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This randomized, open-label, multicenter, parallel study imitating real-world clinical practice assessed the effect of switching to weekly teriparatide in patients with glucocorticoid-induced osteoporosis (GIO) with a lumbar spine/proximal femur bone mineral density (BMD) T-score ≤ −2.0 or ≤−1.0 and a fragility fracture. Forty-four patients were randomized. The mean durations of the corticosteroid and bisphosphonate administrations were 90.0 and 51.3 months. The baseline BMD at L1–L4 was 0.828 and 0.826 g/cm2 in Groups B (bisphosphonate) and T (teriparatide); at the femur (total), these values were 0.689 and 0.661 g/cm2. The mean change in BMD was numerically higher with teriparatide vs. bisphosphonate but not statistically significant. The mean percentage changes from baseline in BMD at L1–L4 after a 72-week treatment were 0.5% and 4.1% in Groups B and T. The incidence of new fractures was higher in the patients taking bisphosphonates vs. those receiving once-weekly teriparatide at 72 weeks (18.2% vs. 11.8%) and 144 weeks (22.7% vs. 17.6%). The mean percentage change in femur (trochanter) BMD (0.035 [0.007–0.063]; p = 0.02) was significantly greater with teriparatide vs. bisphosphonates. Adverse events (AEs) were more frequent with teriparatide vs. bisphosphonates. Switching to once-weekly teriparatide tended to increase lumbar spine BMD and reduce the occurrence of new fractures vs. bisphosphonates.

Introduction Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups. Methods This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician’s discretion to older (O, ≥ 65 years) and younger (Y, 20–64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria. Results Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p

NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.

Nrf2 is a transcription factor that regulates cytoprotective genes in response to oxidative and electrophilic stresses. The activity of Nrf2 is mainly controlled by the protein degradation by Keap1, a ubiquitin E3 ligase adaptor. Most of esophageal squamous cell carcinomas (ESCC) exhibit constitutive Nrf2 activation by Keap1 dysfunction, resulting in the poor prognosis. However, it has not been clarified whether Nrf2 activation serves as the initiation in tumorigenesis of ESCC. We generated tamoxifen-inducible and squamous epithelium-specific Keap1 conditional knockout (Keap1-cKO) mice in which Nrf2 is activated segmentally in esophageal epithelium at the adult stage. Using Nqo1 that is a representative Nrf2 target gene as the marker of Nrf2-acitivated cells, we distinguished Keap1-deleted/Nrf2-activated cells and Nrf2-normal cells in immunohistochemical analysis and gene expression analysis. Single-cell RNA-seq (scRNA-seq) analysis was conducted to compare the gene expression of Nrf2-activated cells and Nrf2-normal cells from Keap1-cKO mice, and control cells from control mice. In Keap1-cKO mice, Nrf2-activated cells accounted for 35% at 1 week and 20% at 4 weeks after induction of Keap1 deletion. This decrease was based on observations that Nrf2-activated cells were eliminated from the epithelium due to the weakened attachment to the basement membrane. In contrast, DNA damage accumulated in Nrf2-normal cells neighboring Nrf2-activated cells. To clarify the cell fate in the esophagus, we compared Nrf2-normal cells to Nrf2-activated cells or control cells in scRNA-seq analysis. Gene sets of G2/M checkpoint and E2F targets, which regulate cell proliferation, were enriched in Nrf2-normal cells. Constitutive Nrf2 activation renders esophageal epithelial cells able to be selectively eliminated via cell competition. Nrf2-normal cells suffered from DNA damage, but not Nrf2-activated cells, have a potency to be an origin of ESCC. These results suggest that Nrf2 activation serves as a tumor promoter of ESCC, but not the initiator. We speculate that the other gene mutations such as Tp53 are needed for the initiation to form ESCC prior to Nrf2 activation.

