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1.
Diabetologia ; 51(10): 1796-802, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18696046

ABSTRACT

AIMS/HYPOTHESIS: Type 1 diabetes is caused by an immune-mediated process, reflected by the appearance of autoantibodies against pancreatic islets in the peripheral circulation. Detection of multiple autoantibodies predicts the development of diabetes, while positivity for a single autoantibody is a poor prognostic marker. The present study assesses whether positivity for a single autoantibody correlates with pathological changes in the pancreas. METHODS: We studied post mortem pancreatic tissue of a child who repeatedly tested positive for islet cell antibodies (ICA) in serial measurements. Paraffin sections were stained with antibodies specific for insulin, glucagon, somatostatin, interferon alpha, CD3, CD68, cyclooxygenase-2 (COX-2), beta-2-microglobulin, coxsackie B and adenovirus receptor (CAR), natural killer and dendritic cells. Apoptosis was detected using Fas-specific antibody and TUNEL assay. Enterovirus was searched for using immunohistochemistry and in situ hybridisation, as well as enterovirus-specific RT-PCR from serum samples. RESULTS: The structure of the pancreas did not differ from normal. The number of beta cells was not reduced and no signs of insulitis were observed. Beta-2-microglobulin and CAR were strongly produced in the islets, but not in the exocrine pancreas. Enterovirus protein was detected selectively in the islets by two enterovirus-specific antibodies, but viral RNA was not found. CONCLUSIONS/INTERPRETATION: These observations suggest that positivity for ICA alone, even when lasting for more than 1 year, is not associated with inflammatory changes in the islets. However, it is most likely that the pancreatic islets were infected by an enterovirus in this child.


Subject(s)
Autoantibodies/immunology , Islets of Langerhans/immunology , Pancreas/immunology , Antibodies, Viral/analysis , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Apoptosis , CD3 Complex/analysis , Child , Cyclooxygenase 2/analysis , Enterovirus/genetics , Enterovirus/immunology , Fatal Outcome , Glucagon/analysis , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Insulin/analysis , Interferon-alpha/analysis , Islets of Langerhans/cytology , Islets of Langerhans/metabolism , Pancreas/cytology , Pancreas/metabolism , Receptors, Virus/analysis , Reverse Transcriptase Polymerase Chain Reaction , Somatostatin/analysis
2.
Clin Exp Immunol ; 151(1): 71-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17991291

ABSTRACT

Enterovirus infections have been diagnosed more frequently in type 1 diabetic patients than in the healthy population, and enteroviruses have also been found in the pancreas of diabetic patients. Primary replication of the virus occurs in the gut, but there are no previous studies evaluating possible presence of virus in the intestine of diabetic patients. The purpose of this study was to investigate if enteroviruses can be found in small intestinal tissue of type 1 diabetic patients. Formalin-fixed, paraffin-embedded upper intestinal biopsy samples were analysed for the presence of enterovirus using in situ hybridization and immunohistochemistry. Enterovirus was detected by in situ hybridization in six (50%) of the type 1 diabetic patients (n = 12) but in none of the control subjects (n = 10, P = 0.015). Immunohistochemistry identified enterovirus in nine (75%) of the patients and one (10%) control subject (P = 0.004). The presence of the virus was confirmed by reverse transcription-polymerase chain reaction in one of the four patients from whom a frozen and unfixed sample was available. Intestinal morphology was normal in all study subjects. The results suggest that a substantial proportion of type 1 diabetic patients have an ongoing enterovirus infection in gut mucosa, possibly reflecting persistent enterovirus infection. This observation opens new avenues for further studies on the possible role of enteroviruses in human type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/virology , Enterovirus Infections/complications , Enterovirus/isolation & purification , Intestinal Mucosa/virology , Intestine, Small , Adolescent , Adult , Case-Control Studies , Chi-Square Distribution , DNA, Viral/analysis , Enterovirus/genetics , Female , Humans , Immunohistochemistry , In Situ Hybridization , Male , Middle Aged , Paraffin Embedding , Reverse Transcriptase Polymerase Chain Reaction
3.
Kidney Int ; 72(8): 977-84, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17667981

