Partial response of angiosarcoma of the scalp to sorafenib: association with decreased expression of vascular endothelial growth factors and their receptors.

The prognosis of angiosarcoma remains very poor, even with combined, multimodal therapy. We report a case with partial response of angiosarcoma of the scalp to sorafenib, which is a new oral, molecular, targeted, multiple-kinase inhibitor. In addition, we confirmed, using immunohistochemistry, that sorafenib suppressed the expression of vascular endothelial growth factors and their receptors on the angiosarcoma tumour cells, and decreased cell numbers by inhibiting cellular proliferation.

Endothelial dysfunction in MELAS improved by l-arginine supplementation.

The authors evaluated endothelial function in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) by flow-mediated vasodilation (FMD) and found a significant decrease vs controls. Two years of supplementation with oral l-arginine, a nitric oxide precursor, significantly improved endothelial function to control levels and was harmonized with the normalized plasma levels of l-arginine in patients. l-Arginine therapy improved endothelial dysfunction and showed promise in treating strokelike episodes in MELAS.

A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins.

BACKGROUND/AIMS: A major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), has previously been shown to induce cell-cycle arrest and apoptosis in various cancers. However, little is known about its effects on hepatocellular carcinomas (HCCs). METHODS: Four HCC cell lines, HLE, HepG2, HuH-7 and PLC/PRF/5, were treated with EGCG or vehicle. Cell viability was assessed by trypan blue staining and WST-8 assay. Cell-cycle, apoptosis and apoptosis-related proteins in HLE cells were evaluated by flow cytometry and Western blotting. The effect of EGCG was also studied in vivo using a xenograft model. The effect of co-treatment with EGCG and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was also assessed. RESULTS: EGCG inhibited the growth of all HCC cell lines at concentrations of 50-100 microg/ml. In HLE cells, EGCG induced apoptosis but not cell-cycle arrest and appears to have down-regulated Bcl-2alpha and Bcl-xl by inactivation of NF-kappaB. Oral administration of EGCG showed similar effects in HLE xenograft tumors. Co-treatment with EGCG and TRAIL synergistically induced apoptosis in HLE cells. CONCLUSIONS: EGCG induced apoptosis in HLE cells, both in vitro and in vivo. Moreover, it enhanced TRAIL-induced apoptosis. Therefore, EGCG treatment may be useful for improving the prognosis of HCCs.

Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Diet and Japanese herbal medicine for recalcitrant atopic dermatitis: efficacy and safety.

We have been utilizing Kampo, a Japanese herbal medicine, together with lifestyle advice, for recalcitrant atopic dermatitis. To estimate the safety and efficacy of the treatment, we administered Kampo formulas to patients in whom conventional treatment failed to improve symptoms, along with dietary advice recommending traditional Japanese food. The therapeutic effects of Kampo formulas were assessed in 95 patients with recalcitrant atopic dermatitis who consulted our clinic from January to June, 2000. The overall result was 'markedly effective" in 19 patients (20%), "moderately effective" in 33 (35%), "slightly effective" in 36 (38%) and "ineffective" in four (4%). Three patients dropped out of the study. No adverse reactions in laboratory data were noted in examined patients. The most commonly used formula was Hochu-ekki-to containing Astragalus root, liquorice, jujube, ginseng, white Atractylodes rhizome, fresh ginger and Chinese Angelica root. Diet and Japanese herbal medicine are thought to be useful as an alternative therapy of intractable atopic dermatitis.

The effects of Hochu-ekki-to in patients with atopic dermatitis resistant to conventional treatment.

Hochu-ekki-to is one of Kampo formulas containing Astragalus root, liquorice, jujube, ginseng, white Atractylodes rhizome, fresh ginger and Chinese angelica root. This formula has been identified as an effective drug to improve the function of digestive systems and to strengthen defensive systems against many kinds of infections. We examined serum IgE levels and eosinophils before and after the administration of Hochu-ekki-to in patients with recalcitrant atopic dermatitis. The increased numbers of eosinophils was statistically decreased after 3 months' use of this formula. Serum IgE levels showed a tendency to decrease after the administration of this substance.

Hochu-ekki-to suppresses development of dermatitis and elevation of serum IgE level in NC/Nga mice.

The Japanese herbal medicine Hochu-ekki-to (Chinese name: Bu-Zhong-Yi-Qi-tang) is composed of ten species of medical plants and is used for many therapeutic purposes such as recovery from weakness, dysfunction of the digestive system and fatigue. In certain groups of patients with intractable atopic dermatitis this prescription has shown clinical effectiveness. We examined the ability of Hochu-ekki-to to inhibit dermatitis and IgE production in atopic NC/Nga mice. Oral administration of Hochu-ekki-to suppressed spontaneous dermatitis and serum IgE levels in NC/Nga mice. This finding provides evidence that Hochu-ekki-to may have immunological effects in atopic dermatitis.

