Hajime Kudo

Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery.

Abstract Background and Aims : Up to one‐third of patients with ulcerative colitis (UC) need to undergo surgery, but the factors that exacerbate inflammation remain unclear. The authors hypothesize that excessive apoptosis reported in active UC may disrupt epithelial defenses and exacerbate the disease. The aim of the present study was to clarify whether apoptotic epithelial cells and histiocytes engulfing them increased in patients with active UC who ultimately require surgery (UC‐S) rather than those receiving medication alone (UC‐M).

Induction of differentiation and peroxisome proliferator-activated receptor γ expression in colon cancer cell lines by troglitazone

Purpose We investigated the relationship between the effects of troglitazone (TGZ) on cellular growth, differentiation and apoptosis induction, and the induction of peroxisome proliferator-activated receptor (PPAR) γ in three human colon cancer cell lines, HCT-15, DLD-1and LoVo.Methods Viable cell number was evaluated by the Alamar blue assay and apoptotic cell death by TUNEL methods. Expression of PPARγ mRNA and protein was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively. The differentiation markers of colonic mucosa, villin and MUC2 mRNAs, were analyzed by real-time RT-PCR.Results HCT-15 and DLD-1 cells proliferated rapidly while LoVo cells grew slowly. TGZ dose-dependently inhibited the proliferation of all the cell lines, and also induced apoptotic cell death. High expression of PPARγ mRNA and protein was demonstrated in DLD-1 and LoVo cells before TGZ treatment. After the treatment, PPARγ mRNA and protein levels were increased in HCT-15 and LoVo cells. Villin and MUC2 mRNAs were increased by TGZ treatment in HCT-15 cells while villin mRNA was repressed in LoVo cells. Changes in expression of PPARγ, villin or MUC2 mRNAs were not observed in DLD-1 cells.Conclusions These results suggest that PPARγ levels are not correlated with the rates of cell proliferation. Differentiation induction by TGZ was only observed in the cell lines with enhanced PPARγ expression.

Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease

Background and Aim: Colorectal Paneth cell metaplasia (PCM) is known to be a sign of idiopathic inflammatory bowel disease (IBD), although its distribution and histogenesis are not fully understood. Objectives of this research were to investigate the spatial distribution of PCM in IBD and other forms of colitis (non‐IBD), and to find stimuli causing PCM.

Differentiation between ulcerative colitis and Crohn’s disease by a quantitative immunohistochemical evaluation of T lymphocytes, neutrophils, histiocytes and mast cells

Mucosal biopsy criteria has limited validity in terms of discrimination between ulcerative colitis (UC) and Crohn’s disease (CD). The aim of this study was to set up quantitative immunohistochemical criteria, with a special focus on inflammatory cell distribution within individual specimens and throughout the large bowel. Quantitative evaluation was performed for the density of CD8+, CD45RO+, neutrophil elastase+, CD68+ and mast cell tryptase+ cells in affected and unaffected mucosa taken from 41 patients with UC and 61 patients with CD. Each slide was examined at the highest and lowest density fields, which were further divided into the upper and deeper half of mucosa. Multiple logistic regression analysis using 51 features as independent variables constructed a predictive equation finding the probability of UC (PUC), and the diagnostic categories were subsequently defined based on a receiver–operating characteristic curve. The analysis disclosed five significant features suggesting UC; these implied intense infiltration of CD8+ and mast cell tryptase+ cells, diffuse infiltration of neutrophil elastase+ and CD68+ cells, and continuous infiltration of CD45RO+ cells. The criteria consisted of three diagnostic categories, ‘suggestive of UC (PUC ≥ 0.7)’, ‘indeterminate (0.3 < PUC < 0.7)’, and ‘suggestive of CD (PUC ≤ 0.3)’; the criteria had values for sensitivity and specificity exceeding 95%. The immunohistochemical criteria distinguishing UC from CD may help to confirm the diagnosis in patients with ambiguous endoscopic and histological diagnosis.

Decreased expression of the peroxisomal bifunctional enzyme and carbonyl reductase in human hepatocellular carcinomas

Abstract Human hepatocellular carcinomas (HCC) are known to frequently exhibit clear-cell or fatty change. The expression of three enzymes related to fatty acid metabolism, the peroxisomal bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, BE), cytosolic carbonyl reductase (CR) and the α-class glutathione S-transferase (GST) was investigated immunohistochemically in 45 HCC samples, to examine their relevance to this phenomenon and to antioxidant cellular defence. The tumour sizes ranged from 3 mm to 37 mm in diameter (mean 19 mm). Of 8 highly differentiated carcinomas (Edmondsons grade I), 5 and 6 showed positive staining for BE and CR respectively, like the surrounding non-hepatoma tissues. Of 37 Edmondsons grade II–IV lesions, 31 exhibited negative or only weakly positive staining for both enzymes, as compared with the surrounding tissues. The combined rates for weakly positive and negative staining for BE or CR were proportional to the degree of dedifferentiation. However, 3 of 26 grade III tumours showed enhanced staining. Intensities of staining for CR were in accordance with those for BE in 40 of the total of 45 HCC. Immunoblot analysis also demonstrated concerted alteration of the two enzymes in carcinoma tissues. The staining of the α-class GST was hardly changed in Edmondsons grade I and II cases but was decreased in 24 of 31 grade III and IV lesions. The great majority of the BE-negative carcinomas did not demonstrate fatty or clear-cell change. These results suggested that BE and CR might be possible markers for the analysis of multistage hepatocarcinogenesis but that decrease or loss was not reflected in increased fat storage.