ABSTRACT

Cardiovascular complications are a major problem in chronic renal failure. We examined the effects of plasma calcium, phosphate, parathyroid hormone (PTH), and calcitriol on cardiac morphology in 5/6 nephrectomized rats. Fifteen weeks after nephrectomy rats were given a control diet, high-calcium or -phosphorus diet, or given paricalcitol treatment for 12 weeks. Sham-operated rats were on a control diet. Blood pressure, plasma phosphate, and PTH were increased, while the creatinine clearance was reduced in remnant kidney rats. Phosphate and PTH were further elevated by the high-phosphate diet but suppressed by the high-calcium diet, while paricalcitol reduced PTH without influencing phosphate or calcium. The high-calcium diet increased, while the high-phosphate diet reduced plasma calcium. Plasma calcitriol was significantly reduced in other remnant kidney groups, but further decreased after paricalcitol. Cardiac perivascular fibrosis and connective tissue growth factor were significantly increased in the remnant kidney groups, and further increased in paricalcitol-treated rats. Hence, regardless of the calcium, phosphate, or PTH levels, cardiac perivascular fibrosis and connective tissue growth factor increase in rats with renal insufficiency in association with low calcitriol. Possible explanations are that aggravated perivascular fibrosis after paricalcitol in renal insufficiency may be due to further suppression of calcitriol, or to a direct effect of the vitamin D analog.


Subject(s)
Calcitriol/deficiency , Cardiovascular System/metabolism , Cardiovascular System/pathology , Ergocalciferols/adverse effects , Renal Insufficiency/metabolism , Renal Insufficiency/pathology , Animals , Atrial Natriuretic Factor/metabolism , Blood Pressure/drug effects , Calcitriol/metabolism , Calcium/metabolism , Calcium/pharmacology , Cardiovascular System/drug effects , Chronic Disease , Creatinine/metabolism , Ergocalciferols/pharmacology , Fibrosis , Male , Nephrectomy , Parathyroid Hormone/metabolism , Peptidyl-Dipeptidase A/metabolism , Phosphorus/metabolism , Phosphorus/pharmacology , Rats , Rats, Sprague-Dawley , Renin/blood
4.
Kidney Int ; 71(4): 343-8, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17191083

ABSTRACT

Many risk factors for progression in immunoglobulin A nephropathy (IgAN) have been found. We focused on renal leukocyte infiltrations and cytokines in IgAN. The subjects were 204 IgAN patients. Renal histopathological changes were semiquantitatively graded. Expression of tubulointerstitial Leukocyte common antigen (LCA), CD3, CD68, interleukin (IL)-1beta, and IL-10 was evaluated by immunohistochemistry. These parameters were correlated with progression of IgAN. The significance of these correlations was tested by a multivariate analysis. Glomerulosclerosis, tubular atrophy, interstitial inflammation, and hyaline arteriolosclerosis correlated with progression in all patients and also in patients with initially normal serum creatinine. Tubulointerstitial LCA, CD3, CD68, and IL-1beta expression correlated with progression. CD3 had the strongest correlation. In the multivariate analysis, tubulointerstitial CD3, hypertriglyceridemia, elevated serum creatinine concentration, and interstitial fibrosis were independently associated with progressive disease in all patients, and tubulointerstitial CD3 expression and hyaline arteriolosclerosis in patients with initially normal serum creatinine. We found parameters reflecting tubulointerstitial inflammation to predict deterioration of renal function in IgAN. This was also seen in patients whose serum creatinine was normal at the time of renal biopsy. Our findings show that, an immunohistochemical evaluation of tubulointerstitial inflammation seems to be a useful tool in determining the prognosis in IgAN.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , CD3 Complex/metabolism , Glomerulonephritis, IGA/diagnosis , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Adolescent , Adult , Aged , Disease Progression , Female , Glomerulonephritis, IGA/metabolism , Glomerulonephritis, IGA/pathology , Humans , Immunohistochemistry , Leukocyte Common Antigens/metabolism , Macrophages/metabolism , Male , Middle Aged , Multivariate Analysis , Prognosis , T-Lymphocytes/metabolism
5.
Int J Oral Maxillofac Surg ; 35(8): 727-32, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16569496

ABSTRACT

The aim of this study was to assess degradation of a novel bioactive guided tissue regeneration (GTR) membrane and to quantify the concurrent tissue responses. Pieces of membrane composed of poly-l-lactide, poly-d,l-lactide, trimethylenecarbonate and polyglycolide were dipped into an N-methyl-2-pyrroline (NMP) solution and implanted in the mandibles of 10 sheep. The animals were sacrificed at 6-104 weeks. Parallel in vitro degradation was analysed by measuring the inherent viscosity, water absorption and remaining mass. One of the 2 in vitro sets of membranes was prehandled with NMP. At 6-26 weeks in vivo, the gradually more degraded implants were surrounded by a fibrous network. At 52 and 104 weeks, the implants and fibrous networks were non-detectable. Foreign body granulomatous reactions were not observed. In vitro, the mass of the NMP-exposed membranes diminished linearly over the 2-year period down to 10%, while the non-NMP-exposed membrane maintained all their mass for the first 16 weeks. The membranes without NMP had absorbed significantly less water at weeks 4 and 8 than the other group. The inherent viscosity decreased relatively uniformly in the in vitro groups. In conclusion, the in vivo degradation was complete in 12 months with only mild histologic responses; the degradation in vitro may be slower. NMP accelerates the degradation.


