[Show abstract][Hide abstract] ABSTRACT: Background
The safety of anti-tumour necrosis factor (TNF) agents during pregnancy is a major concern for child-bearing women and physicians.AimTo assess the impact of anti-TNF therapy on adverse pregnancy and foetal outcomes in women with inflammatory bowel disease (IBD).Methods
Pregnancies occurring during anti-TNF treatment or less than 3 months after its cessation in IBD patients followed in GETAID centres were recorded from January 2009 to December 2010. Ninety-nine pregnancies in women without anti-TNF treatment were identified from the CESAME registry. We compared pregnancy and neonatal outcomes by a case–control study.ResultsIn the 124 IBD patients followed, 133 pregnancies were reported. At the conception time, 23% of patients had active disease. Eighty-eight per cent (n = 117) of the 133 pregnancies followed until delivery resulted in 118 liveborns (one twin pregnancy). Complications were observed in 47 (35%) women and 24 (20%) newborns. In multivariate analysis, factors associated with pregnancy complications were: current smoking (P = 0.004), a B2 (stenotic) phenotype in CD women (P = 0.004), occurrence of a flare during pregnancy (P = 0.006) and a past history of complicated pregnancy (P = 0.007). Current smoking was the only factor associated with severe (i.e. potentially lethal) pregnancy complications (P = 0.02). Having IBD for more than 10 years prior to conception was associated with newborn complications (P = 0.007). No difference was found with the control group for any of the pregnancy and neonatal outcomes.Conclusion
In our series, the safety profile of anti-TNF therapy during pregnancy and the neonatal period appears similar to control group of IBD women not treated with anti-TNF therapy.
[Show abstract][Hide abstract] ABSTRACT: CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn's disease. Crohn's Disease Activity Index (CDAI) scores were 250-450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn's medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00306215.
PLoS ONE 01/2013; 8(3):e60094. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Active inflammatory bowel disease (IBD) is associated with increased activity of inducible nitric oxide synthase (iNOS), which increases both mucosal and plasma nitric oxide (NO) levels. Increased fractional exhaled nitric oxide (FeNO) levels have been described in patients with IBD. Currently, hand-held FeNO measurement devices are available, enabling a fast in-office analysis of this non-invasive disease activity marker. In this pilot study, we investigated the utility of in-office FENO measurements in patients with Crohn's disease (CD). METHODS: Fifty CD patients and 25 healthy controls (HC) were included, all of whom were free of atopic or pulmonary disorders and respiratory symptoms at the time of inclusion. The Crohn's disease activity index (CDAI) was calculated, and the inflammatory parameters and fecal calprotectin levels were assessed. FeNO was measured with a hand-held device. RESULTS: A significant increase in FeNO (median, [interquartile range]) was observed in steroid-free CD patients with clinically active disease (CDAI>150; 22  ppb) compared with CD patients in clinical remission (CDAI<150; 11  ppb; P<0.001) and HC's (17  ppb; P<0.05). Active CD patients treated with corticosteroids had significantly lower FeNO compared with active CD patients without steroids (12  ppb vs 25  ppb; P<0.05). FeNO displayed a strong correlation with the CDAI (R=0.68; P<0.001). Fair correlations were found between FeNO and several systemic inflammatory markers, but no significant correlation was found with fecal calprotectin. CONCLUSION: This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of systemic inflammation in Crohn's disease.
Journal of Crohn s and Colitis 10/2012; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: (Full text is available at http://www.manu.edu.mk/prilozi). To fully understand the cognitive processes occurring in the human brain, high resolution in both spatial and temporal information is needed. Most neuroimaging approaches, however, only possess high accuracy in one of these two domains. Therefore, the multimodal analysis of brain activity is becoming more and more popular among the research community. One of these approaches concerns the integration of simultaneously acquired electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) data. This combination poses a series of challenges, ranging from recovering data quality to the fusion of two types of data of a completely different nature. In this work, several of these challenges will be addressed, and an overview of different integration approaches is provided. Key words: magnetic resonance imaging, EEG, fMRI, multimodal analysis.
Prilozi / Makedonska akademija na naukite i umetnostite, Oddelenie za biološki i medicinski nauki = Contributions / Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences 07/2012; 33(1):373-90.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC).
In this prospective study 53 patients with active UC from 17 centers were treated with infliximab therapy (5 mg/kg) at baseline, week 2, and week 6. Faecal calprotectin was measured every week. Sigmoidoscopies were performed at baseline, week 6 and week 10.
