Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: Relation to intestinal hypermotility

Background and Aim:  We recently reported that cyclooxygenase (COX)-2 is upregulated in the rat small intestine after administration of indomethacin, and this may be the key to non-steroidal anti-inflammatory drug (NSAID)-induced intestinal damage. The present study investigated the mechanism for COX-2 expression induced in the rat small intestine by indomethacin, in relation with ulcerogenic processes.
Methods:  Animals were given indomethacin or SC-560 p.o., and the intestinal mucosa was examined 24 h later.
Results:  Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility, bacterial invasion and inducible nitric oxide synthase (iNOS) activity, as well as the expression of COX-2 mRNA in the mucosa. Although SC-560 did not cause any damage, this agent caused intestinal hypermotility, the bacterial invasion and the upregulation of COX-2 expression. The mucosal PGE₂ content was decreased by SC-560 at 3 h but recovered 12 h later, and this recovery of PGE₂ was attenuated by both atropine and ampicillin, in addition to rofecoxib. The intestinal hypermotility response to indomethacin was prevented by both 16,16-dimethyl PGE₂ and atropine, but not ampicillin. Yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 and iNOS activity in the intestinal mucosa following indomethacin treatment, resulting in the prevention of intestinal lesions.
Conclusion:  These results suggest that COX-2 expression in the intestinal mucosa following the administration of indomethacin is associated with intestinal hypermotility and bacterial invasion. The intestinal hypermotility caused by COX-1 inhibition may be a key to COX-2 expression after administration of NSAIDs and their intestinal ulcerogenic properties.     

Duodenal lymphangitis carcinomatosa: Endoscopic characteristics and clinical significance

Background and Aim: Duodenal lymphangitis carcinomatosa has been sporadically described, but so far little attention has been paid to duodenal lymphangitis carcinomatosa. Methods: Four cases with duodenal lymphangitis carcinomatosa were endoscopically and histologically examined. Results: The four cases exhibited multiple polypoid lesions along the Kerckring's folds and/or were covered by characteristically granular, non‐ulcerated mucosa upon thickening. The granularity seems to been caused by dilated lymph vessels containing the carcinoma cells. The lesions were microscopically characterized by: (i) involvement of lymph vessels located in the upper portion of the lamina propria; (ii) no inflammatory changes; and (iii) no desmoplastic changes. Primary sites were thought to be the stomach in case 1, the pancreas in cases 2 and 4, and unknown in case 3. All patients died within 6 months after admission or endoscopic examination. Conclusions: As duodenal lymphangitis carcinomatosis shows characteristic endoscopic appearance, endoscopic diagnosis is not difficult. We should realize that the lesion represents extremely poor prognosis, and it should be distinguished from ordinary metastatic duodenal carcinoma.     

Detection of hepatocellular carcinoma after interferon therapy for chronic hepatitis C: Clinical study of 26 cases

The clinical findings in 26 patients in whom hepatocellular carcinoma (HCC) was detected after the start of interferon (IFN) therapy for chronic hepatitis C were analysed. Histological study before IFN therapy showed that 34.6% of patients were categorized as stage 3 (septal fibrosis with architectural distortion; the 0–4 scale) and 80.8% demonstrated at least some evidence of septal fibrosis or more advanced features. The AFP levels examined before IFN therapy were more than 20 ng/mL in 13 patients (84.6% of those studied). One of 26 patients had a complete response to IFN therapy, while six of 26 patients had only a partial response. HCC was detected within 1 year after the start of IFN therapy in 76.9% of patients. Thus, the possibility of the early occurrence of HCC or its existence at the time of therapy should be seriously considered when IFN therapy is contemplated. Patients with stage 3 or 3–4 histology may already have a small undetectable HCC before IFN therapy. Thus, for this reason, every patient treated with IFN should be examined at short regular intervals for the development of HCC during and after IFN therapy.     

Melatonin treatment for rhythm disorder

Abstract We tried melatonin treatment in two patients with non-24 h sleep-wake syndrome, who did not respond to treatments by vitamin B₁₂, bright light therapy, or hypnotics. In one patient, melatonin 5–10 mg improved difficulty in falling asleep and in waking, although it failed to improve the sleep-wake rhythm. In another patient, melatonin 3 mg successfully changed the sleep-wake rhythm from free-running pattern to delayed sleep phase pattern. However, melatonin re-administration after a 4-month drug-free interval failed to improve his free-running sleep-wake rhythm. These results suggest that melatonin acted as a sleep inducer in one patient and as a phase setter in the other, although the effect on the latter patient was transient.     

