Leszek Paradowski

Enhanced formation of advanced oxidation protein products in IBD

Background: Advanced oxidation protein products (AOPPs) are new protein markers of oxidative stress with pro‐inflammatory properties, accumulated in many pathological conditions. The issue of their enhanced formation in IBD has not been addressed yet. Methods: The concentration of relative AOPPs (rAOPP; concentration of AOPPs divided by albumin level) were measured in 68 subjects with ulcerative colitis (UC), 50 subjects with Crohns disease (CD) and 45 healthy volunteers, and related to disease phenotype, clinical and biochemical activity, and therapeutic strategy. Diagnostic utility of rAOPP was evaluated by ROC analysis. Results: In comparison with controls (1.367 &mgr;mol/g), rAOPP were increased in inactive (1.778 &mgr;mol/g, P = 0.053) and active (1.895 &mgr;mol/g, P = 0.013) UC and in active (1.847 &mgr;mol/g, P = 0.003) CD. In CD, but not UC, rAOPP correlated with disease activity (r = 0.42, P = 0.013). Significant correlations with the inflammatory/malnutrition indices‐erythrocyte sedimentation rate (ESR) (r = 0.53), leukocytes (r = 0.33), platelets (r = 0.38), IL‐6 (r = 0.36), and transferrin (r = −0.35) were demonstrated in CD. In UC, rAOPP correlated only with ESR (r = 0.35) and IL‐6 (r = 0.30). Instead, associations with antioxidant dismutase (r = 0.29) and catalase (r = 0.22) were observed. The diagnostic power of rAOPP in discriminating diseased from non‐diseased subjects was less than that of C‐reactive protein (CRP). Simultaneous determination of rAOPP and CRP did not significantly improve the power of single CRP determination. Conclusions: IBD was associated with enhanced formation of AOPP, which differed between C and UC with respect to the relationship between rAOPP and disease activity, inflammatory and antioxidant response. These differences may reflect divergent ways that oxidative stress develops in CD and UC. The diagnostic power of rAOPP was insufficient for its clinical application.

Paraoxonase-1 status in Crohn's disease and ulcerative colitis

Background: Paraoxonase 1 (PON1) is an extracellular enzyme, which in the gastrointestinal tract may act as a local detoxifier, antioxidant, immunomodulator, and/or quorum‐quenching factor. There are no data on PON1 activity in Crohns disease (CD). Methods: PON1 phenotype and activity were determined spectrophotometrically in 52 subjects with CD, 67 with ulcerative colitis (UC), and 99 healthy individuals, and related to lipid peroxidation and disease phenotype, clinical and biochemical activity, and therapeutic strategy. Diagnostic utility of PON1 was evaluated by ROC analysis and compared with C‐reactive protein (CRP). Results: In comparison with controls (166 U), PON1 was reduced only in active CD (110 U, P < 0.0001) and UC (126 U, P < 0.0001), and correlated with disease activity (r = −0.47, P = 0.001 in CD and r = −0.50, P < 0.001 in UC). PON1 significantly correlated with erythrocyte sedimentation rate (ESR) (r = −0.36), platelets (r = −0.35), interleukin‐6 (r = −0.45), hemoglobin (r = 0.29), transferrin (r = 0.46), albumin (r = 0.60) in CD, and CRP (r = −0.29), ESR (r = −0.37), platelets (r = −0.43), leukocytes (r = −0.50), interleukin‐6 (r = −0.45), hemoglobin (r = 0.34), transferrin (r = 0.54), and albumin (r = 0.50) in UC. PON1 correlated positively with lipids but not with their peroxidation markers (thiobarbituric acid‐reactive substances, lipid hydroperoxides, ox‐LDL, and ox‐LDL autoantibodies). PON1 phenotype B (protective against IBD) tended to be less frequent in IBD patients than controls, and associated with lower concentration of inflammatory indices. PON1 was a poorer indicator of CD or UC than CRP. Conclusions: PON1 was reduced in IBD, despite treatment with antioxidant 5′‐aminosalicylate derivatives. PON1 reflected disease activity, inflammation severity, and anemia but not lipid peroxidation. The diagnostic power of PON1 was insufficient for its clinical application.

