Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.     

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.     

Induction of reversible cysteine-targeted protein oxidation by an endogenous electrophile 15-deoxy-delta12,14-prostaglandin J2

We have previously shown that a prostaglandin D(2) metabolite, 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), is the potent inducer of intracellular oxidative stress on human neuroblastoma SH-SY5Y cells [Kondo, M., Oya-Ito, T., Kumagai, T., Osawa, T., and Uchida, K. (2001) Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J. Biol. Chem. 276, 12076-12083.]. In the present study, to investigate the correlation between the redox regulation and the 15d-PGJ(2)-induced oxidative stress and to establish the cellular mechanism for protection against the endogenous electrophile, we analyzed S-oxidized proteins using biotinylated cysteine as a molecular probe. In addition, the reversible regulation of protein function by S-oxidation/thiolation was characterized in vitro. When human neuroblastoma SH-SY5Y cells were exposed to 15d-PGJ(2), followed by treatment with biotinylated cysteine, 26 proteins, including glycolytic enzymes, cytoskeletal proteins, redox enzymes, and stress proteins, were identified as substrates for reversible cysteine-targeted oxidation. To investigate the regulatory mechanism of protein function by S-oxidation/thiolation, the binding of a low molecular weight thiol (glutathione) to a glycolytic enzyme alpha-enolase was characterized. Treatment of alpha-enolase with the thiol oxidant diamide in the presence of glutathione in vitro resulted in the binding of glutathione to the protein and concomitant loss of the enzymatic activity, whereas the glutathiolation and inactivation of alpha-enolase were fully reversed by dithiothreitol. Mass spectrometric analysis of the tryptic fragments from native and oxidized alpha-enolase identified two cysteine residues, Cys-118 and Cys-388, as the S-oxidation sites, which may play a role in the regulation of the biological activities of the protein and may be regulated by a reversible S-oxidation/thiolation reaction. These results suggest that cysteine-targeted oxidation/thiolation plays a critical role in the regulation of protein function under conditions of electrophile-induced oxidative stress.     

Cytochrome P450 1A1 (CYP1A1) inhibitor alpha-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats: possible involvement of UGT-P450 interactions

The effects of cytochrome P450 (P450, CYP) ligands and permeabilization of microsomes on 3-hydroxybenzo(a)pyrene [3-OH-B(a)P] glucuronidation mediated by rat hepatic microsomes were studied. While the UDP-glucuronosyltransferase (UGT) activity with non-permeabilized microsomes from 3-methylcholanthrene (MC)-treated rats was markedly reduced by alpha-naphthoflavone (NF), this inhibitor had hardly any effect when permeabilized microsomes were used in which the inhibitor was expected to have easy access to UGT. Kinetic analysis indicated that the inhibitory effect of alpha-NF is competitive. These results suggest that a UGT isoform(s) involved in 3-OH-B(a)P glucuronidation is interfered by a CYP1A inhibitor via a mechanism dependent on the intact nature of microsomal membranes in MC-treated rats. It is likely that P450 functions as a substrate transporter for some isoforms of UGT via possible interactions between UGT and P450.     

3D flash lag illusion

Objective of this research is to study the presence of 3D flash lag illusion created by a moving object that has a motion-in-depth and a flash object. An object consisting of two thin sticks was simulated to approach the subject who observed it with a stereoscope. In the process of approaching, another stick was briefly presented in the middle of the moving sticks. Five human subjects took part in our experiments and all perceived 3D flash lag illusion. The perceived depth created by 3D flash lag illusion was measured by two different psychophysical experiments, by use of a vernier caliper and by a method of nulling with another depth cue. We studied relation between the perceived depth and the presentation distance. The experimental results indicate that the perceived gap by 3D flash lag illusion is independent from the presentation distance.     

