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The title reaction is highly E-selective and provides azetidines in good yields with high enantioselectivities.

Objective The anti-epileptogenic drug levetiracetam has anticonvulsant and anti-epileptogenesis effects. Synergy between cell death and inflammation can lead to increased levels of apoptosis inhibitory factors and brain-derived neurotrophic factor, aberrant neurogenesis and extended axon sprouting. Once hyperexcitation of the neural network occurs, spontaneous seizures or epileptogenesis develops. This study investigated whether the anti-epileptogenic effect of levetiracetam is due to its alternate apoptotic activity. Methods Adult male Noda epileptic rats were treated with levetiracetam or vehicle control for two weeks. mRNA quantification of Bax, Bcl-2 and GAPDH expression were performed from prefrontal cortex and hippocampus tissue samples. Results The levetiracetam-treated group showed a significant increase of Bax/Bcl-2 mRNA expression ratio in the prefrontal cortex than the control group, but no change in the Bax/Bcl-2 mRNA expression ratio in hippocampus. Conclusion Idiopathic generalized epilepsy including childhood absence epilepsy develop at childhood and recover spontaneously during adolescence. The aberrant neural excitable network is pruned by a neural-maturing action. This study suggests the mechanism of acquired anti-epileptogenesis by levetiracetam treatment may be similar to spontaneous recovery of idiopathic generalized epilepsy during adolescence.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 of SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.

The chronic effects of vagus nerve stimulation (VNS) on the occurrence of cataplexy and on the cataplexy modulating effects of central noradrenergic compounds (desipramine and BHT-950), were examined in two genetically narcoleptic dogs. In one dog, VNS significantly aggravated cataplexy with 0.5 mA of current and 500 µs of pulse width. In the second dog, VNS tended to improve cataplexy with 1.5 mA of current and 250 µs of pulse width (stimulation was applied for 30 s every 5 min and the frequency was 20 Hz in both dogs). The VNS had no effect on the cataplexy-suppressing effect of desipramine (a noradrenergic uptake inhibitor), while the cataplexy-aggravating effect of BHT-920 (an alpha-2 agonist) was attenuated by VNS in both dogs. It is therefore suggested that VNS modulates the central adrenergic neurotransmission and modifies cataplexy in the canine model of narcolepsy.

Vanadium-mediated enantioselective Friedel-Crafts (FC)-type reactions were established using the dinuclear vanadium complex (R(a),S,S)-1a. The vanadium complex promoted the FC-type reaction of imines with 2-naphthols or indoles to give corresponding adducts with high enantioselectivities.

The present protocol is applied to the synthesis of the naturally occurring aromatase inhibitor (VII).

Constituents of Ephemerantha fimbriata (BL.) P. F. HUNT et SUMMERH, which is used as a source plant of the Chinese crude drug "Shi-Hu", were examined and two new phenanthrenes, fimbriol-A (2) and fimbriol-B (8), a new dihydrophenanthrene, ephemeranthol-C (6), and dihydroconiferyl dihydro-p-coumarate (5) were isolated together with denbinobin (1), (+)-pinoresinol (3), (+)-syringaresinol (4), 3, 4, 5-trimethoxybenzoic acid (7), lusianthridin (9), and dihydro-p-coumaric acid (10). Structures of the new compounds were elucidated by the use of spectroscopic methods including two-dimensional NMR techniques.

We report a case of recurrent breast cancer with solitary lung metastasis that has shown no recurrence with treatment by trastuzumab alone after partial resection of the right lung upper lobe. A 56-year-old woman, who presented with left breast cancer, underwent quadrantectomy and axillar lymph node dissection in March 2004. Pathological findings were as follows: invasive ductal carcinoma, 3. 7 cm in size, histological grade 3, positive invasion of lymphatic and blood vessels, negative nodal status, negative ER/PgR status, and overexpression of HER2/ neu. She had received adjuvant radiotherapy followed by cyclophosphamide, methotrexate and fluorouracil combination chemotherapy; however, a lung nodule developed 14 months after first operation, which had grown gradually. Partial resection of the lung with thoracoscope assistance revealed metastatic lung cancer from breast cancer. Trastuzumab treatment for 6 months after second operation has maintained no recurrence for 4 years.

The Stark beats of Lyman-α emission due ton=1 − 2 transition of hydrogen atom have been studied by the beam-foil method. After passage through a thin carbon foil, the static electric field of 500 V/cm was applied to the beam in the direction either parallel to or anti-parallel to the the beam velocity. The linearly polarized emission was measured by using a toroidal mirror at a Brewster's angle reflection. When the direction of the applied electric field is reversed, an appreciable phase shift was observed. The analysis of the data leads to the complete determination of the density matrix of the H(n=2) atoms at the time of their production.