Phase I, double‐blind, randomized, placebo‐controlled, dose‐escalation study of NI‐0401 (a fully human anti‐CD3 monoclonal antibody) in patients with moderate to severe active Crohn's disease

Background: NI‐0401 is a fully human monoclonal antibody, which binds to the CD3 subunit of the T‐cell receptor, causing modulation of T‐cell activity. We investigated the safety and the ability to modulate the TCR‐CD3 complex of NI‐0401 in patients with active Crohns disease (CD). Methods: A double‐blind, placebo‐controlled, randomized, multicenter, dose‐escalating trial was conducted in CD patients age 18–70 years, a Crohns Disease Activity Index (CDAI) of 220–450, and detectable levels of C‐reactive protein. The primary outcome was safety and the ability of NI‐0401 to modulate the TCR‐CD3 complex on T cells. Efficacy parameters included the proportion of patients achieving remission (CDAI <150), clinical response (CDAI fall ≥100), and change from baseline in the CD Endoscopy Index of Severity (CDEIS). Results: Forty patients received placebo (n = 7) or NI‐0401 (n = 33) 0.05–10 mg daily for 5 days. NI‐0401 doses ≤1 mg were well tolerated. Infusion reactions occurred at doses ≥2 mg. The extent and duration of TCR‐CD3 modulation increased with dose. No differences between groups were observed in the proportions of patients achieving clinical remission or response. The mean CDEIS at week 6 differed significantly between the 1‐mg and placebo group. Conclusions: NI‐0401 was tolerated at doses ≤1 mg with manageable side effects. NI‐0401 induced a dose‐dependent modulation of the TCR‐CD3 complex. No significant improvement of CDAI was observed but 1 mg NI‐0401 demonstrated an improvement in CDEIS. Inflamm Bowel Dis 2010

Gastroesophageal Reflux Disease and Physical Activity

Gastroesophageal reflux disease (GERD) is one of the most common disorders in the general population. In recent years, a marked increase in the occurrence of the disease worldwide has been noted.Intense exercise belongs to factors that are known to exacerbate symptoms of GERD. Episodes of reflux seem to be associated with the length and the intensity of the physical activity undertaken. Experimental studies suggest that the gastroesophageal reflux may be increased in athletes due to: decreased gastrointestinal blood flow; alterations of hormone secretion; changes in the motor function of the oesophagus and the ventricle; and the constrained body position during exercise. Disturbances of the balance between two areas of opposite pressure: intra-abdominal and intrathoracic, have also been proven to influence GERD events.GERD is found in sportspeople of various disciplines, but specific types of exercise may have significantly different impacts on the gastroesophageal reflux.Basic prevention of GERD comprise lifestyle and dietary interventions. Adjustments of the exercise load and avoiding meals and drinks about the time of physical effort may ease the symptoms. Unfortunately, in most patients, pharmacological measures are necessary. These include occasional application of antacids and blockers of histamine H2 receptors in mild forms of the disease, and a regular therapy with proton pump inhibitors (PPI) in the majority of other cases. An average dose of PPI varies from 20 to 40 mg/day and should be continued for 4–8 weeks. Unfortunately, symptoms of GERD frequently return and in these situations long-term acid suppression with PPI is usually necessary.As regular physical activity exerts beneficial health effects, the necessity of establishing associations between moderate, recreational exercise and GERD is needed.

Impaired Erythrocyte Antioxidant Defense in Active Inflammatory Bowel Disease: Impact of Anemia and Treatment

