Neuropathic Pain Features in Patients with Bone Metastases.

AIMS: The results of previous randomised controlled trials suggest that radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases. Although validated screening tools for neuropathic pain features are currently available, the prevalence of such features among patients with painful bone metastases is still poorly understood. The purpose of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases. MATERIALS AND METHODS: We conducted a cohort survey of consecutive patients who received palliative radiotherapy for painful bone metastases at St Luke's International Hospital between 2013 and 2014. Patients were prospectively assessed before radiotherapy using the validated screening questionnaire to identify neuropathic pain components in Japanese patients. Pain with neuropathic features was prospectively defined using the total score of the seven-item questionnaire and a cut-off score ≥9. The pain response was assessed 2 months after the start of radiotherapy according to the criteria defined by the International Bone Metastases Consensus Working Party. RESULTS: Eighty-seven patients were assessed. Twenty-four per cent of patients (95% confidence interval: 16-35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, no significant correlations were seen between neuropathic pain features and patient characteristics. Sixty-four patients (74%) were assessable 2 months after the start of radiotherapy. Overall response rates were 59% (95% confidence interval: 33-82%) in patients with neuropathic features and 55% (95% confidence interval: 40-70%) in those without such features. CONCLUSIONS: A considerable proportion of the patients were proven to have bone pain with neuropathic features. Further investigations are warranted to validate symptom assessment tools in cooperation with pain distribution and image findings, and to clarify if the presence of neuropathic pain affects the response to palliative radiotherapy.

Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms, promoting Rad51 focus formation and suppressing the toxic effect of nonhomologous end joining.

The E2 ubiquitin conjugating enzyme Ubc13 and the E3 ubiquitin ligases Rad18 and Rnf8 promote homologous recombination (HR)-mediated double-strand break (DSB) repair by enhancing polymerization of the Rad51 recombinase at γ-ray-induced DSB sites. To analyze functional interactions between the three enzymes, we created RAD18(-/-), RNF8(-/-), RAD18(-/-)/RNF8(-/-) and UBC13(-/-)clones in chicken DT40 cells. To assess the capability of HR, we measured the cellular sensitivity to camptothecin (topoisomerase I poison) and olaparib (poly(ADP ribose)polymerase inhibitor) because these chemotherapeutic agents induce DSBs during DNA replication, which are repaired exclusively by HR. RAD18(-/-), RNF8(-/-) and RAD18(-/-)/RNF8(-/-) clones showed very similar levels of hypersensitivity, indicating that Rad18 and Rnf8 operate in the same pathway in the promotion of HR. Although these three mutants show less prominent defects in the formation of Rad51 foci than UBC13(-/-)cells, they are more sensitive to camptothecin and olaparib than UBC13(-/-)cells. Thus, Rad18 and Rnf8 promote HR-dependent repair in a manner distinct from Ubc13. Remarkably, deletion of Ku70, a protein essential for nonhomologous end joining (NHEJ) significantly restored tolerance of RAD18(-/-) and RNF8(-/-) cells to camptothecin and olaparib without affecting Rad51 focus formation. Thus, in cellular tolerance to the chemotherapeutic agents, the two enzymes collaboratively promote DSB repair by HR by suppressing the toxic effect of NHEJ on HR rather than enhancing Rad51 focus formation. In contrast, following exposure to γ-rays, RAD18(-/-), RNF8(-/-), RAD18(-/-)/RNF8(-/-) and UBC13(-/-)cells showed close correlation between cellular survival and Rad51 focus formation at DSB sites. In summary, the current study reveals that Rad18 and Rnf8 facilitate HR by two distinct mechanisms: suppression of the toxic effect of NHEJ on HR during DNA replication and the promotion of Rad51 focus formation at radiotherapy-induced DSB sites.

Freeze-thawing behaviour of highly concentrated aqueous alkali chloride-glucose systems.

