatment on hepatic mitochondrial dysfunction assessed by 13C‐methionine breath test
Authors: BANASCH M. , EMMINGHAUS R. , ELLRICHMANN M. , SCHMIDT W. E. , GOETZE O.
Published: October 2008

Background  Hepatitis C virus (HCV) infection is characterized by remarkable levels of oxidative stress induced by virus interactions with hepatic mitochondria.

Aim  To examine hepatic mitochondrial function in HCV‐infected patients assessed by a non‐invasive 13C‐methionine breath test (MeBT) and to explore longitudinal effects of antiviral treatment.

Methods  Twenty‐one patients with chronic hepatitis C undergoing antiviral treatment with pegIFNα and ribavirin and 20 healthy controls were studied. MeBT was performed at baseline, week 12, end‐of‐treatment and after 24 weeks of follow‐up in all patients with early virological response (n = 15).

Results  Twelve patients achieved sustained virological response (SVR); three patients relapsed for HCV‐RNA replication. Cumulative percentage 13C‐exhalation (cPDR1.5h) was significantly decreased in HCV‐infected individuals compared to controls irrespective of genotype and fibrosis stage (P < 0.001). Antiviral treatment induced a further decay in cPDR1.5h (P < 0.01). After treatment cessation, 13C‐exhalation returned at least to baseline values in all patients. SVR was even associated with a mean cPDR1.5h increase of 70% compared to baseline.

Conclusions  Hepatitis C virus infection and antiviral treatment synergistically impair hepatic mitochondrial function, which may return to normal after sustained virus elimination. MeBT may be a valuable diagnostic instrument for monitoring hepatic mitochondrial function in particular in patients with mitochondrial comorbidities.
Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine‐induced pancreatitis
Authors: BERMEJO F. , LOPEZ‐SANROMAN A. , TAXONERA C. , GISBERT J. P. , PÉREZ‐CALLE J. L. , VERA I. , MENCHÉN L. , MARTÍN‐ARRANZ M. D. , OPIO V. , CARNEROS J. A. , VAN‐DOMSELAAR M. , MENDOZA J. L. , LUNA M. , LÓPEZ P. , CALVO M. , ALGABA A.
Published: October 2008

Background  Pancreatitis is a potentially severe condition. Patients with inflammatory bowel disease (IBD) seem to be at increased risk for acute pancreatitis.

Aim  To describe the incidence, main causes and possible predictive factors of acute pancreatitis in inflammatory bowel disease.

Methods  Information was retrospectively extracted from the clinical records of patients followed in the IBD Units of nine hospitals in Madrid (n = 5073).

Results  A total of 82 acute pancreatitis episodes were diagnosed (cumulative incidence, 1.6%); 98% of them were mild. Recurrent acute pancreatitis developed in 13% of patients. Most cases of acute pancreatitis (63.4%) were attributed to drug exposure [azathioprine/mercaptopurine (AZA/MP) n = 46, mesalazine (mesalamine) n = 6]; 20.7% were idiopathic, and 12.2% were biliary. Incidence of acute pancreatitis in patients treated with AZA/MP was 3.1%. In patients with acute pancreatitis, female gender (OR 3.4 95% CI: 1.3–9.3; P = 0.012) and Crohn’s disease (CD) (OR 5.8 95% CI: 1.6–20.6; P = 0.007) were risk factors for AZA/MP‐associated acute pancreatitis, the latter also when analysed only in patients treated with AZA/MP (n = 1477) (OR 5.2 95% CI: 1.8–14; P = 0.002).