Background: Oxidative stress contributes to the propagation and exacerbation of inflammatory bowel disease (IBD) but the status of erythrocyte antioxidant defense remains unknown. Methods: Erythrocyte activities of superoxide dismutase‐1 (SOD1), catalase, and glutathione peroxidase‐1 (GPx1) were determined in 174 IBD patients and 105 controls and referred to IBD activity, inflammation severity, nutritional status, systemic oxidative stress, anemia, and treatment. Results: Catalase and GPx1 activities were decreased in active IBD, whereas SOD1 became upregulated by IBD‐related oxidative stress. In Crohns disease (CD) corticosteroids decreased SOD1 activity. SOD1 correlated indirectly with CD activity and erythrocyte sedimentation rate (ESR) and directly with transferrin. In ulcerative colitis (UC) anemia downregulated SOD1. Decreases in GPx activity corresponded with IBD activity, anemia, inflammation, and malnutrition. Oxidative stress in UC and corticosteroids in CD also downregulated GPx. Catalase activity was decreased by CD‐related anemia, correlating directly with hemoglobin, and indirectly with CD activity, inflammatory and protein oxidative stress markers. When co‐analyzed, anemia but not CD activity significantly contributed to catalase downregulation. In UC, catalase activity corresponded indirectly with UC endoscopic activity and inflammation and directly with hemoglobin. UC activity, anemia, and treatment with azathioprine negatively affected catalase. As indicators of active IBD, GPx1 showed a diagnostic accuracy of 73%, whereas catalase showed 63% as compared to 74% of C‐reactive protein and ESR. Conclusions: Erythrocyte antioxidant defense is impaired in active IBD. SOD1, GPx1, and CAT activities are differently affected by the disease type, activity, anemia, inflammation, oxidative stress, and treatment. As an active IBD indicator, GPx1 was comparable to C‐reactive protein and ESR. Inflamm Bowel Dis 2010

Anorectal function and dyssynergic defecation in different subgroups of patients with irritable bowel syndrome

PurposeThe purpose of this study was to evaluate anorectal function in different subgroups of patients with irritable bowel syndrome (IBS), including those with mixed bowel habits.Materials and MethodsSixty-six IBS patients selected according to Rome III criteria (39 female and 27 male patients; mean age, 41.5 ± 15.4) and 20 subjects in the control group (13 female and 7 male patients; mean age, 41.4 ± 13.7) were examined. The IBS patients were divided into three subgroups according to bowel movement pattern: patients with constipation (27%), patients with diarrhea (27%), and patients with mixed bowel habits (46%). Anorectal manometry and rectal distension test were performed using a four-lumen water-perfused catheter with a polyethylene balloon.ResultsNo significant differences in manometric parameters between the subgroups of IBS patients and the control group were found, except for pelvic floor dyssynergia (PFD), which was more frequent in all subgroups of IBS (41% of patients) than in controls (5% of subjects) (p < 0.01). Lower rectal pain threshold was observed particularly in IBS patients with diarrhea and mixed bowel habits (p < 0.01).ConclusionManometric parameters characterizing anal sphincter function are not correlated with the predominant bowel movement pattern in IBS. The features of PFD are significantly more frequent in all subgroups of IBS patients than in controls, suggesting that, in general, IBS patients show changes in the mobility of the pelvic floor. Hypersensitivity to rectal distension is commonly observed in IBS, but it does not seem to be a highly specific marker of the disorder.

Lipid peroxidation markers in Crohn’s disease: the associations and diagnostic value

Abstract Background: Crohn’s disease (CD) is an incurable and difficult to diagnose condition. While high sensitive C-reactive protein (CRP) remains the best biochemical marker, we evaluated the diagnostic usefulness of lipid peroxidation indices. Methods: Malondialdehyde/thiobarbituric acid-reactive substances (MDA/TBARS), peroxidation potential (PP), lipid hydroperoxides (ROOH), oxidized-low density lipoprotein (oxLDL), and oxLDL antibodies (OLAB) were assessed in 52 CD patients and 99 volunteers and referred to clinical activity, inflammation, nutritional and antioxidant status. Results: MDA/TBARS were higher in CD while oxLDL and PP decreased in active disease and ROOH and OLAB did not differ. oxLDL and PP negatively and OLAB positively correlated with CD activity. MDA/TBARS positively correlated with IL-6 and SOD-1 and negatively with catalase. IL-6 and SOD-1 explained 24% in MDA/TBARS variability. PP negatively correlated with CRP, platelets, and IL-6 and positively with glutathione peroxidase-1, paraoxonase-1, cholesterol, triglycerides, and albumins. Cholesterol and CRP explained 57% in PP variability. oxLDL negatively correlated with IL-1 and IL-6 and positively with glutathione peroxidase-1, paraoxonase-1, cholesterol, and albumins. Paraoxonase-1 explained 17% of oxLDL variability. OLAB positively correlated with IL-1 explaining 10% in its variability and negatively with cholesterol. MDA/TBARS were the best predictor of CD, comparable to CRP, with high specificity (MDA/TBARS sensitivity and specificity: 75% and 90%; CRP: 76% and 93%). Combined assessment of MDA/TBARS and CRP improved sensitivity (94%) corresponding with acceptable specificity (81%). Conclusions: MDA/TBARS are elevated in CD and may help to rule the disease out, while the combined evaluation with CRP may serve for CD confirmation. oxLDL and PP depended on substrate availability, decreased in CD.