症例は72歳, 男性. 慢性関節リウマチおよび間質性肺炎と診断されたさい, 胸部CT上弓部大動脈に径50mmの大動脈瘤を認めていた. ステロイド投与にて症状, 検査所見の改善を認めていたが, 治療経過中, 副作用と思われる糖尿病, 高血圧を発症したため対症的に治療しコントロールしていた. 治療開始から2カ月目, 意識消失発作にて胸部大動脈瘤破裂を発症した. CT上, 瘤径は60mmと拡大し周囲に血腫を認めた. 緊急で超低体温脳分離体外循環下に全弓部置換術を行い救命しえた. ステロイドが糖尿病, 高血圧などの副作用により, 動脈硬化性病変を増悪進展させ, 今回の急速な瘤径拡大, 破裂の一因となったと考えられた. 本例のように動脈硬化性病変を合併しかつステロイド投与を要する場合, 副作用のコントロールと同時に, 併存する動脈硬化性病変の慎重な経過観察が重要と考えられた.

The antitumor activity of docetaxel in human prostate tumor cells and correlation between cell-growth inhibition and prostate specific antigen (PSA) secretion were investigated. Cultured human prostate tumor cell lines (LNCaP, DU1 45 and PC-3) were treated with test drugs,after which the number of viable cells and PSA levels in the medium were determined. Apoptosis was assessed by changes in chromatin structure, DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and Annexin V assay. Docetaxel inhibited cell proliferation in a dose-dependent fashion in all cell lines,with IC50 levels from 0.90 to 4.2 nM,which were similar to those of paclitaxel,but more potent than mitoxantrone,estramustine,or cisplatin. Docetaxel-treated cells underwent cell-cycle arrest in the G2/M phase and apoptosis as indicated by chromatin condensation and DNA fragmentation. In docetaxel-treated LNCaP cells,there was a linear correlation between growth inhibition and the decline in PSA level in the culture medium. It was demonstrated that docetaxel had potent antitumor activity against human prostate tumor cells,and the decrease in cell growth was associated with a decrease in PSA secretion,suggesting that PSA would be a useful biological marker for monitoring the efficacy of docetaxel in a clinical setting.

The photodissociation dynamics of {tilde A} state ammonia molecules has been further investigated for deuterium-substituted derivatives NH{sub 2}D, NHD{sub 3}, and ND{sub 3} measuring the homogeneous line widths on action spectra. The line widths of the 2{sub 0}{sup 1} vibronic band were determined to be 19, 12, and 1.3 cm{sup {minus}1} fwhm for NH{sub 2}D, NHD{sub 2}, and ND{sub 3}, respectively. In consideration of their previously reported value of 26 cm{sup {minus}1} for NH{sub 3}, the spectral line width decreases in proportion to the number of D atoms. This result shows that the dissociation rate in the {tilde A} state is additive as for the number of H atoms, and it is explained by the fact that the zero-point energies on the potential surface of {tilde A} state are equally shifted among deuterium-substituted ammonias.

A 59-year-old man had received chemotherapy with gemcitabine for nonresectable pancreatic cancer. After 14 months, he was hospitalized for obstructive jaundice and severe pain. Cholangioduodenostomy was performed, and the dose of opioids was increased. Although jaundice improved, the uncontrollable pain persisted. Chemotherapy with S-1 was initiated, and a dramatic improvement in the pain was observed. Consequently, the patient could be discharged from the hospital.