Objective We compared the 52-week effectiveness and safety of tofacitinib (TOF) and abatacept (ABT) in patients with RA in a real-world setting and investigated a role of human leucocyte antigens (HLA)-DRB1 shared epitope (SE) in the effectiveness. Methods RA patients starting TOF (n = 187) and ABT (n = 183) were enrolled. Effectiveness was compared after reducing the selection bias to a minimum using the inverse probability of treatment weighting (IPTW) based on propensity scores. The influence of SE alleles on effectiveness was compared within each treatment group. A treatment group comparison was also performed within SE-positive and SE-negative groups. Results Herpes zoster and some laboratory abnormalities were more frequent in the TOF group than in the ABT group. Patient characteristics did not differ significantly between treatment groups after adjustments with IPTW. The TOF group had a significantly higher proportion of DAS in 28 joints using ESR (DAS28-ESR) remission at week 52 than the ABT group. The DAS28-ESR at week 12 and thereafter was not affected by the copy number of SE alleles in the TOF group, but decreased significantly as the copy number increased in the ABT group. In SE-positive patients, remission and drug retention rates did not differ significantly between the two treatment groups. In SE-negative patients, the TOF group showed significantly higher remission and drug retention rates than the ABT group. Conclusion The present results suggest that TOF is more effective with regard to remission at week 52 based on treatment responses in SE-negative RA patients.

The 2018 Hokkaido Eastern Iburi Earthquake caused a large number of slope failures/landslides over a wide area. In particular, the enormous damage due to slope failures was centered in the towns of Atsuma and Abira which are located to the north of the epicenter. In Atsuma, a seismic intensity (Japan Meteorological Agency) of seven was observed. This was the first time an earthquake of such a large seismic intensity was recorded in Hokkaido, Japan. The geology in this region was mainly formed by three kinds of pyroclastic fall deposits (fa) due to the erupting of Mt. Tarumae, Mt. Eniwa and Shikotsu Caldera. The most serious damage was generated in these tephra stratus. In addition, the large-scale sliding of rock slopes composed of mudstone occurred in the Hidaka-Horonai River Basin in the Horonai district of Atsuma, and its debris flowed into the river and caused the blockage of the river channel. This paper summarizes the earthquake-induced damage to natural slopes, and presents the physical features and the mechanical properties of the collapsed pyroclastic fall deposits distributed over this area.

Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.

Tsunami deposits were collected along the coast of southwestern Hokkaido and Okushiri Island, northern Japan. The distribution of these deposits suggested that large earthquakes and tsunamis have repeatedly occurred off southwestern Hokkaido. Along the southern coast of Okushiri Island, five tsunami sand/gravel layers have been deposited during the last 3000 years. The latest was deposited by the 1741 Oshima–Oshima landslide tsunami and the second by the 12th century tsunami. The later tsunami was probably generated by a large earthquake because submarine seismo-turbidites with similar age exist in the region and a large inland landslide had occurred in Okushiri Island in approximately the 12th century. The ages of paleo-tsunami events prior to the 12th century are 1.5–1.6, 2.4–2.6, 2.8–3.1 ka. In this study, a fault model of the 12th century earthquake was estimated by comparing tsunami deposit distributions and calculated tsunami inundation areas at five sites in Okushiri Island and Hiyama region. Fault model F17, a submarine active fault in the Japan Sea near Oshima–Oshima, is a probable source for this tsunami. Numerical simulation of the tsunami was performed based on fault model F17; we modified the fault parameters (length and slip amount) from the original model to explain tsunami deposit distributions. A shorter length of 104 km and a larger slip amount of 18 m were appropriate for the fault model on the basis of parametric studies. The seismic moment of the earthquake was calculated to be 9.95 × 1020 Nm (Mw 7.9) assuming a rigidity of 3.43 × 1010 N/m2. The estimated fault model is located between the focal regions of the 1993 Hokkaido Nansei-oki earthquake and the 1983 Japan Sea earthquake.

Highlights • We report a case of esophageal cancer treated with PDT followed by esophagectomy. • We assessed the PDT effect on adjacent tissues based on surgery and pathology. • PDT can cause intense inflammation in tissues adjacent to the tumor. • The location should be considered when performing salvage esophagectomy after PDT., Introduction Photodynamic therapy (PDT) is performed as a salvage treatment for patients with residual or recurrent esophageal cancer after chemoradiotherapy (CRT). Although PDT is considered less invasive than salvage surgery, it is unclear how deep its effects are and whether it causes damage to adjacent tissues. Herein, we report a case of esophageal cancer treated with PDT followed by esophagectomy. In this case, we evaluated the effect of PDT on adjacent tissues based on surgical and pathological examination. Presentation of case A 58-year-old man with dysphagia was diagnosed with esophageal squamous cell carcinoma (SqCC; T1N0M0, Stage I) in the upper thoracic esophagus. He underwent definitive CRT with two courses of 5-fluorouracil and cisplatin every 4 weeks with 60 Gy of radiation. Twelve months after CRT, endoscopic examination revealed local recurrence, and PDT using talaporfin sodium was performed. The tumor recurred again 6 months after PDT, and robot-assisted thoracoscopic esophagectomy was performed as a definitive treatment. Tissues around the left side of the esophagus and thoracic duct were tightly adherent with severe fibrosis and were successfully removed by extended resection. Histopathological examinations showed that the esophageal wall and peri-esophageal tissue were replaced by fibrous tissue and this extended even beyond the tumor. Discussion The primary tumor was limited to the submucosal layer, and the target for irradiation had some longitudinal margins. Therefore, PDT can cause intense inflammation in tissues adjacent to the tumor. Conclusions It is necessary to consider the location when performing salvage esophagectomy after PDT.

