Susana Lopes

Anaemia in Patients with Inflammatory Bowel Disease - A Nationwide Cross-Sectional Study

Background: Anaemia is the most common complication in patients with inflammatory bowel disease (IBD). This study aims to assess the prevalence of anaemia in IBD patients and to know its characteristics with regard to the main IBD clinical features. Methods: An observational cross-sectional multicentre study was conducted. We included all patients who had an appointment at the 15 participating centres during the period of 1 month, and who met the following selection criteria: age ≥18, diagnosis of IBD. Disease activity was evaluated by Harvey-Bradshaw Index (HBI) for Crohns disease (CD), and by Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Results: One thousand three hundred and thirteen patients, were included: 54.8% female, mean age 42.8 (interquartile range (25th-75th): 31-53 years), 59% had a diagnosis of CD, 39% of UC and 2% IBD unclassified. The median follow-up since diagnosis was 7 years. The ongoing treatment was aminosalicylates (63.1%), corticosteroids (11.6%), immunomodulators (36.4%) and anti-tumour necrosis factor (27.3%). Anaemia was identified in 244 patients, representing a prevalence of 18.6% (95% CI 16.6-20.9). A majority of cases (90%) have mild/moderate anaemia (mean haemoglobin 11.3 ± 0.8 g/dl). Anaemia was significantly higher in females (p = 0.006), but there were no differences between CDs (19.1%) and UCs (17.7%; p = 0.688). Anaemia was more frequent in patients with active disease (HBI >4; SCCAI >2) than in those in clinical remission (33.6 vs. 15.6%, p < 0.001) and in patients on steroids (36.8%) vs. other treatments (p < 0.001). Only 47% of patients with anaemia were under any specific treatment (oral iron 67%; intravenous iron 41%). Conclusion: Anaemia was more frequent in patients with active disease and in those on corticosteroids. The treatment of anaemia still seems undervalued, whereas more than half of anaemic patients were not receiving any specific treatment and the use of oral iron prevails contrarily to current recommendations.

Ethyl 4-do­decyl-3,5-di­methyl-1H-pyrrole-2-carboxyl­ate: intermolecular interactions in an amphiphilic pyrrole

The title compound, C(21)H(37)NO(2), is a new amphiphilic pyrrole with a long hydrocarbon chain, which will be used as a precursor for the synthesis of Langmuir-Blodgett films of porphyrins. Molecules related by an inversion centre are joined head-to-head into dimers by strong N-H.O hydrogen bonds. The dimers pack in the structure with their carbon chains parallel to one another, thereby forming alternating layers of carbon chains and pyrrole heads. The structure is further stabilized by two weak C-H.pi intermolecular interactions, thereby saturating the hydrogen-bonding capability of the aromatic pi-electron clouds.

Accuracy of Faecal Calprotectin and Neutrophil Gelatinase B-associated Lipocalin in Evaluating Subclinical Inflammation in UlceRaTIVE Colitis-the ACERTIVE study.

Background and AimsnMucosal healing and histological remission are different targets for patients with ulcerative colitis, but both rely on an invasive endoscopic procedure. This study aimed to assess faecal calprotectin and neutrophil gelatinase B-associated lipocalin as biomarkers for disease activity in asymptomatic ulcerative colitis patients.nnnMethodsnThis was a multicentric cross-sectional study including 371 patients, who were classified according to their endoscopic and histological scores. These results were evaluated alongside the faecal levels of both biomarkers.nnnResultsnMacroscopic lesions [i.e. endoscopic Mayo score ≥1] were present in 28% of the patients, and 9% had active disease according to fht Ulcerative Colitis Endoscopic Index of Severity. Moreover, 21% presented with histological inflammation according to the Geboes index, whereas 15% and 5% presented with focal and diffuse basal plasmacytosis, respectively. The faecal levels of calprotectin and neutrophil gelatinase B-associated lipocalin were statistically higher for patients with endoscopic lesions and histological activity. A receiver operating characteristic-based analysis revealed that both biomarkers were able to indicate mucosal healing and histological remission with an acceptable probability, and cut-off levels of 150-250 μg/g for faecal calprotectin and 12 μg/g for neutrophil gelatinase B-associated lipocalin were proposed.nnnConclusionsnFaecal calprotectin and neutrophil gelatinase B-associated lipocalin levels are a valuable addition for assessment of disease activity in asymptomatic ulcerative colitis patients. Biological levels of the analysed biomarkers below the proposed thresholds can rule out the presence of macroscopic and microscopic lesions with a probability of 75-93%. However, caution should be applied whenever interpreting positive results, as these biomarkers present consistently low positive predictive values.

Ethyl 3,5-dimethyl-4-phenyl-1H-pyrrole-2-carboxylate.

