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Biomedical subjects

Markku Mäki

Publications and source records attributed to Markku Mäki.

At least 19 recordsLinked to original sources
PubMed2007

No observed local immunological response at cell level after five years of oats in adult coeliac disease.

OBJECTIVE: Our earlier 5-year follow-up study produced the first evidence to show the long-term safety of oats as part of a coeliac diet. The objective of the present study was to clarify its applicability by analysing local cellular immunological responses after 5 years' consumption of oats by adult coeliac patients. MATERIAL AND METHODS: Forty-two coeliac patients took part in an earlier oats intervention study for 6-12 months. Twenty-two of these patients originally consumed oats as part of their gluten-free diet. During the 5-year follow-up 10 patients had felt uncertain about the safety of long-term consumption of oats and gave up this part of their diet. Finally, 12 of the 22 patients consumed oats for the whole 5-year period. The control group consisted of the remaining 20 coeliac patients using a strict, conventional, gluten-free diet without oats. Intraepithelial CD3, alphabetaTCR (alphabetaIEL) and gammadeltaTCR (gammadeltaIEL) T cells were counted after specific staining of small intestinal biopsy specimens. RESULTS: There were no differences in the densities of CD3, alphabetaIEL and gammadeltaIEL T cells between the oat and the control groups. CONCLUSIONS: Long-term use of oats included in the gluten-free diets of patients with coeliac disease does not stimulate an immunological response locally in the mucosa of the small intestine.

Adult↗
PubMed2006

Gene expression in TGFbeta-induced epithelial cell differentiation in a three-dimensional intestinal epithelial cell differentiation model.

BACKGROUND: The TGFbeta1-induced signal transduction processes involved in growth and differentiation are only partly known. The three-dimensional epithelial differentiation model, in which T84 epithelial cells are induced to differentiate either with TGFbeta1 or IMR-90 mesenchymal cell-secreted soluble factors, is previously shown to model epithelial cell differentiation seen in intestine. That model has not been used for large scale gene expression studies, such as microarray method. Therefore the gene expression changes were studied in undifferentiated and differentiated three-dimensional T84 cultures with cDNA microarray method in order to study the molecular changes and find new players in epithelial cell differentiation. RESULTS: The expression of 372 genes out of 5188 arrayed sequences was significantly altered, and 47 of them were altered by both mediators. The data were validated and the altered genes are presented in ontology classes. For the genes tested the expressions in protein level were in accordance with the mRNA results. We also found 194 genes with no known function to be potentially important in epithelial cell differentiation. The mRNA expression changes induced by TGFbeta1 were bigger than changes induced by soluble factors secreted by IMR-90 mesenchymal cells. The gene expression data was depicted in already known signaling pathway routes. CONCLUSION: Our results reveal potential new signaling pathways and several new genes affected by TGFbeta in epithelial cell differentiation. The differentiation induced by TGFbeta1 appears to be more potent than the differentiation induced by mesenchymal cells. This study indicates that our cell culture model is a suitable tool in studying regulatory mechanisms during epithelial cell differentiation in intestine. Furthermore the present results indicate that our model is a good tool for finding new players acting in the differentiation of epithelial cells.

Cell Culture Techniques↗
PubMed2006

Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989-1998.

OBJECTIVES: Immunoglobulin A (IgA) autoantibodies to tissue transglutaminase (tTG) are commonly used for screening and diagnosing of celiac disease. We examined the hypothesis that elevated IgA anti-tTG antibodies were associated with higher all-cause mortality risk. METHODS: The cohort, 2333 men and 2300 women, was based on the follow-up of participants of a representative population-based survey in Southern Germany (KORA/MONICA Augsburg project) conducted in 1989-1990. The endpoint for the vital status with cause of death was the year 1998. The sera drawn at baseline and stored at -80 degrees C, were recently screened with an IgA enzyme-linked immunosorbent assay (ELISA) using human recombinant tTG. Age-standardized mortality rates and age-adjusted hazard ratios were calculated. RESULTS: From the 4633 sera analyzed, 63 had an IgA anti-tTG concentration>or=7 AU/ml. Of these 63 individuals, 15 died between 1989 and 1998. The age-adjusted hazard ratio (HRa) of all-cause mortality was 1.86 (95% CI: 1.01-3.41) and 3.92 (95% CI: 1.44-10.71) for men and women, respectively. The excess of cancer mortality was even higher with an HR(a) of 2.47 (95% CI: 0.89-6.83) in men and of 6.65 (95% CI: 2.04-21.63) in women. CONCLUSIONS: Individuals with elevated IgA anti-tTG antibodies had a highly increased mortality risk, particularly due to cancer. New studies are necessary to clarify if this increased risk is due to undiagnosed celiac disease or/and if this elevated IgA anti-tTG antibodies level is a marker of serious diseases like cancer, chronic liver disease or end-stage heart failure.