Patients with rheumatoid arthritis (RA) are at an increased risk of Mycobacterium avium complex pulmonary disease (MAC-PD). We aimed to identify factors associated with MAC-PD in RA patients, and investigate their clinical significance for diagnosis of this disease.We examined 396 patients with RA for the presence of MAC-PD, using the criteria of the American Thoracic Society and conducted three years of follow-up on these patients. Multivariate logistic analyses were employed for selecting factors associated with MAC-PD. We developed a point system based on these factors which we call MAC-PD score to improve diagnosis of MAC-PD.During this study, 14 out of 396 patients were newly diagnosed with MAC-PD. Multivariate analyses revealed body mass index (BMI) 18.0 kg/mUsing these data, in the forms of the MAC-PD score, could help to identify patients who should be considered for bronchoscopy more selectively.

We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5- c ]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.).

The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).

Mt. Usu is a stratovolcano located on the southern side of the Toya caldera in Hokkaido, Japan. In historical times it emitted dacitic products associated to remarkable crustal deformations. Usu volcano erupted on March 31st 2000 after 23 yr of dormancy and this eruption was the fourth in the 20th century. Secular variations in water levels, temperature and chemical compositions of thermal water have been observed around Usu volcano. The water levels decreased since October 1999, 6 months prior to the eruption. The decrease in water levels is a precursory change and is probably due to leakage of thermal water from the shallow aquifer hosting it. No variations in temperature and chemical composition of thermal water were evident prior to the eruption. However, in a few wells, the temperature of the thermal water increased by up to 15 °C with respect to the pre-eruptive values. Moreover, the concentration of some solutes (Na, K, Cl and SO4) became higher after the eruption. These thermal and chemical changes are ascribable to increased input of a deep hydrothermal liquid into the shallow groundwater aquifer.

石狩平野・夕張山地・富良野盆地を横断し，山麓に分布する変動地形を観察するとともに，夕張山地の大規模地すべり地形とその移動体を貫通したトンネルの見学を行なう．石狩低地東縁断層帯では，ブラインドスラストが形成した段丘面の緩やかな傾動や撓曲変形を観察する．断層帯周辺は縄文時代以降の遺跡の密集地帯であり，発掘により多くの地震性地すべりの痕跡が発見されている．それらも観察できるかもしれない．富良野断層帯では盆地の両側に分布する断層崖や地形面の傾動を観察するとともに，傾斜した十勝火砕流堆積物とこれを覆う砂礫層や断層の剥ぎ取り標本を観察する．一方，両断層帯に挟まれた夕張山地の蛇紋岩や白亜系蝦夷累層群・新第三系の分布域には大規模な地すべり地形が分布する．道道夕張新得線赤岩トンネルは蛇紋岩と付加体構成岩類からなる大規模地すべり移動体を貫くトンネルである．本コースは，活断層・地すべり・トンネルなど，変化に富む巡検となっている．現地での様々な議論を期待する．