In the title compound, C(15)H(17)NO(2), the ethoxycarbonyl group is anti with respect to the pyrrole N atom. The angle between the planes of the phenyl and pyrrole rings is 48.26 (9) degrees. The molecules are joined into dimeric units by a strong hydrogen bonds between pyrrole N-H groups and carbonyl O atoms. The geometry of the isolated molecule was studied by ab initio quantum mechanical calculations, employing both molecular orbital Hartree-Fock (MO-HF) and density functional theory (DFT) methods. The minimum energy was achieved for a conformation where the angle between the planes of the phenyl and pyrrole rings is larger, and that between the ethoxycarbonyl and pyrrole planes is smaller than in the solid-state molecule.

CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma

Background: Cholangiocarcinoma is the second most frequent primitive liver malignancy and is responsible for 3% of the malignant gastrointestinal neoplasms. The aims of this study were to determine the association of serum levels of CA 19-9 at diagnosis with other clinical data and serum liver function tests and to identify possible factors that influence the survival rates during follow-up. Methods: Retrospective observational study of 89 patients with a diagnosis of cholangiocarcinoma followed at the Department of Gastroenterology during 5 years. Statistical analyses were performed using SPSS version 20.0. Results: Patients were followed up for a median time of 127 days (IQR: 48-564), and the median age at diagnosis was 71.0 years (IQR: 62.0-77.5). The median survival rate was 14.0 months (IQR: 4.3-23.7), and the mortality rate was 79%. Patients with CA 19-9 levels ≥103 U/L had lower albumin levels and higher levels of alanine aminotransferase and γ-glutamyltransferase. CA 19-9 levels ≥103 U/L were associated with a higher probability of metastization (p = 0.001) and lower rates of treatment with curative intent (p = 0.024). In a multivariate analysis, CA 19-9 levels <103 U/L and surgery were independent predictors of survival. Conclusion: Predictive factors for overall survival were identified, namely presence of metastasis, surgery, and chemotherapy. CA 19-9 levels ≥103 U/L were predictive factors for survival and metastization.

Ethyl 4-acetyl-3,5-di­methyl-1H-pyrrole-2-carboxyl­ate

In the title compound, C11H15NO3, the molxadecules are joined into dimers by a pair of strong hydrogen bonds between the pyrrole N atom and the carbonyl O atom of the carboxylxadate substituent [N⋯O 2.861u2005(2)u2005A and N—H⋯O 168u2005(2)°]. A single C—H⋯π intermolecular interaction is observed, with an H⋯π distance of 3.04u2005A, linking the dimers together.

Clinical performance of an infliximab rapid quantification assay

Background: Therapeutic drug monitoring (TDM)-based algorithms can be used to guide infliximab (IFX) adjustments in inflammatory bowel disease (IBD) patients. This study aimed to explore a rapid IFX-quantification test from a clinical perspective. Methods: This manuscript describes a prospective cohort study involving 110 ulcerative colitis (UC) patients on the maintenance phase of IFX. IFX trough levels were quantified using a rapid quantification assay and a commonly-used reference kit. Results: Irrespective of the assay used to measure IFX, its through levels were statistically different between patients with and without endoscopic remission (Mayo endoscopic score = 0), as well as between patients stratified by their faecal calprotectin (FC) levels. Despite the fact that the two methods correlated well with each other [Spearman’s rank correlation coefficient = 0.843, p < 0.001; intraclass correlation coefficients = 0.857, 95% confidence interval (CI): 0.791–0.903], there was a discernible systematic variation; values obtained with the reference kit were on average 2.62 units higher than those obtained with the rapid assay. Notwithstanding, 3 µg/ml was shown to be an acceptable cut-off to assess endoscopic status and inflammatory burden levels using both assays. The percentage of patients that had a positive outcome when the IFX concentration measured by the rapid assay ranked above 3 µg/ml was 88% both for a Mayo endoscopic score ⩽ 1 and for an FC concentration <250 µg/g. Conclusions: Based on this study, we concluded that using the rapid IFX assessment system with a 3 µg/ml threshold is a reliable alternative to the time-consuming enzyme-linked immunosorbent assays in patients on the maintenance phase of IFX.

Hydrogen-bonding and C—H⋯π interactions in ethyl 4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate monohydrate

In the title compound, C(16)H(17)NO(3).H(2)O, the pyrrole ring is distorted slightly from ideal C(2v) symmetry. Three strong hydrogen bonds link the substituted pyrrole and water molecules to form infinite chains, in which the hydrogen bonds form rings and chain patterns. Two intermolecular C-H.pi interactions maintain the internal cohesion between these chains. The molecular structure differs slightly from that of the isolated molecule calculated by ab initio quantum-mechanical calculations. In the latter model, the non-H substituent atoms share the plane of the pyrrole ring, except for the phenyl group, which lies almost perpendicular to this plane.