Conclusions  The incidence of acute pancreatitis in our IBD patients (1.6%) is similar to that previously described. Drugs, mainly AZA/MP, are the leading cause. AZA‐induced acute pancreatitis is always mild. Patients with CD are at a higher risk for AZA/MP‐associated acute pancreatitis. The frequency of idiopathic acute pancreatitis is higher than expected, suggesting that part of these cases could be extraintestinal manifestations of IBD.
Review article: 5‐aminosalicylate formulations for the treatment of ulcerative colitis – methods of comparing release rates and delivery of 5‐aminosalicylate to the colonic mucosa
Authors: LICHTENSTEIN G. R. , KAMM M. A.
Published: October 2008

Background Many oral 5‐aminosalicylic acid (5‐ASA) formulations are designed to maximize 5‐ASA release in the colon where it acts topically on the colonic mucosa. Delayed‐release formulations and azo‐prodrugs minimize 5‐ASA absorption in the upper gastrointestinal (GI) tract.

Aims To review methods for assessing 5‐ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions.

Methods PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5‐ASA release from ulcerative colitis (UC) therapies.

Results In‐vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5‐ASA release kinetics and bioaccessibility. Gamma‐scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5‐ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter‐subject variability and other confounding factors.

Conclusion While assessment of 5‐ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions.
Relationship between rectal sensitivity, symptoms intensity and quality of life in patients with irritable bowel syndrome
Authors: SABATE J.‐M. , VEYRAC M. , MION F. , SIPROUDHIS L. , DUCROTTE P. , ZERBIB F. , GRIMAUD J.‐C. , DAPOIGNY M. , DYARD F. , COFFIN B.
Published: October 2008

Background  Relationships between pain threshold during rectal distension and both symptoms intensity and alteration in quality of life (QoL) in irritable bowel syndrome (IBS) patients have been poorly evaluated.

Aim  To evaluate relationships between rectal sensitivity, IBS symptom intensity and QoL in a multicentre prospective study.

Methods  Rectal threshold for moderate pain was measured during rectal distension in IBS patients (Rome II), while IBS symptoms intensity was assessed by a validated questionnaire and QoL by the Functional Digestive Disorder Quality of Life questionnaire.

Results  Sixty‐eight patients (44.2 ± 12.7 years, 48 women) were included. The mean rectal distending volume for moderate pain was 127 ± 35 mL while 45 patients (66%) had rectal hypersensitivity (pain threshold <140 mL). Rectal threshold was not significantly related either to overall IBS intensity score (r = −0.66, P = 0.62) or to its different components, or to FDDQL score (r = 0.30, P = 0.14). Among FDDQL domains, only anxiety (r = 0.30, P = 0.01) and coping (r = 0.31, P = 0.009) were significantly related with pain threshold.

Conclusions  In this study, two‐thirds of IBS patients exhibited rectal hypersensitivity. No significant correlation was found between rectal threshold and either symptom intensity or alteration in QoL.
Screening differences and risk of cervical cancer in inflammatory bowel disease
Authors: HUTFLESS S. , FIREMAN B. , KANE S. , HERRINTON L. J.
Published: October 2008

Background  Cervical cancer risk is high among immune suppressed women.

Aim  To evaluate inflammatory bowel disease (IBD) with medications and risk of cervical cancer.

Methods  Members of Kaiser Permanente Northern California (KPNC), 15–68 years from 1996 to 2006 with IBD were compared with age‐matched women without IBD. Cervical cancer was ascertained using the KPNC Cancer Registry. IBD medications of interest were aminosalicylates (ASA), corticosteroids, immune modulators and infliximab. Odds of cervical cancer were analysed with adjusted logistic regression. The prevalence of Pap smear testing was compared using a log binomial model.

Results  Ten cervical cancer cases occurred among 1165 women with IBD and 72 cancers among 12 124 controls. The adjusted odds ratio (OR) of IBD with risk of cervical cancer was 1.45 [95% confidence interval (CI) 0.74–2.84]. Medication ORs were 1.65 for ASA, 2.79 for corticosteroids and 3.45 for immune modulators (all P > 0.05). No cancer case used infliximab. The adjusted absolute increase in Pap smears among IBD women compared to women without IBD was 4% (95% CI 2–5%).