Introduction The aim of this study was to investigate the diagnostic performance of measuring antibodies to the glycopeptidolipid (GPL) core antigen specific to Mycobacterium avium complex (MAC) in patients with rheumatoid arthritis (RA). Methods We cross-sectionally investigated anti-GPL antibodies and radiographs of 396 patients with RA. A diagnosis of MAC pulmonary disease (MAC-PD) was made according to the criteria by the American Thoracic Society and the Infectious Diseases Society of America. Serum immunoglobulin A antibodies to MAC-specific GPL core antigen were measured by an enzyme immunoassay. All patients with RA with abnormal shadows on chest x-rays underwent chest computed tomography (CT). Bronchoscopy was performed on patients with negative cultures for MAC by expectorated sputum and positive CT findings compatible with MAC-PD. Results Ten patients were newly diagnosed with MAC-PD. Eight individuals who already had diagnoses of MAC-PD at the time of enrollment and nineteen who had negative expectorated sputum cultures for MAC and positive CT images compatible with MAC-PD and who refused bronchoscopy were excluded from the following analysis. Anti-GPL antibodies were detected in 12 of 369 patients. Eight of the ten patients with MAC-PD and 4 of 359 patients without MAC-PD tested positive for the anti-GPL antibodies. The specificity and sensitivity were 99 % and 80 %, respectively. Positive and negative predictive values were 67 %, and 97 %, respectively. When we analyzed diagnostic performance of the antibodies in 57 patients with RA who had abnormal shadows on chest x-rays, the positive and negative predictive values were 100 %, and 96 %, respectively. Twelve patients underwent bronchoscopy. Bronchoalveolar lavage fluid (BALF) samples from six patients were positive for MAC, and BALF samples from the remainder were negative. Anti-GPL antibodies were detected in the sera of all six patients with positive results for MAC by BALF sampling, whereas the antibodies were not detected in the sera from the remainder with negative results for MAC by BALF sampling. Conclusions The measurement of anti-GPL antibodies is useful as a supplementary diagnostic tool for MAC-PD in patients with RA and may provide a new strategy, in combination with chest x-ray and CT, for differentiating MAC-PD from other pulmonary comorbidities in patients with RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0787-y) contains supplementary material, which is available to authorized users.

Heme oxygenase-1 (HO-1) is a 32 kDa heat shock protein (HSP) that catalyzes heme to biliverdin, free iron and carbon monoxide in the brain. Furthermore, the release of free ferrous ion by HO-1 plays an essential role in ferritin synthesis, and ferritin stores iron either for intracellular utilization, or for detoxification. It is well known that HO-1 immunoreactivity is enhanced greatly in neurons and glia of the hippocampus and cerebral cortex in various pathophysiological conditions. The expression of HSP 70 is well known for the age-associated increase, but the expression modalities of HO-1 and ferritin associated with aging are still unknown. A study was therefore performed to examine the correlations in the expression of HO-1 and ferritin with age using immunohistochemistry. We investigated 31 autopsied brains (3-84-year-olds) without traumatic brain injury and neurodegenerative disease. The specimens were taken from the cerebral cortex and hippocampus. In the cerebral cortex, age (aging) had a statistically significant positive correlation with HO-1 (r=0.894, P

The stratigraphy of tsunami deposits along the Japan Sea, southwest Hokkaido, northern Japan, reveals tsunami recurrences in this particular area. Sandy tsunami deposits are preserved in small valley plains, whereas gravelly deposits of possible tsunami origin are identified in surficial soils covering a Holocene marine terrace and a slope talus. At least five horizons of tsunami events can be defined in the Okushiri Island, the youngest of which immediately overlies the Ko-d tephra layer (1640 AD) and was likely formed by the historical Oshima-Ohshima tsunami in 1741 AD. The four older tsunami deposits, dated using accelerator mass spectrometry 14C, were formed at around the 12th century, 1.5–1.6, 2.4–2.6, and 2.8–3.1 ka, respectively. Tsunami sand beds of the 1741 AD and circa 12th century events are recognized in the Hiyama District of Hokkaido Island, but the older tsunami deposits are missing. The deposits of these two tsunamis are found together at the same sites and distributed in regions where wave heights of the 1993 tsunami (Hokkaido Nansei-oki earthquake, Mw = 7.7) were less than 3 m. Thus, the 12th century tsunami waves were possibly generated near the south of Okushiri Island, whereas the 1993 tsunami was generated towards the north of the island. The estimated recurrence intervals of paleotsunamis, 200–1100 years with an average of 500 years, likely represents the recurrence interval of large earthquakes which would have occurred along several active faults offshore of southwest Hokkaido.

We describe the case of a 46-year-old woman with Sjögren's syndrome (SS) presenting with a 6-year history of polyuria and polydipsia. Laboratory data revealed hyperchloremic metabolic acidosis, a normal anion gap, and an inability to acidify urine following an acid loading test and to concentrate the urine in response to water deprivation and antidiuretic hormone administration. Lymphocyte infiltration in the interstitium was found on renal biopsy. These findings allowed us to diagnose distal renal tubular acidosis (RTA) and nephrogenic diabetes insipidus (NDI). Steroid pulse therapy resulted in normalization of the blood pH, but failed to remit the inability to concentrate the urine. These observations suggest therapeutic applications for RTA in SS, and that further investigation is required to design a therapeutic strategy for NDI in SS.

