Valacyclovir (VACV) is used increasingly to treat herpes zoster, although neuropsychiatric symptoms [VACV neurotoxicity (VAN) or acyclovir neurotoxicity], may accompany use of this drug. To promote awareness of this rare condition, we describe here two clinical cases of VAN we previously reported and review 20 cases from the literature. In all cases, chronic or acute renal failure preceded VAN. The symptoms of VAN varied, but disturbances of consciousness and hallucination occurred most commonly. When acute renal failure was due to the drug, recovery from both the disturbance of consciousness and renal failure followed within several days after discontinuation of VACV. Early recognition and diagnosis will ensure effective treatment of VAN.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno­[3,4-c]­pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.

Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2-deoxyguanosines (8-halo-dGs) during inflammatory events. 8-Bromo-2-dG (8-BrdG) and 8-chloro-2-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl ؊ and Br ؊ . The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halodGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3-bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n ‫؍‬ 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.Oxidative damage is implicated in the pathogenesis of many diseases including atherosclerosis and cancer (1-4). Involvement of myeloperoxidase (MPO), 2 a heme protein secreted by activated leukocytes such as neutrophils and monocytic cells, is a potential cause of oxidative damage during inflammation. At sites of inflammation, activated leukocytes play a major role in host defense against microorganisms using oxidants such as HOCl and HOBr. However, excessive oxidant release can also induce damage; DNA bases (5-8) and proteins and lipids (9 -12), for instance, are putative targets of oxidants. At plasma halide concentrations (100 mM Cl Ϫ , 20 -100 M Br Ϫ ) (13), MPO converts HOCl to HOBr using Br Ϫ as a halide exchange (14). HOBr is also generated by eosinophil peroxidase using H 2 O 2 and Br Ϫ , such as by the MPO-H 2 O 2 -Cl Ϫ system. Because MPO catalyzes halogenation, oxidation, and nitration (15-17), MPO and its product may be important general markers for evaluating oxidative damage to the body during inflammation. Halogenation is a key reaction for the formation of an MPO activity marker because the presence of halogen in the marker molecule directly indicates a contribution of the halogenating species at the site of oxidative damage. Moreover, no other halogenating pathways have been reported except for MPO and eosinophil peroxidase-derived damage. Therefore, halogenated products have the potential to be specific markers of inflammatio...

Neuronavigation has become an effective therapeutic modality and is used routinely for intra-axial tumor removal. This retrospective study was conducted to evaluate the clinical impact of neuronavigation and image-guided extensive resection for adult patients with supratentorial malignant astrocytomas. Between 1990 and 2002, 76 adult patients with pathologically confirmed malignant astrocytomas underwent craniotomy and removal of the tumors at the Toyama Medical and Pharmaceutical University Hospital. Of these 76 patients, 42 were treated using neuronavigation with conventional microneurosurgery and the other 34 were treated with conventional microneurosurgery alone. Postoperative early MRI with contrast enhancement was done, and gross total resection was defined as the complete absence of residual tumor. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the Cox proportional hazards model. In univariate analysis, age (< 65), grade 3, preoperative KPS (>/= 80), use of neuronavigation, and gross total resection were significantly associated with longer survival. However, when the data were submitted to multivariate analysis, grade 3, preoperative KPS (>/= 80), and gross total resection were independent prognostic factors. The median survival periods of patients receiving gross total resection (vs. partial resection) and neuronavigation (vs. no neuronavigation) were 16 (vs. 9) months and 16 (vs. 10) months, respectively. The percentage of a gross total resection was significantly higher in the neuronavigation group compared to that in the no-navigation group (64.3 % vs. 38.2 %, p < 0.05). Neurological deterioration occurred in 4 of 42 (9.5 %) and in 6 of 34 (17.6 %) patients after surgery with neuronavigation and surgery without neuronavigation, respectively, although this difference was not statistically significant. Our results showed that neuronavigation increases the radicality in the resection of malignant astrocytomas and is objectively useful for improving survival time.

Background: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson’s disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. Objective: We treated 4 Parkinson’s disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. Methods: The 2 female and 2 male patients in this study were 60–69 years old, with a disease duration from onset to surgery of 7–13 years and a follow-up period of 18–40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. Results: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. Conclusions: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

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Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.

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