NARCOLEPSY IS A DISABLING SLEEP DISORDER CHARACTERIZED BY EXCESSIVE DAYTIME SLEEPINESS (EDS), SLEEP PARALYSIS, HYPNAGOGIC HALLUCINATIONS, and cataplexy.1,2 Narcolepsy is currently treated with amphetamine-like stimulants (or modafinil for EDS) and antidepressants for cataplexy and REM sleep related symptoms.1 These treatments are purely symptom-oriented and are often problematic due to their limited effectiveness and undesirable side effects.1 Recent studies in animals and humans revealed that a deficit in hypocretin (hcrt, also known as orexin) transmission is the major pathophysiology. Doberman pinschers with autosomal recessive narcolepsy possess null mutations in the gene encoding hcrt receptor2 (hcrtR2),3 one of two hypocretin receptors. Sporadic cases of canine narcolepsy show undetectable levels of the brain and cerebrospinal fluid (CSF) hcrt neuropeptide.4 Preprohypocretin gene knockout mice as well as orexin/ataxin-3-transgenic mice (TG mice) with postnatal death of hcrt-producing neurons by hcrt neuron-specific expression of a truncated Machado-Joseph disease gene product (ataxin-3), also exhibit the narcolepsy phenotype.5,6 In humans, genetic mutation in hcrt-related genes is rare, but a large majority of narcolepsy-cataplexy is found to be associated with the loss of hcrt production in the brain and CSF, possibly due to the postnatal cell death of hypocretin neurons.7–11 Since most human narcolepsy-cataplexy is caused by the loss of the hcrt peptide, hcrt replacement is a promising future therapeutic option. In this regard, the result that central administration of hctr-1 rescues the sleep abnormalities and cataplexy in orexin/ataxin-3-TG mice is very encouraging.12 The potential efficacy of hypocretin replacement therapies in human narcolepsy will however, require the integrity of hypocretin receptors. Functional hcrtRs may disappear gradually following the loss of hypocretin in narcolepsy. In previous studies, the effect of hcrt replacement was only examined in 14- to 15-week-old hypocretin cell deficient narcoleptic mice; whether longer-term changes in the responsiveness to hypocretin occur is unknown. Additionally, the etiological mechanisms of hypocretin cell death in human narcolepsy is currently unknown, and consequent hcrtR changes may well be different from those found in orexin/ataxin-3-TG mice. Thannickal et al. suggested that the loss of hypocretin function in human narcolepsy results from a cytotoxic or immunologically mediated attack focused on hcrtR2.13 If this is the case, then a loss of function of hcrtR2 might also exist in human narcolepsy, and patients may not respond to hcrt replacement, as previously shown in hcrtR2-mutated narcoleptic dogs.14 In the present study, we evaluated the influences of long-term hcrt deficiency on hcrtR1 and hcrtR2 expression in brain samples from canine and murine models of narcolepsy, as well as from a limited number of human narcolepsy-cataplexy patients. The evaluation in humans is critical, since the results may predict responsiveness to the hcrt replacement therapy and the potential usefulness of cell transplantation or gene-based therapies.

Concentrations of Ra in groundwater are thought to be affected by substitution reactions with alkaline earth elements contained in a mineral, because the concentration of Ra is less than the solubility of known Ra containing phases. The substitution reaction was simulated using a partition coefficient. Calcite ubiquitously exists in geological system and easy to access to react with Ra. Therefore, calcite is thought to be an important mineral for the substitution reaction. However, previous identification of reactive layers of calcite or reversibility of the substitution reaction has not been confirmed. A re-distribution experiment was therefore undertaken and it was found that an estimated 21±13 layers near the surface were reactive and within them substitution equilibrium was achieved. Using these results, a model to estimate Ra concentration was established and adopted to analyze Ra migration. The effects of substitution of Ra and Ca were reasonably simulated.

Immunological properties of cefpirome sulfate (CPR) were examined. The immunogenicity and challenging ability of CPR were examined in guinea pigs by active systemic anaphylaxis (ASA) and homologous 4-hr passive cutaneous anaphylaxis (PCA) tests. The animals given CPR alone intraperitoneally for sensitization and their sera were negative for ASA or PCA reactions, like the results with reference substances, ceftazidime (CAZ) and cephalothin sodium (CET). When each antibiotic plus Freund's complete adjuvant (FCA) was used for sensitization, ASA reactions were observed with CPR, cephaloridine (CER), CET, and cefazolin sodium (CEZ), and PCA reactions, with CPR and CET. CPR had the ability to challenge the ASA and PCA reactions. CER and CET also showed the ability to challenge ASA or PCA reactions, though at low incidences. The cross-reactivity of CPR with commercially available antibiotics was examined by heterologous PCA test and by passive hemagglutination test and its inhibition test. The antiserum used was from rabbits immunized with each antibiotic-ovalbumin conjugate plus FCA, and the antigen was each antibiotic-bovine serum albumin conjugate. CPR cross-reacted markedly with cefotaxime sodium (CTX) having the same side chain at position 7 and showed weak, unidirectional reactions with CAZ and CET. In the in vitro direct Coombs test, the positive reactions noted with CPR were stronger than those with latamoxef sodium, equal to those with CEZ and slighter than those with CTX, CET and benzylpenicillin potassium. In conclusion, in the safety evaluation of CPR, its antigenic potential may not be a problem, like the cases of other antibiotics.

In March 2004, we resected a giant retroperitoneal liposarcoma and the transverse colon, spleen and left kidney in a 58-year-old woman. In July, recurrence was detected in the right pelvis and left upper abdomen; therefore, we resected the tumor. In September 2004, computed tomography (CT) revealed multiple recurrences in the right lower abdomen, left upper abdomen, front of the left lobe of the liver, and at the back of the stomach. In October 2004, we started mesna, doxorubicin, ifosfamide, and dacarbazine therapy (MAID); however, after 1 course, the disease progressed, and the patient developed edema in the bilateral legs due to inferior vena cava (IVC) compression. In November 2004, we started weekly paclitaxel therapy (100 mg/m(2), once a week for 3 weeks followed by 1 drug-free week). CT revealed no change as a result of chemotherapy; however, IVC compression had improved, and leg edema had decreased. In August 2005, chemotherapy was stopped; therefore,the patient's condition worsened. She died in September 2005. We performed weekly paclitaxel therapy for the patient with recurrent liposarcoma. This improved her symptoms and quality of life (QOL). Therefore,we consider weekly paclitaxel therapy to be effective for liposarcoma treatment.

