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1.  Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients 
BMC Gastroenterology  2014;14:79.
Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment.
In a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15).
We identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients.
Using specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach.
PMCID: PMC4005617  PMID: 24758565
Ulcerative colitis; Glucocorticosteroids; Steroid refractory; Biomarker; Companion diagnostics
2.  Carcinoma in gut-associated lymphoid tissue in ulcerative colitis: Case report and review of literature 
The colorectal mucosa includes two quantitatively, structurally and functionally dissimilar areas: one, built with columnar and goblet cells, covers the vast majority of the mucosa, and the other consists of scattered minute gut-associated lymphoid tissue (GALT). The overwhelming majority of colorectal carcinomas evolve in GALT-free mucosal areas and very rarely in GALT aggregates. Remarkably, the colonic mucosa in patients with ulcerative colitis (UC) displays a high number of newly formed GALT-aggregates. The patient here described is a 68-year-old female with a history of UC since 1984. At surveillance colonoscopy in 2012, one of two detected polyps was a tubular adenoma with high-grade dysplasia. Beneath this adenoma, a well-circumscribed GALT sheltering a carcinoma was found. Serial sections revealed no connection between the villous adenoma and the GALT-carcinoma. The GALT-carcinoma here reported seems to have evolved in a newly formed, UC-dependent, GALT complex. This notion is substantiated by the fact that 27% or 4 out of the 15 cases of GALT-carcinomas in the colon reported in the literature (including the present case) evolved in patients with UC.
PMCID: PMC3680619  PMID: 23772267
Colon; Advanced adenoma; Gut-associated lymphoid tissue; Carcinoma; Ulcerative colitis
3.  HLA-DRhi and CCR9 Define a Pro-Inflammatory Monocyte Subset in IBD 
It has been demonstrated that circulating monocytes relocate to the intestinal mucosa during intestinal inflammation, but the phenotype and inflammatory mechanisms of these monocytes remain poorly understood. Here, we have investigated blood monocytes expressing high levels of HLA-DR and CCR9 in patients with inflammatory bowel disease (IBD).
Fifty-one patients with mild to severe ulcerative colitis (UC; n=31; UC-DAI 3–12) or Crohn's disease (CD; n=20; Harvey–Bradshaw indices (HBI) 2–16) were included together with 14 controls, during IBD therapy for four consecutive weeks. The frequency of CD14+HLA-DRhi monocytes was monitored weekly in peripheral blood, using flow cytometry. The surface phenotype and cytokine profile of these monocytes were established using flow cytometry and real-time PCR. Clinical parameters were assessed weekly in all patients.
The frequency of circulating CD14+HLA-DRhi monocytes was significantly higher in IBD patients with moderate to severe disease compared with healthy controls (P<0.001). During treatment with corticosteroids and granulocyte/monocyte apheresis, the proportion of circulating CD14+HLA-DRhi monocytes was significantly reduced. CD14+HLA-DRhi monocytes produced high levels of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and expressed the gut-homing receptor CCR9. Furthermore, we found that the CCR9 ligand, CCL25/TECK, was expressed at high levels in the colonic mucosa in IBD patients with active disease.
CD14+HLA-DRhi blood monocytes were increased in patients with active IBD. These monocytes exhibit a pro-inflammatory, gut-homing phenotype with regard to their TNF-α production and expression of CCR9. Our results suggest that these monocytes are important in mediating intestinal inflammation, and provide potential therapeutic targets in IBD.
PMCID: PMC3535076  PMID: 23254312
4.  Gender and the treatment of immune-mediated chronic inflammatory diseases: rheumatoid arthritis, inflammatory bowel disease and psoriasis: an observational study 
BMC Medicine  2012;10:82.
Rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis are immune-mediated inflammatory diseases with similarities in pathophysiology, and all can be treated with similar biological agents. Previous studies have shown that there are gender differences with regard to disease characteristics in RA and IBD, with women generally having worse scores on pain and quality of life measurements. The relationship is less clear for psoriasis. Because treatment differences between men and women could explain the dissimilarities, we investigated gender differences in the disease characteristics before treatment initiation and in the biologic treatment prescribed.
Data on patients with RA or IBD were collected from two registries in which patients treated with biologic medication were enrolled. Basic demographic data and disease activity parameters were collected from a time point just before the initiation of the biologic treatment. For patients with psoriasis, the data were taken from the 2010 annual report of the Swedish Psoriasis Register for systemic treatment, which included also non-biologic treatment. For all three diseases, the prescribed treatment and disease characteristics were compared between men and women.
