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.     

Clinical parameters that predict histology of postchemotherapy retroperitoneal lymph node mass in testicular cancer

BACKGROUND: Since the advent of cisplatin-based chemotherapy, the majority of metastatic testicular cancers can be cured by chemotherapy followed by retroperitoneal lymph node dissection (RPLND). However, postchemotherapy RPLND confers no therapeutic benefit if the residual mass contains no viable cells. Therefore, to determine which parameters predict a patient's likelihood of having only necrosis in the residual mass, we retrospectively analyzed clinical parameters of patients who underwent postchemotherapy RPLND. METHODS: Data from 27 patients with metastatic testicular cancer were analyzed. The histology of the primary tumor was seminoma in 11 cases and non-seminoma in 16 cases. All of the patients with non-seminoma showed a normalization of tumor markers after chemotherapy. Analysis of clinical parameters included data for the initial histology, pretreatment tumor marker levels, postchemotherapy retroperitoneal mass size, and the histology of the dissected RPLNs. RESULTS: Histological examination of dissected RPLNs showed residual tumor in 27% of seminoma patients and 38% of non-seminoma patients. In seminoma patients, no viable cells were found in all six patients with pretreatment lactate dehydrogenase (LDH) levels below 7.5 times the upper limit of normal, or in all five of the patients with postchemotherapy RPLNs less than 2.5 cm. In non-seminoma patients, no viable cells were found in nine of 10 patients with pretreatment alpha-fetoprotein (AFP) levels less than 2700 ng/mL, or in eight of nine patients with residual mass less than 2.5 cm. CONCLUSIONS: Both postchemotherapy RPLN mass size and pretreatment tumor marker levels are possible predictors for necrosis of the residual mass in testicular cancer patients.     

Fibronectin inhibits endocytosis of calcium oxalate crystals by renal tubular cells

BACKGROUND: Fibronectin (FN; 230 kDa) is a multifunctional alpha2-glycoprotein distributed throughout the extracellular matrix and body fluids. We recently reported that FN has a protective effect against injury of renal tubular cells by exposure to oxalate and calcium oxalate (CaOX) crystals and inhibits the adhesion of CaOX crystals to renal tubular cells. In the study presented here, we investigated whether FN has inhibitory effect on crystal endocytosis by renal tubular cells. METHODS: The inhibitory effect of FN on endocytosis of CaOX crystals by MDCK cells was examined by using a radioactivity uptake assay. Also, crystal endocytosis by cells was morphologically assessed by means of transmission electron microscopy (TEM). RESULTS: FN had inhibitory effects on CaOX crystal endocytosis by MDCK cells. The morphological TEM study showed that few crystals were taken into cells when FN was added compared to the number of crystals when FN was not added. CONCLUSION: We found that FN had the inhibitory effects on the interaction between crystals and renal tubular cells, including the adhesion or endocytosis of crystals by cells.     

Prevalence of and risk factors for nocturia: Analysis of a health screening program

BACKGROUND: We examined the prevalence of and risk factors for nocturia in Kurashiki city and the surrounding area, a rural area in Japan. MATERIALS AND METHODS: We collected data on 6517 individuals (4568 men and 1949 women) who participated in a multiphasic health screening. We analyzed the relationships between nocturia assessed by a questionnaire (voiding twice or more during night) and other variables including age, hypertension, cardiovascular disease, cerebrovascular disease, chronic obstructive pulmonary disease, diabetes mellitus (DM), chronic renal failure, benign prostatic hyperplasia (BPH), smoking habit and alcohol intake. RESULTS: Overall, 1856 individuals (28.5%) answered that they arose to urinate at least twice during the night. This rate increased with age from 16.5% in individuals younger than 50 to 60.0% in those older than 69. Logistic regression analysis revealed that cohorts of subjects 50-59, 60-69, and 70 years old or over had, respectively, 1.75, 3.35, and 6.21 times the prevalence of nocturia of the 49 years or younger cohort. Hypertension (odds ratio [OR] 1.64) and DM (OR 1.70) were other independent positive risk factors for nocturia. On the other hand, current smokers who smoked 20 or more cigarettes per day were less likely to have nocturia than non-smokers (OR 0.72). In male individuals, BPH was another independent positive risk factor (OR 1.35). Gender was not associated with nocturia. CONCLUSIONS: Although population bias is an important limitation to this study, nocturia is associated with various factors suggesting that multiple approaches are needed to the treatment of patients with nocturia.     

Experimental Assessment of Right Ventricular Function in Normal Pigs with a Left Ventricular Assist Device

Abstract: Right ventricular (RV) failure during the use of a left ventricular assist device (LVAD) is the leading cause of death in circulatory support patients. Previous work, both experimentally and clinically, has shown the difficulties in predicting the behavior of the right ventricle at the start of LVAD. An experimental study has been designed to evaluate RV functional changes during LVAD and its relation to preload changes. The model used adult mongrel pigs (n = 10). Right ventricular functional parameters were measured with a thermodilution RV ejection fraction catheter. The left ventricle was supported by a Nippon Zeon blood pump. Two groups were studied, the first one was the LVAD–off group (n = 5) and the other was the LVAD–on group (n = 5) which was supported by LVAD at maximum flow. Change of cardiac output, mean pulmonary artery pressure (PAP), RV stroke work, and RV ejection fraction in both groups were not significantly different. However, the relationship between right ventricular end–diastolic pressure (RV–EDP) and right ventricular stroke volume (RVSV) was significantly changed at a high level of RV–EDP. When RV–EDP was over 6. 5 mm Hg in the LVAD–off group, RVSV decreased to 52. 3 ± 11. 5 ml while in the LVAD–on group, RVSV increased to 97. 2 ± 22. 0 ml. The change in PAP in the LVAD–on group was lower than in the LVAD–off group. We conclude that, at the volume overload state, LVAD can reduce the afterload of the right ventricle and maintain Frank–Starling's effect, thus having a beneficial effect on right ventricular performance.     

Augmented Lung Adenocarcinoma Cytotoxicity by the Combination of a Genetically Modified Anti-Lewis Y Antibody and Antibodies to Complement Regulatory Proteins

Nine vervet monkeys ( Cercopithecus aethiops ) were infected intradermally with 8 × 10⁷ virulent L. donovani promastigotes. Four animals developed clinical visceral leishmaniasis and died over a period of 18 months. The remaining five animals have remained asymptomatic for a period of 3 years now. Attempts to isolate parasites from spleen and liver through biopsies were fruitless. Immunological respotises of these subclinically infected animals were examined. Enzyme-linked itnmunosorbent assay ( ELISA ) and western blot analyses demonstrated Leishmania specific antibodies in these animals, but the antibody titres were low. When proliferation of peripheral blood monocytes ( PBMC ) to Con-cunavalin A (Con A) of these animals was compared with control 'disease free animals' there were no significant differences iti response. However L. donovani antigen (fixed promastigotes) specific proliferation was demonstrated in the five subclinically infected animals. High and varying levels of interferon gamma (IFN-γ) were secreted in PBMC cultures from the five vervet monkeys when stimulated with either Con A or L. donovani antigens. In control animals, IFN-γ was only detected wheti PBMC were stimulated with Con A. Marked delayed-type hypersensitivity ( DTH ) responses were demonstrated in the five subclinically infected animals 48 h after injection with formalin fixed promastgotes.
It was concluded that the visceral Leishmania disease spectrum due to L. donovani observed in humans could be induced in vervet monkeys and that L. donovani asymptomatic/cryptic infected animals have competent humoral and cellular responses to homologous parasites.