Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, characterised by thickening of the wall of the right hemicolon with calcification of mesenteric veins. However, the aetiology remains unknown. AIM: To investigate the possible association of herbal medicines with IMP. METHOD: The clinical data of four of our own patients were collected. Furthermore, we searched for previous reports about similar patients with detailed descriptions of herbal prescriptions that they had taken. We compared herbal ingredients to identify the toxic agent as a possible aetiological factor. RESULTS: Clinical data on a total of 25 patients were summarised. Mean age was 61.8 years and there was female predominance (6 men and 19 women). The used Kampo prescription, the number of cases, and the mean duration of use were as follows: kamisyoyosan in 12 cases for 12.8 years, inshin-iseihaito in 5 cases for 13.4 years, orengedokuto in 4 cases for 14.3 years, inchinkoto in 1 case for 20 years, kamikihitou in 1 case for 19 years, seijobofuto in 1 case for 10 years and gorinsan in 1 case for an unknown duration. Only one ingredient, sansisi, was common to the herbal medicines of all 25 patients. This crude drug called geniposide in English is a major constituent of the Gardenia fruits. CONCLUSION: The long-term use of geniposide in herbal medicines appears to be associated with mesenteric phlebosclerosis.

Neuropeptide Y stimulates food intake in the Zebrafish, Danio rerio.

Neuropeptide Y (NPY) is a potent orexigenic neuropeptide implicated in feeding regulation in mammals. However, except for the case of the goldfish, the involvement of NPY in the feeding behaviour of teleost fish has not well been studied. Therefore, we investigated the role of NPY in food intake using a zebrafish (Danio rerio) model because the molecular bases of NPY and its receptor have been well studied in this species. We examined the effect of feeding status on NPY-like immunoreactivity and the expression level of the NPY transcript in the brain. The number of neuronal cells showing NPY-like immunoreactivity in the hypothalamic regions, including the periventricular nucleus of posterior tuberculum and the posterior tuberal nucleus, was significantly increased in fish fasted for 7 days. NPY mRNA levels in the hypothalamus, but not the telencephalon, obtained from fish fasted for 7 days were higher than those in fish that had been fed normally. We then investigated the effect of i.c.v. administration of NPY on food intake. Cumulative food intake was significantly increased by i.c.v. administration of NPY (at 1 and 10 pmol/g body weight; BW) during a 60-min observation period. The NPY-induced orexigenic action (at 10 pmol/g BW) was blocked by treatment with a NPY Y1 receptor antagonist, BIBP-3226, at 100 pmol/g BW. These results indicate that NPY acts as an orexigenic factor in the zebrafish.

Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients

PURPOSE: FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples. PATIENTS AND METHODS: Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method. RESULTS: We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively. CONCLUSION: The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis (AU)

Isolation and characterisation of two cDNAs encoding the neuromedin U receptor from goldfish brain.

Intracerebroventricular administration of neuromedin U (NMU) exerts an anorexigenic effect in a goldfish model. However, little is known about the NMU receptor and its signalling system in fish. In the present study, we isolated and cloned two cDNAs encoding different proteins comprising 429 and 388 amino acid residues from the goldfish brain based on the nucleotide sequences of human NMU receptor 1 (NMU-R1) and receptor 2 (NMU-R2). Hydropathy and phylogenetic analyses suggested that these two proteins were orthologues of NMU-R1 and -R2 of goldfish. We established two human embryonic kidney 293 cell lines stably expressing putative NMU-R1 and -R2, respectively, and showed that NMU induced an increase in intracellular calcium concentration ([Ca(2+)](i)) in these cells. We examined the presence of NMU-R1 and -R2 in the goldfish brain by western blotting analysis using affinity-purified antisera raised against peptide fragments derived from these receptors. NMU-R1-specific and NMU-R2-specific antisera detected a 49-kDa and 45-kDa immunopositive bands, respectively, in the brain extract. The mass of each band corresponded to that of the deduced respective primary structures. Reverse transcriptase-polymerase chain reaction analysis showed that NMU-R1 and -R2 transcripts were detected in several tissues. In particular, both mRNAs were strongly expressed in the goldfish brain. By contrast, NMU-R2 mRNA was also expressed in the gut. These results indicate for the first time that NMU-R orthologues exist in goldfish, and suggest physiological roles of NMU and its receptor system in fish.

