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The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer. From 1988 to 1991. we studied the effects of postoperative adjuvant therapy for Japanese women with stage 11 breast cancer, all seen at 71 institutions in western areas of Japan. Five hundred and ninety four patients with stage II primary breast cancer who had undergone curative surgery, including total mastectomy and axillary lymph node dissection, were enrolled. On the day of surgery, each patient was given 13 mg/m2 of MMC intravenously. Patients with ER+ tumors were then assigned to group A or group B. Group A received 30 mg/day of TAM given orally from postoperative 2 weeks, for 2 years. Group B was additionally given an oral dose of 300 mg/day of UFT for 2 years, given concomitantly with 30 mg/day of TAM. Patients with ER- tumors were assigned to group C or group D. Group C were prescribed 300 mg/day of UFT, orally, from postoperative 2 weeks for 2 years, and group D were additionally given an oral dose of 30 mg/day of TAM together with 300 mg/day of UFT. There were no differences among the groups regarding prognostic factors or doses of MMC and TAM in ER+ patients and MMC and UFT in ER- patients. Toxicity rates for leukopenia, anorexia, and nausea/vomiting were higher in group B than in group A patients. There were no statistical differences in the overall survival and disease-free survival times between groups A and B, or groups C and D, for all eligible cases. In a retrospective subgroup analysis using Bonferroni's adjustments, the additional effect of UFT on the combined treatment of MMC and TAM lengthened the disease-free survival time for patients with premenopausal ER+ cancers (corrected P value by Bonferroni's adjustments0.05). Multivariate analysis showed that effects of the combined treatment of MMC, TAM, and UFT was significantly related to the menopausal status (P0.01). Our findings show that postoperative ingestion of MMC, TAM, and UFT was effective for patients with premenopausal ER+ stage II breast cancer.

A simple technique for ligation and division of the dorsal vein complex during radical retropubic prostatectomy is described. The dorsal vein complex and anterior wall of the membranous urethra were collectively ligated with a "theta theta" suture using 1-0 catgut and then divided during radical retropubic prostatectomy. This technique prevents dislodgment of the catgut during the procedure, enables maximal preservation of the striated urethral sphincter, and guarantees a lower risk of postoperative urinary incontinence.

This study assesses feasibility and diagnostic accuracy of simultaneous stress 99mTc-sestamibi/rest 201 TI dual-isotope myocardial perfusion SPECT with Moore's correction method, in which contamination originating from lead x-rays produced in a collimator was subtracted in the 201TI windows.Eighty-one patients with suspected coronary artery disease received exercise 99mTc-sestamibi injection, followed by rest 201TI injection 50 min later, and dual-isotope SPECT was performed (group 1). These results were compared with coronary angiographic findings. Furthermore, to estimate the accuracy of Moore's correction method, 201TI crosstalk into the 99mTc acquisition window (group 2A, n = 20) and 99mTc crosstalk into the 201TI acquisition windows (group 2B, n = 20) were studied. For group 2A, stress 99mTc-sestamibi SPECT (single 99mTc-sestamibi SPECT) was performed, followed by 201TI injection at rest and dual-isotope SPECT acquisition 50 min later. For group 2B, rest 201TI SPECT (single 201TI SPECT) was performed, followed by 99mTc-sestamibi injection at rest and dual-isotope SPECT acquisition 30 min later.Sensitivity and specificity in group 1 were 83% and 99%, respectively, whenor =75% coronary artery narrowing was considered significant. In groups 2A and 2B, SPECT images were divided into 24 segments, and relative regional uptake in each segment was obtained. In group 2A, relative regional uptake of single 99mTc-sestamibi SPECT correlated well with that of dual-isotope SPECT (r = 0.942). In group 2B, relative regional uptake of single 201TI SPECT correlated well with that of dual-isotope SPECT (r = 0.935). Furthermore, in low 201TI uptake segments with relative regional uptake in both single- and dual-isotope SPECT ofor =70%, the degree of concordance between single- and dual-rest 201TI was considered to be high with Bland-Altman analysis and the kappa statistic. Comparison of perfusion defect type demonstrated that, of 22 stress defects within infarct zones, 95% were irreversible and 5% were reversible. In contrast, of 28 stress defects within stenosed vessel zones in noninfarct zones, 89% were reversible and 11% were irreversible (P0.0001 versus infarct zones).Simultaneous dual-isotope imaging with Moore's correction method is feasible, with acceptable accuracy for detection of coronary artery disease and a small amount of crosstalk into each window.

Although numerous reports have been published on the incidence of second cancers after adjuvant therapy for early breast cancer, there have been few studies on the effect of the development of second cancer on overall survival (OS) of the patients. 1857 female patients younger than 80 years of age with operable breast cancer with UICC Stages I, II, and III who entered 3 trials of adjuvant therapy were studied for the detection of recurrence and second cancer. The median follow-up period for surviving patients was 12 years (range, 5-25 years). 384 of recurrence and 119 of second cancers occurred. 465 deaths were recorded, the causes of which were designated to be due to recurrence of breast cancer in 326 patients, second cancers in 57, and due to other causes in 82. Many background factors that were significantly related to recurrence did not influence the incidence of and death by second cancers after mastectomy: age and menopausal status alone were related. The difference in the Kaplan-Meier curves between the event (recurrence and second cancers)-free and relapse-free survivals indicates the incidence of second cancers is a significant event in post-operation course of early breast cancer patients (P=0.0001). The survival curve of patients who were free from recurrence- and second cancer-death is shown to be significantly lower than that of those free from breast cancer-specific death (P=0.0355), suggesting that death by second cancers is significantly influential to the overall survival. According to the Cox regression model using a recurrence or second cancers as time-dependent variables, the diagnosis of a recurrence or second cancer is shown to be highly significant to OS of the patients (hazard ratio: 49.3, and 6.3, respectively). Second cancers are shown to be not statistically significantly influential to the breast cancer specific survival (P=0.0637), nor a recurrence to second cancer specific survival (P=0.2285). In spite of heterogeneous distribution of sites of second primary cancers and their different natural histories, the incidence of second cancer has a significant effect on the postoperative survival of early breast cancer patients. In the survival analysis of early breast cancer patients, we have to estimate the contribution of second cancers to properly evaluate the effect of treatment.