Conclusions  Although a trend of elevated risk for cervical cancer with IBD and IBD medications was observed, it was not statistically significant. Regular cervical cancer screening for women with IBD is recommended.
Predictive graphical model, network‐based medical tool for the prognosis of chronic hepatitis C patients treated with peg‐interferon plus ribavirin
Authors: TRAPERO‐MARUGAN M. , MARIN M. , PIVEL J. P. , DEL RIO J. M. , NUNEZ O. , CLEMENTE G. , GISBERT J. P. , MORENO‐OTERO R.
Published: October 2008

Background  There are few model networks to predict treatment outcome in viral hepatitis.

Aim  To develop an easy bioinformatics platform based on algorithm decisions (Bayesian network) for a more efficient prediction of treatment response.

Methods  Totally 385 consecutive chronic hepatitis C (CHC) treated patients were included. More than 40 variables were analysed. Data from 308 patients were used to build the variable model network using DLIFE platform based on predictive graphical models. The prediction accuracy of the bioinformatics network was compared with the true data collected in a retrospective study. The model was then validated twice with external data from CHC patients treated in other hospitals.

Results  The accuracy of this bioinformatics network for treatment response in our 308 patients was 83.3%, which is higher than the accuracy obtained by physicians on the basis of study of clinical data and their own experience (50–65%). The receiver operator characteristic curve areas after validation with another cohort of patients were: 0.91 for sustained virological response, one for nonresponse, and 0.81 for relapse. DLIFE offered a diagnostic accuracy of 81.3%, which is a clear improvement compared with unassisted prognosis (50–65%).

Conclusions  This bioinformatics platform (DLIFE) accurately predicts the outcome of CHC combination therapy, improving treatment decisions and reducing costs. This bioinformatics platform allows integrating widespread data sources and permits predicting the clinical outcome of a particular patient using a general predictive graphical model.
Perinatal risk factors and coeliac disease in children and young adults: a record linkage study
Authors: ROBERTS S. E. , WILLIAMS J. G. , MEDDINGS D. , DAVIDSON R. , GOLDACRE M. J.
Published: October 2008

Background  Little is known about perinatal risk factors and coeliac disease.

Aim  To investigate the relationship between perinatal risk factors and subsequent coeliac disease among offspring.

Methods  Record linked abstracts of birth registrations, maternity, in‐patient and day case records in a defined population of southern England.

Results  Using univariate analysis, coeliac disease in the child was associated with maternal coeliac disease (odds ratio = 20.6; 95% CI = 5.04–84.0; based on two cases in both mother and child) and with social class, year of birth, maternal smoking and parity. Multivariate analysis confirmed an increased risk of coeliac disease of 3.79 (95% CI = 1.85–7.79) for classes IV and V compared with I and II, an increased risk of 1.92 (1.06–3.49) for births during 1975–1979 compared with 1970–1974 and an increased risk of 1.80 (1.05–3.09) for ‘subsequent’ compared with ‘first’ births. Smoking during pregnancy was no longer associated with coeliac disease. Because numbers were small, maternal coeliac disease was excluded from the multivariate anaylsis.

Conclusions  This study shows increased risks of coeliac disease for manual social classes, births during the late 1970s and ‘subsequent’ births. Overall, perinatal risk factors seem to have a limited role in the aetiology of coeliac disease in children and young adults.
Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8‐year period
Authors: Raschi Emanuel , Poluzzi Elisabetta , Zuliani Chiara , Muller Arno , Goossens Herman , De Ponti Fabrizio
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Several noncardiovascular drugs with QT liability are currently on the market.

• Previous epidemiological studies have shown significant exposure of the general population to drugs with QT liability with similar consumption in many European countries.

• Several regulatory measures have concerned medicinal products carrying a pro‐arrhythmic risk in humans.

WHAT THIS STUDY ADDS

• The list of antibacterial agents with documented QT liability has grown over the last few years.

• Notwithstanding stringent regulatory measures, population exposure to antibiotics with QT liability is still significant in several countries.

• The magnitude of the problem is clearly heterogeneous, with remarkable diversity between Northern and Southern countries (lower and higher exposure, respectively).