Subject(s)
Biocompatible Materials , Dental Implantation, Endosseous/methods , Guided Tissue Regeneration, Periodontal/methods , Mandible/surgery , Membranes, Artificial , Animals , Biodegradation, Environmental , Dental Implants , Female , Sheep , Time Factors
6.
Neuropathol Appl Neurobiol ; 30(1): 39-45, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14720175

ABSTRACT

We introduce a modification of the tissue microarray technique in which several frozen brain tissue specimens are collected to a single frozen brain array block. In the present application, we use it for the detection of neuronal paraneoplastic anti-Hu autoantibodies. Representative samples from 15 different brain regions were collected according to a standard neuropathological autopsy protocol. Cryostat sections from each block were cut and conventionally stained. From representative areas, cylinder tissue samples from each specimen were punched and then arrayed into a recipient array block. Using the cryostat sections of this brain array, autoantibodies from seven anti-Hu-positive patient sera (confirmed by immunoblotting) were screened by immunohistochemistry. Neuronal architecture was well preserved and immunohistochemical staining was comparable to that of conventional cryostat sections. Because of the variable staining pattern in different brain areas, two anti-Hu-positive sera could be detected immunohistochemically by the one brain array. With the present array technique, it is possible to characterize the variable staining patterns of neuronal paraneoplastic autoantibodies in different locations of the human brain. The frozen brain array also allows the detection of RNA and DNA targets involved in neurological diseases.


Subject(s)
Autoantibodies/immunology , Brain/immunology , Immunohistochemistry/methods , Paraneoplastic Syndromes, Nervous System/immunology , Specimen Handling/methods , Aged , ELAV Proteins , Humans , Male , Middle Aged , Nerve Tissue Proteins/immunology , Neurons/immunology , RNA-Binding Proteins/immunology
7.
Gut ; 52(2): 199-204, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12524400

ABSTRACT

BACKGROUND: Autoantibodies against transglutaminase 2 (TG2) are thought to be responsible for the endomysial (EMA), reticulin (ARA), and jejunal antibody (JEA) tissue binding of serum samples from coeliac patients but the exclusive role of TG2 in these staining patterns has not yet been established. AIMS: To evaluate whether antigens other than TG2 contribute to EMA/ARA/JEA reactions. PATIENTS: Serum samples from 61 EMA/ARA/JEA positive untreated patients with coeliac disease, 40 dermatitis herpetiformis patients, and 34 EMA/ARA/JEA negative non-coeliac controls were tested. METHODS: TG2 knockout (TG2-/-) and wild-type mouse oesophagus, jejunum, liver, and kidney sections, and TG2-/- sections coated with human recombinant TG2 were used as substrates in single and double immunofluorescent studies for patient IgA binding and tissue localisation of TG2, fibronectin, actin, and calreticulin. RESULTS: None of the patient serum samples elicited EMA, ARA, or JEA binding in TG2-/- morphologically normal tissues. In contrast, 96 of 101 gluten sensitive patient samples (95%) reacted with wild-type mouse tissues and all 101 reacted in EMA/ARA/JEA patterns with TG2-/- mouse tissues coated with human TG2. Serum IgA binding to TG2-/- smooth muscle cells was observed in low titres in 31.1%, 27.5%, and 20.5%, and to TG2-/- epithelium in 26.3%, 5.0%, and 8.8% of coeliac, dermatitis herpetiformis, and control samples, respectively. These positivities partly colocalised with actin and calreticulin but not with TG2 or fibronectin. CONCLUSIONS: EMA/ARA/JEA antibody binding patterns are exclusively TG2 dependent both in coeliac and dermatitis herpetiformis patients. Actin antibodies are responsible for some positivities which are not part of the EMA/ARA/JEA reactions.


Subject(s)
Autoantibodies/immunology , Celiac Disease/immunology , Dermatitis Herpetiformis/immunology , GTP-Binding Proteins/immunology , Reticulin/immunology , Transglutaminases/immunology , Adolescent , Adult , Animals , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay/methods , Fluorescent Antibody Technique/methods , Humans , Immunoglobulin A/immunology , Infant , Jejunum/immunology , Mice , Mice, Knockout , Middle Aged , Muscle, Smooth/immunology , Protein Glutamine gamma Glutamyltransferase 2
8.
Gut ; 50(1): 84-9, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11772972