We previously reported that several stresses can induce cytokine-induced neutrophil chemoattractant expression in a nuclear factor kappaB (NF-kappaB)-dependent manner. In this study, we focused further on the regulation of NF-kappaB. The activation of NF-kappaB and the subsequent cytokine-induced neutrophil chemoattractant induction in response to interleukin-1beta (IL-1beta) were inhibited by proteasome inhibitors, MG132 and proteasome inhibitor I. Translocation of NF-kappaB into nuclei occurs by the phosphorylation, multi-ubiquitination, and degradation of IkappaBalpha, a regulatory protein of NF-kappaB. Nascent IkappaBalpha began to degrade 5 min after treatment with IL-1beta and disappeared completely after 15 min. However, IkappaBalpha returned to basal levels after 45-60 min. Interestingly, resynthesized IkappaBalpha was already phosphorylated at Ser-32. These results suggest that 1) the upstream signals are still activated, although the translocation of NF-kappaB peaks at 15 min; and 2) the regulated protein(s) acts downstream of IkappaBalpha phosphorylation. Western blotting showed that the resynthesized and phosphorylated IkappaB molecules were also upward-shifted by multi-ubiquitination in response to IL-1beta treatment. On the other hand, ATP-dependent Leu-Leu-Val-Tyr cleaving activity transiently increased, peaked at 15 min, and then decreased to basal levels at 60 min. Furthermore, the cytosolic fraction that was stimulated by IL-1beta for 15 min, but not for 0 and 60 min, could degrade phosphorylated and multi-ubiquitinated IkappaBalpha. These results indicate that the transient translocation of NF-kappaB in response to IL-1beta may be partly dependent on transient proteasome activation.

According to estrogen receptor (ER) and menopausal status, operable breast cancer patients were randomized for adjuvant endocrine therapy with tamoxifen (TAM) in premenopausal patients, after oophorectomy (OVEX), chemotherapy, CHEM (mitomycin C+ oral cyclophosphamide), or chemo-endocrine therapy (TAM + CHEM). Some 1579 patients were entered in the trial between 9, 1978 and 12, 1991, with a median follow-up of 10 years. In ER-positive, premenopausal patients there were no significant differences in relapse-free (RFS) or overall survival (OS) among the OVEX + TAM, CHEM, and CHEM + TAM arms. On the contrary, in ER-positive, post-menopausal patients, the chemoendocrine therapy showed a significantly better OS (p = 0.0254) with a trend of better RFS (p = 0.0674), as compared with TAM or CHEM groups. ER-negative, premenopausal patients showed no significant differences in RFS or OS between CHEM and CHEM + TAM arms. In ER-negative, postmenopausal patients, there was a non-significantly better RFS (p = 0.0888) and a significantly better OS (p = 0.0332) in CHEM + TAM group than in the CHEM alone group. These results suggest that ER and menopausal status are important criteria to select early breast cancer patients for adjuvant treatments.

The effects of nitrogen monoxide (NO)-related compounds on cytosolic free Ca2+ concentrations ([Ca2+]i) and noradrenaline (NA) release in neurosecretory PC12 cells were investigated. The addition of S-nitroso-cysteine (SNC) stimulated [Ca2+]i increases from an intracellular Ca2+ pool continuously in a concentration-dependent manner. Other NO donors, which stimulate cyclic GMP accumulation, did not cause [Ca2+]i increases. After treatment with 0.2 mM SNC, transient increases in [Ca2+]i from the Ca2+ pool induced by caffeine were completely abolished. The addition of N-ethylmaleimide (NEM) caused sustained [Ca2+]i increases from the intracellular Ca2+ pool. Furthermore, caffeine did not stimulate further [Ca2+]i increases in PC12 cells pretreated with NEM. These findings suggest that SNC and NEM predominantly interact with a caffeine-sensitive Ca2+ pool. The addition of dithiothreitol (DTT) to 0.4 mM SNC-stimulated cells reduced [Ca2+]i to basal levels, and the addition of DTT to NEM-stimulated cells locked [Ca2+]i at high levels. The stimulatory effects of SNC but not NEM were not abolished by pretreatment with DTT. These findings suggest that modification of the oxidation status of the sulfhydryl groups on the caffeine-sensitive receptors by SNC or NEM regulates Ca2+ channel activity in a reversible manner. SNC did not stimulate NA release by itself but did inhibit ionomycin-stimulated NA release. In contrast, NEM stimulated NA release in the absence of extracellular CaCl2 and further enhanced ionomycin-stimulated NA release. Ca2+ mobilization by SNC from the caffeine-sensitive pool was not a sufficient factor, and other factors stimulating NA release may be negatively regulated by SNC.

Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat as a likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.