AIMS

(i) To classify antibacterial agents with QT liability on the basis of the available evidence, and (ii) to assess trends in their consumption over an 8‐year period (1998–2005) in 14 European countries.

METHODS

Current published evidence on QT liability of antibiotics was retrieved through MEDLINE search and joined to official warnings from regulatory agencies. Each drug was classified according to an already proposed algorithm based on the strength of evidence: from group A (any evidence) to group E (clinical reports of torsades de pointes and warnings on QT liability). Consumption data were provided by the European Surveillance of Antibacterial Consumption (ESAC) project and were expressed as defined daily doses per 1000 inhabitants per day (DID).

RESULTS

Among 21 detected compounds, nine [six fluoroquinolones (FQs) and three macrolides (MACs)] belonged to group E. Use of group E drugs ranged from 1.3 (Sweden) to 4.1 DID (Italy) in 1998 and from 1.2 (Sweden) to 6.5 DID (Italy) in 2005. Significant exposure was observed in Italy and Spain (6.5 and 3.8 DID, respectively, in 2005). Only Denmark, Sweden and UK showed a slight decrease in use. Exposure to clarithromycin increased in 10 out of 14 countries, with a marked increment in Italy (3 DID in 2005).

CONCLUSIONS

Notwithstanding regulatory measures, in 2005 there was still significant exposure to antibacterials with strong evidence of QT liability and, in most countries, it was even increased. This warrants further investigation of appropriateness of use and suggests closer monitoring of group E drugs. Physicians should be aware when prescribing them to susceptible patients.
Oxycodone is associated with dose‐dependent QTc prolongation in patients and low‐affinity inhibiting of hERG activity in vitro
Authors: Fanoe Søren , Jensen Gorm Boje , Sjøgren Per , Korsgaard Mads P. G. , Grunnet Morten
Published: October 2008

WHAT IS ALREADY KNOWN

• During recent years some opioids have been associated with prolonged QT and torsade de pointes (TdP).

• In vitro testing has shown that most opioids can block the cardiac potassium channels.

• This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs.

WHAT THIS PAPER ADDS

• This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293.

• Neither morphine nor tramadol doses are associated with the QT interval length.

AIMS

During recent years some opioids have been associated with prolonged QT interval and torsade de pointes (TdP). In vitro patch clamp testing has shown that most opioids can block human ether‐a‐go‐go related gene (hERG) channels that are known to underlie cardiac repolarizing IKr current. This indicates that QT prolongation and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro.

METHODS

One hundred chronic nonmalignant pain patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross‐sectional study. The QTc was estimated from a 12‐lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing hERG channels.

RESULTS

There were no differences in gender distribution or age between the treatment groups. The known association between methadone dose and QTc was confirmed (R2 = 0.09; P = 0.02). Higher oxycodone dose was also associated with longer QTc (R2 = 0.21; P = 0.02). A 100 mg higher oxycodone dose was associated with a 10 ms1/2 (95% CI 2–19) longer QTc. Neither morphine nor tramadol dose was associated with the QTc. Electrophysiological testing revealed low‐affinity inhibition of the potassium current through hERG channels expressed in HEK293 cells (IC50 = 171 µM oxycodone).

CONCLUSIONS

Among patients treated with methadone or oxycodone, higher doses were associated with longer QTc. Oxycodone is capable of inhibiting hERG channels in vitro.
In vivotreatment with a monoclonal chimeric anti-CD4 antibody results in prolonged depletion of circulating CD4+ cells in chimpanzees
Authors: JONKER M , SLINGERLAND W , TREACY G , van EERD P , PAK K Y , WILSON E , TAM S , BAKKER K , LOBUGLIO A F , RIEBER P , RIETHMULLER G , DADDONA P E , IULIUCCI J
Published: October 2008