ABSTRACT

BACKGROUND AND AIMS: Coeliac disease is characterised by atrophy of the villi and hyperplasia of the crypts in the mucosa of the small intestine. It is caused by an environmental trigger, cereal gluten, which induces infiltration of the mucosa by inflammatory cells. We hypothesised that these inflammatory cells express cyclooxygenase 2 (COX-2), an enzyme that contributes to the synthesis of pro and anti-inflammatory prostaglandins and is known to be expressed at sites of inflammation in the stomach and colon. We have investigated expression of COX-2 in the coeliac disease affected small intestinal mucosa where it may be an indicator of either disease induction or mucosal restoration processes. PATIENTS AND METHODS: Small intestinal biopsy samples from 15 coeliac patients and 15 non-coeliac individuals were stained immunohistochemically for COX-2. Samples from 10 of the patients were also stained after these patients had been on a gluten free diet for 6-24 months. Various cell type marker antigens were used for immunohistochemical identification of the type of cell that expressed COX-2. To further verify colocalisation of the cell type marker and COX-2, double immunoperoxidase and immunofluorescence methods were employed. Immunoelectron microscopy was used to investigate the subcellular location of COX-2. RESULTS: In all samples taken from coeliac patients, clusters of cells with strong immunoreactivity for COX-2 were found in those areas of the lamina propria where the epithelium seemed to blister or was totally detached from the basement membrane. These clusters were reduced in number or totally absent in samples taken after a gluten free diet. No such clusters were seen in any control samples. The density of COX-2 positive cells lining the differentiated epithelium decreased significantly from 13.5 (5.1) cells/10(5) microm(2) (mean (SD)) in the untreated patient samples to 6.5 (2.0) cells/10(5) microm(2) after a gluten free diet (p<0.001), and was 3.3 (1.9) cells/10(5) microm(2) in control samples (p<0.001 compared with untreated or diet treated coeliac samples). Staining for COX-2 was localised to CD3+ T cells and CD68+ macrophages in the mucosal lesions but not all of these cells were positive for COX-2. Immunoelectron microscopy revealed that the ultrastructure of the COX-2 positive cells resembled that of lymphocytes, and the immunoreaction was localised to the rough endoplasmic reticulum and the nuclear envelope. CONCLUSIONS: Our results show that in coeliac disease, blistering of small intestinal epithelial cells is associated with accumulation of COX-2 positive T cells, and the number of these cells decreases after a gluten free diet. These observations suggest that COX-2 mediated prostanoid synthesis contributes to healing of the coeliac mucosa and may be involved in maintenance of intestinal integrity.


Subject(s)
Blister/enzymology , Celiac Disease/enzymology , Prostaglandin-Endoperoxide Synthases/metabolism , T-Lymphocytes/enzymology , Adolescent , Adult , Aged , Blister/pathology , CD3 Complex/metabolism , Case-Control Studies , Celiac Disease/diet therapy , Celiac Disease/pathology , Cell Count , Female , Humans , Image Processing, Computer-Assisted , Intestinal Mucosa/enzymology , Leukocyte Common Antigens/metabolism , Male , Microscopy, Immunoelectron , Middle Aged
9.
Lab Invest ; 81(12): 1647-51, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11742035

ABSTRACT

Mechanisms of prostate cancer (CaP) recurrence during a combined androgen blockade (CAB) are poorly understood. Previously, the role of androgen receptor (AR) gene mutations underlying the CAB therapy relapse has been raised. To investigate the hypothesis that AR gene aberrations are involved in CAB relapse, 11 locally recurrent CaP samples from patients treated with orchiectomy and bicalutamide were analyzed for copy number changes and DNA sequence alterations of the AR gene by fluorescence in situ hybridization and single-strand conformation polymorphism, respectively. Altogether, base changes were detected in four tumors (36%). Three of them were missense mutations (G166S, W741C, M749I) and two were silent polymorphisms. Interestingly, none of the tumors had AR amplification. These data suggest that different AR variants are developed and selected for during various types of hormonal treatments, and also, that CAB achieved by orchiectomy and bicalutamide does not act as a selective force for AR amplification.


Subject(s)
Androgen Antagonists/therapeutic use , Anilides/therapeutic use , Mutation , Orchiectomy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Receptors, Androgen/genetics , Combined Modality Therapy , Humans , Male , Neoplasm Recurrence, Local , Nitriles , Tosyl Compounds
12.
J Neurooncol ; 55(1): 29-37, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11804280