(2009). Reevaluation of antibody titers 1 year after influenza vaccination in patients with rheumatoid arthritis receiving TNF blockers. Modern Rheumatology: Vol. 19, No. 2, pp. 216-218.

The recent widespread employing of potent biologic agents targeting tumor necrosis factor (TNF) for the therapy of rheumatoid arthritis (RA) raises the question as to whether patients treated in this way respond normally to the infl uenza vaccine. To the best of our knowledge, there are only a few articles in the English language literature discussing this issue, and no data have been reported from Japan. We therefore studied the humoral immune response to infl uenza vaccination in Japanese patients with RA who were treated/not treated with anti-TNF biologics in comparison with healthy controls.

We present a case of fatal adrenal crisis due to isolated adrenocorticotropic hormone (ACTH) deficiency. Autopsy revealed each adrenal gland weighed 0.9 g and the adrenal cortexes were very thin and atrophic. Additionally, cortisol could not be observed in the adrenal cortex by immunohistochemical staining. Furthermore, urine cortisol and 17-OHCS concentration had decreased to a very low level, 20 mg/L and 0.8 mg/L respectively. The anterior pituitary gland was atrophic, and showed fibrosis and lymphocytosis was suspected. Immunohistochemically growth hormone (GH)-stained pituitary gland cells were observed, but there were no cells stained with anti-ACTH antibody. From the history and pathological findings, no other deficiencies of pituitary hormones were evident. Therefore, isolated ACTH deficiency was suspected. Furthermore, as the thyroid gland showed lymphocytic thyroiditis, is was considered that isolated ACTH deficiency was associated with an autoimmune cause. Generally, as patients of chronic adrenocortical insufficiency are exposed to stress and, therefore, have an increased requirement for glucocorticoids, the blood pressure falls, leading to hypovolemic shock called " an adrenal crisis." Without treatment, patients die in crisis within several hours. In our case, the deceased had drunk alcohol without sleep for 2 days. We believe that the stress of drinking and sleeplessness induced adrenal crisis and caused his death.

A double-blind comparative study among 9 medical centers was conducted in order to investigate the optimal daily administration schedule of UHAC62 (Generic name: Meloxicam), a kind of non-steroidal anti-inflammatory oxycam agent. The daily 10 mg of UHAC62, which had been considered as an optimal dose, was administered either once daily, immediately after supper (Group O), or given twice a day divided into 5 mg immediately after breakfast and supper (Group T), both for weeks to patients with rheumatoid arthritis.Out of the total 52 patients, 1 patient was excluded from the analyses; and 41 patients (Group O: 23 cases, Group T: 18 cases), 51 patients (Group O: 27 cases, Group T: 24 cases) and 44 patients (Group O: 24 cases, Group T: 20 cases) were subjected to the ratings of Final Global Improvement, Overall Safety, and Usefulness, respectively. The results showed the following:(1) The ratio of the patients who showed a better than “Moderate Improvement” in the Final Global Improvement Rating was 30.4 % and 27.8 % in the Group O and Group T, respectively.(2) The ratio of the patients on whom the test drug was shown to be “Completely Safe” in the Overall Safety Rating was 88.9% and 91.7% in the Group O and Group T, respectively. All of the adverse drug reactions which were seen in the patients of Group O and the 2 patients of the Group T were assessed as “mild”.(3) The ratio of the patients on whom the test drug was rated as better than “Useful” was 29.2% and 25.0 % in the Group O and Group T, respectively.There was no significant difference in the overall evaluations and the improvement rating of the symptoms between the groups.According to these results, it was considered that the once daily administration of UHAC62 might be more promising for materializing a higher compliance in the patients who need long-term administration, although both regimens, the once and the twice daily administrations are applicable.

Using immunohistochemical staining, the histological changes and the presence of neuropeptides (enkephalin and VIP) in the carotid body have been investigated in medico-legal autopsy cases, especially asphyxia cases. Only in cases of manual and/or ligature strangulation cases that sustained a force near the carotid body, were the chief cells mainly lightly stained, indicating that they had been "active" cells. Furthermore, these cells and their nuclei were enlarged in comparison to the chief carotid body cells in other autopsy groups. It was thus felt that these changes had resulted from the force that had directly affected the carotid body. Based on these findings, it was concluded that immunohistochemical investigation of the carotid body offers a useful possibility for diagnosing manual asphyxia, especially in autopsy cases involving strangulation.