An 81-year-old woman with a right breast tumor exposed through the skin surface visited our clinic in June 2004. Pathological findings of the resected tumor specimen indicated invasive ductal carcinoma of the breast,positive ER/PgR status,and negative HER 2/neu status. The enlarged right axillary lymph nodes were palpable. Ultrasonography and computed tomography revealed that the tumor invaded the chest wall without any metastasis to remote organs. On July 5, 2004, we started anastrozole treatment. Its effects were confirmed in the first month,and the treatment was continued for 8 months. Substituting anastrozole with exemestane was not effective. However, the exposed part of the tumor completely responded to tamoxifen that was administered for 2 months. The effect of tamoxifen continued until February 2006, and most of the subcutaneous part of the tumor became nonpalpable. Thus, sequential endocrine monotherapy proved useful for an elderly woman with locally advanced breast cancer.

Prognosis of esophageal carcinoma with multiple metastatic lymph nodes is dismal despite radical operation and adjuvant therapy. We investigated prognostic factors for curatively resected esophageal carcinoma with multiple positive nodes.From January 1983 to December 2002, 343 patients with thoracic esophageal carcinoma underwent an esophagectomy with curative intent. Of these patients, 82 patients were associated with 4 or more histopathologically positive nodes. Of these patients, 59 patients underwent a curative resection. Of these 59 patients, 7 patients who died of postoperative complications during the hospital stay were excluded. Therefore, 52 patients were enrolled in this study. Survival curves were compared after stratifications according to 14 clinicopathologic variables. Independent prognostic factors were detected using a multivariate Cox proportional hazard model.The cumulative 5-year survival rate for the subjects was 10.6%. The factors affecting cumulative survival rate by a univariate analysis were intramural metastasis (absence vs. presence) (p=0.03), and postoperative therapy (performed vs. not performed) (p=0.02). A multivariate analysis detected the performance of postoperative therapy (Hazard Ratio= 0.390, p= 0.002) and the absence of intramural metastasis (Hazard ratio=0.429, p=0.01) as positive prognostic factors.The positive prognostic factors for esophageal carcinoma with multiple lymph node metastases were the absence of intramural metastasis and the performance of adjuvant therapy.

We report two cases of recurrent breast cancer with regional lymph node metastases that responded completely to treatment with trastuzumab and paclitaxel. Case 1: A 52-year-old woman, who presented with left breast cancer, underwent mastectomy and axillary lymph node dissection in July 2002. Pathological findings were as follows: invasive ductal carcinoma (scirrhous type), 2.2 cm in size, histological grade 3, positive invasion to the lymphatic and blood vessels, negative nodal status (0/11), negative ER/PgR status, and overexpression of HER 2/neu. Left axillary lymph node metastasis was noted after five months, ie, in December 2002. Four cycles of chemotherapy with doxorubicin and cyclophosphamide were administered from January 2003; however, they were not effective. The patient showed a complete response after three months of chemotherapy with trastuzumab and paclitaxel. This treatment was stopped in September 2003. She has maintained a complete response for two and a half years and was not administered any further treatment as of February 2006. Case 2: A 59-year-old woman, who presented with right breast cancer, underwent mastectomy and axillary lymph node dissection in May 2002. Pathological findings were as follows: invasive ductal carcinoma (scirrhous type), 1.8 cm in size, histological grade 2, positive invasion to the lymphatic and blood vessels, negative nodal status (0/5), positive ER and uncertain PgR status, and overexpression of HER 2/neu. She had received adjuvant hormonal therapy with tamoxifen; however, a right supraclavicular lymph node metastasis was noted in October 2004. Treatment with exemestane was not effective. However, a complete response was observed with trastuzumab and paclitaxel for four months. She has maintained a complete response for six months and was not administered any further treatment as of February 2006.