Sagittalis nucleus: a novel hypothalamic nucleus.

The sagittalis nucleus (SGN) of the hypothalamus is a newly-identified nucleus that is located in the interstitial area between the arcuate and ventromedial nuclei of the rat hypothalamus and for which the long axis of the nucleus is oriented sagittally. Interestingly, the SGN exhibits structural and physiological sex differences, as defined by Nissl staining and oestrogen receptor (ER)alpha immunoreactivity (-ir), being larger in males than females. The structural sex difference is established by sex steroid action in neonates because the treatment of female pups with testosterone propionate masculinised the SGN. The phenotypical sex difference in ERalpha-ir is mediated hormonally in adulthood. Ovariectomy of female rats caused a significant increase in ERalpha-ir in the SGN, and eliminated the physiological sex difference, but with recovery to the level of gonad-intact females when given oestradiol replacement. Adult females have oestrous cycle-related variations in ERalpha-ir in the SGN, with levels at a nadir during the evening of pro-oestrous. The discovery of the SGN, a target of sex steroid action, provides a new opportunity for explaining hormonal regulation of sexually-differentiated behavioural and endocrine functions.

Isolation and characterisation of four cDNAs encoding neuromedin U (NMU) from the brain and gut of goldfish, and the inhibitory effect of a deduced NMU on food intake and locomotor activity.

In rodents, neuromedin U (NMU; U for its original effects examined in the uterus) is a multifunctional neuropeptide implicated in the regulation of the circulatory and digestive systems and energy homeostasis, especially appetite. However, there is no available information on the nature and physiological roles of NMU in fish. Therefore, we attempted to isolate and characterise transcripts encoding NMU from the brain and gut of the goldfish, and to examine the involvement of NMU in the regulation of feeding behaviour in this species. We identified four cDNAs encoding three NMU orthologs from the brain and gut. Putative peptides consisting of 21, 25 and 38 amino acid residues (NMU-21, NMU-25 and NMU-38) were deduced from their nucleotide sequences. Two mRNAs for NMU-25 were strongly expressed in the gut and weakly expressed in the brain and testis. By contrast, mRNA for NMU-21 was strongly expressed in the brain and weakly expressed in the peripheral tissues. Expression of mRNA for NMU-38 was weakly expressed only in the brain. Therefore, we examined the effect of feeding status on the expression of NMU-21 mRNA in the brain. Fasting for 7 days induced a significant decrease in the expression levels of NMU-21 mRNA in the brain. We also synthesised NMU-21 after deducing its C-terminal amide from the NMU-21 mRNA, and then investigated the effect of intracerebroventricular (i.c.v.) administration of NMU-21 on food intake and locomotor activity in the goldfish. NMU-21, injected i.c.v., suppressed food intake and locomotor activity in a dose-dependent manner. These results suggest that NMU orthologs exist in fish, and that the NMU-21 deduced from them can potently inhibit food intake and locomotor activity in goldfish.

Functional characterization of Musca glutamate- and GABA-gated chloride channels expressed independently and coexpressed in Xenopus oocytes.