A combination of carboplatin (CBDCA) and radiation therapy was performed in patients with head and neck cancer. The intravenous administration of CBDCA at a weekly dose of 100 mg/body was combined with external irradiation at a dose of 1.8 Gy/day x 5/week during the same therapy period. We evaluated the effects of this method not only on survival and neoadjuvant chemotherapy in patients with advanced cancer but also on local control and prevention of distant metastases in patients with early cancer. The subjects consisted of 31 patients with head and neck cancer who visited the Department of Otolaryngology, Showa University Hospital, Kanto Rosai Hospital and Yokohama Rosai Hospital between March 1993 and March 1995. Squamous cell carcinoma was found in all but one patient who had adenocarcinoma in the parotid gland. The patients were 27 males and 4 females ranging between 40 and 81 years of age (mean, 59 years). Twenty-six patients had previously untreated tumor, while 5 patients had recurrent tumor. The clinical stage was Stage I in 6, Stage II in 10, Stage III in 5 and Stage IV in 10 patients. The original site of cancer was the larynx in 9, hypopharynx in 6, nasopharynx in 6 and elsewhere in 10 patients. The combined therapy was repeated for 2-9 courses (mean, about 5 courses). The total dose of CBDCA was 500 mg on average with a maximum of 900 mg. The total effective rate of the combined therapy was 93.3% with 12 cases of complete response (CR) and 16 cases of partial response (PR). The effective rate in patients with previously untreated tumor was 92% because one patient showed a minor response (MR) and one patient showed no change (NC). The effective rate in patients with recurrent tumor was 100%. Concerning the clinical stage, all patients with Stage I-III disease showed CR or PR, while MR was found in 1, NC in 1 and progressive disease (PD) in 1 of 10 patients with Stage IV disease, resulting in an effective rate of 71.4%. There were no CRs in Stage IV patients. Therapy was terminated due to side effects in 2 patients. Excellent safety was confirmed by laboratory data.

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6-49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6-100) days to onset of and median duration of response was 125 (36-305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1-3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1-3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.

Evidence from case-control studies suggests, although not entirely consistently, that soy intake may protect against breast cancer. The designs and findings of studies conducted in Asian women living in Japan, Singapore, China, and the United States are reviewed. Because of the considerably higher intake of soy by native Asians than by Asian Americans living in California and Hawaii, these studies investigated different segments of the dose-response relation between soy intake and breast cancer risk. Data are not sufficient to determine the amount or frequency of soy intake effective in protecting against breast cancer. Of concern is that soy intake may be homogeneously high in Asia, making it difficult to identify differences in breast cancer risk between high and moderate daily consumers. In studies conducted in Asian Americans, it is difficult to be certain that soy intake is not a marker of other factors related to Western lifestyle that are causally associated with risk of breast cancer. Additional studies assessing the role of soy and breast cancer are needed. These studies should assess intake of all food sources of soy, considering portion size as well as other dietary and nondietary factors that may confound the soy-breast cancer association. A better understanding of the mechanisms whereby soy intake may influence the risk of breast cancer is also needed. Dietary intervention studies with soy will provide information on the acute effects of soy on endogenous hormone concentrations. Cross-sectional and longitudinal studies are necessary to investigate the longer-term relations between hormone concentrations and soy intake in women.

A novel whole cell biosensor was constructed for the detection of anionic surfactants in aquatic environments. The analysis was rapid, convenient and did not require organic reagents. In this report, the application of this sensor to river water samples was investigated when applied to environmental samples; other organic substances present in river water may affect the measurement of linear alkylbenzene sulfonates. In order to deal with this problem, a correction system was developed using whole cells of Trichosporon cutaneum. This system was applied to in situ 24 h continuous monitoring in the Saka river.

We performed a retrospective study to determine the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis G virus (HGV) genomes in formalin-fixed, paraffin-embedded liver tissues from hepatocellular carcinoma (HCC) patients in various geographic areas. The prevalence of each hepatitis virus in the liver tissues that have both carcinoma and noncarcinoma regions was different among the countries. HCV was the most prevalent in Japan (75 of 122 [61.5%]), Spain (9 of 15 [60%]), and the United States (27 of 65 [41.5%]); HBV was the most prevalent in Korea (45 of 55 [82%]) and among Japanese Americans in Hawaii (4 of 8 [50%]). Genotype II/1b was the most common genotype of HCV encountered in HCCs in these countries. In contrast, HGV RNA was undetectable in all tested HCCs. "Cryptogenic HCC," defined as HCC of unknown etiology, was seen 4 (3%) and 4 (6.2%) of Japanese and American patients, respectively, but this was not found in other countries. Interestingly, patients with HCC related to primary biliary cirrhosis (4.6%), who were excluded from analysis as hepatitis virus infections, were present only in the United States, but not in other countries. This study suggests that HCV, particularly genotype II/1b, and HBV may play an important role in hepatocarcinogenesis in these countries. There was no evidence of any relation between HGV infection and development of HCC.