Anastrozole and tamoxifen have mild toxicity. However, we noticed that more patients treated with anastrozole complained of joint symptoms than expected. In particular, digital stiffness as is seen with rheumatoid arthritis is a problem. Some clinical trials of anastrozole in Europe and the United States reported musculoskeletal disorders as adverse events, however, joint symptoms were not described in detail. At our clinic from August 2001 to March 2005, 53 postmenopausal women with estrogen receptor-positive breast cancer were treated with anastrozole. We calculated the incidence and classified the grade of joint symptoms by interviewing patients. We also investigated the patients’ characteristics and their relevance to joint symptoms. Of 53 patients, 14 patients (26%) had joint symptoms (13 patients with digital stiffness and 3 patients with arthralgias of wrist and shoulders). Joint symptoms tended to occur in the patients who had previously undergone chemotherapy; however, there has no relationship between prior hormonal therapy and joint symptoms. Seven patients who discontinued anastrozole treatment showed improved symptoms. Five patients with grade 1 digital stiffness continued anastrozole treatment without additional treatment. Two patients with grade 1 digital stiffness, who took a Chinese herbal medicine showed improved symptoms and continued anastrozole treatment. Benefits to the patients may possibly be lost by discontinuation of anastrozole or changing to tamoxifen since the clinical superiority of anastrozole to tamoxifen has been reported. We should continue anastrozole in patients with low grade symptoms, while ensuring that patients are aware of the toxicity of anastrozole.

A 75-year-old man underwent partial resection of the small intestine for GIST in January 2000. A recurrent tumor revealed in the intra pelvic space was removed by two operations, and imatinib (400 mg/day) was given after the third operation. As successive administration was not able to be continued due to side effects such as anorexia and fatigue, the recurrent tumor enlarged. After imatinib was given at 200 mg/day, the defecation trouble was improved and the tumor decreased partially on CT image. His partial response has continued over one year. Mutation analysis revealed deletion and point mutation in exon 11 of c-kit gene. Low-dose imatinib administration should be considered in case of side effects at the standard dose.

Case 1: A 34-year-old woman,who had a right breast cancer with axillary lymph node metastasis and multiple bone metastases, was referred to our clinic. She developed paralysis of lower extremities and disorder of the bladder and rectum due to metastasis to the thoracic vertebra, and also had renal dysfunction due to severe hypercalcemia and hemorrhagic cystitis. Correcting the serum calcium level with intravenous infusion, elcatonin, pamidronate and betamethasone, she underwent radiation therapy for the vertebral metastasis. The first hormonal therapy (leuprorelin/exemestane) had been effective for about 4 months, however the second hormonal therapy (leuprorelin/tamoxifen) was not effective. Chemotherapy with paclitaxel (80 mg/m(2), day 1, 8, 15, every 4 weeks) brought about a stable general condition and a normal level of serum calcium with zoledronate in the ninth month of treatment. Case 2: A 32-year-old woman, who had a right breast cancer with multiple bone metastases and axillary and hilar lymph node metastases, came to our clinic, complaining of nausea due to severe hypercalcemia. After successful correction of hypercalcemia by the intravenous infusion and administration of elcatonin, pamidronate and dexamethasone, the hormonal therapy(goserelin/tamoxifen) caused rapid re-elevation of serum calcium and tumor marker, so that a tumor flare was suspected. After 3 cycles of EC therapy (EPI 90 mg/m(2), CPM 600 mg/m(2), every 3 weeks), 2 cycles of paclitaxel therapy (80 mg/m(2), day 1, 8, 15, every 4 weeks) brought about tumor reduction and the normal level of serum calcium. After 7 cycles of paclitaxel therapy,the hormonal therapy (goserelin/tamoxifen) proved effective for several months. To achieve tumor reduction and stabilize the serum calcium level, we need to start immediately the treatment of breast cancer with severe hypercalcemia, considering the general condition of the patient.

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

The importance of the hypocretin/orexin system in vigilance control has rapidly emerged from the discovery of narcolepsy genes in canines and mice and from the findings of ligand deficiency in human narcolepsy (1, 2, 3, 4). (An earlier anatomical study suggested this involvement [5].) Narcolepsy, a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, and dissociated manifestations of REM sleep (6), is now known to be caused by the loss of hypocretin neurotransmission. The loss could be caused either by a malfunction in hypocretin ligand production or by a loss of function of one of the two hypocretin receptors (i.e., hypocretin receptor 2/orexin 2 receptor) (1).

Intracerebroventricular (ICV) or PVN local injections of oxytocin induce yawning and penile erection, for which a positive feedback mechanism for the PVN oxytocinergic activation is suggested, but this had not been directly substantiated in vivo. We have assessed the behavioral effects and activity of oxytocinergic neurons with double-staining for c-Fos and oxytocin in the PVN after ICV administration of oxytocin in adult male rats. ICV oxytocin injections (50 and 200 ng) dose-dependently induced yawning and penile erection and significantly increased the percentage of c-Fos positive oxytocin neurons in the medial, dorsal and lateral parvocellular subdivision of the PVN. However, increases in the magnocellular portion were not significant. We also found that lithium chloride (LiCl, 0.5 and l.0 mEq), a compound known to activate oxytocinergic neurons, also significantly increased the percentage of c-Fos positive oxytocin neurons in all PVN portions. However, LiCl did not induce yawning and penile erection, but counteracted the oxytocin-induced yawning and penile erection. These results suggest that if the activation of oxytocinergic neurons in the PVN is important for mediating oxytocin-induced yawning and penile erection, a selective activation of parvocellular oxytocinergic neurons in the PVN is likely to be involved.

