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Serum immune-activation potency and response to anti-TNF-α therapy in Crohn's disease

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World Journal of Gastroenterology 2010年第46期16卷 5845-5851页

作者： Hanne Rintamki Taina Sipponen Harri M Salo Outi Vaarala kaija-leena kolho Division of Gastroenterology Hospital for Children and Adolescents and Helsinki University Central HospitalUniversity of Helsinki Department of Medicine Division of GastroenterologyHelsinki University Central HospitalUniversity of Helsinki Immune Response Unit Department of Vaccination and Immune ProtectionNational Institute for Health and Welfare

AIM:To study whether immune-activation stage in serum of adult Crohn's disease (CD) patients correlates with disease activity and with treatment response to antitumor necrosis factor-α (TNF-α) ***:Serum samples were obtained from 15 adult CD patients introduced to anti-TNF-α *** individual stage of immune activation was studied applying our new in vitro assay,in which target cells (donor derived peripheral blood mononuclear cells) were cultured with patient serum and the T-cell activation induced by the patient serum was studied using a panel of markers for effector [interferon γ (IFNγ),interleukin (IL)-5] and regulatory T-cells [forkhead transcription factor 3 (FOXP3) and glucocorticoid-induced tumour necrosis factor receptor (GITR)].The endoscopic disease activity was assessed with the Crohn's disease endoscopic index of severity (CDEIS) before and 3 mo after therapy with an anti-TNF-α ***:Low induction of FOXP3 and GITR in target cells cultured in the presence of patient serum was associated with high disease activity *** assessed before therapy (r=-0.621,P=0.013 and r=-0.625,P=0.013,respectively).FOXP3 expression correlated inversely with pre-treatment erythrocyte sedimentation rate (r=-0.548,P=0.034).Low serum induced FOXP3 (r=-0.600,P=0.018) and GITR (r=-0.589,P=0.021) expression and low IFNγ secretion from target cells (r =-0.538,P=0.039) associated with treatment response detected as a decrease in ***:The immune-activation potency in the patient serum prior to anti-TNF-α therapy reflected intestinal inflammation and the therapeutic response.

关键词： Crohn’s disease endoscopic index of severity Forkhead transcription factor 3 Glucocorticoid-induced tumour necrosis factor receptor Infliximab Inflammatory bowel disease

Molecularly defined adult-type hypolactasia in school-aged children with a previous history of cow's milk allergy

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World Journal of Gastroenterology 2006年第14期12卷 2264-2268页

作者： Heli Rasinper Kristiina Saarinen Anna Pelkonen Irma Jrvel Erkki Savilahti kaija-leena kolho Department of Medical Genetics University of Helsinki Finland Hospital for Children and Adolescents University of Helsinki Finland Department of Allergology Skin and Allergy Hospital Helsinki University Central HospitalHelsinkiFinland Department of Medical Genetics University of Helsinki Finland Laboratory of Molecular GeneticsHelsinki University HospitalHelsinkiFinland

AIM： To assess the role of lactase non-persistence/per- sistence in school-aged children and their milk-related symptoms. METHODS： The genotypes for the C/T-13910 variant associated with lactase non-persistence/ persistence were determined using PCR-minisequencing in a group of 172 children with a mean age of 8.6 years （SE = 0.02, 93 boys） participating in a follow-up study for cow＇s milk allergy. The parents were asked to assess their children＇s milk consumption and abdominal symptoms. RESULTS： The presence of allergy to cow＇s milk was not associated with the C/C-13910 genotype related with a decline of lactase enzyme activity during childhood （lactase non-persistence）. The frequency of the C/C-13910 genotype （16%） was similar to published figures for the prevalence of adult-type hypolactasia in Finland. The majority of the children （90%） in this series consumed milk but 26% of their families suspected that their children had milk-related symptoms. Forty-eight percent of the children with the C/C-13910 genotype did not drink milk at all or consumed a low lactose containing diet prior to the genotyping （P〈 0.004 when compared to the other genotypes）. CONCLUSION： Analysis of the C/T-13910 polymorphism is an easy and reliable method for excluding adult-type hypolactasia in children with milk-related symptoms. Genotyping for this variant can be used to advise diets for children with a previous history of cow＇s milk allergy.