Ligand-gated chloride channels (LGICs) are important targets for insecticides and parasiticides. Genes encoding subunits of two LGICs, a glutamate-gated chloride channel (MdGluCl-alpha) and a gamma-aminobutyric acid (GABA)-gated chloride channel (MdRdl), were cloned from house-flies (Musca domestica L.). These genes were first expressed independently in Xenopus laevis oocytes by cRNA injection in order to investigate the pharmacology of these ligand-gated channels using two-electrode voltage-clamp electrophysiology. It was found that L-glutamate and GABA activated the MdGluCl-alpha homo-oligomers with an EC(50) value of 30 microM and the MdRdl homo-oligomers with an EC(50) value of 101 microM, respectively. Both channels were chloride ion-permeable, and the MdRdl channel was more sensitive to chloride channel blockers, such as gamma-hexachlorocyclohexane (gamma-HCH), fipronil and picrotoxinin, than the MdGluCl-alpha channel. MdGluCl-alpha required only 1-2 days of incubation after cRNA injection to be expressed in oocytes, whereas 4-7 days of incubation was necessary to achieve MdRdl expression. However, when the cRNA of MdGluCl-alpha was injected at a dose of 1% (w/w) 1 day after the injection of the cRNA of MdRdl, a significant increase in the current amplitude of responses to GABA was observed, and the incubation period necessary for MdRdl expression became shorter. These results suggest that MdGluCl-alpha assists in the expression of MdRdl when the two are coexpressed.

Developmental changes in the expression of growth-associated protein-43 mRNA in the monkey thalamus: northern blot and in situ hybridization studies.

The expression of growth-associated protein-43 has been related to axonal elongation and synaptic sprouting. Using the Northern blot analysis, we investigated the developmental changes of growth-associated protein-43 mRNA in the thalamus of macaque monkeys. The amount of growth-associated protein-43 mRNA was high at embryonic day 125, and decreased at postnatal day 1. It increased again at postnatal day 8, reached its peak value at postnatal days 50-70, and then decreased gradually until postnatal year 1. We previously reported that the amount of growth-associated protein-43 mRNA in the cerebral cortex decreased roughly exponentially during perinatal and postnatal periods and that it approached the asymptote by postnatal day 70 [Oishi T, Higo N, Umino Y, Matsuda K, Hayashi M (1998) Development of GAP-43 mRNA in the macaque cerebral cortex. Dev Brain Res 109:87-97]. The present findings may indicate that extensive synaptic growth of thalamic neurons continues even after that of cortical neurons has finished. We then performed in situ hybridization to investigate whether the expression level of growth-associated protein-43 mRNA was different among various thalamic nuclei. In the infant thalamus (postnatal days 70-90), moderate to intense expression of growth-associated protein-43 mRNA was detected in all thalamic nuclei. Quantitative analysis in the infant thalamus indicated that the expression levels were different between the nuclear groups that are defined by the origin of their afferents. The expression in the first order nuclei, which receive their primary afferent fibers from ascending pathways [Guillery RW (1995) Anatomical evidence concerning the role of the thalamus in corticocortical communication: a brief review. J Anat 187 (Pt 3):583-592], was significantly higher than that in the higher order nuclei. While moderate expression was also detected in the adult dorsal thalamus, the expression in the first order nuclei was almost the same as that in the higher order nuclei. Thus, the in situ hybridization experiments indicated that the transient postnatal increase in the amount of growth-associated protein-43 mRNA, which was shown by the Northern blot analysis, was mainly attributed to enhanced expression in the first order nuclei during the postnatal period. This may be a molecular basis for environmentally induced modification of thalamocortical synapses.

The phytochemical lindleyin, isolated from Rhei rhizoma, mediates hormonal effects through estrogen receptors.

Some plant compounds or herb mixtures are popular alternatives to conventional therapies and contain organic compounds that bind to some nuclear receptors, such as the estrogen receptor (ER), to exert various biological effects. We studied the effect of various herbal extracts on ERalpha and ERbeta isoforms. One herbal extract, Rhei rhizoma (rhubarb), acts as an agonist to both ERalpha and ERbeta. The phytochemical lindleyin, a major component of rhubarb, might contribute to this estrogenic activity through ERalpha and ERbeta. 4-Hydroxytamoxifen, an ER antagonist, completely reversed the estrogenic activity of lindleyin. Lindleyin binds to ERalpha in vitro, as demonstrated using a fluorescent polarization assay. The in vivo effect of rhubarb extract was studied using a vitellogenin assay system in the freshwater fish, Japanese medaka (Oryzias latipes). There were marked increases in serum vitellogenin levels in male medaka exposed to rhubarb extract. We conclude that lindleyin, a component of some herbal medicines, is a novel phytoestrogen and might trigger many of the biological responses evoked by the physiological estrogens.