Adult↗
PubMed2006

Murine ortholog of the novel glycosyltransferase, B3GTL: primary structure, characterization of the gene and transcripts, and expression in tissues.

Glycosylation of proteins and lipids is important in cellular communication and maintenance of tissues. B3GTL (beta3-glycosyltransferase-like) is a novel glycosyltransferase that is found in multicellular animals ranging from mammals to insects and nematodes. The aim of this work was to identify and characterize the B3GTL gene in the mouse and to study its expression in various tissues. The murine gene codes for a protein which shares 84% amino acid sequence identity with its human ortholog, and contains all the primary structural features that characterize B3GTL proteins. The murine and human B3GTL genes share an identical exon/intron organization, and both genes utilize multiple polyadenylation signals. Their promoter regions show extensive conservation, implying that the two genes also share regulatory similarities. This notion was reinforced by Northern hybridization analysis of mouse tissues, which showed the tissue distribution of B3GTL mRNA to be similar to that previously found in human tissues, with the heart, kidney, and brain being major sites of expression in both species. The localization of B3GTL mRNA was studied by in situ hybridization in an extensive collection of mouse tissues, of which the granular cells of the olfactory bulb and the epithelium of the seminal vesicle displayed particularly strong signals. Together, these analyses indicate that the B3GTL mRNA is subject to strong tissue-specific and developmental regulation. The findings reported here make possible the design of a B3GTL "knock-out" mouse, provide a framework for analyzing the regulation of the gene, and provide an extensive catalog of tissues in which this novel protein acts.

Amino Acid Sequence↗
PubMed2005

Celiac disease-related antibodies in an epilepsy cohort and matched reference population.

Celiac disease (CD) is a common immunologically mediated enteropathic condition manifesting in genetically predisposed individuals after exposure to wheat gluten. CD may be associated with a number of neurological disorders, and the prevalence of epilepsy is reported to be increased in patients with CD. We studied the prevalence of CD-associated antibodies in a cohort of 968 patients with epilepsy and in a population-based reference group of 584 subjects. There was no difference in the prevalence of IgA and IgG class antigliadin antibodies (AGAbA and AGAbG, respectively), endomysial antibodies (EMA), and tissue transglutaminase antibodies (tTGAbA) between patients with epilepsy and the control population. This suggests the presence of CD to be the same in patients with epilepsy and the reference population. However, AGAbA was more prevalent in patients with primary generalized epilepsy (19.6%) than in the reference population (10.6%, relative risk 1.8, 95% confidence interval 1.1-3.0, P=0.012).

Antibodies↗
PubMed2005

Antimitochondrial antibodies in patients with epilepsy.

Immune mechanisms have been implicated in the pathogenesis of epilepsy. An increased prevalence of autoantibodies, as well as changes in serum immunoglobulin concentrations, has been reported in patients with epilepsy. The presence of unspecific antimitochondrial antibodies (AMAs) and their possible associations with other immunological markers were evaluated in a cohort of 1386 adult patients with epilepsy and population-based reference subjects. Unspecific AMAs were more frequent in epilepsy patients than in the reference group. Thirty-seven epilepsy patients (3.9%) and eleven control subjects (1.9%) had unspecific AMAs (RR 2.1, CI 1.05-4.1, P=0.03). These antibodies were associated with long duration of epilepsy and old age at the onset of epilepsy among patients with epilepsy. Their presence was independent of other immunological markers, comorbidity, and epilepsy medications.

Adult↗
PubMed2005

Small-bowel mucosal transglutaminase 2-specific IgA deposits in coeliac disease without villous atrophy: a prospective and randomized clinical study.

OBJECTIVE: In coeliac disease, autoantibodies directed against transglutaminase 2 are produced in small-bowel mucosa, and they have been found to be deposited extracellularly. The aim of this study was to investigate whether such mucosal IgA deposits are important in the diagnostic work-up of early-stage coeliac disease without small-bowel mucosal villous atrophy. MATERIAL AND METHODS: Forty-one adults suspected of coeliac disease owing to increased density of mucosal gamma(delta)+ intraepithelial lymphocytes but normal villous morphology were randomized to gluten challenge or a gluten-free diet for 6 months. Clinically and histologically verified gluten dependency was compared with existence of small-bowel mucosal transglutaminase 2-specific extracellular IgA deposits and (coeliac disease-type) HLA DQ2 and DQ8; 34 non-coeliac subjects and 18 patients with classical coeliac disease served as controls. RESULTS: Of the 41 patients, 5 in the challenge group and 6 in the gluten-free diet group were clinically gluten sensitive; all 11 had HLA DQ2 or DQ8. Ten of these 11 patients showed transglutaminase 2-targeted mucosal IgA deposits, which were dependent on gluten consumption. Minimal IgA deposits were seen in only 3 out of 30 patients with suspected coeliac disease without any clinically detected gluten dependency. The deposits were found in all classical coeliac patients and in none of the non-coeliac control subjects. CONCLUSIONS: Clinically pertinent coeliac disease exists despite normal small-bowel mucosal villous architecture. Mucosal transglutaminase 2-specific IgA deposits can be utilized in detecting such patients with genetic gluten intolerance.