ABSTRACT

Using the novel tissue microarray technique, we studied immunohistochemical expression of cell cycle regulators p53, p21, pRb in 42 grade II oligodendrogliomas, 16 grade III anaplastic oligodendrogliomas, 10 primary and 4 recidive grade II oligoastrocytomas, 10 grade III oligoastrocytomas and 2 other grade II mixed gliomas. The p53 immunopositivity associated with malignant histology of the tumor (p = 0.01, Mann-Whitney test) and high pRb expression (p = 0.015). The p21 score associated strongly with histological grade (p < 0.001). The immunopositive tumors had a significantly higher rate of proliferation (p = 0.021). The p21 immunopositivity correlated positively with p53 immunopositivity: among the 33 p21 immunopositive tumors 30 (91%) were p53 immunopositive and only 3 were p53 immunonegative (p = 0.017). Patients with p21 immunonegative primary tumors had significantly better prognosis: among them 42 of the 46 (91%) survived, whereas only 18 of the 30 patients (60%) with p21 immunopositive primary tumors survived until the follow-up date (p = 0.0017). Statistical significance was reached in multivariate analysis as well (p = 0.01, exp(B) = 5.5). The pRb immunopositive tumors had higher proliferation rate than immunonegative tumors (p = 0.002). In multivariate variance analysis, comparing the effects of different regulatory proteins on cell proliferation, only the amount of pRb expression reached statistical significance (p = 0.004). In conclusion, the expression of p21 in oligodendrocytic tumors seems to be upregulated by p53 expression which rises with cell proliferation and malignancy as in attempt to halt cell cycle but seems to be overrun by other factors. The amount of p21 expression has independent prognostic significance and could be used in diagnosis to help the difficult evaluation of the malignancy potential of oligodendrogliomas and oligoastrocytomas.


Subject(s)
Astrocytoma/metabolism , Brain Neoplasms/metabolism , Cyclins/metabolism , Oligodendroglioma/metabolism , Retinoblastoma Protein/metabolism , Tumor Suppressor Protein p53/metabolism , Adolescent , Adult , Aged , Astrocytoma/pathology , Brain Neoplasms/pathology , Cell Cycle Proteins/metabolism , Child , Cyclin-Dependent Kinase Inhibitor p21 , Female , Humans , Immunoenzyme Techniques , Male , Middle Aged , Oligodendroglioma/pathology , Prognosis
13.
J Nephrol ; 14(6): 440-6, 2001.
Article in English | MEDLINE | ID: mdl-11783599

ABSTRACT

Impairment of renal function, severe proteinuria and arterial hypertension are the strongest clinical predictors of an unfavorable outcome in IgA nephropathy (IgAN). Glomerulosclerosis and interstitial fibrosis are the most reliable histologic prognostic markers. Metabolic syndrome and insulin resistance probably affect the clinical course of the disease. Among the known gene polymorphism it seems that there is a link between the ACE gene D allele and the progression of IgAN. Elevated blood pressure should be actively treated. The target blood pressure is 130/80 mmHg or less and the goal should also be to reduce proteinuria. Several large-scale trials are currently testing corticosteroids and other drugs in the treatment of IgAN.


Subject(s)
Glomerulonephritis, IGA/physiopathology , Glomerulonephritis, IGA/therapy , Disease Progression , Glomerulonephritis, IGA/genetics , Humans , Polymorphism, Genetic , Renin-Angiotensin System/genetics
14.
Scand J Immunol ; 52(6): 602-8, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11119267

ABSTRACT

BACKGROUND AND AIMS: In coeliac disease, the gut involvement is gluten-dependent. Following the introduction of a gluten-free diet, inflammatory cell infiltration decreases in the small intestinal mucosa. Our hypothesis was that the oral mucosa might mirror the changes found in coeliac disease similarly to the mucosa of the small intestine. Thus, the number of inflammatory cells in the oral mucosa would decrease in patients with coeliac disease on a gluten-free diet. METHODS: The distribution CD45RO+ and CD3(+) T cells, T-cell subpopulations (CD4(+), CD8(+), T-cell receptor (TCR)alpha beta+ and TCR gamma delta+ cells) and HLA DR expression were studied in the buccal mucosa of 15 untreated and 44 gluten-free diet treated coeliac disease patients, and of 19 controls. All 15 patients with untreated coeliac disease were immunglobulin (Ig)A endomysial antibody positive and all 44 patients on gluten-free diet except one were endomysial antibody negative, as were all control subjects. RESULTS: Untreated coeliac disease patients did not differ from controls in the densities of CD45RO+ cells, CD3(+) cells or of T-cell subsets. In contrast, in treated coeliac disease patients, a significant increase in the numbers of mast cells, CD3(+) and CD4(+) lymphocytes was found in the lamina propria of oral mucosa as compared with patients with untreated coeliac disease and controls. The increase in CD3(+) T cells was in part owing to an increase in lymphocytes expressing no TCR. No differences were found in the expression of human leucocyte antigen (HLA) DR in the epithelium or in the lamina propria in the patient groups studied or in the controls. In treated coeliac disease patients only a few TCR gamma delta+ T cells were found intraepithelially and in the lamina propria, but these cells were not detected in the lamina propria of oral mucosa of patients with untreated coeliac disease or in the controls. CONCLUSIONS: The infiltration of T cells into oral mucosa was increased in treated coeliac disease patients in spite of adherence to a gluten-free diet. Because the CD3(+) T cell count was higher than those of the TCR alpha beta+ and TCR gamma delta+ T cells, there must be other cells involved, probably natural killer (NK) cells. The increase in T-cell subsets in the treated coeliac disease patients seems not to result from poor dietary compliance, but might occur as a late immune response in coeliac disease and reflect chronic immunologic stimulation followed by regeneration of memory T cells.