The freeze-thawing behaviour of highly concentrated aqueous alkali chloride-glucose systems was investigated by differential scanning calorimetry (DSC). In the aqueous NaCl-glucose solution system, single or double glass transitions followed by the corresponding devitrification exotherms were observed during rewarming. In the aqueous KCl-glucose solution system, on the other hand, a single glass transition followed by an exotherm was observed during rewarming. The presence of double glass transitions observed for a certain composition of the aqueous NaCl-glucose solution was taken as an evidence for the liquid-liquid immiscibility at low temperatures. Two kinds of crystallisation accompanied by exotherms during rewarming were identified by X-ray diffraction as ice and ice/NaCl x 2H(2)O, or ice/KCl eutectic component.

[Outcomes of stroke survivors in Yamagata Prefecture].

PURPOSE: To clarify the long-term outcomes of Stroke survivors registered for the first onset of Stroke in Yamagata Prefecture and to find out problems in community-based-rehabilitation (CBR). SUBJECTS AND METHODS: The present study was performed using stroke survivors as of September 1, 1991 as subjects from residents registered for the onset of Stroke in 1985 and 1989. The subjects were composed of 1,013 residents registered in 1989 (2 years after onset) and 626 registered in 1985 (6 years after onset). RESULTS: The percent of functionally-independent Stroke survivors at 2 and 6 years (indicated in parentheses) after onset is shown by ADL items as follows: 82% (81%) for urination, 78% (78%) for eating, 78% (78%) for walking, 76% (78%) for dressing, and 66% (64%) for bathing. The lowest percent was seen in Bathing. Percentage of cases maintaining the ability to have functionally-independent ADL for all items examined (expressed as persons independent for personal care) were 62% (60%). Of the the cases 91% (91%) resided at home (their own houses or relatives' houses). With regard to overall locomotion, an item used to evaluation the range of going out doors, 45% (44%) could go out alone to visit neighbors or use public transportation. Among persons independent for personal care, 99% (98%) were living at homo, 70% (69%) used public transportation, 23% (23%) went out alone to visit neighbors and 7% (8%) did not go out. CONCLUSION: The results of the present research indicate a great in CBR for that bothpsychological and social health approaches in cooperation with public health centers, medical centers, and welfare agencies not only for persons with decreased ADL, but also for those maintaining high activity potential.

Effects of tri-, di- and monobutyltin on synaptic parameters of the cholinergic system in the cerebral cortex of mice.

Triorganotin compounds like tributyltin have been reported to be biodegraded to diorganotin, monoorganotin and then inorganic tin in animals after they have been ingested. Effects of tributyltin, dibutyltin and monobutyltin on various cholinergic parameters that are involved in synaptic transmission in the mouse cerebral cortex were investigated in vitro. Tributyltin and dibutyltin, but not monobutyltin, inhibited the activity of choline acetyltransferase, both the high-affinity and low-affinity uptakes of choline into synaptosomes, and the binding of [3H]quinuclidinyl benzilate to muscarinic acetylcholine receptors. Tributyltin and dibutyltin, but not monobutyltin, had a slightly suppressive effect on the K(+)-induced release and synthesis of acetylcholine in slices of the cortex. All three butyltins at concentrations from 10(-6) to 10(-4) M had no effect on the activity of acetylcholinesterase. The extent of the inhibitory effects on the cholinergic parameters, apart from the activity of acetylcholinesterase, was slightly greater in the case of tributyltin than dibutyltin, in particularly at the highest concentration (10(-4) M) tested. Therefore, it is concluded that tributyltin metabolites inhibit various parameters of cholinergic activity with a potency ranking of tributyltin > dibutyltin > monobutyltin.

Woodfruticosin (woodfordin C), a new inhibitor of DNA topoisomerase II. Experimental antitumor activity.