Chimeric M-T412 (cM-T412). an anti-CD4 antibody, was tolerated in chimpanzees at a dosage of 5 mg/kg per day for up to 7 consecutive days, or 5 mg/kg per dose, twice weekly for 4 weeks. All cM-T412-treated chimpanzees showed a prolonged CD4 cell depression. Weak chimpanzee antibody responses to chimeric M-T412 were observed. One of the chimpanzees on the biweekly dosage regimen exhibited a hypersensitivity reaction immediately after receiving its seventh dose. Following supportive treatment, the animal recovered and remained asymptomatic during the non-treatment observation period. The hypersensitivity reaction was not an unexpected response considering the animal received repeated intermittent i.v. administration of a foreign protein. This animal also showed a chimpanzee antibody response to chimeric M-T412 after the seventh dose. Chimeric M-T412 also induced an anti-cM-T412 response in some of the other animals. The level of this response was lower than the anti-mouse responses observed in animals treated with murinc anti-CD4. Moreover, the anti-cM-T4l 2 response was mainly directed to idiotypic determinants. The decrease in CD4+ cells observed for all chimeric M-T412-treated chimpanzees is an expected effect of the anti-CD4 antibody. The duration of this CD4+ cell decrease is. however, much longer than observed for other CD4-specific MoAbs described. No selective loss of either memory or naive CD4+ cells was observed after cither the single, 7-day or twice-weekly treatments. The CD4+ cell depression was reversible, although individual variation in time to recovery was observed. Therefore, cM-T412 could be a good candidate for clinical use in autoimmune conditions.
Immune stimulatory and anti-tumour properties of haemin
Authors: TSUJI A , WANG J , STENZEL K H , NOVOGRODSKY A
Published: October 2008

IL-2 induces tumour regression in some patients with metastatic disease, but the dose of IL-2 is limited by severe toxicity. Agents that increase the expression of IL-2 receptors in the effector cells could be used to improve the effectiveness of IL-2 in mediating its anti-tumour effect. We have reported that haemin increased the expression of IL-2 receptors in human peripheral blood mononuclear cells (PBMC) and synergized with IL-2 in the induction of mitogenicity, cytotoxicity and cytokine production. We now report on haemin-induced immune stimulation and tumour regression in mice. Haemin-induced mitogenicity in mouse splenocytes was potentiated up to twofold by IL-2. The combination of haemin and IL-2 was also effective in inducing cytotoxicity for natural killer (NK)-resistant target cells. Maximal induction of cytotoxicity was attained at an optimal concentration of haemin of 10 μm. Higher concentrations were less effective. Splenocytes isolated from mice that had been treated in vivo with haemin and IL-2 incorporated twice the amount of 3H-thymidine compared with splenocytes from mice treated with either haemin or IL-2 alone. Cytotoxicity of splenocytes for NK-rcsistant target cells was not increased following in vivo administration of haemin and IL-2 when fresh splenocytes were tested. Cytotoxicity was enhanced, however, up to five-fold following 48 h in vitro incubation with IL-2. Administration of haemin and IL-2 resulted in a significant decrease (40%) of established hepatic metastases in mice. Either IL-2 or haemin alone at the dose used were ineffective. The anti-tumour effect of haemin and IL-2 was enhanced (63% decrease in metastases) by administration of the thiol compound, N-acetylcysteine. Since haemin can safely be administered to patients, it may represent a new class of biologic response modifiers that could enhance IL-2-mediated anti-tumour effects.
Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155
Authors: APPLEBY P , TELFORD G , NAYLOR G B
Published: October 2008

Autoimmune disease in NZB/W F1 mice was treated from 23 weeks of age with the novel immunomodulator BTS 63155 and, for comparative purposes, the established immunosuppressive agent cyctosporin A. Both drugs significantly improved survival compared with untreated controls. Lupus nephritis was also significantly reduced in the drug–treated groups, and this was related to reduced glomerular deposition of IgG. Autoantibody (ANA) levels were lowered by treatment with cyclosporin A, but not by BTS 63155. This latter finding may indicate a different mode of action for the two drugs. In a long term study, neither drug effected a complete cure, as autoimmune disease recurred on withdrawal of drug treatment.
The anti-arthritic and immunosuppressive effects of cyclosporin A on collagen-induced arthritis in the rhesus monkey
Authors: BAKKER N P M , VAN BESOUW N , GROENESTEIN R , JONKER M , 'tHART L A
Published: October 2008

