Usefulness of hepatic arterial infusion chemotherapy using lecithin-added lipiodol emulsion in hepatocellular carcinoma

After implanting a reservoir in the hepatic artery, we performed intra-arterial chemotherapy with a smaller particle size lipiodol emulsion and examined its therapeutic effect. Subjects were 21 patients with advanced/recurrent hepatocellular carcinoma (HCC). Arterial infusion was performed once every 2 weeks on an outpatient basis using 2 mL lipiodol emulsion with lecithin added as a surface active agent and 10 mg doxorubicin hydrochloride. As of 6 months after the start of treatment, the response rate was 38.1%. Median survival was 17.0 months. Serious adverse events were not noted in any of the subjects;during the course of treatment, catheter occlusion was observed in 2 patients. This therapy allows fewer visits and provides a relatively substantial therapeutic effect while maintaining QOL, so it may serve as an effective treatment for highly advanced/multiple HCC not suited to other treatments.     

Polycystic ovary syndrome and hepatocellular adenoma related to long-term use of sodium valproate in a young woman

Previous studies have reported a high prevalence of polycystic ovary syndrome (PCOS) among women taking sodium valproate (VPA). We report the case of a 28 year-old epileptic female taking VPA, who developed PCOS and later hepatocellular adenoma. She had been taking VPA for intractable epilepsy since the age of 15 months. At the age of 22 years, she suffered spontaneous rupture of a liver tumor that was diagnosed as hepatocellular adenoma. At the age of 24 years, bilateral polycystic ovaries were found by transabdominal ultrasonography, and PCOS was diagnosed. VPA may directly influence steroidogenesis in the ovary and cause hyperandrogenemia with ensuing PCOS. It is known that abnormality in the sex hormones contributes to the onset of hepatocellular adenoma. Therefore, we speculate that hyperandrogenemia due to VPA contributed to the development of hepatocellular adenoma in this case.     

Pacemaker contact dermatitis: The effective use of a polytetrafluoroethylene sheet

A 52-year-old man with Down's syndrome was implanted with a DDDR pacemaker for advanced atrioventricular block. He was admitted with development of skin eczema and partial exposure of the generator 1 year after reimplantation. There was no evidence of infection on laboratory data. A skin patch test was positive for the metal of the generator (purity 99.9% titanium) after 72 hours. These findings indicated pacemaker contact dermatitis. After the patient was reimplanted with a pacemaker wrapped with a polytetrafluoroethylene sheet, there has been no recurrence of the contact dermatitis during a follow-up period of 3 years.     

Effects of papaverine on twitches in mouse diaphragm

This study examined the inhibitory effects of papaverine on twitches directly elicited by electrical stimulation of the mouse diaphragm. Papaverine (3-100 μM) inhibited twitches in a dose-dependent manner. Papaverine increased the cyclic adenosine monophosphate (cAMP) but not cyclic guanosine monophosphate (cGMP) content. IBMX, Db-cAMP and 8-br-cGMP did not affect twitches, whereas verapamil and NaCN inhibited twitches. Increases in extracellular Ca2+ removed the twitch inhibition caused by verapamil but not that caused by papaverine. Papaverine (30 and 100 μM) and NaCN (1 mM) decreased creatine phosphate and ATP contents. These results suggest that the relaxing effects of papaverine on mouse diaphragm are mainly due to inhibition of aerobic energy metabolism.     