Anorectal function and visceral hypersensitivity in celiac disease.

Objective To evaluate anorectal function and rectal sensitivity thresholds in patients with celiac disease (CD). Methods In 25 unselected patients with CD (16 female, 9 male; mean age 45, range 24 to 75 y) and 20 controls (12 female, 8 male; mean age 41, range 20 to 65 y) anorectal manometry and rectal balloon distension test were conducted using a 4 lumen water perfused catheter with a polyethylene balloon (Zinectics Manometric Catheter, Medtronic). Results In celiac patients the maximal anal resting pressure, reflecting the internal anal sphincter function, was significantly higher than that in the controls: 87.8±21.7 mm Hg versus 66.7±15.2 mm Hg (P<0.001). There were no considerable differences between both the groups neither in the maximal anal squeeze nor in the cough pressures. Celiac patients had significantly lower first sensation threshold: 25.6±10.8 mL versus 37.5±12.5 mL (P<0.05). Visceral hypersensitivity (rectal pain/discomfort threshold ≤100 mL) was observed in 36% of celiac patients and in none of the controls (P<0.01). Conclusions The increased anal resting pressure and rectal hypersensitivity are observed in CD. Disturbances in gastrointestinal motility and visceral perception in the course of CD may occur at different levels of the brain-gut axis including direct changes in the enteric nervous system.

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10−04, Sweden P=7.44 × 10−05). Combining all five European data sets – Central Europe, Italy, Spain, Poland and Sweden – the insertion is achalasia associated with Pcombined=1.67 × 10−35. In addition, we observe that the frequency of the insertion shows a geospatial north–south gradient. The insertion is less common in northern (around 6–7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

A 'cocoon immunization strategy' among patients with inflammatory bowel disease.

Background and aims A ‘cocoon strategy’ is defined as the strategy of protecting vulnerable patients from infectious diseases by vaccinating those in close contact with them. In our study, we evaluate the vaccination status among children living with patients with inflammatory bowel disease (IBD) to determine the realization of the cocoon strategy and to identify characteristics associated with pediatric vaccine refusal. Patients and methods A self-completed survey was conducted on 136 hospitalized patients with IBD. The survey comprised questions about household child vaccination coverage, the reasons for vaccine refusal, and the history of infectious diseases among the patients. Results Fifty-six patients reported living with children. Forty percent of children were vaccinated with at least one of the recommended vaccines. Most frequently, children received pneumococcal (26%) and rotaviruses (22%) vaccines. The most common reason for nonimmunization was patients’ opinion that immunizations are not necessary for them (52%). There was a statistically significant association between the nonreimbursed vaccines coverage and the educational level of the patients (P<0.0001). Despite the fact that 28% of the patients could not definitively recall varicella infection, none of them and none of the children in their household had been vaccinated against chickenpox. Conclusion The use of nonmandatory vaccines recommended in family members of patients with IBD is insufficient. Further vaccine promotion and education of patients as well as their healthcare providers is required. A particular concern is associated with the pneumococcal, influenza, rotaviruses, and varicella infections. Nonimmunized and varicella-zoster virus-seronegative patients should be vaccinated, and in case of immunosuppression, vaccination of children in the household is required.