DN-108 (5-(4-(1-phenyl-1-cyclopropanecarbonylamino)benzyl)thiazolidine-2, 4-dione, CAS 195604-21-8) is a newly synthesized thiazolidinedione derivative. Pharmacological and pharmacokinetic studies of DN-108 were done. In diabetic animal models KKAy and db/db mice, DN-108, orally given at doses of 3-30 mg/kg for 10 consecutive days, improved hyperglycemia, hypertriglyceridemia or hyperinsulinemia from day 1 or day 4 and the effects were almost maintained through the experiment. In KKAy mice, DN-108, orally given at doses of 3-30 mg/kg for 4 consecutive days, potently decreased serum glucose level as compared with troglitazone (CAS 97322-87-7) and the ED25 values of DN-108 and troglitazone were 7 and 283 mg/kg/day, respectively. DN-108 increased 2-deoxyglucose uptake in L6 muscle cell line to the same extent as troglitazone. Moreover, DN-108 inhibited aldose reductase activity in vitro as potently as troglitazone did. Pharmacokinetic parameters, Cmax and AUC of DN-108 after oral administration in rats were higher than those of troglitazone. These results suggest that DN-108 has antidiabetic effect with tissue sensitization for glucose uptake and high absorption after oral administration. It is expected that DN-108 will be a promising oral antidiabetic agent.

Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective.In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996.Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen.Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer.

The efficacy and safety of TAT-59 (miproxifene phospate) were compared with tamoxifen citrate (TAM) in ER-positive or ER-unknown patients with advanced or recurrent breast cancer, using the double-blind method. TAT-59 and TAM were both given 20 mg/body orally for over 12 weeks in daily doses. Eligible cases were 93 in the TAT-59 group and 102 patients in the TAM group. The response rate was shown to be 30.1% (28/93) in the TAT-59 group and 26.5% (27/102) in the TAM group. Statistical equivalence between both treatments was proven at 90% confidence interval (-8.5%or =,or = 12.8%). Adverse reactions observed in the patients receiving TAT-59 were hot flush, nausea and vomiting, sweating, anorexia, abnormal values in liver function tests, and anemia, showing no differences from the TAM group. Leukopenia (4.9%) and thrombopenia (2.9%) reactions were found only in the TAM group. Two patients in the TAT-59 group and three in the TAM group discontinued treatment due to adverse reactions. However, these adverse reactions were reversible in both groups. In conclusion, TAT-59 was showed comparable efficacy and safety with TAM in ER-positive or ER-unknown patients with advanced or recurrent breast cancer.

We report a 14-year-old girl who developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) during the course of myasthenia gravis. Myasthenia gravis, which was clinically of ocular type, but with waning phenomenon of the extremities, occurred at 2 years and 4 months of age. Muscle weakness of the lower extremities gradually developed over the next 6 years. The electrophysiological and pathological findings fulfilled the criteria of "possible CIDP" with severe axonal involvement. The signs of myasthenia gravis and CIDP fluctuated synchronously. A common immunological abnormality was suggested to underlie this rare association of myasthenia gravis and CIDP in childhood.

Within the recent four years, there have been substantial advances in understanding the molecular pathogenesis of HNPCC. As one of the result of investigation, microsatellite instability has been observed in hereditary non-polyposis colorectal cancer (HNPCC) and other sporadic cancers. Moreover, there is strong supporting evidence that mismatch repair genes play a role in HNPCC. Here, we present our investigational results and discuss possible molecular mechanisms governing DNA mutation and genomic instability, leading to the development of neoplasm. We investigated replication error (RER) of 4 microsatellite markers (dinucleotide repeats) in 131 patients with colorectal cancer (10 met the criteria of HNPCC group B), using fluorescence-based DNA sequencer. We detected RER positivity (at more than two loci) in 12 of 131 patients (9.2%). PCR-SSCP and direct sequencing of the mismatch repair genes, hMSH2 and hMLH1, revealed that two patients in HNPCC group B had germline mutations of hMSH2. The fluorescence-based techniques, such as the present RER analysis do not require radioactive materials and specialized rooms, and can easily be performed in a clinical laboratory.

Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation) is an autosomal dominant, childhood onset, postural dystonia and the first hereditary basal ganglia disorder whose causative enzyme and gene defect were clarified. The initial symptom is unilateral pes equinovarus with marked diurnal fluctuation. Progression becomes slower after mid-teens and stationary after thirties. Postural tremor may occur after 10 years of age, especially after thirties. Parkinsonian resting tremor action and torsion dystonia. and disturbed locomotion do not occur. L-Dopa shows marked and sustained effect without side effects. F-Dopa PET and [11C] raclopride PET of over 20-year-old cases are normal. Deficiency of GTP cyclohydrolase I (GCH-I) was suggested from low CSF biopterin and neopterin. Mutation of GCH-I gene and decreased GCH-I were clarified as etiology. Twenty-five mutations discordant among families have been found. Autopsy of a gene proven case revealed decreased striatal tyrosine hydroxylase (TH) and dopamine (DA) in ventral striatum where direct pathway is predominant. Decreased GCH-I causes decreased tetrahydrobiopterin (BH4), TH and DA in nigrostriatal (NS) terminal. The lowest affinity of BH4 to TH causes selective involvement of DA. Postural dystonia is caused by decreased TH and DA affecting D1-direct pathway. Thalamic ventrolateral and pedunculo-pontine nuclei are spared. Diurnal fluctuation of symptoms is due to diurnal fluctuation of TH and DA at NS-DA terminal. Decreased DA to below 20% of normal, shown by polysomnographical studies, and its physiological age related decremental changes in NS-DA terminal underlies characteristic clinical course. High D2 receptor before early thirties masks D1 related hypertonus and manifest progression before 20 years of age. Other pteridine abnormalities also cause dopa responsive postural dystonia with diurnal fluctuation. A case of juvenile parkinsonism without dystonia showed decreased TH in dorsolateral putamen where indirect pathway is predominant. These suggest that decreased TH due to decreased BH4 involves D1-direct pathway causing dystonia, and decreased TH itself involves D2-indirect pathway causing parkinsonism.