Subject(s)
Celiac Disease/diet therapy , Celiac Disease/immunology , Mouth Mucosa/immunology , T-Lymphocyte Subsets/immunology , Adult , Aged , Antigens, CD , Female , Glutens/immunology , HLA-DR Antigens , Humans , Male , Middle Aged , Receptors, Antigen, T-Cell
15.
Neuropathol Appl Neurobiol ; 26(6): 504-12, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11123716

ABSTRACT

The role of molecular markers predicting the prognosis and the selection of patients for further adjuvant therapies is not well established in oligodendroglioma patients. A potential prognostic as well as a therapeutically predictive factor, topoisomerase IIalpha (topoIIalpha), is a molecular target for certain cytotoxic drugs. Its expression has been shown to correlate with the prognosis in a number of different cancers and with the chemosensitivity of cancer cells in vitro. The expression of topoIIalpha was evaluated immunohistochemically in 59 oligodendrogliomas and in 29 mixed gliomas with a predominating oligodendroglioma component by the use of a tissue microarray technique. In the gliomas, the percentage of topoIIalpha immunopositive cells protein expression varied from 0.0 to 49.1% (5.2 +/- 8.3%, mean+/- SD). In oligoastrocytomas, the mean topoIIalpha score was significantly higher in the oligodendroglioma than in the astrocytoma component of the tumour (5.37 +/- 5.58% vs. 1.89 +/- 2.49%, P = 0.018). A significant association was found between the high proportion of topoIIalpha positive cells and high grade of the tumour (P < 0.0001), high tumour proliferation rate (P < 0.0001), p53 overexpression (P = 0.01) and high expression of tumour suppressing retinoblastoma protein (P = 0.023). TopoIIalpha expression was not associated with the age or sex of patient, and the rate of apoptosis. TopoIIalpha expression associated highly significantly with patient prognosis; a significantly higher proportion of patients with low rather than with high topoIIalpha score was alive at the end of the 5-year follow-up (P = 0.03). Cox analysis was used to demonstrate that topoIIalpha had an independent prognostic value for survival (P = 0.034). In conclusion, high topoIIalpha expression characterizes oligodendrogliomas and oligoastrocytomas which are poorly differentiated, have high proliferation rate, and has prognostic value for overall survival of these patients. Therefore, topoIIalpha may be a useful marker for better targeted selection of poor prognosis oligodendroglioma patients for adjuvant therapy.


Subject(s)
Brain Neoplasms/enzymology , Brain Neoplasms/pathology , DNA Topoisomerases, Type II/metabolism , Isoenzymes/metabolism , Oligodendroglioma/enzymology , Oligodendroglioma/pathology , Adolescent , Adult , Aged , Antigens, Neoplasm , Apoptosis , Astrocytoma/enzymology , Astrocytoma/pathology , Cell Division , Child , DNA-Binding Proteins , Humans , Immunohistochemistry , Middle Aged , Prognosis , Proportional Hazards Models , Survival Analysis
16.
Am J Gastroenterol ; 95(10): 2880-7, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11051363

ABSTRACT

OBJECTIVE: Gluten-derived peptides (e.g., amino-acids 31-49 of alpha-gliadin) have been shown to cause changes typical of celiac disease in the gut. Gluten-derived peptides have mostly been used in in vitro studies. The easiest access to the gastrointestinal system may be the mouth. In the present study we were interested to see whether a synthetic peptide corresponding to amino-acids 31-49 of alpha-gliadin could induce inflammatory changes in the oral mucosa after a local challenge in celiac disease patients. METHODS: The challenge was made by injecting the peptide solution at a concentration of 10 microg/ml submucosally into the oral mucosa of 10 celiac disease patients after a gluten-free diet (GFD) and 12 healthy control subjects. B and CD45RO+ T cells, mast cells, CD3+, CD4+, CD8+ lymphocytes, and alphabeta and gammadelta T-cell receptor-bearing (TcR alphabeta, TcR gammadelta) lymphocytes were counted and HLA DR expression was determined. The expression of CD25 and Ki-67 antigen was also examined. RESULTS: The peptide significantly increased the total number of T cells in the lamina propria of the celiac disease patients. The expression of T-cell activation marker CD25 (IL-2 receptor), but not that of cell proliferation marker Ki-67, was also significantly increased in the lamina propria after peptide challenge. Such a reaction was not observed in the controls. The numbers of CD3+ and CD4+ T cells in the lamina propria were also increased in celiac disease patients after the challenge. The count of TcR gammadelta+ cells was very small in the oral mucosa in celiac disease and showed no increase when the oral mucosa was challenged with the peptide. The expression of HLA DR staining was enhanced after the submucosal peptide challenge in celiac disease; however, the difference was not statistically significant. CONCLUSIONS: The results show that in the celiac disease patients after the peptide challenge the oral mucosal lamina propria responds with a nonproliferative increase of lymphocytes. Thus, submucosal challenge with the peptide 31-49 can be used as an aid in the diagnosis of celiac disease. However, further studies with optimized methodology, including various concentrations of the peptide, adjuvants, other peptides, etc., are warranted, especially because the oral mucosa provides the easiest access to an in vivo peptide challenge in celiac disease.