Juvenile Parkinson's disease with widespread Lewy bodies in the brain

SummaryA clinico-pathological case report on a case of juvenile Parkinsons disease (JPD) with widespread Lewy bodies (LBs) in the brain is presented with comparative morphological studies on two demented cases of “classical” Parkinsons disease (CPD) with disease onset at an older age. The clinical and histological pictures of this JPD case were typical of Parkinsons disease, excepting numerous Lewy bodies in the cerebrum. There were no neurofibrillary change nor senile plaques throughout the CNS. The distribution and histochemical and ultrastructural characters of the histological lesions (i.e., LBs) in the JPD and the two CPD cases were investigated and compared. The comparison showed no qualitative but only quantitative differences between the two types of Parkinsons disease. The present study also revealed that in CPD cases significant numbers of LBs could be present in the cerebral cortex, amygdaloid and claustrum. These lesions can be in part responsible for dementia in CPD.

Is 2‐Propyl‐4‐Pentenoic Acid, a Hepatotoxic Metabolite of Valproate, Responsible for Valproate‐Induced Hyperammonemia?

Summary: To investigate the association between valproate metabolism (VPA) and VPA‐induced hyperammonemia together with the contribution of VPA hepatotoxicity risk factors such as young age, polypharmacy, and high serum VPA levels to VPA‐induced hyperammonemia, plasma ammonia (NH3) levels, serum levels of VPA and its metabolites, and biochemical parameters were determined in 98 patients treated with VPA (53 monopharmacy cases and 45 polypharmacy cases). In monopharmacy patients, plasma NH3 levels did not depend on age, VPA dosage or serum levels. Serum level of 2‐propyl‐4‐pentenoic acid (4‐en) showed a negative correlation with plasma NH3 level in the monopharmacy group. In polypharmacy patients, plasma NH3 levels, serum glutamic pyruvic transaminase, and γ‐glutamyltranspeptidase were significantly higher, while level/dose VPA ratio, 2‐en‐VPA serum level, and bilirubin were significantly lower than those in monopharmacy patients. These results suggest that young age and relatively high VPA serum levels within the therapeutic range were unlikely to be risk factors for common hyperammonemia associated with VPA therapy and that 4‐en was not causally related to this adverse effect. The decreased serum level of 2‐en‐VPA in polypharmacy patients may be a reflection of a certain mitochondrial dysfunction, which might be a mechanism of the increased NH3 levels. The changes in biochemical parameters in polypharmacy patients were considered results of the enzyme‐inducing activity of coadministered antiepileptic drugs (AEDs).

Biopsy Pathology Predicts Patients with Ulcerative Colitis Subsequently Requiring Surgery

Background : The clinical course of patients with ulcerative colitis (UC) is unpredictable, and 17%-38% ultimately require surgery. We hypothesized that mucosal histology may differ between patients requiring surgery and those receiving medication alone. The aim of this study was to elucidate comprehensive criteria consisting of specific histologic features enabling the prediction of failure to medical treatment. Methods : We studied colorectal biopsy specimens from 67 patients ultimately requiring surgery (UC-S) and 90 receiving medication alone for more than 3 years (UC-M), and conducted multiple logistic regression analysis on 70 histologic features together with endoscopic disease extent and patient age. The analysis constructed an equation finding probability of UC-S ( P UC-S ). Based on a receiver-operating characteristic curve, we selected four cut-off values of P UC-S, and determined criteria of five categories: highest-risk, higher-risk, unpredictable, lower-risk and lowest-risk of surgery. Sensitivity and specificity of criteria were evaluated in a 2 × 5 table. Results : Statistically significant features predicting UC-S were deep ulceration (X 1 ), frequent crypt abscesses (X 2 ), focal and segmental mononuclear cell infiltration (X 3 and X 4 ), paucity of eosinophils (X 5 : eosinophil infiltration) and wide extent of the disease (X 6 ). The regression equation was as follows: logit P UC-S =-16.26 + 3.20X 1 + 4.83X 2 + 11.65X 3 + 5.10X 4 - 5.59X 5 + 5.53X 6. Higher-risk and lower-risk showed sensitivity exceeding 91.0% and specificity exceeding 98.5% in predicting the outcome. Conclusions : Our criteria incorporating specific histologic features and endoscopic disease extent reliably predict eventual clinical outcome, and are expected to prove useful in determining the necessity of surgery.

Observer variation of diagnoses based on simple biopsy criteria differentiating among Crohn's disease, ulcerative colitis, and other forms of colitis.

Abstract Background and Aim: Simple mucosal biopsy criteria proposed by authors reliably differentiate idiopathic inflammatory bowel disease (IBD) from other forms of colitis (non‐IBD) and Crohns disease involving the colon (CD) from ulcerative colitis (UC). The aim of this study is to investigate the reproducibility of these criteria.

Colonic intra-epithelial carcinoma occurring in a hyperplastic polyp via a serrated adenoma.

We present a case of intra‐epithelial carcinoma occurring in a serrated adenoma of the colon. The pedunculated polyp, which measured 12 × 10 × 6 mm, was endoscopically removed from the ascending colon of a 78‐year‐old woman. Histologically, the polyp mainly consisted of serrated adenomatous glands, and had foci of intra‐epithelial carcinoma at the top. Hyperplastic (metaplastic) areas were also present in both borders between the serrated adenomatous area and the surrounding normal mucosa. A sequential increase in the degree of dysplasia, and in the number of nuclei positively reactive for Ki‐67 and p53 was evident from the hyperplastic areas toward the foci of carcinoma. The polyp described here may represent a carcinogenic potential of hyperplastic polyp via serrated adenoma.