Adult↗
PubMed2005

Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study.

OBJECTIVE: To investigate the value of serum antitissue transglutaminase IgA antibodies (IgA-TTG) and IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of coeliac disease in cohorts from different geographical areas in Europe. The setting allowed a further comparison between the antibody results and the conventional small-intestinal histology. METHODS: A total of 144 cases with coeliac disease [median age 19.5 years (range 0.9-81.4)], and 127 disease controls [median age 29.2 years (range 0.5-79.0)], were recruited, on the basis of biopsy, from 13 centres in nine countries. All biopsy specimens were re-evaluated and classified blindly a second time by two investigators. IgA-TTG were determined by ELISA with human recombinant antigen and IgA-EMA by an immunofluorescence test with human umbilical cord as antigen. RESULTS: The quality of the biopsy specimens was not acceptable in 29 (10.7%) of 271 cases and a reliable judgement could not be made, mainly due to poor orientation of the samples. The primary clinical diagnosis and the second classification of the biopsy specimens were divergent in nine cases, and one patient was initially enrolled in the wrong group. Thus, 126 coeliac patients and 106 controls, verified by biopsy, remained for final analysis. The sensitivity of IgA-TTG was 94% and IgA-EMA 89%, the specificity was 99% and 98%, respectively. CONCLUSIONS: Serum IgA-TTG measurement is effective and at least as good as IgA-EMA in the identification of coeliac disease. Due to a high percentage of poor histological specimens, the diagnosis of coeliac disease should not depend only on biopsy, but in addition the clinical picture and serology should be considered.

Adolescent↗
PubMed2005

Nutritional status in adolescents and young adults with screen-detected celiac disease.

OBJECTIVE: To describe the nutritional status in patients with screen-detected celiac disease (CD). METHODS: Nutritional status was assessed by serum tests and anthropometric measures in 26 subjects (16 to 25 years of age) with biopsy-proven CD and 29 healthy control subjects (16 to 21 years of age) with negative tissue transglutaminase antibodies (16 to 22 years of age); all the subjects were selected from the cohort of 3654 schoolchildren. RESULTS: Compared with control subjects, CD patients had lower median values of whole blood folic acid (91 versus 109 nmol/L; P = 0.01), serum ferritin (14 versus 27 microg/L; P = 0.028) and pre-albumin (0.21 versus 0.28 g/L; P </= 0.001) and higher transferrin receptor (1.3 versus 1.1; P = 0.008) and serum transferrin receptor-ferritin index (1.2 versus 0.7; P = 0.006). Folic acid concentration was subnormal in 31% of the CD subjects (versus 14% of the controls) and iron status (transferrin receptor-ferritin index) was subnormal in 30% (versus 14%). Body mass index was not different in females of the CD and control groups (22 versus 22 kg/m2) or in the males of the respective groups (25 versus 24 kg/m2). Females with CD were shorter than the controls (mean 162 versus 167 cm; P = 0.018), but no difference was found in males. No association was found between the nutritional status and the markers of mucosal injury (villous-crypt measures), but titer of transglutaminase was associated with whole blood folic acid (r = -0.5; P = 0.016) and with transferrin receptor-ferritin index (r = 0.4, P = 0.05). CONCLUSIONS: One third of screen-detected adolescent CD subjects have abnormalities in folate or iron status that call for early diagnosis and dietary treatment of the disease to prevent nutritional deficiencies.

Adolescent↗
PubMed2005

Celiac disease: from inflammation to atrophy: a long-term follow-up study.