A putrefied cadaver of a middle-aged woman was found drifting in the 'Kii" water course. Autopsy findings indicated that the postmortem duration was about one week, and the cause of death was assumed to be drowning. In this case, a nail was collected as a sample for personal identification. After five months of police investigation, persons thought to be her family, husband and child, were found. A combination of D1S80 and the short tandem repeat (STR) typing system using an AmpFISTR Profiler PCR Amplification kit was performed for identification. Nine STRs (D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317 and D7S820) and Amelogenin were analyzed by this kit. Those DNA typings successfully confirmed the family relation for personal identification of the cadaver. This analysis system may be useful for identification of a decomposed cadaver.

The Y-chromosome short tandem repeat (STR) systems including DYS19, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS385 and YCAII were investigated in 121 Japanese males (Tokushima area). Analysis of the nine loci permitted classification of the samples into 107 haplotypes, and the haplotype diversity was estimated to be 0.989. DYS385 showed the highest gene diversity (GD) value (GD=0.946), while DYS391 showed the lowest GD value (GD=0.27). Furthermore, in DYS392, we found a new mutant allele that added a T within the repeat region (a mutation in the repetitive region), and the allele was designated 13.1 according to the sequence structure. We also detected allele 20 in DYS392 as a new allele. In DYS385, a new allele 26 that has not been previously reported was observed.

Allergic rhinitis is an inflammatory disease of the nasal mucosa, induced by histamine, leukotrienes, and other substances released from mast cells. Fexofenadine hydrochloride, the active metabolite of terfenadine, is a novel, nonsedating antiallergic drug having H1 receptor antagonistic activity. Fexofenadine is effective for the treatment of allergic rhinitis. However, its mechanism of action in attenuating nasal congestion has not yet been elucidated. Therefore, we first examined the effects of fexofenadine on a guinea pig model of antigen-induced rhinitis. We also evaluated the effects of mepyramine, zafirlukast and ramatroban in this model; these drugs are an H1 receptor antagonist, a selective leukotriene antagonist and a selective thromboxane antagonist, respectively. Rhinitis was induced by ovalbumin (OVA) instillation into the nasal cavity of animals that had been sensitized by two earlier OVA injections (s.c. and i.p.). The nasal airway resistance was measured for 45 min after the challenge. Fexofenadine hydrochloride (20 mg/kg) and terfenadine (20 mg/kg) administered orally 70 min prior to the challenge significantly inhibited (fexofenadine, p < 0.001, terfenadine, p < 0.05) the increase in nasal airway resistance. Ramatroban (30 mg/kg) administered orally 60 min prior to the challenge also significantly inhibited (p < 0.05) the increase in nasal airway resistance. In contrast, mepyramine (3 mg/kg i.v.) and zafirlukast (3 mg/kg p.o.) failed to reduce the increase in nasal airway resistance. These results suggest that thromboxane may be involved in the increase in the nasal airway resistance in this model. Accordingly, fexofenadine may reduce the increase in nasal airway resistance by inhibiting the release of chemical mediators, including thromboxane, that are involved in the increase in nasal airway resistance in this model.

Study objectives Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined. Design SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays. Measurements and results Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone. Conclusions Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.

Leflunomide is a disease-modifying antirheumatic drug that inhibits paw swelling and joint destruction in type II collagen-induced arthritis in mice and it also delays disease progression in patients with rheumatoid arthritis (RA), through inhibiting proliferation and cytokine production of T cells, via the blocking of de-novo pyrimidine biosynthesis by its active metabolite, A771726. However, the direct action of leflunomide on cells of osteoclast lineage responsible for bone destruction in RA remains to be clarified. In this study, we examined the effect of A771726 on osteoclast formation and bone-resorbing activity in vitro, using cultures of bone marrow-derived osteoclast progenitors and purified functionally mature osteoclasts, and then we elucidated the molecular mechanism of action of the effect of A771726 on osteoclasts. A771726 inhibited osteoclast formation from macrophage colony-stimulating factor (M-CSF)-dependent osteoclast progenitors in the presence of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL), without any other types of cells present, in a dose-related manner, similar to the inhibition in cultures of unfractionated bone marrow cells. In addition, A771726 suppressed bone resorption by isolated mature osteoclasts. These results indicate that A771726 directly and intrinsically inhibited the differentiation and function of osteoclast lineage cells without any mediation by other cells. The inhibition by A771726 was not restored by the simultaneous addition of uridine, and may be independent of the blockade of NF-kappaB activation and the tyrosine phosphorylation of proteins. Thus, leflunomide, through its active metabolite, has the potential to prevent bone loss by directly inhibiting osteoclastogenesis and osteoclast function. This inhibition suggests a novel mechanism for leflunomide in the retardation of the joint destruction observed in RA patients.

