Differential expression of CCR5 and CRTH2 on infiltrated cells in colonic mucosa of patients with ulcerative colitis

BACKGROUND AND AIM: The pathogenesis of ulcerative colitis (UC) is unclear, but abnormal infiltration of T lymphocytes in the colonic mucosa has been implicated in the mucosal tissue damage. The abnormal cytokine production because of a T helper (h)1/Th2 imbalance may play an important role in continuing inflammation in the colonic mucosa. In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients. METHODS: Tissue samples were obtained by colonic biopsies from patients with UC or colonic polyps, with informed consent. Immunohistochemical analysis was performed on periodate, lysine-paraformaldehyde-fixed serial cryostat sections using the labeled streptavidin biotin method. Monoclonal antibodies against CD4, CCR5 or CRTH2 were used as primary antibodies. The number of cells expressing CD4, CCR5 or CRTH2 per unit area was calculated by using an image analyzer. RESULTS: In the patients with UC, the numbers of CD4- and CCR5-positive cells were significantly increased in inflamed mucosa, and appeared to be correlated with the disease activity. The infiltration of CRTH2-positive cells was predominantly observed in the mildly inflamed or the margin of inflamed mucosa of UC patients. CONCLUSION: There is a possibility that Th1 responses significantly occur in colonic mucosa with severe inflammation, while Th2 responses mainly occur with mild inflammation in UC patients. The Th1/Th2 imbalance in colonic mucosa may be related to the disease progression of UC.     

A failed case to diagnose cardiac sarcoidosis presenting advanced atrioventricular block

A 53-year-old-male developed atrioventricular block in January 2001. A chest X-ray and laboratory tests, including serum angiotensin converting enzyme, were normal. The patient underwent permanent pacemaker implantation and attended for semiannual follow-up after discharge since the etiology of advanced atrioventricular block remains unknown. One year later, the patient was diagnosed with uveitis related to sarcoidosis. No clinical finding specific to cardiac sarcoidosis was notable at that time. Four years after onset, the patient developed congestive heart failure. An echocardiogram revealed diffuse LV hypokinesis, but no asymmetric interventricular septal thinning. Laboratory tests showed normal angiotensin converting enzyme. Noncaseating granuloma was not confirmed by transbronchial biopsy. Despite normal myocardial uptake of gallium-67, uptake of (18)F-Fluorodeoxyglucose increased in the myocardium. Nevertheless, clinical manifestations did not match the criteria for cardiac sarcoidosis. Prednisolone was administered daily. Two months after tapering dosage, the patient developed multiple organ failure and died. Post mortem histological findings were consistent with cardiac sarcoidosis. We experienced great difficulty in detecting cardiac involvement in the early stage of sarcoidosis. A specific method with greater sensitivity is required to diagnose cardiac involvement in the early stages of sarcoidosis.     

Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF

Existence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody and treatment with recombinant GM-CSF are new topics in idiopathic pulmonary alveolar proteinosis (PAP). We have hypothesized inhaled GM-CSF is effective and neutralizing capacity of GM-CSF, not concentration of anti-GM-CSF antibody in serum reflect disease severity. A 57-year-old female smoker with idiopathic PAP was treated with inhaled GM-CSF. The response to the treatment was evaluated by diffusing capacity for carbon monoxide (DLCO), alveolar-arterial oxygen gradient ([A-a]DO2). Conventional serum markers, including KL-6, surfactant apoprotein (SP)-A, SP-D, carcino-embryonic antigen and cytokeratin fragment 19 (CYFRA), and concentration of anti-GM-CSF antibody were examined. The neutralizing capacity of GM-CSF in serum was evaluated using a GM-CSF dependent cell line, TF-1. Ground glass opacity disappeared at the end of the treatment. Her DLCO, [A-a]DO2 remarkably improved after treatment. The neutralizing capacity of GM-CSF declined in line with disease remission and it correlated significantly with DLCO (P = 0.0137). The concentration of anti-GM-CSF antibody had no significant relation with disease severity and serum markers including neutralizing capacity. Conventional serum markers other than CYFRA showed no significant correlation with Inhaled GM-CSF was effective for idiopathic PAR Serial measurement of neutralizing capacity of GM-CSF was useful to evaluate disease severity and the anti-GM-CSF antibody was proved to be a causative factor for PAR In the future, inhaled GM-CSF may replace whole lung lavage and response to GM-CSF and its optimal amount may be decided by the capacity.     

Resection of gallbladder cancer with hepatic metastasis after chemotherapy with gemcitabine

A 69-year-old man diagnosed as having gallbladder cancer with liver invasion and metastasis to Couinaud’s hepatic segment 8 (S8) was referred to our hospital. Because of the presence of liver metastasis, gemcitabine administration was chosen. Although gemcitabine was effective for the liver metastasis, his serum carcinoembryonic antigen (CEA) level had gradually increased after 12 cycles of gemcitabine administration. There was no distant metastasis other than the liver metastasis (manageable with gemcitabine) on detailed radiological examination. Therefore, we performed surgery for the primary lesion, after obtaining informed consent. Pathological examination demonstrated viable cancer cells with necrosis and fibrosis in the gallbladder, and fibrosis without viable cancer cells in the induration in liver S8. Gemcitabine was re-administered as postoperative adjuvant chemotherapy. Twenty months after the surgery, there was no sign of recurrence. In selected patients, gemcitabine treatment may be effective against gallbladder cancer with metastasis.     