Low power diode laser treatment using indocyanine green for eradication of esophageal varices.

BACKGROUND AND STUDY AIMS: Endoscopic variceal ligation (EVL) is an alternative to sclerotherapy for the treatment of esophageal varices, but is associated with higher rates of recurrence and subsequent bleeding than sclerotherapy. To prevent recurrence of varices after EVL, we have developed a low-dose diode laser therapy combined with the injection of indocyanine green, which allows enhanced tissue absorption of the laser beam selectively around varices. In this study we investigated the efficacy and safety of this technique. PATIENTS AND METHODS: Eight patients with F2 or F3 esophageal varices were enrolled. At 1 week after EVL, indocyanine green solution (1 mg/ml) was injected submucosally around the remaining varices. A diode laser (power 10 watts) was applied to the surface from the esophagogastric junction to 5 cm above it. The spot size was kept to 5 mm in diameter. RESULTS: Laser irradiation was performed safely, without bleeding from the varices, or perforation. There were no major complications. Endoscopy 1 month later showed F0 forms in seven patients, F1 in one patient, and no red color sign in any patient. No recurrence of varices has been observed in any of the patients during the follow-up period of at least 12 months. CONCLUSION: This technique may provide a simple, safe and effective procedure, as an additional treatment to EVL, for the prevention of recurrence of esophageal varices.

Expression and properties of human liver beta-ureidopropionase.

A cDNA encoding beta-ureidopropionase (BUP) was isolated from a human liver cDNA library, expressed in E. coli, and purified from the culture extract. The 2,006 bp cDNA contained a 1,152 bp open reading frame encoding a protein of 384 amino acids with a molecular weight of 43,165 Da. The subunit molecular weight of the enzyme expressed was about 43,000 Da. The enzyme was inhibited by 1 mM propionate, but not by 10 mM beta-alanine. Chemical analysis of the purified human BUP showed 0.54 zinc atoms per subunit, and the sequence of BUP cDNA contained one putative zinc-binding site motif. The purified enzyme had a pI of 5.65, and exhibited positive cooperativity with N-carbamoyl-beta-alanine as the substrate with a Hill coefficient 2.0. These properties of human BUP, except the inhibition by beta-alanine, were similar to the rat liver purified enzyme. Beta-alanine inhibits rats BUP activity. The complex regulatory function and the negative cooperative mechanism of BUP by beta-alanine have been observed in rats. This kind of mechanism may not exist in humans, because beta-alanine did not inhibit human BUP.

Retrospective radiographic analysis of nonpedunculated colorectal carcinomas with special reference to tumor doubling time and morphological change.

OBJECTIVE: Our aim was to characterize the development of nonpedunculated colorectal carcinomas by retrospective radiographic analysis, with special reference to tumor doubling time and morphological change. METHODS: Eleven colorectal carcinomas, which were observed for >6 months by barium enema examinations, were collected and retrospectively reviewed. There were five early and six advanced carcinomas, including submucosally invasive, superficial depressed carcinomas. RESULTS: Mean diameter of lesions at initial barium enema examination was 13.5 mm (early, 10.4 mm; advanced, 16.0 mm) and that at final barium enema examination was 30.9 mm (early, 18.2 mm; advanced, 41.5 mm). Initial morphology of the lesions was superficial in three, sessile in seven, and semipedunculated in 1. There was no pedunculated lesion. Macroscopic morphology of the five early carcinomas was superficial depressed (IIc) in two cases, mostly depressed but partly elevated (IIc+IIa) in one case, and superficial elevated with a depressed component (IIa+IIc) in two cases; all of the advanced carcinomas were of the ulcerated type. Mean doubling time was 6.8 months (early, 9.4 months; advanced, 4.7 months). Early carcinomas had significantly longer doubling times than advanced carcinomas (p = 0.017, Wilcoxon's text). The lesions with the longest doubling times were superficial depressed lesions. CONCLUSIONS: Early carcinomas have longer doubling times than advanced carcinomas. Most nonpedunculated colorectal carcinomas grow without significant morphological changes. Superficial depressed type tumors grow slowly, maintaining their macroscopic morphology.