The influence of cyclosporin A (CsA) on type II collagen-induced arthritis (CIA) in the rhesus monkey has been investigated. CsA was administered subcutaneously in a dose of 25 mg/kg per day during 9–18 days and additionally 12·5 mg/kg per day for 7 days. At this dosing regime no significant alterations of hacmalologic parameters were found, indicating that the toxicity of CsA was negligible. Administration of CsA after onset of arthritis had no beneficial effect, but when given between immunization and manifestation of clinical symptoms, CIA could be prevented completely. Moreover, these monkeys became resistant to the disease, because no arthritic activity could be observed upon a booster immunization with type II collagen (CII). The suppression of disease by CsA is reflected in reduced antibody levels to CII.
T cell activation and disease severity in HIV infection
Authors: MAHALINGAM M , PEAKMAN M , DAVIES E T , POZNIAK A , McMANUS T J , VERGANI D
Published: October 2008

In vitro studies have indicated that T lymphocyte activation may be of importance in the pathogenesis of HIV infection. In order to define the role of immune activation in vivo, we assessed the expression of the T cell activation markers HLA-DR and CD25 by flow cytometry in peripheral blood in relation to disease severity and the surrogate markers CD4 and β2-microglobulin in 157 patients with HIV infection and 53 healthy seronegative blood donors. Percentage levels of CD3+HLA-DR+ T lymphocytes were significantly higher (P<0·0001) and percentage levels of CD3+CD25+ T lymphocytes significantly lower (P<0·0001) in all HIV+ patients compared with controls. A significant correlation was observed between increasing percentage levels of CD3+HLA-DR+ T lymphocytes and both declining CD4 counts (r = 0·52; P<0·001) and increasing β-microglobulin levels (r = 0·56; P<0·001). Percentage levels of CD4+HLA-DR+ and CD4+CD25+ lymphocytes were significantly higher in all HIV+ patients compared with controls (P< 0·001). Levels of activated (HLA-DR+ and CD25+) CD4+ lymphocytes showed a significant step-wise linear increase with increasing disease severity (P < 0·001). High levels of CD3+ HLA-DR+ T lymphocytes were found in a greater proportion (81·8%) of asymptomatic HIV+ patients (Centres for Disease Control (CDC) group II) than low CD4 counts (51·5%) (P<0·001). Compared with controls, HIV+ patients had higher percentage levels of CD8+HLA-DR+ lymphocytes (P<0·001), but similar levels of CD8+CD25+ lymphocytes. These results indicate that T cell activation is not only a consistent but also an early feature in HIV infection. Monitoring levels of activated T cells and their subsets is of value in assessing progression of HIV-related disease.
Increased CD11/CD18 expression on the peripheral blood leucocytes of patients with HIV disease: relationship to disease severity
Authors: PALMER S , HAMBLIN A S
Published: October 2008

