Allogeneic cell stimulation enhances cytomegalovirus replication in the early period of primary infection in an experimental rat model.

BACKGROUND: Cytomegalovirus (CMV) diseases commonly occur in allograft recipients in the early post-transplant period. However, factors responsible for the high incidence of CMV diseases during this period are not yet fully defined. METHODS: Wistar-Furth (WF; RT-1(u)) rats were inoculated with 10(4) plaque-forming units (PFU) of rat CMV (RCMV) intraperitoneally, and then transplanted with allogeneic lungs from Dark Agouti (DA; RT-1avl) rats or stimulated with 10(7) mitomycin C-treated spleen cells from DA rats by daily sub-cutaneous injections for 2 weeks. No immunosuppressive agent was used. Naive WF rats and WF rats grafted with syngeneic lungs or cells were used as controls. The level of RCMV replication in rats was assessed by infectious virus titers in tissues. RESULTS: The virus titers in salivary glands of allogeneic and syngeneic lung graft recipients were significantly higher than in naive WF rats. The level of RCMV replication in rats stimulated with allogeneic spleen cells was significantly higher than in the syngeneic recipient rats: virus titers in the salivary gland of allogeneic and syngeneic recipients reached 4.61 +/- 0.33 and 4.00 +/- 0.37 log(10) PFU/g tissue, respectively, at 14 days post-infection (p = 0.015). The augmented viral replication in allogeneic recipients was confirmed by an increase in the number of RCMV antigen-positive macrophages present in tissue sections of the salivary gland. CONCLUSIONS: Acute lung allograft rejection and allogeneic spleen cell stimulation enhance CMV replication in the salivary gland of rats. Various responses to allogeneic antigens occurring in the process of acute allograft rejection could be risk factors for post-transplant CMV replication and infection.     

Neutrophil elastase inhibitor reduces hepatic metastases induced by ischaemia-reperfusion in rats.

OBJECTIVE: To investigate the possibility in rats that ONO-5046 Na, a new recombinant inhibitor of neutrophil elastase, can reduce hepatic metastases induced by ischaemia-reperfusion. DESIGN: Laboratory experimental study. SETTING: Research laboratory, Japan. SUBJECTS: Male Fischer rats. INTERVENTIONS: Rats underwent 60 min of 70% partial hepatic ischaemia, after which rat colon adenocarcinoma cells (RCN-H4) were injected into the spleen. The animals were divided into two test groups and a control group. One group was given ONO-5046 Na intravenously at 10 mg/kg/hour. A second group was given a saline solution for the same period, while the controls were not made ischaemic. MAIN OUTCOME MEASURES: Three weeks after inoculation, the number of tumour nodules on the liver surface was counted. The anti-cancer effect of ONO-5046 Na was measured by monotetrazolium assay. RESULTS: Hepatic ischaemia-reperfusion increased the number of liver metastases of RCN-H4 in both clamped and unclamped hepatic lobes. ONO-5046 Na significantly inhibited this in unclamped lobes, but had no anti-cancer effect. CONCLUSION: Neutrophil elastase may have an important role in increasing haematogenous liver metastases by ischaemia-reperfusion, particularly in unclamped lobes.     

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation.

Several reports claim that portal hypertension after living-donor liver transplantation (LDLT) adversely affects graft function, but few have assessed the impact of portal venous pressure (PVP) on graft regeneration. We divided 32 adult LDLT recipients based on mean PVP during the 1st 3 days after LDLT into a group with a PVP > or = 20 mm of Hg (H Group; n = 17), and a group with a PVP < 20 mm of Hg (L Group; n = 15). Outcome in the H Group was poorer than in the L Group (58.8 vs. 92.9% at 1 year). Peak peripheral hepatocyte growth factor (HGF) during the 1st 2 weeks was higher in the H Group (L: 1,730 pg/mL, H: 3,696 pg/mL; P < .01), whereas peak portal vascular endothelial growth factor (VEGF) level during the 1st week was higher in the L Group (L: 433 pg/mL, H: 92 pg/mL; P < .05). Graft volume (GV) / standard liver volume (SLV) was higher in the H Group (L / H, at 2, 3, and 4 weeks, and at 3 months: 1.02 / 1.24, .916 / 1.16, .98 / 1.27, and .94 / 1.29, respectively; P < .05). Peak serum aspartate aminotransferase, bilirubin levels, and international normalized ratio after LDLT were significantly higher in the H Group, as was mean ascitic fluid volume. In conclusion, early postoperative PVP elevation to 20 mm of Hg or more was associated with rapid graft hypertrophy, higher peripheral blood HGF levels, and lower portal VEGF levels; and with a poor outcome, graft dysfunction with hyperbilirubinemia, coagulopathy, and severe ascites. Adequate liver regeneration requires an adequate increase in portal venous pressure and flow reflected by clearance of HGF and elevated VEGF levels.     

Pancreatic tumor antigen in transplantable adenocarcinomas induced by N-bis(2-hydroxypropyl)nitrosamine in hamsters

An attempt was made to detect a pancreatic tumor antigen (PTA) in transplantable pancreatic adenocarcinomas induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) in hamsters. Antibody against antigenic protein was raised by immunizing rabbits with whole homogenate of the tumors transplanted into the back of hamsters. PTA was purified by affinity chromatography and shown to have the physicochemical properties of a glycoprotein with a molecular weight of 800,000, migrating in the beta regions upon agarose gel electrophoresis. Loss of immunological properties was observed after heating at 65 degrees C for 30 min. Enzyme immunoassay revealed that the levels of PTA in the serum and tissue showed a positive correlation with the induction of the presence of tumor, and size of the tumor. It is tentatively suggested that PTA values above 150 ng/ml serum are indicators of tumors, because in normal hamsters the PTA range is from 25 to 130 ng/ml serum. Immunohistochemically, PTA was demonstrated to be localized within the cytoplasm of epithelial tumor cells of well-differentiated tubular adenocarcinomas.     