Effect of chronic treatment with perindopril on endothelium-dependent relaxation of aorta and carotid artery in SHRSP.

Endothelium-dependent relaxation of aorta and carotid artery from stroke-prone spontaneously hypertensive rats (SHRSP) and the effect of chronic treatment of SHRSP with perindopril, an angiotensin converting enzyme inhibitor, on endothelium-dependent relaxation were studied. Endothelium-dependent relaxation was induced by acetylcholine (ACh) in preparations of SHRSP and normotensive Wistar Kyoto rats (WKY) precontracted with noradrenaline. The ACh-induced relaxation in both preparations was abolished by L-nitroarginine. The ACh-induced relaxation was impaired in preparations from SHRSP and contraction was observed at high concentrations of ACh. In the presence of indomethacin, impairment of endothelium-dependent relaxation in SHRSP was minimized and the contraction was inhibited. The relaxation with sodium nitroprusside did not differ between the preparations from WKY and SHRSP. Treatment of SHRSP with perindopril (2 mg/kg/day) for 6 weeks decreased systolic blood pressure and improved the ACh-induced relaxation of aorta and carotid artery. The treatment inhibited the contraction by higher concentrations of ACh in the presence of L-nitroarginine. These results indicate that the impairment of endothelium-dependent relaxation in aorta and carotid artery of SHRSP may be caused by the reduced availability of nitric oxide. The perindopril-treatment may prevent these changes in SHRSP.

Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method.

BACKGROUND: Thymidylate synthase (TS) is regarded as a parameter of 5-fluorouracil (5-FU) chemosensitivity for colorectal carcinoma. Recent researchers indicate that the chemosensitivity of 5-FU for colorectal carcinoma with low expression of TS is better than tumors with high expression of TS. But the relation between TS expression and overall survival of curatively resected colorectal cancer patients has been less studied. METHODS: Specimens of curatively resected colon carcinoma from 148 patients were included in this study. TS expression in the tumor was assessed by immunohistochemical staining technique, and the patients were categorized into TS-(+) and TS-(-) groups. First, the relation between TS expression and survival of patients was examined. Next, for each group, we compared survival between the chemotherapy-(+) and the chemotherapy-(-) subgroup. RESULTS: Overall survival was significantly better in the TS-(-) group (n = 107) than in the TS-(+) group (n = 41) (P = .0003). In the TS-(-) group, there was little difference between the chemotherapy-(+) and the chemotherapy-(-) subgroup. In the TS-(+) group, the survival of the chemotherapy-(+) subgroup was significantly better than the chemotherapy-(-) subgroup (P = .0439). CONCLUSIONS: TS, itself, may be a prognostic factor for colon carcinoma; and 5-FU adjuvant chemotherapy may be appropriate for colon carcinoma with high expression of TS.

Selective and continuous degradation of carbazole contained in petroleum oil by resting cells of Sphingomonas sp. CDH-7.

Microbial degradation of carbazole (CA), a model of hard-removal heterocyclic nitrogen compounds contained in petroleum oil, was examined using Sphingomonas sp. CDH-7 isolated from a soil sample by screening for CA-assimilating microorganisms. CDH-7 used CA as a sole source of carbon and nitrogen, and metabolized CA to ammonia via anthranilic acid as an intermediate product. When CDH-7 was cultivated in the medium containing CA at the concentration of 500 mg/l (2.99 mM), CA was completely degraded within 50 h. By the reaction with the resting cells of CDH-7, 500 mg/l of CA was completely degraded within 4 h, with 1.64 mM of ammonia accumulated in the reaction mixture. When CA was added at the concentration of 100 mg/l (0.599 mM) periodically to the reaction mixture ten times, 925 mg/l (5.54 mM) of CA was degraded within 48 h by the resting cells, and 4.50 mM of ammonia was accumulated in the reaction mixture with a 75.1% molar conversion yield based on total CA added. The resting cells could almost completely degrade CA in a two-liquid-phase system which consists of water and organic solvent, even in the presence of 20% (v/v) isooctane, n-hexane, cyclohexane, and kerosene as a model petroleum oil. In the presence of an organic solvent system such as 20% (v/v) pxylene, toluene, and heptanol, however, CA degradation yields decreased.