Topical administration of iganidipine, a new water-soluble Ca2+ antagonist, increases ipsilateral optic nerve head circulation in rabbits and cynomolgus monkeys

PURPOSE: To evaluate the effects of topically administered iganidipine hydrochloride, a novel water-soluble Ca2+- channel blocker, on optic nerve head (ONH) circulation in Dutch rabbits and cynomolgus monkeys. METHODS: ONH tissue blood velocity (NBONH) was determined using the laser speckle method. In rabbits, NBONH was measured for 90 minutes before and after a single iganidipine administration, or before and after twice-daily ad- ministrations for 21 days (0.03%). In monkeys, NBONH was measured before and after twice-daily administrations of iganidipine for 7 days (0.03 or 0.1%). RESULTS: Iganidipine (0.03% solution) significantly increased NBONH by 8 to 10% in treated eyes after a single administration (p < 0.05) or by 18 to 35% after 7-, 14-, or 21-day twice-daily administration in rabbits (p < 0.05). In monkeys, 0.03% and 0.1% iganidipine significantly increased NBONH in treated eyes by 20 and 41% after 7-day (p < 0.05) twice-daily administration, respectively. CONCLUSION: Topical iganidipine significantly increased ONH blood velocity in treated eyes.     

Flavonoids from the seeds of Sphaerophysa salsula

Two new flavonoids, named sphaerophyside SA and sphaerophyside SB, together with 15 known flavonoids were isolated from the ethanolic extract of the seeds of Sphaerophysa salsula (Pall.) DC. The structures of the new compounds were elucidated mainly on the basis of the 1D and 2D NMR data.     

Comparison of in vivo anti-melanoma effect of enantiomeric alpha-methyl- and alpha-ethyl-4-S-cysteaminylphenol

Melanogenesis appears to be a unique target to develop anti-tumour agents specific for malignant melanoma. Among the anti-melanoma compounds that we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve the efficacy as anti-melanoma agents, we have recently synthesized enantiomers of alpha-Me-4-S-CAP and alpha-Et-4-S-CAP. The enantiomers were found to be good substrates for tyrosinase. In vitro experiments showed that the enantiomers were highly cytotoxic to B16-F1 melanoma cells, and the cytotoxic effect was proved to be tyrosinase-dependent. In the present study, in vivo cytotoxicity experiments showed that i.p. administration of R-alpha-Me-4-S-CAP and S-alpha-Et-4-S-CAP (and 4-S-CAP) strongly inhibited the subcutaneous growth of B16 melanoma in mice, while the corresponding enantiomers were much less effective. Similarly, i.p. treatment with R-alpha-Me-4-S-CAP or S-alpha-Et-4-S-CAP, but not with 4-S-CAP, caused strong depigmentation of follicular melanocytes in C57BL black mice. Among 4-S-CAP and the enantiomers, only R-alpha-Et-4-S-CAP caused a moderate decrease in blood pressure in spontaneously hypertensive rats. These results confirm that the use of enantiomers increases the efficacy of tyrosinase-dependent cytotoxic phenolic amines.     

Percutaneous ethanol and lipiodol injection therapy for hepatocellular carcinoma

Radiofrequency ablation (RFA) therapy is of great significance in the treatment of hepatocellular carcinoma (HCC) or metastatic liver tumors. RFA is able to achieve widely coagulated necrosis in a few sessions without major complications. However, HCC cases exist that are resistant to RFA therapy for several reasons. In the present study, we performed injection of the mixture of ethanol and lipiodol (percutaneous ethanol-lipiodol injection therapy: PELIT) for HCCs that lacked clear visuality of the entire shape of the tumor by ultrasonography (US) or computed tomography (CT), or that were difficult to treat with RFA alone due to their locations in the liver or due to severe liver dysfunction of the patients. Local recurrence rates of HCC treated with PELIT were shown to be low in patients followed up for at least 4 months. In all patients treated with PELIT, lipiodol was accumulated in the entire region of the tumor after several trials of PELIT and the accumulation was kept for many months. The biopsy examination from the tumor treated with PELIT showed that HCC cells were totally destroyed by the PELIT. Although RFA therapy serves as a central role for the treatment of HCCs, PELIT, considered to be milder therapy, is likely to be important as a supportive treatment for HCCs and useful for the treatment of HCCs that are difficult to treat with RFA.