A tephrostratigraphic and petrological study of the Chikurachki (1816 m)-Tatarinov-Lomonosov volcanic chain (CTL volcanic chain) and Fuss (1772 m), located at the southern part of Paramushir Island in the northern Kurile Islands, was carried out to reveal the explosive eruption history during the Holocene and the temporal change of the magma systems of these active volcanoes. Tephra successions were described at 54 sites, and more than 20 major eruptive units were identified, consisting of pumice fall, scoria fall and ash fall deposits, each of which are separated by paleosol or peat layers. The source volcano of each recognized tephra layer was confirmed by correlation with proximal deposits of each eruption center with respect to petrography and whole-rock and glass chemistry. The age of each layer was determined by radiocarbon dating and the stratigraphic relationship with the dated, widespread tephra from Kamchatka according to the thickness of paleosols bracketed between tephra layers. The Holocene activity in this region was initiated by eruptions from the Tatarinov and Lomonosov volcanoes. After the eruptions, the Fuss and Chikurachki volcanoes started their explosive activities at ca. 7.5 ka BP, soon after the deposition of widespread tephra from the Kurile Lake caldera in southern Kamchatka. Compared with Fuss located on the back-arc side, Chikurachki has frequent, repeated explosive and voluminous eruptions. Whole-rock compositions of the rocks of the CTL volcanic chain and Fuss are classified into medium-K and high-K groups, respectively. These suggest that magma systems beneath the CTL volcanic chain and Fuss differ from each other and have been independently constructed. The rocks of the Chikurachki volcano are basalt-basaltic andesite and have gradually evolved their chemical compositions; when graphed on a SiO2-oxide diagram, these form smooth trends from mafic to more felsic. This suggests that the magma system evolved mainly by fractional crystallization. In contrast, matrix glass chemistries for Fuss pumices are distinct for each eruption and show different K2O levels on a SiO2-K2O diagram. This implies that the magma system of Fuss has been frequently replaced. Both volcanoes have been active under the same subduction system. However, the Chikurachki volcano will continue eruptive activity under a stable magma system with a higher magma discharge rate, whereas Fuss may continue construction with an intermittent supply of distinct, small magma batches.

Active uptake of a free fatty acid, oleate, and its incorporation into triacylglycerol and phospholipid in the human monocytic cell line, U937, was identified using 14C-labelled oleate. Excess triacylglycerol accumulates in the form of lipid droplets in the cytoplasm. The extent of lipid droplet formation in each cell can be assessed in the absence of any staining by 90° light scatter intensity, one of the basic parameters of flow cytometry.Key words: monocyte, free fatty acid, triacylglycerol, flow cytometry.

A straightforward, efficient method for the synthesis of 5-formyl-2′-deoxyuridine (dfU) and solid-phase synthesis of oligodeoxynucleotides containing dfU using a phosphoramidite method are described. The synthesis of dfU is achieved by oxidation of the 5-methyl group in thymidine derivatives. However, incorporation of the dfU 3′-O-phosphoramidite into oligodeoxynucleotides proceeds in low yield, due to instability of the 5-formyl group under conditions used for automated DNA synthesis. Therefore, oligodeoxynucleotides containing a 5-(1,2-dihydroxyethyl)uracil derivative are first prepared and finally oxidized by periodate to give the desired oligodeoxynucleotides containing 5-formyluracil. Curr. Protoc. Nucleic Acid Chem. 35:1.21.1-1.21.19. © 2008 by John Wiley & Sons, Inc. Keywords: 5-formyl-2′-deoxyuridine; thymidine; oligodeoxynucleotide; oxidation; oxidative damage; chemical synthesis

5-Formyl-2'-deoxyuridine (fdUrd) is derived from the oxidation of thymidine and is known to induce mutation (A:T to G:C) in DNA. We planned to develop a novel selective detection method for fdUrd in oligodeoxynucleotide (ODN) based on specific fluorescent derivatization of fdUrd using 2-aminothiophenol derivatives (ATs) as fluorogenic reagents. To achieve this goal, we first synthesized 5-(benzothiazol-2-yl)-2'-deoxyuridine derivatives (btdUrds) via the reaction between fdUrd and 5-substituted ATs. We report herein the synthesis and UV absorbance and fluorescence properties of btdUrds in different pH conditions.