A 68-year old Japanese male with alcohol related rhabdomyolysis, hepatitis, and hematological disorders is presented. Biochemical data showed markedly elevated levels of serum hepatobiliary enzymes, lactate dehydrogenase and myoglobin, and decreased levels of serum sodium and phosphate. The serum creatine kinase level was approximately 40 times higher than the normal upper limit with 97% of MM fraction. Clinical manifestations of rhabdomyolysis, such as myalgia, muscle weakness and acute renal failure, were not recognized. Hematological examinations revealed mild neutropenia, lymphopenia, monocytopenia and thrombocytopenia but no anemia or macrocytosis. Initial treatment of an intravenous infusion of saline (30 mL/Kg body weight) and subsequent low sodium diet was successfully completed without severe complications. All the abnormal laboratory data were normalized within three weeks of his hospitalization. We suggest that hyponatremia and hypophosphatemia may be involved in the development of rhabdomyolysis, hepatitis and hematological disorders.

Different potencies for hypocretin-1 and -2 in sleep–wake regulation and feeding after intracerebroventricular (ICV) administration have been reported. These differences were often explained by the selectivity of the two hypocretins for hypocretin receptor-1 and -2, but little attention has been paid to kinetics of hypocretin peptides. We investigated the kinetics of the ICV hypocretin-1 and -2 in rats. ICV hypocretin-1 (10 nmol) increased hypocretin-1 peptide level in the CSF by 800-fold from baseline with the elevation lasting over 4 h. In contrast, after ICV hypocretin-2 (10 nmol), no significant rise in the CSF was found. CSF hypocretin levels were significantly correlated with the biological activities of CSF hypocretin-1 and -2 using the Ca2+ mobilization assay. Difference in the kinetics of hypocretins should be considered for interpreting ICV effects of hypocretins.

Cataplexy, an emotion-triggered sudden loss of muscle tone specific to narcolepsy, is tightly associated with hypocretin deficiency. Using hypocretin receptor 2 gene (hcrtr 2)-mutated narcoleptic Dobermans, we have previously demonstrated that altered dopamine (DA) D(2/3) receptor mechanisms in mesencephalic DA nuclei are important for the induction of cataplexy. In the current study, we also found that the administration of D(2/3) agonists into diencephalic dopaminergic cell groups, including the area dorsal to the ventral tegmental area (DRVTA) and the periventricular gray (PVG) matter of the caudal thalamus (corresponding to area A11), significantly aggravated cataplexy in hcrtr 2-mutated narcoleptic Dobermans. A D(1) agonist and antagonist and a DA uptake inhibitor perfused into the DRVTA had no effect on cataplexy, suggesting an involvement of D(2/3) receptors located on DA cell bodies (i.e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D(2/3) receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy.

This paper provides some evidence of dividend-motivated earnings management using pure accruals defined as accruals and deferrals (A&D) by Japanese banks under the governmental guideline. This guideline had until August 1992 explicitly limited dividend payments by banks to 40 percent or less of their current net income. A bank with the potential to violate the guideline would increasingly manage its A&D to stay within the upper limits. Bias caused by measurement error and research method seems to remain in our tests. Though, under the comparative study, our empirical results consistently support the direct relationship between earnings management and dividend payment policies of Japanese banks: the magnitude of income increasing A&D management becomes significantly smaller when dividend-driven motivation disappears.

In vitro functional analyses of hypocretin/orexin receptor systems were performed using [(125)I]hypocretin radioreceptor and hypocretin-stimulated [(35)S]GTP gamma S binding assay in cell lines expressing human or canine (wild-type and narcoleptic-mutation) hypocretin receptor 2 (Hcrtr 2). Hypocretin-2 stimulated [(35)S]GTP gamma S binding in human and canine Hcrtr 2 expressing cell lines, while cell lines expressing the mutated canine Hcrtr 2 did not exhibit specific binding for [(125)I]hypocretin or hypocretin-stimulated [(35)S]GTP gamma S. In rat brain homogenates, regional specific hypocretin-stimulated [(35)S]GTP gamma S binding was also observed. Hypocretin-stimulated [(35)S]GTP gamma S binding, may thus be a useful functional assay for hypocretin receptors in both cell lines and brain tissue homogenates.