Median calprotectin levels decreased from 1260 (IQR 278.5- 3418) at baseline to 72.5 (IQR 18.5 - 463) at week 10 (p<0.001). After 10 weeks, infliximab therapy induced endoscopic remission and a decrease in calprotectin to<50 mg/kg or at least a 80% decrease from baseline level in 58% of patients. A significant and steep decrease of calprotectin levels was seen at week 2 for patients with an endoscopic remission at week 10 as compared to patients who did not show a remission. (p<0.001). At week 10 an excellent correlation was found between endoscopic remission and clinical Mayo score reflected by an AUC of ROC analyses of 0.94 (0.87-1) and with calprotectin measurements (AUC 0.91 (0.81-1)) : all patients with calprotectin levels <50 mg/kg, and a normal clinical Mayo score (=0) were in endoscopic remission.
Infliximab induces a fast and significant decrease of faecal calprotectin levels in anti-TNF naïve patients with ulcerative colitis predictive for remission of disease.
Journal of Crohn s and Colitis 12/2011; 6(5):557-62. · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigates whether deoxy-2-[18F]fluoro-d-glucose (FDG) micro-positron emission tomography (μPET)/computed tomography (CT) can serve as a tool for monitoring of the commonly used dextran sodium sulfate (DSS)-induced murine model of inflammatory bowel disease (IBD).
DSS-colitis was induced in Sv129 mice. In a first experiment, four animals were serially scanned with CT and FDG-μPET on days 0, 3, 7, 11, and 14. The ratio of the mean voxel count of the PET images in the colon and the brain was compared with the histological inflammation score and the colonic myeloperoxidase levels. A second experiment was performed to investigate whether FDG-μPET was able to detect differences in inflammation between two DSS-treated groups, one receiving placebo (n = 4) and one receiving dimethyloxalylglycine (DMOG) (n = 4), a compound that protects against DSS-induced colitis.
The progression of the colonic/brain FDG-signal ratio (over days 0-14) agreed with the predicted histological inflammation score, obtained from a parallel DSS-experiment. Moreover, the quantification of normalized colonic FDG-activity at the final timepoint (day 14) showed an excellent correlation with both the MPO levels (Spearman's rho = 1) and the histological inflammation score (Spearman's rho = 0.949) of the scanned mice. The protective action of DMOG in DSS colitis was clearly demonstrated with FDG-μPET/CT (normalized colonic FDG-activity DMOG versus placebo: P < 0.05).
FDG-μPET-CT is a feasible and reliable noninvasive method to monitor murine DSS-induced colitis. The implementation of this technique in this widely used IBD model opens a new window for pathophysiological research and high-throughput screening of potential therapeutic compounds in preclinical IBD research.
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) are major regulators of pathological angiogenesis, which is a prominent feature of both Crohn's disease (CD) and peripheral synovitis in spondyloarthritis.
To investigate the presence of VEGF-A and PlGF in the gut of spondyloarthritis patients and to link this finding with subclinical gut inflammation in these patients.
Intestinal biopsies from healthy controls, CD patients, spondyloarthritis patients with or without subclinical gut inflammation and rheumatoid arthritis (RA) patients were stained for VEGF-A, PlGF, CD31 and vascular cell adhesion molecule 1 (VCAM-1) and digitally analysed.
Spondyloarthritis patients with subclinical gut inflammation had markedly increased intestinal VEGF-A expression (p<0.001), mucosal vascularisation (p<0.001) and VCAM-1 expression (p<0.01) compared with healthy controls and RA patients, which, unlike in CD patients, was also seen when the gut inflammation was in a quiescent state. PlGF expression was highly increased in the subclinically inflamed gut of spondyloarthritis (p<0.01 compared with healthy controls), but not at all in CD.
A pro-angiogenic intestinal phenotype is observed in spondyloarthritis patients with quiescent chronic gut inflammation. This favours an environment for enhanced trafficking of immune cells in this subpopulation.
Annals of the rheumatic diseases 08/2011; 70(11):2044-8. · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The description and evaluation of algorithms using Independent Component Analysis (ICA) for automatic removal of ECG, pulsation and respiration artifacts in neonatal EEG before automated seizure detection.