Subject(s)
Celiac Disease/diagnosis , Gliadin , Mouth Mucosa/immunology , Peptide Fragments , Adult , Biopsy , Celiac Disease/immunology , Celiac Disease/pathology , Female , Humans , Immunoenzyme Techniques , Injections , Ki-67 Antigen/analysis , Lymphocyte Count , Lymphocyte Subsets/immunology , Lymphocyte Subsets/pathology , Male , Middle Aged , Mouth Mucosa/pathology , Predictive Value of Tests , Receptors, Interleukin-2/analysis , Stomatitis/immunology , Stomatitis/pathology
17.
Oncol Rep ; 7(5): 1141-4, 2000.
Article in English | MEDLINE | ID: mdl-10948353

ABSTRACT

Proliferative and apoptotic activities, as well as p53 protein expression, of ten untreated primary prostate carcinomas that showed extremely poor response to hormonal therapy (primary androgen independent prostate carcinomas) were compared with the stage- and grade-matched primary tumor specimens with favorable response to hormonal therapy (androgen dependent prostate carcinomas). The mean proliferative activity measured by Ki-67 immunohistochemistry was slightly higher in the primary androgen independent prostate carcinomas (8.70+/-5.24) than in the androgen dependent prostate carcinomas (7.09+/-2.68; p=0.27). The mean apoptotic activity by in situ end-labeling technique in the primary androgen independent prostate carcinomas (0.96+/-1.03) was less than half of that in the androgen dependent prostate carcinomas (2.75+/-0.98; p=0.0001). Ten percent of the androgen dependent prostate tumors showed p53 protein expression, whereas 30% of the primary androgen independent prostate tumors were immunopositive for p53 (p=0.30). In summary, we have shown that apoptotic activity in the primary androgen independent prostate carcinomas is significantly lower than in the matched androgen dependent prostate carcinomas while the proliferative activity remains unaffected. These results suggest that primary androgen independent prostate carcinomas may have genetic properties, such as inactivation of the p53 gene, that enable them to escape apoptosis caused by androgen ablation.


Subject(s)
Androgens/physiology , Apoptosis/physiology , Neoplasms, Hormone-Dependent/pathology , Prostatic Neoplasms/pathology , Aged , Aged, 80 and over , Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Cell Division/physiology , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms/drug therapy , Survival Analysis , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/immunology
18.
Neuropathol Appl Neurobiol ; 26(4): 319-31, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10931365

ABSTRACT

The aim of the study was to evaluate the applicability of quantitative histopathology as an aid for grading diffusely infiltrating astrocytomas. Primary astrocytomas were analysed for parameters (mean nuclear size, mitosis count, area fraction of endothelial cells and tumour necrosis, area fraction of nuclei, and Ki-67 (MIB-1) labelling index), which are closely related to the World Health Organization (WHO) 1979 and WHO 1993 grading criteria. All estimates correlated with the WHO histopathological grade and patient outcome. According to the receiver-operating characteristics curve, the presence of tumour necrosis and mitosis count (cut-off at 3 mitoses/mm2 of neoplastic tissue) showed the best sensitivity and specificity in separating patients with different survival. The multivariate survival analyses confirmed this result. A decision-tree model was constructed based on these two variables: twig I with less than 3 mitoses/mm2, twig II with equal or more than 3 mitoses/mm2 but no necrosis, and twig III with tumour necrosis. This model was found to be more strongly associated with survival than the WHO 1979 or WHO 1993 grading schemes. Low-malignancy astrocytomas (WHO grade II or twig I tumours) could be further divided into two prognostic categories by the image cytometric DNA analysis. The results put an emphasis on astrocytoma grading on mitosis counts (grade II vs. III) and tumour necrosis (grade III vs. IV). To standardize the sampling for mitosis counting, it is suggested that a parallel Ki-67 immunostaining be used for the identification of the most proliferative areas.