OBJECTIVES: Celiac disease develops gradually from lymphocytosis, crypt hyperplasia and minor villous atrophy to overt villous atrophy. It IS NOT known how such minor mucosal changes predict eventual celiac disease. The aim of this study was to evaluate the role of intraepithelial lymphocytosis and marginally decreased villous height/crypt depth ratio in the development of overt villous atrophy in a long-term follow-up. METHODS: The authors evaluated 980 small bowel biopsies of children who had previously been studied and found to be histologically negative for celiac disease between 1976 and 1992. Villous height/crypt depth ratio and the number of intraepithelial lymphocytes were measured in these initial biopsies. Cases with slight biopsy changes were identified for further study and sex and age matched subjects with normal biopsies from same group were selected as controls. They all were asked to submit serum samples for gliadin, endomysial and tissue transglutaminase antibodies 8 to 28 years after the initial biopsy. Those with positive screening tests were asked to undergo endoscopy and small intestinal biopsy. RESULTS: 236 cases with slight changes were identified, and 236 with normal mucosa served as controls; 76 cases and 68 controls participated in the follow-up study. Ten individuals had positive screening test results. Two new celiac disease patients, one in each group, were found. Four patients in the case group had been diagnosed with celiac disease by routine procedures during the follow-up. Thus, five cases and one control had developed celiac disease. CONCLUSIONS: Small bowel mucosal lymphocytosis or slight reduction in villous height/crypt depth ratio are common findings in patients with suspicion of celiac disease. These findings alone are poor predictors of celiac disease.

Adolescent↗
PubMed2004

Oats can diversify a gluten-free diet in celiac disease and dermatitis herpetiformis.

Finnish celiac disease and dermatitis herpetiformis patients have used oat-containing gluten-free diets since 1997. The aim of this study was to evaluate how the use of oats has been adopted. The use of oats and the effect of oats on symptoms and quality of life were investigated in 1,000 randomly selected members of the Celiac Society. Altogether, 710 patients responded: 423 (73%) with celiac disease and 70 (55%) with dermatitis herpetiformis were currently consuming oats. Patients appreciated the taste, the ease of use, and the low costs; 94% believed that oats diversified the gluten-free diet; 15% of celiac disease and 28% of dermatitis herpetiformis patients had stopped eating oats. The most common reasons for avoiding oats were fear of adverse effects or contamination. There is a market demand for oats, and celiac societies and dietitians should make efforts to promote the development of products free of wheat contamination.

Adolescent↗
PubMed2003

TGF-beta induces the expression of SAP30L, a novel nuclear protein.

BACKGROUND: We have previously set up an in vitro mesenchymal-epithelial cell co-culture model which mimics the intestinal crypt villus axis biology in terms of epithelial cell differentiation. In this model the fibroblast-induced epithelial cell differentiation from secretory crypt cells to absorptive enterocytes is mediated via transforming growth factor-beta (TGF-beta), the major inhibitory regulator of epithelial cell proliferation known to induce differentiation in intestinal epithelial cells. The aim of this study was to identify novel genes whose products would play a role in this TGF-beta-induced differentiation. RESULTS: Differential display analysis resulted in the identification of a novel TGF-beta upregulated mRNA species, the Sin3-associated protein 30-like, SAP30L. The mRNA is expressed in several human tissues and codes for a nuclear protein of 183 amino acids 70% identical with Sin3 associated protein 30 (SAP30). The predicted nuclear localization signal of SAP30L is sufficient for nuclear transport of the protein although mutating it does not completely remove SAP30L from the nuclei. In the nuclei SAP30L concentrates in small bodies which were shown by immunohistochemistry to colocalize with PML bodies only partially. CONCLUSIONS: By reason of its nuclear localization and close homology to SAP30 we believe that SAP30L might have a role in recruiting the Sin3-histone deacetylase complex to specific corepressor complexes in response to TGF-beta, leading to the silencing of proliferation-driving genes in the differentiating intestinal epithelial cells.

Amino Acid Sequence↗
PubMed2003

A novel human glycosyltransferase: primary structure and characterization of the gene and transcripts.

We report the identification and primary structure of a novel human glycosyltransferase, B3GTL (beta3-glycosyltransferase-like). The 498 residue protein consists of a short cytoplasmic N-terminal "tail" (residues 1-4), a single transmembrane domain with type II topology (residues 5-28), a "stem" region (residues 29-260), and a catalytic domain (residues 261-498). The genomes of Anopheles gambiae, Drosophila melanogaster, and Caenorhabditis elegans encode potential orthologs which share 31-39% sequence identity with B3GTL, as well as the following features: a conserved catalytic domain containing a triple aspartate motif (DDD) at its core, a conserved pattern of cysteine residues, a C-terminal KDEL-like motif, and conserved residues and motifs that affiliate this novel group with a family of beta3-glycosyltransferases (GT31 in the CAZY classification). The B3GTL gene lacks canonical TATA and CAAT boxes and contains three functional polyadenylation sites. It is transcribed in a wide range of tissues and in TGF-beta-treated T84 epithelial cells.

Amino Acid Motifs↗