Calprotectin and the Magnitude of Antibodies to Infliximab in Clinically-stable Ulcerative Colitis Patients are More Relevant Than Infliximab Trough Levels and Pharmacokinetics for Therapeutic Escalation

Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62 μg/mL vs. 1.15 μg/mL, p = 0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI concentration below 3 μg/mL (HR = 0.119, p = 0.010), and increased for patients with fecal calprotectin (FC) level above 250 μg/g (HR = 9.309, p = 0.018). In clinically-stable UC patients, IFX pharmacokinetic features cannot predict therapeutic response on a short-term basis. However, high levels of ATIs or FC may be indicative of a future therapeutic escalation.

Crystal structure of iminodiacetic acid monomethyl ester monohydrate, C5H9NO4 · H2O

C5H11NO5, monoclinic, P12i/cl (No. 14), a = 5.212 Â, b= 16.881 Â,c= 10.116 Â,/?= 119.09°, V= 777.8 Â, Ζ = 4, R#(F) = 0.058, wRrefiF) = 0.180, Τ = 293 Κ. Source of material A mixture of iminodiacetic acid (16.8 g, 0.13 mol), thionyl chloride (30.9 g, 0.26 mol) and methanol (85 ml) was placed in a 250 ml round bottoned flask fitted with a reflux condenser and a silica guard tube. The mixture was stirred and heated under reflux for 4 hours. The solution was then washed with water/dichloromethane and the organic layer dried with anhydrous Na2SC>4, evaporated under reduced pressure and left to crystallise from dichloromethane/n-hexane. The (methoxycarbonylmethylamino)-acetic acid was obtained with 15% yield. Melting point: 411 Κ 413 Κ. Ft-IR (cm; group): (1643; C=0 ketone form), (3503; Ν—H). Experimental details The structure was solved by direct methods. The hydrogen atoms of the main residue were placed at calculated positions and refined as riding using the SHELXL-97 defaults [1], The crystal structure contains one water molecule disordered over three positions, sum of the their freely refined occupancies is 1.00(3). The isotropic temperature factors of the three water O atoms were constrained to be equal, the water Η atoms could not be located. Discussion Iminodiacetic acid and its derivatives are important compounds in coordination chemistry. The presence of two close carboxylic groups makes this molecule and its derivatives excellent ion coordination agents. This property has been fully exploited in the preparation of modified polymers and resins for ion capture, both for analytical [2-4] or industrial uses [5,6]. In medical related sciences, iminodiacetic acid derivatives are used as solid phase supports for peptide synthesis [7] and as base for chemical libraries in combinatory chemistry [8]. Iminodiacetic acid is also of great importance in organic chemistry, namely on the synthesis of maleimides [9] and 3,4 di-substituted pyrroles [10] by Friedman method. Following the preparation of the manganese complex of -octaphenyl-porphyrin for our studies of metalloporphyrin-based oxidation of hydrocarbons [11], we synthesised several iminodiacetic derivatives as pyrrole precursors, amongst them, the title compound. The conformation of the zwitterion is close to that found in the second polymorph form of iminodiacetic acid, IMDA2 [12]. The C4 atom is gauche to C1 when the ion is viewed along Ν—C3 and with C3 trans to C2 when viewed along Ν—C1. The formal negative charge is spread over the carboxylate group 03-C4-04 (C—O distances are: d(C4—03) = 1.250(2) Â, d(C4—04) = 1.243(3) Â). The bond distances of the carboxylic acid group indicate one double bond (d(C2=02) = 1.196(3) Â) and one single bond (d(C2—Ol) = 1.326(3) Â). The substituted half of the iminodiacetic acid molecule is approximated planar with Cl, C2, 01,02, C5 lying in a plane (rms deviation from L.S. plane 0.02 A), the nitrogen atom is 0.186(3) Â away from that plane. The zwitterions are bonded together by hydrogen bonds forming layers. The nitrogen atom donates its two hydrogen atoms to the oxygen atoms of the carboxylate groups of neighbouring molecules (N-Hl —03: 2.670(3) Â, 176.2°, 1: x+l, -y-1/2, z+1/2; N-H2-04: 2.986(3) A, 139.0°, ii: x+l.y, z). Using graph-set analysis [13] one recognise at the unitary level, chains of degree 5 running along the [ 100] and [201] directions. In the second polymorph form of iminodiacetic acid, one of the N-H—O bonds also forms a chain of degree 5 while the other displays only discrete patterns [13]. Table 1. Data collection and handling. Crystal: colourless prism, size 0.08 χ 0.10 χ 0.42 mm Wavelength: Cu Ka radiation (1.54180 Â) ft11.06 cm Diffractometer, scan mode: Enraf-Nonius Mach 3, ω/2θ 20max: 144.88° Admeasured, JVfAWjunique: 3178, 1550 Criterion for lobs, Nfhktfe: Jobs > 2 af/obs), 1346 N(param)Knaai: 105 Programs: SHELXS-97 [14], SHELXL-97 [1], PLATON [15], ORTEPn [16] * Correspondence author (e-mail: manuela@pollux.fis.uc.pt)