Woodfruticosin (woodfordin C) (WFC), a new inhibitor of DNA topoisomerase II (topo-II), was isolated from methanol extract of Woodfordia fruticosa Kurz (Lythraceae) and studied for in vitro and in vivo antitumor activities in comparison with Adriamycin (ADR) and etoposide (ETP), well known inhibitors of topo-II. The inhibitory activity against DNA topo-II shown by WFC was much stronger than that shown by ETP or ADR. WFC inhibited strongly intracellular DNA synthesis but not RNA and protein synthesis. On the other hand, WFC had a weaker growth inhibitory activity against various human tumor cells than ETP or ADR, but it showed remarkable activity against PC-1 cells and moderate activity against MKN45 and KB cells. Furthermore, WFC had in vivo growth inhibitory activity against s.c. inoculated colon38. These results indicate that the mechanism by which WFC exhibits antitumor activity may be through inhibition of topo-II.

[Contributing factors to intellectual impairment in patients with multiple lacunar infarctions].

The author investigated factors leading to intellectual impairment in patients with multiple lacunar infarctions. The subjects consisted of 40 patients with multi-infarct dementia (MID) and 17 nondemented patients with multiple infarctions (MI) who showed multiple lacunar infarctions in the deep penetrating arterial territory on CT. MID patients showed more marked and extensive periventricular lucency (PVL), a higher degree of ventricular index (VI) measured on CT, and were of a higher age, and had poorer activity of daily living (ADL) compared with MI patients. There were significant correlations between the PVL score, VI, ADL score, age and Hasegawa's dementia rating score (HDS). However, no significant differences in sex, site of infarct, and the count of low density areas reflected lacunar infarction on CT, and vascular risk factors were shown between MID and MI patients. Multiple regression analysis demonstrated that the PVL score and VI showed the highest partial correlations for HDS, and that the ADL score and age were also independently contributing factors. Our results suggest that deep white matter lesions observed as PVL on CT and ventricular enlargement were the most important factors contributing to intellectual impairment in patients with multiple lacunar infarcts, and that physical factors such as ADL and age can be considered to be related to the development of dementia.

Cell killing mode of liblomycin (NK313), a novel dose-survival relationship different from bleomycins.

Liblomycin (NK313) is a novel derivative of bleomycin (BLM) and peplomycin (PEP). The cell kill kinetics of NK313 on rat ascites hepatoma AH66 were compared with those of PEP. NK313 induced intracellular DNA cleavage and arrested cell cycle progression at the G2 phase similarly to PEP. The cytocidal effect of NK313, however, was found to be different from that of PEP as described below: 1) The dose-survival curve for cells exposed to PEP for 1 hour was upward concave, whereas in case of NK313, the survival curve was linear. PEP was more effective to AH66 than NK313 at lower concentration, but at higher concentration, NK313 was much more effective. 2) The time-survival curve for cells treated with either NK313 or PEP was biphasic. NK313, however, did not induce temporary resistance of AH66 cells to NK313, while PEP induced resistance to PEP. 3) NK313 was effective against the cells which became temporarily resistant to PEP by the treatment of PEP. These differences suggest that NK313 might be of value to treat PEP-insensitive tumor cells.

Factor analysis of in vitro antitumor activities of platinum complexes.

Factor analysis was applied to the data matrix of in vitro growth inhibitory activities of 52 platinum complexes against 9 tumor cell lines, L1210, P388, Lewis lung, AH66, AH66F, HeLa S3, KB, HT-1197 and HT-1376 cell lines. Three factors were obtained by the principal factor analysis method. After the varimax rotation of these three factors, tumor cell lines were classified into four groups according to their factor loadings. The platinum complexes were characterized by the factor scores. Cisplatin was situated in an extreme position as compared with the other platinum complexes. In vivo antitumor activities of the platinum complexes were tested against L1210 and LL murine tumor models. The in vivo activity against L1210 showed a negative correlation with that against LL. Factor 2 scores of the complexes obtained by factor analysis of in vitro antitumor activities showed a good correlation with these in vivo antitumor activities. Then, the structure-factor 2 score relationships among platinum complexes were analyzed by the Free-Wilson method. From this analysis, structure-activity relationships for carrier ligands and leaving groups are proposed. Factor analysis is suggested to be a useful method to establish an efficient screening system for platinum complexes.