Female patients (n=371) with metastatic breast cancer were treated with endocrine or chemoendocrine therapy as the first-line treatment. Clinical prognostic factors for response and survival were compared between the treatments, including age of the patients, menopausal status, estrogen receptor (ER), disease-free interval (DFI), dominant site of metastasis, number of metastatic organs, performance status (PS), and prior therapy. Although a significantly higher response rate was obtained by the chemo-endocrine therapy compared with the endocrine therapy, the median survival time of patients in endocrine therapy was much longer than those in chemo-endocrine therapy. Multivariate analyses with the logistic regression model showed that in women treated with endocrine therapy ER was shown to be the sole determinant for response, while PS and dominant site of metastasis were selected to be influential in chemotherapy group. For overall survival, the Cox proportional hazard model analysis showed that by endocrine therapy, ER and dominant site were significant determinants of survival, but that of chemotherapy the survival was determined by PS, dominant site, and age of the patients. When response to therapy was included in the Cox survival analysis at the time of 3-month after therapy in the landmark method, the response was the most important factor for survival in both treatment groups, however dominant site in endocrine therapy, and dominant site, PS, and age in chemo-endocrine therapy significantly modified survival. It is concluded that endocrine therapy and chemo-endocrine therapy have different determinants for response and survival in metastatic breast cancer, and that in the survival analysis treatment modality should be included as a prognostic factor.

Inflammatory/immunological processes underlie the survival/damage of neurons after brain ischemia. In glial cells, cytokines such as IL-1 beta and TNF-alpha are produced following ischemic stresses. On the other hand, it is suggested that NO/iNOS is involved in neuronal apoptosis. We here review the ischemia-induced production of cytokine/iNOS and the neurotrophic/neurotoxic effects. It is not clear whether or not the neuronal death after brain ischemia is apoptosis or necrosis. Under the condition of transient forebrain ischemia, however, we obtained results suggesting apoptosis in the delayed neuronal death of the CA1 pyramidal neurons. The time course and cellular localization of postischemic iNOS expression depend on the properties of the ischemic insult. The iNOS induction is detected primarily in astrocytes after the transient forebrain ischemia when the neuronal apoptosis is observed. We discuss a variety of cytokines with neurotrophic/neurotoxic actions that are produced by ischemia or environmental stresses in glial cells. From the neurotoxicological aspect of the neuro-glial interaction, we also review recent findings on signalling pathways of the iNOS induction in glial cells and the mechanisms of the cytotoxic actions of NO.

Phase I study of TAT-59 (Miproxifen), an antiestrogen developed in Japan for breast cancer, was conducted with the collaboration of 12 hospitals. A single dose of 1.25, 5, 10, 20, 40 and 80 mg, or 5 consecutive daily doses of 1.25, 5, 10, 20 and 40 mg/day, were given orally. After single dosing, no clinical adverse effects were found. Decrease of serum Na, Cl, Ca level and increase of serum LDH level were observed in one patient after a single dose of 5 mg of TAT. An increase in the serum LDH level was also observed in one patient after a single dose in the of 10 mg of TAT. An increase in the serum LDH level and total bilirubin, increase of eosinophil, K and milky serum were also observed in one patient after a single dose of 40 mg of TAT, respectively. All of these abnormal values returned to the normal level within 26 days after final administration of TAT. No adverse clinical findings nor abnormal laboratory findings were observed after consecutive administration of TAT. After postprandial single dosing, the time to reach the maximum serum concentration (Tmax) of DP-TAT, dephosphorylated metabolite of TAT, and its demethylated metabolite, DMDP, ranged from 5.0 to 7.3 hr and from 17.0 to 42.8 hr, respectively. The maximum serum concentration (Cmax) and AUC of DP and DMDP elevated in a dose-dependent manner. T1/2 of DP and DMDP ranged from 24.2 to 41.5, and from 91.9 to 214.7 hr, respectively. There were no significant differences between pharmacokinetics of TAT before and after food intake. Based on the above results, we concluded that a Phase II study should be conducted to evaluate the efficacy, safety and optimal dose of TAT.

We present a case of IgA nephropathy (IgAGN) which developed rapidly progressive glomerulonephritis and showed marked clinical improvement with treatment. The patient was a 7-year-old boy who initially presented with acute nephritic syndrome with hypocomplementemia. Although the renal function improved with normalization of the serum complement level, it deteriorated again progressively. The first renal biopsy revealed cellular crescents in about 70 percent of 43 glomeruli. Immunofluorescent microscopy demonstrated deposits of IgA, C3 and IgG in the mesangium; they were also deposited along the glomerular capillary walls. He was treated with plasma exchange associated with hemodialysis and methylprednisolone pulse therapy, followed by oral administration of prednisolone, cyclophosphamide and warfarin. Renal function recovered to the normal range about two months after the initiation of treatment. The second biopsy demonstrated a marked decrease in histological activity. In this case, transient hypocomplementemia at onset may indicate that acute glomerulonephritis caused exacerbation of clinically silent IgAGN. Aggressive therapy may be effective in patients with rapidly progressive IgAGN if treated at an early stage.