关键词： Adult-type hypolactasia Primary lactose malabsorption Genetic testing Cow's milk allergy

Low trypsinogen-1 expression in pediatric ulcerative colitis patients who undergo surgery

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World Journal of Gastroenterology 2013年第21期19卷 3272-3280页

作者： Maija Piekkala Jaana Hagstrm Maarit Tanskanen Risto Rintala Caj Haglund kaija-leena kolho Children's Hospital University of HelsinkiFIN-00029 HUSHelsinkiFinland Department of Pathology Haartman InstituteUniversity of HelsinkiFIN-00029 HUS HelsinkiFinland Department of Surgery Helsinki University Central HospitalFIN-00029 HUS HelsinkiFinland

AIM: To investigate whether matrix metalloproteinases-9 (MMP-9) or trypsinogens could serve as histological markers for an aggressive disease course in pediatric ulcerative colitis (UC). METHODS: We identified 24 patients with pediatric onset (≤ 16 years) UC who had undergone surgery during childhood/adolescence a median of 2.1 years (range 0.1-7.4 years) after the diagnosis (between 1990 and 2008) in Children's Hospital, Helsinki, Finland. We also identified 27 conservatively treated UC patients and matched them based on their age at the time of diagnosis and follow-up at a median of 6 years (range 3-11 years) to serve as disease controls. Twenty children for whom inflammatory bowel disease (IBD) had been excluded as a result of endoscopy served as non-IBD controls. Colon biopsies taken by diagnostic endoscopy before the onset of therapy were stained using immunohistochemistry to study the expression of MMP-9, trypsinogen-1 (Tryp-1), Tryp-2, and a trypsin inhibitor (TATI). The profiles of these proteases and inhibitor at diagnosis were compared between the surgery group, the conservatively treated UC patients and the non-IBD controls. RESULTS: The proportions of Tryp-1 and Tryp-2 positive samples in the colon epithelium and in the inflammatory cells of the colon stroma were comparable between the studied groups at diagnosis. Interestingly, the immunopositivity of Tryp-1 (median 1; range 0-3) was significantly lower in the epithelium of the colon in the pediatric UC patients undergoing surgery when compared to that of the conservatively treated UC patients (median 2; range 0-3; P = 0.03) and non-IBD controls (median 2; range 0-3; P = 0.04). For Tryp-2, there was no such difference. In the inflammatory cells of the colon stroma, the immunopositivities of Tryp-1 and Tryp-2 were comparable between the studied groups at diagnosis. Also, the proportion of samples positive for TATI, as well as the immunopositivity, was comparable between the studied groups in the colon ep

关键词： Children Ulcerative colitis Inflammatory bowel disease Matrix metalloproteinase-9 resection Trypsin inhibitor

Cognitive functioning and depressive symptoms in adolescents with inflammatory bowel disease

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World Journal of Gastroenterology 2013年第10期19卷 1611-1617页

作者： Anu E Castaneda Annamari Tuulio-Henriksson Eeva T Aronen Mauri Marttunen kaija-leena kolho Department of Mental Health and Substance Abuse Services National Institute for Health and Welfare00271 HelsinkiFinland Research Department Social Insurance Institute00250 HelsinkiFinland Child Psychiatry Children's HospitalUniversity of Helsinki and Helsinki University Central Hospital00250 HelsinkiFinland Department of Adolescent Psychiatry University of Helsinki and Helsinki University Central Hospital00271 HelsinkiFinland Department of Mental Health and Substance Use Services National Institute for Health and Welfare00271 HelsinkiFinland Hospital for Children and Adolescents Department of Pediatric GastroenterologyUniversity of Helsinki00250 HelsinkiFinland