The developed algorithms decompose the EEG using ICA into its underlying sources. The artifact source was identified using the simultaneously recorded polygraphy signals after preprocessing. The EEG was reconstructed without the corrupting source, leading to a clean EEG. The impact of the artifact removal was measured by comparing the performance of a previously developed seizure detector before and after the artifact removal in 13 selected patients (9 having artifact-contaminated and 4 having artifact-free EEGs).
A significant decrease in false alarms (p=0.01) was found while the Good Detection Rate (GDR) for seizures was not altered (p=0.50).
The techniques reduced the number of false positive detections without lowering sensitivity and are beneficial in long term EEG seizure monitoring in the presence of disturbing biological artifacts.
The proposed algorithms improve neonatal seizure monitoring.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 06/2011; 122(12):2345-54. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TPMT deficiency is associated with azathioprine (AZA)-induced myelosuppression (MS). However, in one previous study, only about ¼ of MS episodes in Crohn's Disease patients under AZA can be attributed to TPMT deficiency. Recently, new TPMT mutations have been described and our aim is to investigate their clinical relevance before and after a first MS episode on thiopurine therapy.
Clinical data from 61 IBD patients having developed MS during AZA therapy were collected. Sequencing analysis was carried out on TPMT cDNA for the presence of all currently known mutations.
Only TPMT *2, *3A and *3C mutations were found in this cohort. TPMT mutations were observed in 15 out of 61 patients (25%). Four out of 15 were homozygous for a TPMT mutation (low methylator, LM genotype) and 11 were heterozygous (intermediate methylator, IM genotype). Median delays of MS onset were 2, 2.75 and 6months in the LM, IM and HM (high methylator, wild type TPMT) groups, respectively. After the first MS episode, 36 patients resumed thiopurine treatment of which 13 experienced a second MS episode. This second episode was also rarely associated with TPMT mutations.
One quarter of MS episodes during AZA were associated with TPMT deficient genotype. After a first leucopenia episode, thiopurine therapy may be resumed in a majority of patients independently of their TPMT genotype.
[Show abstract][Hide abstract] ABSTRACT: The important co-existence of spondylarthritis (SpA) and inflammatory bowel disease (IBD) within the same individual suggests common etiopathogenic mechanisms. This is supported by intriguing similarities between both diseases at the subclinical and molecular level. The recent advances in IBD genetics have led to the identification of common pathways involved in both IBD and SpA, including bacterial recognition and ER stress. This offers the opportunity to develop potential new therapeutic strategies for both diseases. Transgenic animals which develop both joint and gut inflammation (like the TNF(ΔARE) mice and the HLA-B27 transgenic rats) are a very useful tool to test such novel therapeutics and to get further mechanistic insight into the pathogenetic link between SpA and IBD. This review will focus on the recent scientific progress in our understanding of the link between SpA and IBD. Based on this, potential novel therapeutic strategies are discussed.
Best practice & research. Clinical gastroenterology 04/2011; 25 Suppl 1:S19-26. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To validate an improved automated electroencephalography (EEG)-based neonatal seizure detection algorithm (NeoGuard) in an independent data set.
EEG background was classified into eight grades based on the evolution of discontinuity and presence of sleep-wake cycles. Patients were further sub-classified into two groups; gpI: mild to moderate (grades 1-5) and gpII: severe (grades 6-8) EEG background abnormalities. Seizures were categorised as definite and dubious. Seizure characteristics were compared between gpI and gpII. The algorithm was tested on 756 h of EEG data from 24 consecutive neonates (median 25 h per patient) with encephalopathy and recorded seizures during continuous monitoring (cEEG). No selection was made regarding the quality of EEG or presence of artefacts.
Seizure amplitudes significantly decreased with worsening EEG background. Seizures were detected with a total sensitivity of 61.9% (1285/2077). The detected seizure burden was 66,244/97,574 s (67.9%). Sensitivity per patient was 65.9%, with a mean positive predictive value (PPV) of 73.7%. After excluding four patients with severely abnormal EEG background, and predominantly having dubious seizures, the algorithm showed a median sensitivity per patient of 86.9%, PPV of 89.5% and false positive rate of 0.28 h(-1). Sensitivity tended to be better for patients in gpI.