The metabolism of bile acids in 30 pregnant women was evaluated by analyzing the urinary composition of bile acids during late gestation (weeks 30-41) and again in these women and their newborn infants during the first week after delivery. The levels of individual bile acids were determined by gas chromatography-mass spectrometry after solvolysis and hydrolysis of bile acid conjugates. The mean total bile acid/creatinine ratio in pregnant women decreased from 1.22 micromol/mmol creatinine at 30-32 weeks of gestation to 0.15 micromol/mmol creatinine at 6-7 days after delivery. The mean percentage of 1beta-hydroxylated bile acids peaked at 27% at 3-4 days after delivery. In newborn infants, the mean total bile acid/creatinine ratio rapidly increased from 3.39 micromol/mmol creatinine at birth to 54.33 micromol/mmol creatinine at 7 days. During this period, large amounts (40-50%) of unsaturated ketonic bile acids, especially 7alpha,12alpha-dihydroxy-3-oxo-5beta-chol-1-en-24-oic acid and 7alpha,12alpha-dihydroxy-3-oxo-4-cholen-24-oic acid, were observed in the infants' urine. These data suggest that, during the perinatal period, the formation of polyhydroxylated and unsaturated ketonic bile acids probably represents a mechanism for the excretion of bile salts, and that the metabolism of bile acids in both the mother and the infant changes significantly after birth.

Infective endocarditis is extremely rare in early pregnancy. We report an emergency mitral valve replacement performed successfully on a 16 week pregnant woman for infective endocarditis without preexisting heart disease. On admission, the patient was in acute heart failure, and the fetus had been already dead. Induced abortion was performed uneventfully 6 days after the cardiac operation.

The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of worldwide evidence has demonstrated that a few years of adjuvant tamoxifen produces a moderate but definite benefit in long-term survival. However, there is major uncertainty regarding the optimal duration of tamoxifen treatment and in particular, as to whether, after a few years on tamoxifen, most women should stop or should continue for several years longer. ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) is a large international randomized trial designed to assess reliably the balance of benefits and risks of prolonging tamoxifen duration by an additional five years in women who have already had some years of adjuvant tamoxifen and for whom there is uncertainty about whether to stop, or to continue for longer. It is important that most of the clinicians are aware of the uncertainties regarding the optimal duration of tamoxifen and should consider entering their patients into ATLAS, which has the potential to provide reliable evidence to answer this question that affects the management of many hundreds of thousands of women worldwide and thereby may contribute to the further downward trend in breast cancer mortality which is already being seen.

The basal ganglia play important roles in the pathophysiology of various types of involuntary movement disorders, such as chorea, ballism, athetosis, dystonia, tremor and tics. These involuntary movements when occur in the childhood show the specific ages of onset and the courses. For example postural dystonia occurs in childhood but action dystonia tend to occur in later ages. Postural tremor occurs after the second decades but resting tremor does not occur in childhood. Furthermore drug induced dystonia but not levodopa induced dyskinesia occurs in childhood. The age dependent clinical features observed in these involuntary movements are thought to be due to the specific developmental processes of the pathway in the basal ganglia and its efferent projections, which are involved in the pathophysiology in the each disorder. For example, the dopamine activity is known to be increased in the striatum before ten years of age which decreases, rapidly during the first decade and further decreases in the next decade with the moderate degree till adult level. The direct pathway, which is predominant in the ventral area in the basal ganglia, matures earlier than the indirect pathway, which is predominant in the dorsal area. In this paper the pathophysiologies of the hereditary progressive dystonia with marked diurnal fluctuation, juvenile parkinsonism, idiopathic torsion dystonia, chorea, ballismus and tics, all of which occur in the childhood, are discussed from the view point of the age dependent specificities of the involved pathways in the basal ganglia and their projections during development.

Objective To investigate the role of vascular endothelial growth factor (VEGF) in tumour angiogenesis in renal cell carcinoma (RCC). Materials and methods The expression of VEGF was examined in tissue samples from 25 patients with RCC using the reverse-transcriptase polymerase chain reaction (RT-PCR). Cellular localization of VEGF was studied in normal kidney and RCC tissues. Tube formation by human omental microvascular endothelial (HOME) cells co-cultured with A498 RCC cells was quantified in a three-dimensional collagen gel using computer-image analysis. Results RT-PCR detected VEGF m-RNA in tissue from 20 of 25 patients with RCC. An immunohistochemical study revealed that VEGF was primarily localized in the cytosol of normal renal tubule cells and RCC cells. Tube formation by HOME cells was increased in the presence of A498 cells overexpressing VEGF mRNA, induced by exogenous VEGF in a dose-dependent manner and completely inhibited by an anti-VEGF antibody. Conclusion VEGF, which is produced and released from RCC cells, may elicit tumour angiogenesis by inducing microvessel tubulogenesis in patients with RCC. The co-culture system may be useful for screening inhibitors of tumour angiogenesis in RCC.

We evaluated the antithrombogenicity of 4F-catheters coated with the new antithrombogenic material fluorine-acryl- styrene-urethane-silicone (FASUS) graft-block copolymer by dissecting microscopic and scanning electron microscopic observations. These catheters were temporarily used for the infusa-A-port, which was prepared for the treatment of four patients with bladder cancer. Two heparin-coated catheters were also evaluated. All FASUS-coated catheters contained thrombi consisting of red thrombi and/or fibrin thrombi. Massive red thrombus was seen at the site of curvature of the catheters, 1 cm distal to the tip of the catheter. However, the portion 20 cm distal to the tip of the catheter had no red thrombus, but contained minimal fibrin thrombus or plasma protein. The heparin-coated catheters showed the same findings as the FASUS catheters. The FASUS-coated catheters were not superior in antithrombogenicity to the heparin-coated catheters. It was concluded that the FASUS-coated catheters used in this study seemed to have problems in regard to their preshaped curvature and the material used in catheter. These aspects need to be improved.