AIM:To investigate cognitive functioning and depressive symptoms in adolescents with inflammatory bowel disease(IBD).METHODS:A neuropsychological test battery,including subtests of the Wechsler Adult Intelligence ScaleRevised and Ⅲ,Wechsler Memory Scale-Revised,California Verbal Learning Test(CVLT),Stroop Color-Word Test,and Trail Making Test,which assessed verbal and visual short-and long-term memory,processing speed,logical reasoning,verbal intelligence,attention,and executive functioning,was administered to 13-to 19-year-old patients with IBD(n = 34;active disease n = 20).Depressive symptoms were measured with the Beck Depression *** findings were compared with peers with non-acute juvenile idiopathic arthritis(JIA;n = 23).Patients with coexisting psychiatric disorders were ***:The IBD group,especially patients in the acute phase,made more perseverative errors in the CVLT test that assessed verbal memory than the JIA group(6.0 ± 4.3 vs 3.3 ± 2.9,P < 0.01),but no other differences between the IBD and JIA groups were observed in the neuropsychological *** difference was close to statistical significance,even when glucocorticoid medication was controlled for(P < 0.052).The IBD group had more depressive symptoms than the JIA group(7.9 ± 7.6 vs 4.0 ± 4.0,P < 0.05).Approximately one third of the IBD group had at least mild depressive symptoms,and those with acute illness had the highest ***,depressive symptoms were not related to the difference in the verbal memory test(perseverative errors in the CVLT) between the IBD and JIA ***:Adolescents with acute IBD may have mild verbal memory problems but no major cognitive deficits compared to peers with JIA.

关键词： Cognitive impairment Inflammatory bowel disease Crohn’s disease Depressive symptoms Ulcerative colitis Adolescents

Infliximab in pediatric inflammatory bowel disease rapidly decreases fecal calprotectin levels

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World Journal of Gastroenterology 2011年第47期17卷 5166-5171页

作者： Anssi Hmlinen Taina Sipponen kaija-leena kolho Hospital for Children and Adolescents Helsinki University Central Hospital University of Helsinki Division of Gastroenterology Helsinki University Central Hospital

AIM: To study the response to infliximab in pediatric inflammatory bowel disease (IBD), as reflected in fecal calprotectin levels. METHODS: Thirty-six pediatric patients with IBD [23 Crohn's disease (CD), 13 ulcerative colitis (UC); median age 14 years] were treated with infliximab. Fecal calprotectin was measured at baseline, and 2 and 6 wk after therapy, and compared to blood inflammatory markers. Maintenance medication was unaltered until the third infusion but glucocorticoids were tapered off if the patient was doing well. RESULTS: At introduction of infliximab, median fecal calprotectin level was 1150 μg/g (range 54-6032 μg/g). By week 2, the fecal calprotectin level had declined to amedian 261 μg/g (P < 0.001). In 37% of the patients, fecal calprotectin was normal (< 100 μg/g) at 2 wk. By week 6, there was no additional improvement in the fecal calprotectin level (median 345 μg/g). In 22% of the patients, fecal calprotectin levels increased by week 6 to pretreatment levels or above, suggesting no response (or a loss of early response). Thus, in CD, the proportion of non-responsive patients by week 6 seemed lower, because only 9% showed no improvement in their fecal calprotectin level when compared to the respective figure of 46% of the UC patients (P < 0.05). CONCLUSION: When treated with infliximab, fecal calprotectin levels reflecting intestinal inflammation normalized rapidly in one third of pediatric patients suggesting complete mucosal healing.

关键词： Crohn's disease Ulcerative colitis Surrogatemarkers Pediatrics Monoclonal antibodies Infliximab

Milk protein IgG and IgA:The association with milk-induced gastrointestinal symptoms in adults

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World Journal of Gastroenterology 2009年第39期15卷 4915-4918页

作者： Sari Anthoni Erkki Savilahti Hilpi Rautelin kaija-leena kolho Hospital for Children and Adolescents University of Helsinki Department of Bacteriology and Immunology Haartman InstituteUniversity of Helsinki and Helsinki University Central Hospital Laboratory

