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.     

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.     

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.     

Effect of relaxation training on cardiac parasympathetic tone

To examine the hypothesis that the relaxation response is associated with an increase in cardiac parasympathetic tone, the frequency components of heart rate variability during relaxation training were investigated in 16 college students. Electrocardiograms and pneumograms were recorded during a 5-min baseline period followed by three successive 5-min sessions of the autogenic training (relaxation) or by the same periods of quiet rest (control), while subjects breathed synchronously with a visual pacemaker (0.25 Hz). Although neither the magnitude nor the frequeney of respiration showed a significant difference between relaxation and control, the amplitude of the high-frequency component of heart rate variability increased only during relaxation (p= .008). There was no significant difference in the ratio of the low-frequency (0.04–0.15 Hz) to the high-frequency amplitudes. The increased high-frequency amplitude without changes in the respiratory parameters indicates enhanced cardiac parasympathetic tone. Thus, our results support the initial hypothesis of this study. Enhanced cardiac parasympathetic tone may explain an important mechanism underlying the beneficial effect of the relaxation response.     

Reduced protein tyrosine phosphatase (PTPase) activity of CD45 on peripheral blood lymphocytes in patients with systemic lupus erythematosus (SLE)

To disclose the mechanism of aberrant function of peripheral blood lymphocytes (PBL) in SLE, we focused on the catalytic function of CD45, and determined the CD45 PTPase activity in SLE patients. The sample population consisted of 32 SLE patients with different disease activity. PTPase activity of cell lysates immunoprecipitated by anti-CD45 MoAb was assayed against phosphotyrosine analogue PNPP, followed by measuring the release of para-nitro phenol at 410 nm. CD45 PTPase activity of PBL was significantly decreased in SLE patients, compared with that of normal controls and patients with systemic sclerosis (964 ± 265, 1202 ± 172, 1210 ± 125, respectively; SLE versus normal, P < 0.05). It was correlated with SLE Disease Activity Index (SLEDAI) score (r = 0.597, P = 0.0006), but not with the dose of prednisolone (r = 0.214, P = 0.2657), indicating that CD45 PTPase activity became reduced when the disease was active, but it was not affected by prednisolone. Moreover, it was not corrected by in vitro culture with or without stimulation. The expression of CD45 on PBL was comparable between normal and SLE, raising a possibility that it may be due to aberrant regulation of catalytic function of CD45 in SLE. Given the evidence that tyrosine phosphorylation of cellular proteins by tyrosine kinases and phosphatases is one of the key biochemical events in the signal transduction pathway, the decreased CD45 PTPase activity in SLE may account for the defective signal transduction via TCR/CD3, leading to dysregulated effector function of the lymphocytes.     

Diagnosis of Small Pancreatic Carcinoma

A retrospective analysis was performed to evaluate the clinicalsymptoms and abnormal test findings in small pancreatic carcinoma.Five hundred and thirty-six cases of pancreatic carcinoma withthe histology of duct cell carcinoma were collected from 14medical centers in Japan. In 440 of the cases, tumor size wasmeasured at the time of laparotomy or from the resected specimen.Three hundred and seventy-seven patients (86%) had a carcinomalarger than 3.0 cm; only 30% of these were resectable. Sixty-threepatients (14%) had a carcinoma of 3.0 cm or less, with resectabilityof 97%. Detecting a tumor of "3 cm or less" with a high probabilityof resectability is the objective of early diagnosis with theresulting possibility of a cure. In most cases these small carcinomaswere found easily when obstructive jaundice was present (73%).However, the estimated occurrence of obstructive jaundice associatedwith carcinomas of 3 cm or less was only 10% among the totalcases of pancreatic carcinoma studied. Therefore, it is necessaryfor early diagnosis to detect carcinomas of 3 cm or less presentingwithout jaundice. The symptoms of small carcinoma without jaundiceare weight loss, anorexia, upper abdominal pain, back pain anda palpable abdominal mass. Among the various available examinations,endoscopic retrograde cholangiopancreatography, computerizedtomography and ultrasonography were valuable in diagnosing thesesmall carcinomas.     

Importance of Hydrostatic Pressure and Irrigation for Hemostasis in Neuroendoscopic Surgery

Recently neurosurgical operations have been carried out with water irrigation such as endoscopic third ventriculostomy and tumor resections in ventricles. Water irrigation is one of several published methods that promote hemostasis; however, not enough experimental evidence exists on its efficacy. In this study, we investigate whether hydrostatic pressure and persistent irrigation promote hemostasis in neuroendoscopic surgery. We dissected tails of 12–16-week-old C57BL/6 male mice at 5 mm proximal from the tip and checked for bleeding times under dry and wet conditions at pressures of 0 cmH₂O, 10 cmH₂O, 15 H₂O, and 20 cmH₂O without persistent irrigation to bleeding point and 10 cmH₂O with persistent irrigation. We then examined the dissected edge with hematoxylin–eosin staining and measured the size of vessels. The average bleeding time of each group is as follows: dry: 203.4 sec, wet: 164.4 sec, 5 cmH₂O: 138.6 sec, 10 cmH₂O: 104.6 sec (P <0.001), 20 cmH₂O: 56 sec (P <0.001), and 10 cmH₂O with persistent irrigation: 72.8 sec (P <0.01 compared to 10 cmH₂O without persistent irrigation). The maximum caliber of mice’s tail artery was 50–60 μm. Hydrostatic pressure and irrigation are important factors contributing to hemostasis.