DNA cleavage activity of liblomycin (NK313), a novel analog of bleomycin.

Liblomycin (NK313), a novel analog of bleomycin and peplomycin (PEP), produced acid soluble DNA, base propenals and nucleo bases from isolated DNA. This was similar to the action of PEP. However, the DNA cleavage activity of NK313 was 1/2-1/10 of that of PEP in the absence of reducing agents. In the presence of reducing agents such as 2-mercaptoethanol and ascorbic acid, the activity of NK313 was stimulated more strongly than PEP. NK313 was also different from PEP in the formation and decomposition of active intermediates. This result suggested that differences in DNA cleavage activity between NK313 and PEP may be due to the different properties of their active intermediates. NK313 released preferentially pyrimidine bases from DNA, and the molar ratio of the released pyrimidine bases to the total of the released bases was little affected by the concentration of NK313 relative to DNA. In contrast, the ratio of the released purine bases by PEP increased with the concentration of PEP relative to DNA. NK313 induced double strand cleavage on pBR322 DNA as efficiently as did PEP. The major cleavage sites of NK313 on pBR322 DNA were similar to those of PEP. However, certain minor cleavage sites of NK313 were specific for NK313. Increase of PEP concentration led to increased degradation of DNA fragments; this was not the case with NK313. These results indicate that the cleavage sites of NK313 were similar to, but more limited than those for PEP.

Action of ubenimex on aminopeptidase activities in spleen cells and peritoneal macrophages from mice.

The action of ubenimex on aminopeptidase (APase) activity was studied in intact spleen cells and peritoneal macrophages from mice. Ubenimex strongly inhibited hydrolyzing activities against arginine-beta-naphtylamide (Arg-NA), Lys-NA and Pro-NA in both cells. Inhibition of hydrolysis of Leu-NA, Met-NA and Ala-NA was relatively small or not observed. When both cells were incubated in HANKS' solution, hydrolyzing activities against Arg-NA, Lys-NA and Pro-NA were released to the medium, while Leu-NA and Met-NA-hydrolyzing activities were mostly bound. In addition, the Leu-NA-hydrolyzing activity in the spleen cells was kinetically studied. The Arg-NA and Leu-NA-hydrolyzing activities in four fractions prepared from the homogenate of spleen cells were also studied kinetically. From these studies it was suggested that ubenimex inhibits aminopeptidase B and a Pro-NA-hydrolyzing enzyme more effectively than Leu-APase in intact spleen cells and peritoneal macrophages from mice.

Plasmid R46 provides a function that promotes recA-independent deletion, fusion and resolution of replicon.

We report that plasmid R46 provides a function which promotes recA-independent deletion, replicon fusion, and resolution of the fusion. R46 belongs to the incompatibility group N and specifies resistance to ampicillin, tetracycline, streptomycin and sulfonamide. Four kinds of deletion derivatives were observed by selection for susceptability to tetracycline from ampicillin-resistant clones. A common region, will be called alpha region thereafter, was postulated to be involved in these deletions. The replicon fusion occurred by a conjugative mobilization of each derivative with plasmid R388. The fusion was suggested to contain both replicons linked at each junction by the sequence in the alpha region in direct orientation. The resolution of the replicon fusion was found between two alpha regions and a consequently generated, parental deletion derivative and an R388 derivative which gained one alpha region. It is possible that the alpha region contains one potential Insertion Sequence (IS) element. These events were also speculated to occur as a consequence of insertion of the potential IS onto the intramolecular or intermolecular target sequence, or reciprocal recombination between two potential IS elements.