In HIV disease increased adhesion between leucocytes themselves and between leucocytes and endothelium may contribute to cell loss and viral spread. Using a novel method for the preparation of blood leucocytes for flow cytometry, we report increased expression of leucocyte adhesion molecules (LeuCAMs) (CD11/CD18) on peripheral blood leucocytes of patients with HIV disease compared with normal controls. Patients were divided into two groups on the basis of CD4 T lymphocyte numbers (those with >0·5 × 109/l and those with <0·2 × 109/l), and assessed for p24 antigen expression, viral load and serum tumour necrosis factor (TNF) levels as well as LeuCAM expression. Patients with < 0·2 × 109/l CD4 cells had more p24 antigen and more HIV infectious virus and more serum TNF than those with > 0×5 × 109/l. Whilst the percentages of only monocytes and polymorphs expressing CD11b were significantly increased in patients with the least CD4 cells, the density of LeuCAMs, expressed as mean fluorescence intensity (MFI), was significantly increased on all leucocytes, with the most significant increases being seen on patients with the fewest CD4 T cells. Our findings are consistent with leucocyte activation by a soluble factor, although we could find no correlation between levels of TNF and LeuCAM expression. The increased expression of adhesion molecules on peripheral blood leucocytes could play a role in the cellular extravasation and aggregation seen in HIV disease.
Soluble tumour necrosis factor receptors (sTNF-R) and HIV infection: correlation to CD8+ lymphocytes
Authors: KALINKOVICH A , LIVSHITS G , ENGELMANN H , HARPAZ N , BURSTEIN R , KAMINSKY M , WALLACH D , BENTWICH Z
Published: October 2008

The objective or this study was to determine sTNF-R, type I (p55) and type II (p75) in sera of HIV-infected male homosexuals and correlate them to T lymphocyte subpopulations and course of HIV infection. Serum samples were obtained from 39 HIV-1+ asymptomatic male homosexuals, 10 symptomatic (ARC and AIDS) male homosexuals and 44 HIV non-homosexual healthy controls. sTNF-R levels were determined by ELISA with specific MoAbs and polyclonal antibodies to the sTNF-R proteins. sTNF-RI and II levels were significantly elevated in 72% and 74%, respectively of HIV+ asymptomatic male homosexuals and in all of the symptomatic male homosexuals. In sequential studies a highly significant positive correlation was found between sTNF-RI and sTNF-RII (r=0·8, P<0·00))and between both sTNF-R and CD8+ lymphocyte counts (r= 0·6 and 0·92. respectively, P<0.01–0.001) during the asymptomatic stage of the infection. All these correlations were lost, however, during the symptomatic phase of the disease. These results suggest that: (i) HIV infection is associated with elevation of sTNF-R serum levels; (ii) sTNF-R levels arc strongly correlated to CDS+ lymphocytes during the asymptomatic stage of HIV infection.
Lysis of CD4+ lymphocytes by non-HLA-restricted cytotoxic T lymphoe from HIV-infected individuals
Authors: GRANT M D , SMAILL F M , ROSENTHAL K L
Published: October 2008

Individuals infected with HIV have elevated numbers of total and activated CD8+ lymphocytes in peripheral blood. CD8+ lymphocytes from HIV-infected individuals have been shown to mediate non-human histocompatibility-linked antigen (HLA)-restricted suppression of viral replication, HLA-restricted killing of cells expressing HIV antigens, and killing of uninfected lymphocytes. We studied CD8+ T lymphocytes that lysed autologous CD4+ lymphocytes, hetcrologous CD4+ lymphocytes from HIV-infected individuals and uninfected CD4+ lymphocytes. Killing in all cases required T cell receptor (TCR)-mediated recognition or triggering. However, these CD8 cytotoxic T lymphocytes (CTL) killed HLA class I mismatched CD4+ lymphocytes and CD4+ lymphocytes treated with a MoAb against HLA-A, B and C antigens (PA2.6) which blocks HLA class I-restricted killing. HLA class H-negativc CD4+ T lymphoma cells (CEM.NKR) were also killed by anti-CD3 inhibited CTL. Stimulation of peripheral blood lymphocytes (PBL) from HIV-infected individuals, but not uninfected controls, with concanavalin A (Con A) and IL-2, induced non-HLA-restricted TCR αβ+, CD8+ CTL which lysed CD4+ lymphocytes. Activation of CD4+ lymphocytes increased their susceptibility to CD8+ CTL-mediated lysis. In HIV infection, a population of non-HLA-restricted CTL which lyse activated CD4+ lymphocytes is expanded. The expansion of CTL with unusual characteristics is interesting, because the stimulus for this expansion is unknown. CTL which recognize activated CD4+ cells could play a role in immune regulation and the pathogenesis of A IDS.