A case of alpha-fetoprotein–producing adenocarcinoma of the endometrium with a hepatoid component as a potential source for alpha-fetoprotein in a postmenopausal woman

Although case reports of alpha-fetoprotein (AFP)-producing adenocarcinoma other than hepatocellular carcinoma have gradually increased in number, AFP-producing adenocarcinoma of the endometrium is very rare. The patients universally complain of abnormal vaginal bleeding. The patient presented with complaints of epigastric discomfort. No vaginal bleeding was observed. Serum AFP concentration was 453 ng/mL, and lens culinaris agglutinin-reactive AFP percentage of total AFP was increased to 67%. Radiologic imaging and endoscopy did not provide evidence of any primary carcinoma in the liver and gastrointestinal tract. To investigate the unknown origin of high AFP, Pap smear of the endometrium followed by fractional curettage was performed and revealed adenocarcinoma of the endometrium. Radical hysterectomy with pelvic lymph node dissection and partial omentectomy was performed. Histologic study showed a mixture of major AFP-negative endometrioid adenocarcinoma and minor medullary proliferation of the AFP-positive hepatoid adenocarcinoma cells with eosinophilic cytoplasm and hyaline globules. After the surgery followed by four courses of weekly carboplatin and paclitaxel administration, serum levels of AFP dropped into normal range. The possible existence of AFP-producing adenocarcinoma of the endometrium should be considered in a postmenopausal woman even if there is no vaginal bleeding, when AFP-producing tumor is clinically suspected and the imaging studies fail to confirm the diagnosis.     

Effects of obstructive jaundice on neutrophil production and acquisition of chemotactic activity in the bone marrow

Background and Aims:  Increased numbers and enhanced functions of peripheral neutrophils have been observed in obstructive jaundice. However, the effects of obstructive jaundice on the bone marrow, that is neutrophil production and acquisition of neutrophil chemotactic activity, have been poorly understood. In the present study, differentials of bone marrow cells and chemotactic activity of bone marrow neutrophils were evaluated in bile duct-obstructed rats.
Methods:  Male Wistar rats underwent either bile duct obstruction for 10 days or bile duct obstruction for 4 days followed by 6 days' internal biliary drainage. Differentials of peripheral blood and bone marrow cells were sequentially determined. Chemotactic activity of peripheral and bone marrow neutrophils was evaluated with a modified Boyden method using interleukin-8 (recombinant rat Gro-β) as a chemoattractant.
Results:  Numbers of peripheral neutrophils significantly increased after bile duct obstruction. Significant increases in the myeloid/erythroid (M/E) ratio of bone marrow cells were observed after bile duct obstruction. The neutrophil proliferative pool (promyelocytes and myelocytes) increased initially, followed by an increased neutrophil storage pool (metamyelocytes, bands, and segmented neutrophils). The M/E ratio as well as the neutrophil proliferative and storage pools normalized after internal biliary drainage. Chemotactic activity was enhanced in both peripheral and bone marrow neutrophils after bile duct obstruction, and enhanced chemotaxis was alleviated with internal biliary drainage.
Conclusion:  The present results strongly suggest the principal role of the bone marrow in increasing the number of neutrophils and their chemotactic activity during obstructive jaundice.     

Proliferation and cellular kinetics of villous epithelial cells and M cells in the chicken caecum

The proliferation sites and cellular kinetics of villous epithelial cells and M cells in the intestine of the adult chicken have never been clarified. In this study, we determined the proliferation sites in the chicken caecum using colchicine treatment and detection of proliferative cell nuclear antigen (PCNA). The cellular kinetics of these cells were also studied using bromodeoxyuridine (BrdU) as a tracer. Enterocytes in their mitotic period were observed along the entire length of the intestinal crypt of the caecum, with a denser distribution in the middle portion of the crypt, except for the caecal tonsil. The centres of distributions were at 49% of the distance from the bottom of the crypt in the base and 41% in the apex of the caecum. In the caecal tonsil, the centres of distributions were at 64% in the long type of crypt from the bottom of the crypt and at 44% in the short type of crypt. On the other hand, the PCNA-positive enterocytes were distributed more densely at the bottom of the crypt, except for the caecal tonsil. The centres of distributions were at 36% in the base from the bottom of the crypt, 37% in the body, and 34% in the apex. In the caecal tonsil, they were at 54% in the long type of crypt and 44% in the short type. The BrdU-labelled enterocytes reached to the basement of the intestinal villi in all caecal portions at 1 d after the BrdU administration. The leading edge of the labelled enterocytes disappeared from the villous tips at 4 d in the base and the body and 3 d in the apex. In the caecal tonsil, the BrdU-labelled microvillous epithelial cells and the M cells appeared near the orifice of the crypt at 1 d, and BrdU-labelled M cells were not observed in the crypt. Thereafter, almost all of these cells disappeared at 5 d from the follicle associated epithelium (FAE). These results suggest that M cells are transformed from their precursors within 1 d, and the turnover time for M cells occurs within 4 d after the cell division of the precursors.