AIM:To study the association between serum levels of milk protein IgG and IgA antibodies and milk-related gastrointestinal symptoms in ***:Milk protein IgG and IgA antibodies were determined in serum samples of 400 subjects from five outpatient clinics in Southern *** were randomly selected from a total of 1900 adults undergoing laboratory investigations in primary *** 400 participants had completed a questionnaire on abdominal symptoms and dairy consumption while waiting for the laboratory *** questionnaire covered the nature and frequency of gastrointestinal problems,the provoking food items,family history and *** serum samples were disqualifi ed due to insuff icient amount of *** levels of specif ic milk protein IgG and IgA were measured by using the ELISA *** association of the milk protein-specific antibody level was studied in relation to the milk-related gastrointestinal symptoms and dairy ***:Subjects drinking milk(n=265) had higher levels of milk protein IgG in their sera than non-milk drinkers(n=123,P<0.001).Subjects with gastrointestinal problems related to milk drinking(n=119) consumed less milk but had higher milk protein IgG levels than those with no milk-related gastrointestinal symptoms(n=198,P=0.02).Among the symptomatic subjects,those reporting dyspeptic symptoms had lower milk protein IgG levels than non-dyspeptics(P<0.05).However,dyspepsia was not associated with milk drinking(P=0.5).The association of high milk protein IgG levels with constipation was close to the level of statistical signif *** had no association with milk protein IgG level(P=0.5).With regard to minor symptoms,flatulence and bloating(P=0.8),were not associated with milk protein IgG *** protein IgA levels did not show any association with milk drinking or abdominal *** levels of milk protein IgA and IgG declined as the age of the subjects increased(P<0.004).CONCLUSION:Milk

关键词： Abdominal symptoms Cow's milk Food hypersensitivity

High-sensitivity C-reactive protein in paediatric inflammatory bowel disease

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World Journal of Gastroenterology 2010年第23期16卷 2901-2906页

作者： Marianne Sidoroff Riitta Karikoski Taneli Raivio Erkki Savilahti kaija-leena kolho Division of Gastroenterology and Endocrinology Hospital for Children and AdolescentsUniversity of Helsinki Department of Pathology HUSLABHelsinki University Central Hospital

AIM:To study whether high-sensitivity C-reactive protein(hs-CRP) measurement can aid the assessment of disease activity and glucocorticoid treatment in paediatric inflammatory bowel disease(IBD).METHODS:CRP levels were measured in 39 children with IBD undergoing colonoscopy [median age 12.8 years,Crohn's disease(CD) n=20],in 22 other children with IBD followed for acute response to glucocorticoids,and in 33 paediatric non-IBD *** standard CRP level was below detection limit(<5mg/L),hs-CRP was ***:Sixty-four percent(25/39) of the children with IBD undergoing colonoscopy displayed undetectable(<5mg/L) standard CRP *** these,the hs-CRP measurement could not differentiate between active(median,0.2 mg/L,range,0.007-1.37,n=17) or quiescent(0.1 mg/L,0.01-1.89,n=8,P=NS) *** with ileocolonic CD had higher CRP levels(14mg/L,0.06-45,n=13) than patients with no ileal involvement(0.18 mg/L,0.01-9,n=7,P<0.01) or ulcerative colitis(UC)(0.13 mg/L,0.007-23,P<0.05).In children with active IBD treated with systemic glucocorticoids,the standard CRP was undetectable in 59% of the *** hs-CRP levels did not differ between patients that responded to steroid therapy and in ***:The measurement of hs-CRP did not prove useful in the assessment of disease activity or glucocorticoid treatment in paediatric IBD patients that had undetectable standard CRP.

关键词： C-reactive protein Crohn’s disease Ulcerative colitis Children Inflammatory markers

Molecularly defined adult-type hypolactasia among working age people with reference to milk consumption and gastrointestinal symptoms

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World Journal of Gastroenterology 2007年第8期13卷 1230-1235页

作者： Sari R Anthoni Heli A Rasinper Antti J Kotamies Hanna A Komu Harri K Pihlajamki kaija-leena kolho Irma E Jrvel Hospital for Children and Adolescents University of Helsinki Finland Department of Medical Genetics University of Helsinki Finland Helsinki Centre of Economic Research Helsinki Finland Central Military Hospital Helsinki Finland Helsinki University Central Hospital Laboratory of Molecular Genetics Helsinki Finland