Iodine-123-BMIPP washout at rest and after exercise was investigated in relation to cardiac work in normal and ischemic myocardium.Sixteen healthy volunteers and 10 patients with ischemic heart disease were examined. After injection of 111 MBq of 123I-BMIPP, successive SPECT imaging was performed to evaluate washout ratio (WR) at rest and after mild and maximal exercise.In the healthy volunteers, the mean WR was 3.3 +/- 3.5% after 1 hr of rest and increased during both mild and maximal exercise. The WR showed a better correlation with net pressure rate product (PRP) than with the peak PRP. After maximal exercise, the WR showed a distinct correlation with the net PRP in the range from 200-300 x 10(3) mmHg/min and then showed a plateau greater than 10%. In five ischemic heart disease patients with the net PRPor = 300 x 10(3) mmHg/min, the exercise WR values were significantly elevated in normal segments relative to ischemic segments.BMIPP washout increased with the increase in cardiac work during exercise in normal myocardium but not in ischemic myocardium. A certain amount of exercise is necessary to evaluate fatty acid metabolism in normal and ischemic myocardium.

Several studies have shown that the nervous (and hormonal) system controls immune functions. In the present study, we examined the presence of muscarinic acetylcholine receptors and the effect of carbachol on DNA fragmentation in adult rat thymocytes. Rat thymocytes possessed high affinity binding sites for the muscarinic antagonist [3H]3-quinuclidinyl benzilate (QNB). The average number of binding sites per cells was 3000, and the equilibrium dissociation constant of [3H]QNB on intact cell was approximately 80 nM. The binding was inhibited by an M1- and M3-selective antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodine (4-DAMP). Hydrocortisone (100 mg/kg, s.c.) treatment of rats for 2 days prior to sacrifice increased the average number of [3H]QNB binding sites on thymocytes by 82 +/- 33%. The gel electrophoresis of DNA extracted from carbachol-treated thymocytes revealed a ladder pattern typical of intranucleosomal fragmentation. The addition of oxotremorine-M also induced DNA fragmentation and the effects of muscarinic agonists were inhibited by the addition of atropine or 4-DAMP. The results suggest the existence of muscarinic receptors and the possible involvement in apoptosis in thymocytes.

Prognostic factors and the influence of response to therapy on survival in advanced breast cancer patients remains to be fully elucidated. One hundred and two patients with advanced breast cancer refractory to a combination chemotherapy (FAC) were investigated for response and survival in a randomized trial comparing MMV chemotherapy (mitomycin C, methotrexate, vincristine) alone, or with medroxyprogesterone acetate, or with prednisolone. A total response rate of 28.4% (29/102) was obtained in MMVX. In this second-line chemo-endocrine treatment, univariate and multivariate analyses using 14 clinical factors were performed for response as well as for overall survival of the patients. The logistic regression analysis showed that age, period between recurrence and MMVX, and PS were significant factors for response. According to the Cox's proportional hazard model, factors of PS, period between recurrence and MMVX, dominant site of metastasis and performance of adjuvant therapy were significant for survival. The landmark method (3-month) showed that there was a significant difference in survival by the response category (Kaplan-Meier method with logrank test, p0.0001). In the patient population at the landmark time, the Cox model indicated that the response was the most important for survival, but was significantly modified by some factors such as PS. In advanced breast cancer patients treated with a 2nd-line chemo-endocrine treatment, the response to therapy might be a significant determinant for survival of the patients. Prognostic factors for survival should be defined in this stage of malignancy.

Clinical observations and physiological evidence suggest involvement of the autonomic nervous system (ANS) in Rett syndrome (RS). We studied sympathetic skin response (SSR) and sleep-wakefulness-rhythm (SWR) in patients with RS and discussed involvement of the ANS in reference to the pathophysiology. The age dependent alteration in the parameters in SSR was suggested. Some patients showed absence of SSR and some showed asymmetric involvement of the parameters of the SSR, which suggested involvement of the ANS at a peripheral level and possible influences from higher centers. The asymmetry correlated with side of the scoliosis, but not with handedness or position of the hand on stereotypy. In reference to the scoliosis of RS, asymmetrical involvement of dopamine neurons is suggested, but reduced secretion of melatonin was proposed and possible influence of the sympathetic nervous system for it was discussed. Long lasting abnormalities of SWR as well as leakage of axial atonia into NREM stage are due to an early involvement of noradrenergic neurons. The latter implied the loss of integration of the central ANS. Based on these observations and references, it was speculated that the ANS is involved in RS at various levels from the central to peripheral nervous system.

aFGF injection s.c. once a week into SAMP8 was begun at 3 weeks after birth and continued for 10 months. Saline was injected as a control. learning and memory and cellular immunological functions in the aFGF group were enhanced significantly, while those of the saline group deteriorated. 1. The number of cholinergic neurons was decreased by less than 20% and ChAT activity in individual neurons in the medial septum which send monosyonaptic terminals to the hippocampus was significantly decreased in the saline group, but not so much in the aFGF group. 2. The respective densities of muscarinic and aFGF receptors, on the hippocampal neurons were significantly higher in the aFGF group than in the saline group. 3. The LTP in hippocampal slice preparations was significantly facilitated in the aFGF group, but not in the saline group. 4. The DTH, (T cell immune response) measured at the end of the 2nd and 7th months were reduced in the 7th month as compared with the 2nd month in the saline group, but aFGF group protected against this reduction. 5. These results show that aFGF provides protection against impairment of not only learning and memory but also the DTH immunoreactivity in SAMP8.