Unilateral transpedicular percutaneous vertebroplasty using puncture simulation

Purpose The aim of this study was to improve the accuracy of puncture to the median vertebral body using the unilateral transpedicular approach on percutaneous vertebroplasty (PVP). We have developed and evaluated a simple puncture simulation method based on the puncture angle determined by preoperative computed tomography (CT). Materials and methods Two groups were evaluated. The first (group A) comprised 23 patients (34 vertebral bodies) who had undergone PVP without preoperative puncture simulation before May 2004, and the second group (group B) comprised 24 patients (39 vertebral bodies) who had undergone preoperative puncture simulation and PVP after May 2004. CT in the prone position was performed, and the puncture angle on CT (PAC) via the vertebral arch pedicle targeting the anterior one-third median site of the vertebral body was determined. Puncture was performed by targeting the isocenter established on a fluoroscopic monitor based on the PAC. Determinations were made of the success rate (SR) of the median puncture of the vertebral body, the effect of treatment using the visual analogue score, and the overall procedural time between groups A and B. Results The SR was 56% (19/34 vertebral bodies) in group A, and 97% (37/38 vertebral bodies), including only one vertebral body in which it was difficult to perform the unilateral approach on CT images, in group B, with the difference being significant by Student's t-test (P < 0.001). Among patients with available follow-up data, the unipedicular and bipedicular approaches achieved adequate pain relief with mean decreases in pain severity of 5.1 ± 2.6 and 5.9 ± 2.8, respectively. No significant differences in the treatment effect between the two groups was observed (P = 0.811). The overall procedure time per puncture was shorten for the simulation group (36.0 min) than for group A (73.1 min), as shown by regression analysis. Conclusion The preoperative PAC determination for PVP under fluoroscopy increased the completion rate of PVP by the unilateral transpedicular approach. This method should be accepted from the viewpoint of burden reduction on patients and surgeons. This work was presented at the 64th Academic Meeting of the Japan Medical Radiology Society, Yokohama, 2005.     

Combined effects of fangchinoline from Stephania tetrandra Radix and formononetin and calycosin from Astragalus membranaceus Radix on hyperglycemia and hypoinsulinemia in streptozotocin-diabetic mice

The anti-hyperglycemic action of Stephania tetrandra Radix (Stephania) is potentiated by Astragalus membranaceus BUNGE Radix (Astragali) in streptozotocin (STZ)-diabetic ddY mice (Tsutsumi et al., Biol. Pharm. Bull., 26, 313 (2003)). Fangchinoline (0.3-3 mg/kg), a main constituent of Stephania, decreased the high level of blood glucose and increased the low level of blood insulin in STZ-diabetic mice. Here, we investigated the combined effects of fangchinoline with isoflavone or isoflavonoid components (formononetin, calycosin and ononin) of Astragali on the hyperglycemia and hypoinsulinemia of STZ-diabetic mice. Formononetin, calycosin and ononin (0.03-0.1 mg/kg) alone did not affect the blood glucose or blood insulin level of the diabetic mice. Formononetin and calycosin (0.03-0.1 mg/kg) potentiated the anti-hyperglycemic action of fangchinoline (0.3 mg/kg), but ononin did not. Formononetin (0.1 mg/kg) facilitated the fangchinoline-induced insulin release, and calycosin (0.1 mg/kg) also facilitated it, though without statistical significance. In conclusion, the combined effect of fangchinoline with formononetin and calycosin on hyperglycemia in the diabetic mice accounted well for the therapeutic effect of the combination of Stephania with Astragali in Boi-ogi-to. The anti-hyperglycemic action of formononetin appeared to be due to its potentiating action on insulin release. Our strategy for studying combinations of crude drugs and their components in Kampo medicine has uncovered new potentiating effects of formononetin and calycosin on the anti-hyperglycemic action of fangchinoline in STZ-diabetic mice.     

Overproduction of N(epsilon)-(carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of aged rat

N(epsilon)-(carboxymethyl)lysine (CML) adduct, a major structure of advanced glycation end product, facilitated production of immature microvessels from choroidal explant cultured in fibrin gel. The present study was investigated an action of endogenous CML adduct on neovascularization of cultured choroidal explants of aged Wistar rats with 9 months of age. The number of microvessels budded from explants was counted under optical microscope and used as an index of in vitro neovascularization. Aged choroidal explants increased the neovascularization in an age-dependent manner. Anti-CML antibody decreased age-facilitated neovascularization as well as CML-human serum albumin (HSA)-facilitated neovascularization. Both the aged explant and CML-HSA-treated explant significantly released vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) alpha and platelet-derived growth factor (PDGF)-B during the culture period. The release of TNF alpha and PDGF-B was earlier than that of VEGF from the aged explants. The antibodies against these factors decreased the CML-facilitated and age-facilitated neovascularization in the choroidal explants. The inhibitory capacity of anti-TNF alpha antibody was greater than those of anti-VEGF and anti-PDGF-B antibodies. In conclusion, endogenous CML adduct overproduced the neovascularization of the aged choroidal explant. The CML adduct releases TNF alpha which might induce the production and release of VEGF for the abnormal choroidal neovascularization in the patients of age-related macular degeneration.     