[Effects of cernitin pollen-extract (Cernilton) on inflammatory cytokines in sex-hormone-induced nonbacterial prostatitis rats].

Cernitin pollen-extract (Cernilton, CN) is a preparation made from eight kinds of pollen and has been used for various prostatic diseases in Japan and Europe. We reported previously that CN possessed a recovery action on the sex-hormone-induced nonbacterial prostatitis in rats. To clarify the possible mechanism of action of CN, we investigated the effects of CN on inflammatory cytokines (IL-1 beta, IL-6 and TNF-alpha) in the same model. Aged Wistar rats were castrated and injected 17 beta-estradiol (0.25 mg/kg/day, s.c.) for 30 days. CN (630 and 1,260 mg/kg, p.o.) or testosterone (2.5 mg/kg, s.c.) was administered for the last 14 days of the treatment of 17 beta-estradiol. In control rats, prostatic IL-6 and TNF-alpha contents were increased approximately 2-3 fold, and acinar glandular inflammation and stromal proliferation were found histopathologically, as compared with those of intact rats. On the other hand, CN decreased the increased contents of cytokines in a dose-dependent manner. The histopathological changes mentioned above were restored in rats treated with 1,260 mg/kg. Testosterone also ameliorated them significantly. These results indicate that CN has an anti-inflammatory action, and that the inhibitory effect of CN on the prostatic inflammatory cytokine is an important factor in its action.

Studies of the constituents of Gardenia species. II. Terpenoids from Gardeniae Fructus.

Four new terpenoids, gardenate A (1), 2-hydroxyethyl gardenamide A (2), (1R,7R,8S,10R)-7,8,11-trihydroxyguai-4-en-3-one 8-O-beta-D-glucopyranoside (3) and Jasminoside F (4), were isolated from Gardeniae Fructus. Their structures were established on the basis of spectral analysis.

SIN-1-induced cytotoxicity in cultured endothelial cells involves reactive oxygen species and nitric oxide: protective effect of sepiapterin.

The purpose of this study was to examine whether tetrahydrobiopterin (BH4), one of the cofactors of nitric oxide (NO) synthase, attenuates endothelial cell death induced by 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1), which is known to produce both superoxide and NO. Endothelial cell death was assessed by the release of intracellular lactate dehydrogenase (LDH). Addition of SIN-1 (500, 1,000 microM) to endothelial cells induced cell death from 6 h after its addition. The SIN-1-induced endothelial cell death was strongly reduced by treatment with carboxy-PTIO, a NO scavenger, or superoxide dismutase (SOD). Iron chelators and hydroxyl radical scavengers also reduced the SIN-1-induced endothelial cell death. Interestingly, the SIN-1-induced endothelial cell death was also reduced by treatment with catalase. Thus NO, superoxide, hydroxyl radical, and hydrogen peroxide are likely to be implicated in SIN-1-induced endothelial cell death. Moreover, pretreatment with sepiapterin, a precursor of BH4 synthesis, reduced the SIN-1-induced endothelial cell death and increased the intracellular BH4 content. Both the protective effect of sepiapterin and the increase in intracellular BH4 content were prevented by co-pretreatment with N-acetylserotonin (NAS), an inhibitor of BH4 synthesis. The protective effect of sepiapterin also was observed when up-take of trypan blue was used as another marker of cell death. These findings suggest that BH4 has a protective effect against endothelial cell death caused by the presence of NO and superoxide. The protective effect of BH4 may at least partly involve scavenging of superoxide or hydrogen peroxide or both, because we and other groups previously found that BH4 has a scavenging activity for reactive oxygen species.

Minor daphnane-type diterpenoids from Wikstroemia retusa.

In addition to huratoxin, pimelea factor P2, and wikstroelides A-G from the fresh bark, eight daphnane-type diterpenoids, wikstroelides H-O, were isolated from the bark and stem, and their structures established. Cytotoxicity was assayed on some wikstroelides.

Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.

Oral adjuvant chemotherapy with carmofur (HCFU) for colorectal cancer: five-year follow-up. Tokai HCFU Study Group--third study on colorectal cancer.

BACKGROUND: A joint study was performed by the Tokai HCFU study group, which included seven institutions, to examine the value of oral administration of Carmofur (HCFU), a 5-fluorouracil (5-FU) derivative, for postoperative adjuvant chemotherapy in patients with colorectal cancer undergoing curative resection. METHODS: The patients were divided into two groups, a control group receiving no HCFU and a group administered HCFU for 1 year, using a centralized registration system by telephone. Among 173 patients entered into this study, 159 evaluable cases were analyzed for evaluation of the drug. RESULTS: The cumulative 5-year disease-free rate of patients who received HCFU was significantly increased compared with the control group. In particular, the rate was much higher in patients with colon cancer. No severe side effects arose from adjuvant chemotherapy with HCFU. CONCLUSION: Adjuvant chemotherapy with oral HCFU appears to provide a useful and safe postoperative treatment.