AIM: To study milk consumption and subjective milk- related symptoms in adults genotyped for adult-type hypolactasia. METHODS: A total of 1900 Finnish adults were genotyped for the C/T-13910 variant of adult-type hypolactasia and filled in a structured questionnaire concerning milk consumption and gastrointestinal problems. RESULTS: The C/C-13910 genotype of adult-type hypolactasia was present in 18% of the study population. The prevalence of the C/C-13910 genotype was higher among subjects who were undergoing investigations because of abdominal symptoms (24%, P < 0.05). Those with the C/C-13910 genotype drank less milk than subjects with either the C/T-13910 or the T/T-13910 genotype of lactase persistence (18% vs 38%; 18% vs 36%, P < 0.01). Subjects with the C/C-13910 genotype had experienced more gastrointestinal symptoms (84%) during the preceding three-month period than those with the C/T-13910 (79%, P < 0.05) or the T/T-13910 genotype (78 %, P < 0.05). Only 9% (29/338) of the subjects with the C/C-13910 genotype consumed milk and reported no symptoms from ***: Gastrointestinal symptoms are more common among adults with the C/C-13910 genotype of adult-type hypolactasia than in those with genotypes of lactase persistence.

关键词： Lactase persistence Lactose malabsorption C/T-13910 genotype Abdominal symptoms Milk consumption

Matrix metalloproteinases in the restorative proctocolectomy pouch of pediatric ulcerative colitis

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World Journal of Gastroenterology 2012年第30期18卷 4028-4036页

作者： Laura Mkitalo Maija Piekkala Merja Ashorn Mikko Pakarinen Antti Koivusalo Riitta Karikoski Johanna Natunen Ulpu Saarialho-Kere Risto Rintala kaija-leena kolho Hospital for Children and Adolescents Helsinki University Central HospitalUniversity of HelsinkiFIN-00029 HelsinkiFinland Department of Pediatrics Tampere University HospitalTeiskontie 3533521 TampereFinland Department of Pathology HUSLABHelsinki University Central HospitalHaartmaninkatu 3FI-00029 HelsinkiFinland Department of Clinical Science and Education and Section of Dermatology Karolinska Institutet at Stockholm Sder Hospital11883 StockholmSweden

AIM:To investigate matrix metalloproteinases(MMPs) and their tissue inhibitors(TIMPs) in pouch mucosa of pediatric onset ulcerative colitis(UC).METHODS:In this cross-sectional study,28 patients with pediatric onset UC underwent ileal pouch biopsy 13 years(median) after *** of MMPs-3,-7,-8,-9,-12 and-26 and TIMPs-1,-2 and-3 in samples was examined using immunohistochemichal methods,and another biopsy was used to evaluate the grade of histological *** investigators independently graded the immunohistochemical specimens in a semiquantitative fashion,using a scale marking staining intensity as follows:0 = less than 20 positive cells;1 = 20-50 positive cells;2 = 50-200 positive cells;3 = over 20 positive *** calprotectin and blood inflammatory markers [serum C-reactive protein(CRP) and erythrocyte sedimentation rate] were determined during a follow-up visit to examine correlations between these markers and the expression of MMPs and ***:Of the 28 patients with pediatric onset UC,nine had not experienced pouchitis,whereas thirteen reported a single episode,and six had recurrent pouchitis(≥ 4 episodes).At the time of the study,six patients required *** all of the others,the most recent episode of pouchitis had occurred over one month earlier,and none were on *** four samples depicted no sign of inflammation,and these were all from patients who had not had *** samples were too small to determine the grade of inflammation,but both had suffered pouchitis,the other *** sample depicted signs of colonic *** pouch samples showed expression of epithelial(e) and stromal(s) MMP-3(e,n = 22;s,n = 20),MMP-7(e,n = 28;s,n = 27),MMP-12(e,n = 20;s,n =24),TIMP-2(e,n = 23;s,n = 23) and MMP-3(e,n = 23;s,n = 28) but MMP-8(e,n = 0;s,n = 1),MMP-9(e,n = 0;s,n = 9) and MMP-26(e,n = 0;s,n = 3) and TIMP-1(n = 0,both) were *** samples with low grade of inflammatory activity,the epithe

关键词： Children Matrix metalloproteinase 3 Tissue inhibitor of matrix metalloproteinase 3 Matrix metalloproteinase 7 Pouchitis Ulcerative colitis