Subject(s)
Astrocytoma/pathology , Brain Neoplasms/pathology , DNA, Neoplasm/analysis , Glioblastoma/pathology , Image Cytometry/methods , Astrocytoma/chemistry , Astrocytoma/classification , Brain Neoplasms/chemistry , Brain Neoplasms/classification , Cell Division , Cell Nucleus/pathology , Decision Support Techniques , Endothelium, Vascular/pathology , Female , Glioblastoma/chemistry , Glioblastoma/classification , Humans , Immunohistochemistry , Male , Middle Aged , Necrosis , Neoplasm Invasiveness , Predictive Value of Tests , Prognosis , ROC Curve , Sensitivity and Specificity , Survival Analysis , Survival Rate
19.
Hum Reprod ; 15(7): 1484-9, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10875854

ABSTRACT

Chlamydia trachomatis infection is associated with pelvic inflammatory disease (PID) and tubal factor infertility (TFI). We investigated the role of C. trachomatis as a target antigen of endometrial and salpingeal tissue lymphocytes derived from PID and TFI patients. Antigen specificity of the tissue originated T lymphocyte lines (TLL) was tested against C. trachomatis elementary bodies and chlamydial heat shock protein 60 (CHSP60). C. trachomatis antigen stimulated proliferation in two out of eight endometrial TLL derived from PID patients and three out of four TLL derived from TFI patients. All (n = 4) TLL derived from the salpingeal specimens responded to CHSP60 compared with only one out of 12 TLL derived from the endometrial specimens. In-vivo expression of interferon-gamma (IFN-gamma) mRNA revealed that it was present in nine of 13 specimens obtained from PID patients. The dominant activity of type-1 T lymphocytes was confirmed by the in-vitro production of IFN-gamma (median 1007 pg/ml) from all (n = 5) C. trachomatis specific TLL while IL-5 secretion was lower (median 779 pg/ml). In conclusion, C. trachomatis reactive TLL were established from in-vivo activated lymphocytes from the upper genital tract tissue of PID and TFI patients. The reactivity of the salpingeal TLL to CHSP60 provided further evidence that immunoreactivity to CHSP60 is a predominant response in patients with tubal damage.


Subject(s)
Chlamydia trachomatis/immunology , Genitalia, Female/immunology , Infertility, Female/immunology , Pelvic Inflammatory Disease/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Cell Division/drug effects , Cell Line/metabolism , Chaperonin 60/immunology , Chlamydia trachomatis/metabolism , Cytokines/metabolism , Female , Genitalia, Female/pathology , Humans , Infertility, Female/metabolism , Infertility, Female/pathology , Interleukins/pharmacology , Middle Aged , Pelvic Inflammatory Disease/metabolism , Pelvic Inflammatory Disease/pathology , T-Lymphocytes/pathology
20.
Respiration ; 67(2): 209-12, 2000.
Article in English | MEDLINE | ID: mdl-10773796

ABSTRACT

Hard metal lung diseases (HML) are rare, and complex to diagnose. We describe the case of a patient with allergic alveolitis accompanied by rheumatoid arthritis. A sharpener of hard metal by trade, our patient was a 45-year-old, nonsmoking Caucasian female who experienced symptoms of cough and phlegm, and dyspnea on exertion. Preliminary lung findings were inspiratory rales in both basal areas, decreased diffusion capacity and a radiological picture resembling sarcoidosis. A high-resolution computed tomography scan indicated patchy alveolitis as well. An open lung biopsy revealed non-necrotizing granulomas consisting of epitheloid cells and surrounded by lymphocytes, plasma cells and a few eosinophils. These cells also occupied the thickened alveolar interstitium. Macrophages in the alveolar spaces, some of them multinuclear, contained dust particles. Hard metal alveolitis is clinically well known and, in this patient, has been described histologically. After the patient had quit working with hard metal and following corticosteroid therapy, pulmonary symptoms and signs were relieved. During this recovery period, however, she contracted rheumatoid arthritis.


Subject(s)
Alloys/adverse effects , Alveolitis, Extrinsic Allergic/diagnosis , Alveolitis, Extrinsic Allergic/etiology , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/etiology , Cobalt/adverse effects , Tungsten/adverse effects , Alveolitis, Extrinsic Allergic/drug therapy , Biopsy , Female , Granuloma, Respiratory Tract/etiology , Granuloma, Respiratory Tract/pathology , Humans , Lung/diagnostic imaging , Lung/pathology , Middle Aged , Prednisolone/therapeutic use , Tomography, X-Ray Computed , Treatment Outcome
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