Inflammatory changes (synovitis and bone marrow edema) and destructive changes (bone erosion) were evaluated by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA), and their relations with disease activity were assessed during treatment with tumor necrosis factor (TNF) inhibitors. Ten patients with early active RA underwent MRI at 0 and 16 weeks of TNF-inhibitor treatment. The carpal bones of the dominant hand were evaluated by the outcome measures in rheumatology clinical trials MRI score for RA. After 16 weeks, the mean disease activity score (DAS 28) decreased significantly from 5.54 to 2.70, while the number of tender joints, number of swollen joints, and inflammatory parameters were also significantly improved. The mean synovitis and marrow edema scores determined by MRI showed a significant decrease from 6.1 to 2.2 and 12.8 to 6.2, respectively, while the annual bone-erosion progression score decreased from 12.6 to 2.0. Although synovitis persisted in some patients, imaging remission was achieved in two patients. In conclusion, TNF-inhibitor therapy achieved an early decrease of disease activity and MRI revealed amelioration of joint destruction. The MRI score for RA is useful for assessing the early response to TNF inhibitors.

Tyatya Volcano, situated in Kunashir Island at the southwestern end of Kuril Islands, is a large composite stratovolcano and one of the most active volcanoes in the Kuril arc. The volcanic edifice can be divided into the old and the young ones, which are composed of rocks of distinct magma types, low- and medium-K series, respectively. The young volcano has a summit caldera with a central cone. Recent eruptions have occurred at the central cone and at the flank vents of the young volcano. We found several distal ash layers at the volcano and identified their ages and sources, that is, tephras of ad 1856, ad 1739, ad 1694 and ca 1 Ka derived from three volcanoes of Hokkaido, Japan, and caad 969 from Baitoushan Volcano of China/North Korea. These could provide good time markers to reveal the eruptive history of the central cone, which had continued intermittently with Strombolian eruptions and lava flow effusions since before 1 Ka. Relatively explosive eruptions have occurred three times at the cone during the past 1000 years. We revealed that, topographically, the youngest lava flows from the cone are covered not by the tephra of ad 1739 but by that of ad 1856. This evidence, together with a report of dense smoke rising from the summit in ad 1812, suggests that the latest major eruption with lava effusion from the central cone occurred in this year. In 1973, after a long period of dormancy, short-lived phreatomagmatic eruptions began to occur from fissure vents at the northern flank of the young volcano. This was followed by large eruptions of Strombolian to sub-Plinian types occurring from several craters at the southern flank. The 1973 activity is evaluated as Volcanic Explosivity Index = 4 (approximately 0.2 km3), the largest eruption during the 20th century in the southwestern Kuril arc. The rocks of the central cone are strongly porphyritic basalt and basaltic andesite, whereas the 1973 scoria is aphyric basalt, suggesting that magma feeding systems are definitely different between the summit and flank eruptions.

5-Formyl-2'-deoxyuridine (fdUrd) is a product of the oxidation of thymidine and is known to induce mutation (A:T to G:C) in DNA. Therefore, a selective detection method for fdUrd is needed, but convenient methods have not been developed. We planned to develop a novel selective method to detect fdUrd in damaged DNA based on a specific fluorogenic derivatization of fdUrd using 2-aminothiophenol derivatives (ATs) as fluorogenic reagents. To achieve this goal, we first investigated the synthesis and fluorescence properties of some 5-(benzothiazol-2-yl)-2'-deoxyuridine derivatives (btdUrds). We also report the reaction between oligodeoxynucleotides (ODNs) containing fdUrd and ATs.

A three-allele variant with Gc 2, Gc 1F and Gc 1A2 alleles was detected in both a baby and his mother during paternity testing by isoelectric focusing. His father had a normal Gc phenotype, Gc 2-1F. Further examination of his mother's relatives revealed that his grandfather also had the same three-allele variant, while his grandmother and his aunt had normal Gc 2-1F and Gc 2-2. From these results, it was considered that the Gc 1F and Gc 1A2 alleles were on the same single chromosome. It was suggested that recombination had occurred between two chromosomes that had the Gc 1F and Gc 1A2 allele, respectively, forming the variant allele Gc 1F1A2 on a single chromosome.