The algorithm detects neonatal seizures well, has a good PPV and is suited for cEEG monitoring. Changes in electrographic characteristics such as amplitude, duration and rhythmicity in relation to deteriorating EEG background tend to worsen the performance of automated seizure detection.
cEEG monitoring is important for detecting seizures in the neonatal intensive care unit (NICU). Our automated algorithm reliably detects neonatal seizures that are likely to be clinically most relevant, as reflected by the associated EEG background abnormality.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 03/2011; 122(8):1490-9. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Simultaneous EEG-fMRI measurements can combine the high spatial resolution of fMRI with the high temporal resolution of EEG. Therefore, we applied this approach to the study of peripheral vision. More specifically, we presented visual field quadrant fragments of checkerboards and a full central checkerboard in a simple detection task. A technique called "integration-by-prediction" was used to integrate EEG and fMRI data. In particular, we used vectors of single-trial ERP amplitude differences between left and right occipital electrodes as regressors in an ERP-informed fMRI analysis. The amplitude differences for the regressors were measured at the latencies of the visual P1 and N1 components. Our results indicated that the traditional event-related fMRI analysis revealed mostly activations in the vicinity of the primary visual cortex and in the ventral visual stream, while both P1 and N1 regressors revealed activation of areas in the temporo-parietal junction. We conclude that simultaneous EEG-fMRI in a spatial detection task can separate visual processing at 100-200 ms from stimulus onset from the rest of the information processing in the brain.
[Show abstract][Hide abstract] ABSTRACT: Recurrent acute pancreatitis is a rare clinical entity in childhood with unknown incidence (Rosendahl et al., 2007) and often occurring in a familial context. Genetic factors such as PRSS1 mutations (cationic trypsinogen gene) can be found in some patients. However, many remain idiopathic. The natural history remains poorly documented and the most frequent complications reported are pain, exocrine pancreatic insufficiency, diabetes mellitus, and pancreatic adenocarcinoma after long-standing hereditary pancreatitis. We describe a patient with hereditary pancreatitis in whom a mild pancreatitis episode was complicated by a perforation of the ductus choledochus.
Case reports in gastrointestinal medicine. 01/2011; 2011:413268.
[Show abstract][Hide abstract] ABSTRACT: A new, automated way to obtain signatures of active motor units (MUs) from high density surface EMG recordings during voluntary contractions is presented. It relies on clustering of repetitive shapes corresponding to different MU action potentials (MUAPs) present. The number of clusters and the mean shapes of the MUAPs as observed on the electrode grid, are estimated in a fast way without user interaction. The algorithm is tested on simulated signals mimicking a small muscle. Our results show that at least 8 MUAPs can be reliably reconstructed and their MU mean firing frequencies can be estimated.
Engineering in Medicine and Biology Society,EMBC, 2011 Annual International Conference of the IEEE; 01/2011
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
[Show abstract][Hide abstract] ABSTRACT: Blind Source Separation (BSS) techniques are frequently needed in the processing of biomedical signals. This need comes from the fact that these signals are often composed of many different sources, which are mixed in the measured signal. However, we are usually only interested in examining one or a limited set of sources of interest separately. A variety of algorithms exist for separating multichannel mixtures into its independent sources (e.g. different Independent Component Analysis (ICA) techniques). These techniques only work if the number of channels is larger than, or equal to the number of sources present in the signal. On the other hand, only a few algorithms have been reported for the analysis of single channel sources, or other mixtures where the number of sources is higher than the number of channels. In this work we show a new technique which combines Empirical Mode Decomposition (EMD) and Independent Component Analysis (ICA). We will show that this technique is capable in separating independent sources when the number of these sources is higher than the number of channels available. We show the performance in single channel and two-channel biosignal processing.
Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 10/2010
[Show abstract][Hide abstract] ABSTRACT: A common cause for damage to the neonatal brain is a shortage in the oxygen supply to the brain or asphyxia. Neonatal seizures are the most frequent manifestation of neonatal neurologic disorders. Multichannel EEG recordings allow topographic localization of seizure foci.
We want to objectively determine the spatial distribution of the seizure on the scalp, the location in time and order the dominant sources in the brain based on their strength.
In this paper we combine a method based on higher order CP-decomposition with subsequent singular value decomposition (SVD).
We illustrate the abilities of the method on simulated as well as on real neonatal seizure EEG.
The proposed method provides reliable time and spatial information about the seizure, gives a clear overview of what is going on in the EEG and allows easy interpretation.
Methods of Information in Medicine 01/2010; 49(5):473-8. · 1.08 Impact Factor