Sixteen patients out of 58 children with congenital hydrocephalus were retrospectively investigated in terms of their psychomotor development and morphological findings of the brain by magnetic resonance imaging (MRI), and morphological backgrounds of the brain in patients affected by "intractable hydrocephalus" were intended to be clarified. The 16 patients were primarily diagnosed as having aqueductal stenosis or communicating hydrocephalus during the era before introduction of MRI. On the basis of the rate of head growth, sixteen patients were divided into three groups; group-1: overt neonatal hydrocephalus (5 cases) ; group-2: rapidly progressive hydrocephalus with normal head circumference at birth (5 cases); and group-3: slowly progressive hydrocephalus with its onset after the neonatal period (6 cases). Psychomotor development of the 16 cases was analyzed by using various methods including the Tanaka-Binet intelligence test and WISC-R. Four cases in group-1 and all cases in group-2 were found to have IQ or DQ below 50, while the other remaining cases were found to have IQ of 82 in group-1 (one case) and IQ ranging from 67 to 113 in group-3. MRI performed in those 9 cases with IQ below 50 revealed various morphological abnormalities of the brain. Those abnormalities were characterized by disturbance of organogenesis and/or histogenesis of the brain dating from the first 20 weeks of fetal life. It is strongly suggested that in the pathogenesis of intractable hydrocephalus developmental malformation of the brain occurring during the first 20 weeks of gestation are involved. Functional and morphological impairments of the brain possibly caused by progression of fetal hydrocephalus and delay of CSF diversion before and after birth seem important in the pathogenesis of intractable hydrocephalus.

The authors investigated the anti-inflammatory actions of ketoprofen using a battery of tests: in the rat paw oedema test induced by five different inciters, in the capillary permeability test, and in measuring the interleukin-8 (IL-8) production and superoxide dismutase (SOD) activity. The findings in these studies show that ketoprofen inhibits rat paw oedema, suppresses capillary permeability, reduces IL-8 production and increases SOD activity in the acetic-acid-induced inflammatory state. These results would seem to provide a clear rationale for exploring the usefulness of ketoprofen in the treatment of acute and chronic inflammatory diseases.

Home management for cancer-related pain in a terminal cancer patient is usually performed by oral or intrarectal administration with analgesics. If such treatment fails to reduce cancer-related pain, we have to treat them with epidural, intravenous or subcutaneous injection of these agents in some cases. We encountered a terminal lung cancer patient with metastatic bone cancer who was treated with continuous subcutaneous injection of morphine hydrochloride at home. As a result, the patient's quality of life has been remarkably improved. The management of cancer-related pain with analgesics and terminal care at home are discussed.

The significance of doxorubicin (ADR) was reviewed in the treatment of advanced as well as early breast cancer. The history of ADR treatment, mainly as a combination of CAF, or FAC, has revealed that ADR is still the key drug for breast cancer, the response rate being 40-60%. A multivariate analysis in 182 advanced breast cancer cases showed that the predictive factor was the dominant site of metastasis, and performance status (PS). Overall survival was determined with the age, the dominant site of metastasis, and PS. Recently the combination chemotherapy including ADR was evaluated to be equivalent to CMF type chemotherapy in the adjuvant settings.

Recent studies have shown that mastoparan, an amphiphilic peptide derived from wasp venom, modifies the secretion of neurotransmitters and hormones from a variety of cell types. Mastoparan interacts with heterotrimeric guanine nucleotide-binding proteins (G proteins) such as Gi and G(o), which are ADP-ribosylated by pertussis toxin (PTX) and thereby uncoupled from receptors. Previously, some of the effects of mastoparan including secretion were reported to be modified selectively by PTX but not by cholera toxin (CTX). In the present study, we examined the influence of bacterial toxins on the effects of mastoparan in PC12 cells. Mastoparan stimulated [3H]noradrenaline (NA) release from prelabeled PC12 cells in the absence of CaCl2, although high K+ or ATP-stimulated the release in a Ca(2+)-dependent manner. Pretreatment with CTX, not PTX, for 24 h inhibited mastoparan-stimulated [3H]NA release. Mastoparan inhibited forskolin-stimulated cyclic AMP accumulation in a dose-dependent manner, although mastoparan had no effect by itself. Pretreatment with PTX completely abolished the inhibitory effect of carbachol via Gi on cyclic AMP accumulation and partially reduced the effect of mastoparan. However, the inhibitory effect of 20 microM mastoparan was not modified by pretreatment with PTX. Thus, we investigated the effect of mastoparan on CTX-catalyzed [32P]ADP-ribosylation of proteins in PC12 cells. A subunit of CTX (CTX-A) catalyzed [32P]ADP-ribosylation of many proteins in the cytosolic fraction of PC12 cells. One of these was a 20 kDa protein, named ADP-ribosylating factor (ARF). The addition of mastoparan to assay mixtures inhibited ADP-ribosylation of many proteins including ARF and CTX-A in the presence of the cytosolic fraction. In the absence of the cytosolic fraction, however, mastoparan slightly enhanced ADP-ribosylation of bovine serum albumin and auto-ADP-ribosylation by CTX-A. Mastoparan did not inhibit ADP-ribosylation of the alpha subunit of Gs in the membrane fraction. These findings suggest that 1) mastoparan interacts with PTX-insensitive and CTX-sensitive factor(s) to stimulate NA release, and 2) mastoparan interacts with ARF inhibiting its activity to enhance the ADP-ribosylation reaction by CTX. ARF may be an exocytosis-linked G protein.