The completely reduced skeleton was found in a mountain stream. We presumed that the skeleton was a woman from a morphology feature of the skull and the pelvis bone. The level of the suture of the skull indicated that the age was the first half of the 70-years old from the 60-years old. As a result of the police investigation, the possibility of 66 years old woman who was missing for about six months was suspected. To inquire into her identification, a skull and left thighbone were cut off, and blood was collected from the suspect's daughters. We examined blood (ABO) and DNA types (D1S80, HLA DQA1 TH01 and polymarker system) for the skeleton and the suspect's families. Blood and DNA types analysis of two daughters revealed that their patients have 19 alleles in 9 blood and DNA types. Twelve alleles were admitted in the skeletal remain among presumed 19 alleles. There was no blood and DNA type to deny the mother and daughter relation all of nine types. The skeletal remain was not contradicted from the above-mentioned result though thought daughters' mother.

Background: Prior to 2012, bevacizumab was contraindicated for patients with brain metastases in Japan due to concerns about cerebral hemorrhage. The package insert changed in 2012 to allow careful administration of bevacizumab; however, we still have insufficient data describing the safety and efficacy of bevacizumab-containing chemotherapy. Because bevacizumab may be effective in the treatment of edema associated with brain metastases and radiation necrosis, it may have additional clinical uses. Methods: We retrospectively evaluated non-small cell lung cancer (NSCLC) patients with brain metastases who had received chemotherapy containing bevacizumab at Chiba Cancer Center between April 2012 and December 2013. Results: Thirty patients were eligible for participation in this study. Of the patients in this study, 15 were men, and 15 were women; patients had a median age of 62.5 years, and all except one had histological adenocarcinoma. Surgery, stereotactic radiosurgery, whole brain radiation, and other therapies were performed in 9, 13, 2, and 1 patients, respectively; 5 patients were not treated. Additionally, 26, 1, 2, and 1 patients received the following chemotherapies: CBDCA + PTX + BEV, CDDP + PEM + BEV, PEM + BEV, or BEV monotherapy, respectively. RECIST classifications of brain metastases were complete response in 2 patients, partial response in 7 patients, stable disease in 11 patients, progressive disease in 1 patients, and NE in 9 patients. Grade 3 adverse events included sensory neuropathy in 1 patient, epileptic seizure in 1 patient, dysbasia in 1 patient, viral encephalitis in 1 patient, febril neutropenia in 1 patient, and subcutaneous abscess of the buttocks in 1 patient. Grade 4 epileptic seizure was occurred in 1 patient. There were no cerebral hemorrhage. Conclusion: Bevacizumab did not increase toxicities in patients with brain metastases and appeared to be effective in the treatment of NSCLC patients with brain metastases.

Hypocretin-1 is consistently detectable in the CSF of healthy human subjects, but is absent in narcoleptics. However, functional roles of CSF hypocretin are largely unknown. We examined fluctuation of CSF hypocretin-1 across 24 h and in response to food restriction in rats. Hypocretin-1 levels were high during the dark period when animals were active, but decreased by 40% toward the end of the light (rest) period. After 72 h food deprivation hypocretin-1 levels during the rest phase increased to concentrations similar to those seen during the baseline active phase; however, no increase in response to food deprivation was observed during the active phase. These results indicate an important link between circadian control of sleep and energy homeostasis via the hypocretin system.

This paper provides some evidence of dividend motivated earnings management by Japanese banks under the governmental guideline. The Guideline had limited dividend payment of banks under 40 percent of their current net income until August 1992. A bank potentially violating the Guideline would increasingly manage its earnings in the same fiscal year to stay within the upper bound. The paper examines several banks' earnings models such as Wahlen (1994) and Ahmed and Takeda (1995) and develops a new accruals model of banks. Empirical results significantly support the existence of such earnings management. However, unexplained selection bias may remain.

Prostaglandin (PG) E 2 reportedly augmented wakefulness when continuously infused into the third ventricle of the rat brain, whereas it promoted sleep when continuously infused into the subarachnoid space of the ventral surface zone of the rostral basal forebrain, which was designated previously as a PGD 2 -sensitive sleep-promoting zone (PGD 2 -SZ). In the present study, we investigated the effects of PGE (EP)-receptor agonists on sleep-wakefulness activities by infusing agonists into the third ventricle or into the subarachnoid space of the PGD 2 -SZ. Our results indicated that the waking effect is mediated by EP 1 and EP 2 receptors situating around the third ventricle, whereas the sleep-promoting effect is brought about mainly through activation of EP4 receptors located at or near the subarachnoid space of the PGD 2 -SZ.

We encountered two cases expressing excessive daytime sleepiness (EDS) and manifesting two or more sleep-onset rapid eye movement (REM) periods in the multiple sleep latency test. Unbearable daytime sleepiness occurred abruptly, which usually led to short-lasting naps, after which the patients felt refreshed. The EDS was successfully reduced by treatment with methylphenidate. In spite of these features similar to narcolepsy, these cases of REM hypersomnia did not present cataplexy or other auxiliary symptoms of narcolepsy, and, furthermore, the class-II human leukocyte antigen DR2 appeared to be negative.