Squamous cell carcinoma of the scrotum.

A patient with psoriasis was found to have a large skin tumor on his scrotum. He had received psoralen and ultraviolet A radiation therapy to control psoriasis. Histopathologic study revealed that the tumor was a well-differentiated squamous cell carcinoma. We present this rare case and suggest that the genitalia be shielded during ultraviolet therapy.

Mechanisms of thrombin receptor agonist specificity. Chimeric receptors and complementary mutations identify an agonist recognition site.

Identification of the docking interactions by which peptide agonists activate their receptors is critical for understanding signal transduction at the molecular level. The human and Xenopus thrombin receptors respond selectively to their respective hexapeptide agonists, SFLLRN and TFRIFD. A systematic analysis of human/Xenopus thrombin receptor chimeras revealed that just two human-for-Xenopus amino acid substitutions, Phe for Asn87 in the Xenopus receptor's amino-terminal exodomain and Glu for Leu260 in the second extracellular loop, conferred human receptor-like specificity to the Xenopus receptor. This observation prompted complementation studies to test the possibility that Arg5a in the human agonist peptide might normally interact with Glu260 in the human receptor. The mutant agonist peptide SFLLEN was a poor agonist at the wild type human receptor but an effective agonist at a mutant human receptor in which Glu260 was converted to Arg. An "arginine scan" of the receptor's extracellular surface revealed additional complementary mutations in the vicinity of position 260 and weak complementation at position 87 but not elsewhere in the receptor. Strikingly, a double alanine substitution that removed negative charge from the Glu260 region of the human receptor also effectively complemented the SFLLEN agonist. The functional complementation achieved with single Arg substitutions was thus due at least in part to neutralization of a negatively charged surface on the receptor and not necessarily to introduction of a new salt bridge. By contrast, charge neutralization did not account for the gain of responsiveness to SFLLRN seen in the human/Xenopus receptor chimeras. Thus two independent approaches, chimeric receptors and arginine scanning for complementary mutations, identified the Glu260 region and to a lesser degree Phe87 as important determinants of agonist specificity. These extracellular sites promote receptor responsiveness to the "correct" agonist and inhibit responsiveness to an "incorrect" agonist. They may participate directly in agonist binding or regulate agonist access to a nearby docking site.

Endemic occurrence of glomerulonephritis associated with streptococcal impetigo.

We report here a case of type 1 mesangiocapillary glomerulonephritis as well as a case of mesangial proliferative glomerulonephritis associated with streptococcal skin infection superimposed on atopic dermatitis. Both were endemic occurrences of postinfectious glomerulonephritis developed after repeated dirty-skin treatments for atopic dermatitis performed by unauthorized individuals under unsanitary conditions. Of 20 patients who were similarly treated and subsequently admitted to our hospital because of skin infection and fever, 8 (40%) showed urinary abnormalities. Four patients had renal dysfunction with acute nephritic onset. Almost all showed a decrease in CH50 values and an increase in levels of antistreptolysin O and IgE. In the 2 cases presented here, the disease eventually regressed in association with improvement of the skin infection. Although the occurrence of postinfectious glomerulonephritis has recently become uncommon, we must take care to note urinary abnormalities as early as possible in order to prevent the progression of glomerulonephritis.

Effect of green tea rich in gamma-aminobutyric acid on blood pressure of Dahl salt-sensitive rats.

gamma-Aminobutyric acid (GABA) is known to be involved in the regulation of blood pressure by modulating the neurotransmitter release in the central and peripheral sympathetic nervous systems. This study investigated the antihypertensive effect of green tea rich in GABA (GABA-rich tea) in young and old Dahl salt-sensitive (S) rats. GABA-rich tea was made by fermenting fresh green tea leaves under nitrogen gas. In experiment 1, 21 11-month-old rats, fed a 4% NaCl diet for 3 weeks, were given water (group W), an ordinary tea solution (group T), or a GABA-rich tea solution (group G) for 4 weeks. The average GABA intake was 4.0 mg/rat per day. After 4 weeks of the treatment, blood pressure was significantly decreased in group G (176 +/- 4; P < .01) compared with group W (207 +/- 9) or group T (193 +/- 5 mm Hg). Plasma GABA levels were more elevated in group G (111 +/- 54) than in group W (not detectable) or group T (14 +/- 8 ng/mL; P < .01 v G). In experiment 2, 21 5-week-old rats, fed a 4% NaCl diet, were divided into groups W, T, and G. The average GABA intake was 1.8 mg/rat per day. Body weight or chow and beverage consumption did not differ significantly among the three groups. After 4 weeks of the treatment, although blood pressure was comparable in groups W and T (165 +/- 3 v 164 +/- 5 mm Hg, mean +/- SE), it was significantly lower in group G (142 +/- 3 mm Hg) than in the other groups (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)