Modulation of infection-induced inflammation and locomotive deficit and longevity in senescence-accelerated mice-prone (SAMP8) model by the oligomerized polyphenol Oligonol.

Oligonol is produced from the oligomerization of polyphenols (typically proanthocyanidin from a variety of fruits such as lychees, grapes, apples, persimmons, etc.) and contains catechin-type monomers and oligomers of proanthocyanidins. The ability of Oligonol to affect infection-dependent eye inflammation, locomotion and longevity in senescence-accelerated prone mice (SAMP8) (a model of senescence acceleration and geriatric disorders with increased oxidative stress and neuronal deficit) was investigated. Oligonol (60mg/kg) significantly modulated the extent of inflammation scores in the eye of SAMP8 mice. Examination of the mice indicated infection with mouse hepatitis virus and pinworm (Syphacia obvelata) in both males and females and with the intestinal protozoa (trichomonad) in males. A comparison of the two groups (using log-rank test) and the difference in the mean life span between groups (using Student's t-test) indicated significant differences in survival (p=0.043) and the mean life span (p=0.033) in male SAMP8 mice. Oligonol increased the mean life span and this was statistically significant. In the open-field locomotive test, the 7-week-old SAMP8 mice crossed more than 40 partitioned lines in 1min. At 48-week-old control untreated male SAMP8 crossed 2 lines. The Oligonol-treated 48-week-old male SAMP8 mice crossed 17 lines however. The improved locomotive activity was statistically significant even after 36weeks in the Oligonol-treated male SAMP8 but this was not the case throughout the time course of the study in the Oligonol-treated female SAMP8. Thus Oligonol treatment to SAMP8 mice modulated the severity of infection-dependent inflammation, prolonged life-span and significantly improved locomotive activity indicating potential benefit to aging-associated diseases such as Alzheimer's or Parkinson's diseases. This presents potential for further research to define infection-dependent inflammation associated with degenerative conditions and the molecular mechanism of dietary antioxidant protection.     

Relationship of Diet to Small and Large Adenomas of the Sigmoid Colon

The relation of dietary factors to the risk of adenomas of the sigmoid colon was examined in men receiving a retirement health examination at the Self-Defense Forces Fukuoka Hospital between October 1986 and 1990. A total of 187 adenoma cases and 1557 controls with normal colonoscopy were identified in the series. Cases were further classified into small-adenoma (<5 mm, n=78) and large-adenoma (≥5 mm, n=67) groups. The consumptions of selected foods and beverages were ascertained before colonoscopy by means of a self-administered questionnaire. After adjustment for smoking, alcohol use, rank and body mass index, low rice consumption and high meat intake were independently associated with an increased risk of large adenomas. The risk of small adenomas was not related to either rice consumption or meat intake. Adjusted odds ratios of large adenomas for the low, intermediate and high consumption levels of rice were estimated to be 1.0 (referent), 0.83 and 0.43, respectively (trend P = 0.08), and the corresponding figures for meat consumption were 1.0 (referent), 1.58 and 2.38, respectively (trend P =0.02). The findings suggest that low rice consumption and high meat intake may promote the growth of colon adenomas, thereby increasing the risk of colon cancer.     

Carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydroxypropyl)amine in rats administered bis(2-hydroxypropyl)amine and sodium nitrite

The carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydroxypropyl)amine(BHP) was investigated in male Wistar rats administered bis(2-hydroxypropyl)amine(BHPA) mixed in powder diet at a concentration of 1%, and sodiumnitrite (SN) dissolved in distilled water at concentrationsof 0.15 and 0.3%, for 94 weeks. Urinary excretion of BHP wasdetected in rats given 1% BHPA and 0.3% SN but not in the groupsreceiving either of these precursors alone. Nasal cavity, lung,esophagus, liver and urinary bladder tumors were found in animalstreated with combinations of 1% BHPA and 0.15 or 0.3% SN, suggestingthat the target organs of the endogenously synthesized BHP aresimilar to those affected when the carcinogen is administeredexogenously. The incidences of nasal cavity and lung tumorsreached 74 and 58% in rats given 1% BHPA and 0.3% SN, respectively.Tumors at sites other than target organs were only found atlevels similar to those previously reported for spontaneoustumors in male Wistars. The present results clearly indicatedthe tumor inducibility of a nhrosatable amine, BHA, throughan endogenous nitrosation by feeding to rats in conjunctionwith nitrite, and provide further suggestive evidence that endogenousnitrosations of environmental nitrosatable amines can be a potentialrisk factor in human cancer development.     

Dorsal skin responses to topical application with hydrogen peroxide in Mini and Wistar rats.

Mini rats (Jcl: WistarTGN(ARGHGEN) 1Nts) (MRs) are Wistar rat (WR)-derived transgenic rats in which the expression of growth hormone (GH) gene is suppressed under the presence of antisense RNA transgene. In order to evaluate the effects of GH-deficiency on the acute injury by external stimuli, the dorsal skin responses to a single topical application with 20% hydrogen peroxide (HPO), one of the environmental oxidative stressors, were histologically compared between male MRs and WRs of 8 weeks old, whose hair cycle was under the telogen phase. As a result, formation of granulation tissues, reepithelialization and regrowth of hair follicles were delayed in MRs compared with WRs. While hair follicles of MRs of this age are under a long-lasting telogen phase after their 2nd cycle, a new hair cycle started not only in the HPO-applied area but also in the solvent-applied area with a little time lag. These findings suggest that GH-deficiency may influence the skin responses to the external chemical stimuli.