Clinical evaluation of hepatic arterial infusion of low dose-CDDP and 5-FU with hyperthermotherapy: a preliminary study for liver metastases from esophageal and gastric cancer.

BACKGROUND/AIMS: The prognosis for gastric and esophageal cancer patients with liver metastases remains very poor. In most cases, liver metastasis is unresectable because of its number, size and location and therefore, other approaches need to be considered. METHODOLOGY: In this study we examined 4 patients. We showed the therapeutic benefits of employing hepatic arterial infusion of low-dose CDDP and 5-FU combined with hyperthermia for the treatment of liver metastases of gastric and esophageal cancer. RESULTS: All patients showed partial response, and bone marrow toxicities and gastrointestinal toxicities were extremely slight while liver toxicities were not observed at all. Moreover, 3 of the patients excluding patient 3 who had metastatic lesions other than liver metastases have still been alive for more than 17 months (17-28 months) maintaining a good quality of life. CONCLUSIONS: Therefore, it is suggested that the merits of both low dose-FP and hepatic arterial infusion chemotherapy contribute to ideal clinical effects, and that hyperthermotherapy could enhance clinical responses without potentiating any toxicities. However, this is just a preliminary study, and therefore, a prospective randomized control study is necessary to evaluate the efficiency of this therapy.

The correlation between feed-intake cycle and nutritional zinc-deficient status in rats.

The characteristic cyclic variation in feed intake of rats fed a Zn-deficient diet (Mills et al, Am J Clin Nutr 22: 1240-1249 (1969)) followed a Cosinor curve, as determined by computer analysis (Tamaki et al, Br J Nutr 73: 711-722 (1995)). The values of amplitude for the feed-intake cycle had a positive correlation to their own day-to-day variations and to the correlation value of their own simulated cycles (r2 = 0.764, df = 50, p < 0.001 and r2 = 0.682, df = 50, p < 0.001, respectively). The cyclic variation in feed intake was accompanied by a cyclic variation in body-weight change in rats fed the Zn-deficient diet, and cyclic variation in body-weight change occurred similarly in pair-fed control rats. There were no differences in the mesors of body-weight change cycles of Zn-deficient rats and pair-fed control rats (Zn-deficient rats: 2.5 +/- 1.0 g/d, pair-fed rats: 2.8 +/- 1.0 g/d, mean +/- SD, df = 18, t = -0.674, ND). Rats fed the Zn-deficient diet were given different amounts of Zn supplementation by daily subcutaneous injection. The amplitude of the feed-intake cycle was decreased with increasing Zn supplementation (r2 = 0.919, df = 5, p < 0.001). The concentration of Zn for the appearance of the feed-intake cycle was estimated to be 71.6 +/- 6.6 micrograms/d per rat. The Zn level in the serum showed a significant decrease in the Zn-deficient diet groups, but the supplement of Zn did not vary in the Zn-deficient rats injected with up to 47.3 micrograms/d per rat. From these results, an analysis of the feed-intake cycle allowed us to estimate the quantitative Zn-deficient status of rats.

Possible associations of rectal carcinoma with Schistosoma japonicum infection and membranous nephropathy: a case report with a review.