In total, 4493 adult patients were included in the study (1912 with RA, 131 with IBD, and 2450 with psoriasis). Most of the treated patients with RA were women, whereas most of the patients with IBD or psoriasis were men. There were no significant differences between men and women in the choice of biologics. At treatment start, significant gender differences were seen in the subjective disease measurements for both RA and psoriasis, with women having higher (that is, worse) scores than men. No differences in objective measurements were found for RA, but for psoriasis men had higher (that is, worse) scores for objective disease activity measures. A similar trend to RA was seen in IBD.
Women with RA or psoriasis scored significantly higher on subjective, but not on objective, disease activity measures than men, and the same trend was seen in IBD. This indicates that at the same level of treatment, the disease has a greater effect in women. These findings might suggest that in all three diseases, subjective measures are discounted to some extent in the therapeutic decision-making process, which could indicate undertreatment in female patients.
PMCID: PMC3414735  PMID: 22853635
5.  Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1) 
PLoS ONE  2011;6(12):e29523.
neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).
Principal Findings
we identified one promoter SNP (rs2530547 [−103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.
these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.
PMCID: PMC3244468  PMID: 22216302
6.  Increased lysozyme expression in gastric biopsies with intestinal metaplasia and pseudopyloric metaplasia 
Lysozyme is an innate enzyme with potent non-immunological antibacterial properties in the upper intestinal tract. Lysozyme expression (ly-ex) was investigated in 80 consecutive sets of gastric biopsies having normal gastric mucosa (n=20), chronic gastritis (n=20), gastric intestinal metaplasia (IM, n=20), and pseudopyloric metaplasia (PpM, n=20). In biopsies with normal mucosa and with chronic gastritis, the foveolar epithelium and the mucus neck cells of the fundic mucosa as well as the antropyloric glands had moderate (++) to marked (+++) ly-ex whereas the fundic glands proper did not express lysozyme. In IM the goblet and the Paneth cells showed marked (+++) ly-ex. PpM, developing in patients with autoimmune (corpus) gastritis, had moderate ly-ex (++), thus contrasting with the negative ly-ex in the normal or inflamed fundic mucosa. The Helicobacter pylori did not proliferate in areas with IM or with PpM. The lysozyme production in IM and in PpM might be upregulated to eradicate ingested, proliferating bacteria in acid-deficient stomachs.
PMCID: PMC2773612  PMID: 19918317
Lysozyme; gastric intestinal metaplasia; pseudopyloric metaplasia; chronic gastritis
7.  Concordance of Helicobacter pylori Strains within Families 
Journal of Clinical Microbiology  2003;41(12):5604-5608.
Helicobacter pylori infection is typically acquired in early childhood, and a predominantly intrafamilial transmission has been postulated. To what extent family members share the same strains is poorly documented. Our aim was to explore patterns of shared strains within families by using molecular typing. Family members of H. pylori-infected 10- to 12-year-old index children identified in a school survey were invited to undergo gastroscopy. Bacterial isolates were typed with random amplified polymorphic DNA and PCR-restriction fragment length polymorphism of the genes ureA-B, glmM, or flaA. The presence or absence of the cag pathogenicity island, a bacterial virulence factor, was determined by PCR. GelCompar II software, supplemented with visual inspection, was used in the cluster analysis. In 39 families, 104 individuals contributed 208 bacterial isolates from the antrum and corpus. A large proportion, 29 of 36 (81%) of the offspring in a sibship, harbored the same strain as at least one sibling. Mother-offspring strain concordance was detected in 10 of 18 (56%) of the families. Of 17 investigated father-offspring relations in eight families, none were strain concordant. Spouses were infected with the same strains in 5 of 23 (22%) of the couples. Different strains in the antrum and corpus were found in 8 of 104 (8%) of the subjects. Our family-based fingerprinting study demonstrates a high proportion of shared strains among siblings. Transmission between spouses seems to be appreciable. The data support mother-child and sib-sib transmission as the primary transmission pathways of H. pylori.
PMCID: PMC309035  PMID: 14662948
8.  Rapid PCR Detection of Helicobacter pylori-Associated Virulence and Resistance Genes Directly from Gastric Biopsy Material 
Journal of Clinical Microbiology  1998;36(12):3689-3690.
We have developed a PCR-based method to detect macrolide resistance and the virulence gene cagA in Helicobacter pylori within 24 h, thereby improving the lengthy process of culture-based approaches. Total DNA was prepared directly from stomach biopsy specimens. The procedure proved to be rapid and reliable and could be utilized for diagnostic purposes.
PMCID: PMC105265  PMID: 9817898

Results 1-8 (8)