Changes in localization of cytochrome P450 cholesterol side-chain cleavage (P450scc) in Japanese eel testis and ovary during gonadal development

In this study, we generated and characterized a polyclonal antiserum against eel P450 cholesterol side-chain cleavage (P450scc) using a recombinant protein as the antigen. We examined the localization and abundance of P450scc by immunohistochemistry in Japanese eel testes and ovaries during artificially induced gonadal development. P450scc mRNA localization was also examined by in situ hybridization. In male eels, testicular development was induced by a single injection of human chorionic gonadotropin (HCG). In females, ovarian development was induced by weekly injections of salmon pituitary homogenate (SPH). Before HCG injection, the testis contained germ cells that were primarily type A spermatogonia. Additionally, several clusters of immunoreactive cells for P450scc were localized in the interstitial Leydig cells, but no P450scc mRNA signals were detected. This suggests that P450scc is either a relatively stable protein or it is produced by a mRNA that is present at too low a level to detect. Shortly after a single injection of HCG, expression of P450scc mRNA was stimulated and the number of immunoreactive clusters and their staining intensity were both increased. P450scc mRNA fell to an undetectable level 3 days after hormonal stimulation. Although the P450scc protein also decreased at the same time as the mRNA, it remained at a detectable level throughout this period. P450scc mRNA, but not the P450scc protein, was also detected in the spermatids and spermatozoa. The biological significance of P450scc mRNA expression at this stage is unknown. Prior to experimentation, the ovary contained oocytes that were developed to the oil-droplet stage, with several clusters of immunoreactive cells localized in the thecal layer and ovigerous lamella epithelium. Expression of P450scc mRNA was also stimulated by SPH injections in the ovary. In contrast to the testis, P450scc mRNA was continuously detected in the thecal cell layer throughout artificially induced maturation, possibly due to a repeated stimulus by the SPH injection every week. Clusters of immunoreactive cells in the thecal cell layer increased in number as ovarian development progressed. This increase in P450scc mRNA and protein may explain, at least in part, the increase in serum steroid hormones in female eels. The P450scc antiserum clearly immunostained interrenal steroidogenic cells in the head kidney of not only eel but also goldfish, indicating that this antibody could also be used in other teleost species.     

Loss of circadian rhythm and light‐induced suppression of pineal melatonin levels in Cry1 and Cry2 double‐deficient mice

Cryptochrome 1 and 2 (Cry1 and Cry2) are considered essential for generating circadian rhythms in mammals. The role of Cry1 and Cry2 in circadian rhythm expression and acute light‐induced suppression of pineal melatonin was assessed using Cry1 and Cry2 double‐deficient mice (Cry1^?/?/Cry2^?/?) developed from the C3H strain that synthesizes melatonin. We examined the circadian variation of pineal melatonin under a 12:12‐h light–dark (LD) cycle and constant darkness (DD). Light suppression of pineal melatonin concentration was analyzed by subjecting a 30‐min light pulse at the peak phase of melatonin concentration. Wild‐type mice showed significant rhythmicity in pineal melatonin concentration with the highest level at Zeitgeber time 22 (ZT22, where time of light on was defined as ZT0) under LD or ZT18 on the first day of DD. In contrast, Cry1^?/?/Cry2^?/? mice did not show significant circadian rhythmicity, with only a small peak observed at ZT22 in LD. Nevertheless, a significant daily variation could be observed under DD, with a small increase at ZT6 and ZT18 h. Melatonin concentration was significantly suppressed by acute light pulse at ZT22 in wild‐type mice but not in Cry1^?/?/Cry2^?/? mice. The present results suggest that Cry genes are required for regulating pineal melatonin synthesis via circadian and photic signals from the suprachiasmatic nucleus of the hypothalamus (SCN).