Predicting factors for survival of patients with unresectable pancreatic cancer: a management guideline

BACKGROUND/AIMS: When pancreatic cancer cannot be resected, palliative procedures including gastroenteric bypass and biliary bypass may be selected. However, since predicting survival is difficult, indication of these procedures remains unclear. This study was designed to elucidate the prognostic factors of patients with unresectable pancreatic cancer in order to improve their quality of life. METHODOLOGY: We treated 187 consecutive patients with unresectable pancreatic cancer at the Kobe University Hospital. Fifteen prognostic variables for survival were analyzed (sex, age, the degree of pain, diet, presence of jaundice, main site of the tumor, tumor size, major vessel invasion, liver metastasis, peritoneal dissemination, distal metastasis and operative procedures) in surgically treated patients (n = 125). All patients were followed until death. Cox's proportional hazard model and logistic regression models were used to determine the factors influencing the survival of patients with unresectable pancreatic cancer. RESULTS: Cox's proportional hazard model revealed that duodenal invasion (p = 0.001) and liver metastasis (p < 0.0001) significantly influenced the survival of the patients with unresectable pancreatic cancer. In multivariate logistic regression analysis, liver metastasis (p = 0.009) and peritoneal dissemination (p = 0.004) were significant factors on the six-month survival after palliative operation. CONCLUSIONS: Liver metastasis and peritoneal dissemination were negative predictive factors for the six-month survival of patients with unresectable pancreatic cancer. Palliative bypass surgery is recommended for patients expected to survive long-term (more than six-months).     

Omnipotent decoding potential resides in eukaryotic translation termination factor eRF1 of variant-code organisms and is modulated by the interactions of amino acid sequences within domain 1

In eukaryotes, a single translational release factor, eRF1, deciphers three stop codons, although its decoding mechanism remains puzzling. In the ciliate Tetrahymena thermophila, UAA and UAG codons are reassigned to Gln codons. A yeast eRF1-domain swap containing Tetrahymena domain 1 responded only to UGA in vitro and failed to complement a defect in yeast eRF1 in vivo at 37 degrees C. This finding demonstrates that decoding specificity of eRF1 from variant code organisms resides at domain 1. However, the wild-type eRF1 hybrid fully restored the growth of eRF1-deficient yeast at 30 degrees C. Tetrahymena eRF1 contains a variant sequence, KATNIKD, at the tip of domain 1. The TASNIKD variant of hybrid eRF1 rendered the eRF1-nullified yeast viable, although in an in vitro assay, the same hybrid eRF1 responded only to UGA. Nevertheless, the yeast eRF1 bearing the KATNIKD motif instead of the TASNIKS heptapeptide present in higher eukaryotes remains omnipotent in vivo. Collectively, these data suggest that variant genetic code organisms like Tetrahymena have an intrinsic potential to decode three stop codons in vivo, and that interaction within domain 1 between the KAT tripeptide and other sequences modulates the decoding specificity of Tetrahymena eRF1.     

Change of plasma leukotriene c4 during myocardial ischemia in humans

Changes in leukotriene C4 levels during different degrees of myocardial ischemia in humans were examined by comparing radioimmunoassay measures of leukotriene C4 plasma levels obtained during transient and prolonged myocardial ischemia. Leukotriene C4 levels in systemic arterial and coronary sinus blood were determined in patients with chronic stable angina before and after myocardial ischemia induced either by exercise (supine bicycle ergometer exercise stress testing; n = 14; age, 52 ± 8 years) or by coronary occlusion during angioplasty (n = 14; age 53 ± 7 years). Temporal changes of leukotriene C4 were also followed in arterial and pulmonary artery blood within 24 h after the onset of chest pain (acute phase), and 1 day, 1 week, and 1 month later in 22 patients with acute myocardial infarction (AMI) (12 patients with thrombolytic therapy, age 61 ± 10 years; 10 patients without thrombolytic therapy, age 60 ± 11 years). Clinical characteristics, including coronary risk factors and the severity of coronary artery disease, were not significantly different among the groups. Exercise-induced myocardial ischemia and coronary occlusion did not induce any significant leukotriene C4 changes in the chronic stable angina patients, whereas AMI patients had significantly higher plasma leukotriene C4 levels in both arterial and pulmonary artery blood in the acute phase compared with those of chronic stable angina patients (arterial blood, 471 ± 164 pg/ml and 477 ±235 pg/ml vs. 275 ± 254 pg/ml or 240 ± 66 pg/ml, p< 0.05; pulmonary artery blood in AMI, 543 ± 162 pg/ml vs. 234 ± 125 pg/ml or 225 ±64 pg/ml, coronary sinus blood in chronic stable angina, p < 0.05). These results suggest that leukotriene C4 is involved more in prolonged myocardial ischemia than in transient myocardial is chemia, and that leukocyte function might play a significant role in the pathogenesis of patients with AMI.     

Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

Background & Aims: Regenerating gene (Reg) has been isolated from rat regenerating pancreatic islets, and Reg protein is mitogenic to islet cells. We have recently shown that Reg gene and Reg protein are expressed in gastric enterochromaffin-like (ECL) cells. This study aimed to clarify whether gastrin enhances Reg protein production in ECL cells and whether Reg protein is mitogenic to gastric mucosal cells. Methods:Reg gene expression in response to acute and chronic hypergastrinemia was investigated in rats. Immunohistochemical studies, Northern blotting, and in situ hybridization were performed to investigate the expression of Reg protein and Reg gene. The direct effect of gastrin on Reg gene expression was investigated using isolated ECL cells, and the trophic effect of Reg protein on cultured gastric epithelial cells was assessed by [³H]thymidine uptake. Results: Both chronic hypergastrinemia and short-term gastrin administration stimulated Reg gene expression and Reg protein production in fundic mucosa. Reg gene expression was also augmented in isolated ECL cells after incubation with rat gastrin. Reg protein was mitogenic to cultured rat gastric epithelial cells. Conclusions: Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.GASTROENTEROLOGY 1998;115:1483-1493