Catechol and hydroquinone have different redox properties responsible for their differential DNA-damaging ability.

We examined the redox properties of the "carcinogenic" catechol and the "noncarcinogenic" hydroquinone in relation to different DNA damaging activities and carcinogenicity using 32P-labeled DNA fragments obtained from the human genes. In the presence of endogenous NADH and Cu2+, catechol induces stronger DNA damage than hydroquinone, although the magnitudes of their DNA damaging activities were reversed in the absence of NADH. In both cases, DNA damage resulted from base modification at guanine and thymine residues in addition to strand breakage induced by Cu+ and H2O2, generated during the oxidation of catechol and hydroquinone into 1,2-benzoquinone and 1,4-benzoquinone, respectively. EPR and 1H NMR studies indicated that 1,2-benzoquinone is converted directly into catechol through a nonenzymatic two-electron reduction by NADH whereas 1,4-benzoquinone is reduced into hydroquinone through a semiquinone radical intermediate through two cycles of one-electron reduction. The reduction of 1,2-benzoquinone by NADH proceeds more rapidly than that of 1,4-benzoquinone. This study demonstrates that the rapid 1,2-benzoquinone two-electron reduction accelerates the redox reaction turnover between catechol and 1,2-benzoquinone, resulting in the enhancement of DNA damage. These results suggest that the differences in NADH-mediated redox properties of catechol and hydroquinone contribute to their different carcinogenicities.     

Crystal structure of oxygen-evolving photosystem II from Thermosynechococcus vulcanus at 3.7-A resolution

Photosystem II (PSII) is a multisubunit membrane protein complex performing light-induced electron transfer and water-splitting reactions, leading to the formation of molecular oxygen. The first crystal structure of PSII from a thermophilic cyanobacterium Thermosynechococcus elongatus was reported recently [Zouni, A., Witt, H. T., Kern, J., Fromme, P., Krauss, N., Saenger, W. & Orth, P. (2001) Nature 409, 739-743)] at 3.8-A resolution. To analyze the PSII structure in more detail, we have obtained the crystal structure of PSII from another thermophilic cyanobacterium, Thermosynechococcus vulcanus, at 3.7-A resolution. The present structure was built on the basis of the sequences of PSII large subunits D1, D2, CP47, and CP43; extrinsic 33- and 12-kDa proteins and cytochrome c550; and several low molecular mass subunits, among which the structure of the 12-kDa protein was not reported previously. This yielded much information concerning the molecular interactions within this large protein complex. We also show the arrangement of chlorophylls and cofactors, including two beta-carotenes recently identified in a region close to the reaction center, which provided important clues to the secondary electron transfer pathways around the reaction center. Furthermore, possible ligands for the Mn-cluster were determined. In particular, the C terminus of D1 polypeptide was shown to be connected to the Mn cluster directly. The structural information obtained here provides important insights into the mechanism of PSII reactions.     

Microcystic adnexal carcinoma with lymph node metastasis

Microcystic adnexal carcinoma (MAC) affects predominantly the face and seldom metastasizes. We report a case occurring in the axilla of a 63-year-old male. Histology revealed the characteristic features of MAC. Eleven months after the excision, he underwent a reexcision with wide margins because of local recurrence. Histologically, the central area of the recurrent lesion revealed the typical histologic features of MAC, and the periphery showed a proliferation of irregular duct-like and glandular structures with a mixed pattern. Two lymph nodes that were not adherent to the tumor had metastatic tumor cells. The present case confirms that MAC can metastasize, although it may also be hypothesized that the recurrent lesion represented transformation into a higher-grade carcinoma.     

Perineural invasion has a negative impact on survival of patients with gallbladder carcinoma

BACKGROUND: The clinical significance of perineural invasion of gallbladder carcinoma remains unclear. The aim of this study was to elucidate the incidence and mode of perineural invasion of gallbladder carcinoma and clarify its prognostic significance. METHODS: A clinicopathological study was conducted on 68 patients who underwent attempted curative resection for gallbladder carcinoma. According to the pathological tumour node metastasis (pTNM) classification of the Union Internacional Contra la Cancrum, there were five (7 per cent), nine (13 per cent), 20 (29 per cent) and 34 (50 per cent) patients with pT1, pT2, pT3 and pT4 disease respectively. Twenty patients (29 per cent) had pM1 disease, including involved para-aortic nodes, liver metastases and localized dissemination. RESULTS: The overall incidence of perineural invasion was 71 per cent (48 of 68 patients). Forty-four (96 per cent) of 46 patients with extrahepatic bile duct invasion had perineural invasion. Although several histological factors were associated with perineural invasion, multivariate analysis demonstrated that extrahepatic bile duct invasion was the only significant factor correlated with perineural invasion (odds ratio 99.0, P < 0.001). The perineural invasion index, defined as the ratio of the number of involved nerves to the total number of nerves examined, was significantly higher at the centre than in the proximal and distal parts of the tumour in the 46 patients with extrahepatic bile duct invasion (P < 0.001). The 5-year survival rate for patients with perineural invasion was significantly lower than that for patients with no invasion (7 versus 72 per cent; P < 0.001). Cox proportional hazard analysis identified perineural invasion (relative risk (RR) 5.3, P < 0.001) and lymph node metastasis (RR 2.5, P = 0.008) as significant independent prognostic factors. CONCLUSION: Perineural invasion is common in advanced gallbladder carcinoma and has a significant negative impact on patient survival.     