We report the first case of rectal carcinoma associated with S. japonicum and membranous nephropathy. A 57-year-old Japanese man noticed narrowing of his feces. He had lived in Yamanashi prefecture, an endemic area of S. japonicum. He had suffered from nephrotic syndrome for about 1 year. Barium enema study showed a severe stricture in the upper rectum and biopsy specimens from the tumor demonstrated well differentiated adenocarcinoma and many ova of S. japonicum. Sonography of the liver showed a network pattern and a linear high echoic area. Low anterior resection with incisional biopsy of the liver and the right kidney was performed. Histopathological findings showed well differentiated adenocarcinoma and schistosomal ova. The total number of ova in the resected colon amounted to 15,133, consisting of 2243 inside and 12,890 outside the carcinoma. The nearer to the carcinoma the area was, the higher was the density of ova. The findings of light microscopy and electron microscopy of the biopsy specimen from the kidney were compatible with membranous nephropathy (stage II). This case suggests that schistosomal ova have some effect on carcinogenesis and nephrotic syndrome. In patients with nephrotic syndrome of unknown cause, especially in inhabitants of endemic areas of S. japonicum, gastrointestinal malignancy should be ruled out as an etiological factor. Sigmoidoscopy would be useful for colorectal carcinoma surveillance in S. japonicum patients.

A schwannoma of the cecum: case report and review of Japanese schwannomas in the large intestine.

A 66-year-old Japanese man had a positive fecal occult blood test at a regular check-up, and a large polypoid mass was detected in the cecum by barium enema study. Colonoscopy showed a submucosal tumor with ulcer protruding into the cecal lumen. A large-forceps biopsy specimen was taken from the bottom of the ulcer. With the tentative diagnosis of neurogenic tumor, ileocecal resection was performed. The tumor showed spindle-cell proliferation in a concentric or fascicular pattern. Immunohistochemically, the tumor cells were diffusely positive for S-100 protein, and they had intracytoplasmic periodic acid Schiff (PAS)-positive crystalloids. The mitosis count was low (about 1 per 20 high-power fields). The pathological diagnosis of this tumor was benign gastrointestinal schwannoma. A large number of schwannoma cases have been reported since 1910 when Verocay reported it as a true tumor that stemmed from Schwann cells and did not contain neuroganglion cells. However, gastrointestinal schwannomas are rare, and schwannomas of the large intestine are extremely rare. We reviewed 40 cases already reported in Japan and this present case in order to clarify the clinicopathological features of this tumor.

Physiological mechanism-based analysis of dose-dependent gastrointestinal absorption of L-carnitine in rats.

We evaluated the dose-dependent (saturable) gastrointestinal absorption of L-carnitine, a lipid-lowering agent, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. The intestinal absorption rate constant (ka), which was estimated by the analysis of gastrointestinal disposition, decreased markedly from 0.1061 to 0.0042 min(-1) when the dose was increased from 0.05 micromol rat(-1) (low dose) to 100 micromol rat(-1) (high dose). The dose-dependence in ka was attributable to the saturability of intestinal transport that, in the perfused intestine, was similar to the saturability in ka. At the high dose, the apparent absorption rate constant (k'a) of 0.0021 min(-1), which was estimated by the analysis of plasma concentrations after oral administration, was an order of magnitude smaller than the gastric emptying rate constant (kg) of 0.059 min(-1) and comparable with the ka of 0.0042 min(-1), suggesting that the gastrointestinal absorption of L-carnitine is absorption-limited in the intestine. At the low dose, where intestinal L-carnitine absorption was far more efficient, the k'a of 0.0172 min(-1) was smaller than the ka of 0.1061 min(-1) and closer to the kg of 0.072 min(-1), suggesting that apparent absorption was retarded by gastric emptying which is less efficient than intestinal absorption. This shift in the rate-determining process with an increase in dose explains the less marked dose dependence in k'a compared with ka. The bioavailability decreased from 100 to 42% with an increase in dose. This could be accounted for quantitatively by a reduction in the fraction absorbed (F(a,oral)) due to a reduction in ka, assuming first-order absorption during the transit time of T(si) through the small intestine (F(a,oral) = 1 - exp(-ka x T(si))). Thus, using L-carnitine as a model, this study has successfully demonstrated that the saturability in gastrointestinal absorption can be correlated with the intestinal transport in a quantitative and mechanism-based manner. This should be of help not only for developing more efficient oral L-carnitine delivery strategies, taking advantage of in vitro (in situ) information about the intestinal transport mechanism, but also for establishing a more generally applicable in vitro (in situ)-in vivo correlation in gastrointestinal absorption.