Three-dimensional analysis of nystagmus in benign paroxysmal positional vertigo. New insights into its pathophysiology

Nystagmus is a rhythmical rotation of the eyeball. Its characteristics can be defined mathematically by the axis of rotation and the angular velocity around this axis. We analysed the axis of rotation for the nystagmus in benign paroxysmal positional vertigo (BPPV) to elucidate its pathophysiology. Thirteen patients with typical unilateral BPPV participated in the present study. The axis of rotation for the nystagmus was calculated from images recorded on digital videotape with an infrared CCD camera, using an algorithm that we developed. The patients' responsiveness to Semont's liberatory maneuver was also assessed. The results showed that patients could be assigned to one of two groups based on the rotation axis of the nystagmus. In one group of patients (n = 7; Group A), the axis of rotation was almost vertical to the plane containing the posterior semicircular canal (PSC) on the presumed affected side. In the other group of patients (n = 6; Group B), it was clustered around the naso-occipital axis. These results suggest that in the patients in Group A the responsible lesion is confined to the PSC, whereas the pathogenesis underlying the conditions in those in Group B is considered to be more complicated. This speculation was reinforced by the difference in responsiveness to Semont's liveratory maneuver. All of the patients in Group A showed remission of vertigo within 10 days (mean, 2.4 days) after onset of treatment using Semont's liberatory maneuver, whereas the patients in Group B required much longer periods of time for remission to occur (mean, 25.7 days). Our findings lead to the conclusion that by considering the spatial orientation of individual semicircular canals, in the patients in Group B the pathophysiology is not confined to the PSC, but most probably all three semicircular canals are involved. Received: 16 January 2002, Received in revised form: 22 May 2002, Accepted: 6 June 2002 Correspondence to Yujiro Hayashi, MD     

How can we prevent alveolar echinococcosis? Ecosystem and risk management viewpoints

PURPOSE: This article focuses on understanding epidemiological features of alveolar echinococcosis and discussing its prevention and control, especially from a viewpoint of the ecosystem and risk management. METHOD: Publications on alveolar echinococcosis throughout the world were systematically reviewed with special reference to ecology, epidemiology and countermeasures. RESULTS: Alveolar echinococcosis, caused by accidental infection with larva of the parasite Echinococcus multilocularis is fatal to humans unless diagnosed at an early stage. No effective control measures have been identified so far because it is difficult to fully understand the ecology of the parasite and its intermediate and definitive hosts. It is also not easy to determine the precise infection route to humans mainly because of the long latent period. In Hokkaido, infection rates among red foxes have recently risen even in low endemic districts. Not only stray and domestic dogs but also some pigs in Hokkaido have been found to be infected. While the number of reported human cases is still small, around 10 cases per year, local residents seem to be threatened with the risk of infection. DISCUSSION AND CONCLUSIONS: We predict that the incidence of alveolar echinococcosis among humans in Japan will increase in the near future if no effective preventive measures are conducted. In addition, Echinococcus multilocularis infection has the potential to affect the economy of Hokkaido because of its impact on the agricultural and tourist industries. Well-designed epidemiological surveys are therefore urgently required, in the context of ecosystem and risk management prior to large outbreaks. International collaboration is also desired.     

IFN gamma-induced up-regulation of PD-ECGF/TP enhances the cytotoxicity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in bladder cancer cells

BACKGROUND: PD-ECGF/TP is an essential enzyme in converting 5'DFUR and 5FU to their active metabolites and can be up-regulated by some cytokines. MATERIALS AND METHODS: PD-ECGF/TP mRNA and protein expressions were determined by RT-PCR and Western blot, respectively. The cytotoxicity of 5FU, 5'DFUR or MMC against RT-4 and T24 cells was evaluated by MTS assay. The PD-ECGF/TP expressions in primary bladder cancers were also analyzed. RESULTS: Levels of PD-ECGF/TP mRNA and protein were concomitantly elevated in RT-4 and T24 cells after IFN gamma treatment. IFN gamma decreased the IC50 of 5FU and 5'DFUR in both cell lines, while it did not alter the IC50 of MMC, which is not a substrate of PD-ECGF/TP. PD-ECGF/TP expression correlated with tumor stage and grade in primary bladder cancers. CONCLUSION: IFN gamma enhances the cytotoxicity of 5FU and 5'DFUR against human bladder cancer cells through induction of PD-ECGF/TP. The results imply that an IFN gamma/5FU or IFN gamma/5'DFUR combination therapy may be applicable to clinical bladder cancers.