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To our knowledge, there have been no reports of first-line lenvatinib (LEN) and LEN re-challenge following atezolizumab/bevacizumab (Atezo-Bev) failure in the same patient. We herein report a patient with advanced hepatocellular carcinoma who failed either 1st line LEN and 2nd line Atezo-Bev, and successfully achieved complete response to LEN rechallenge with sequencial TACE. This patient had a poor response to TACE before immunotherapy and introduction of molecular-targeted drugs but showed a good response to selective TACE after LEN rechallenge. Our findings suggest the need to reconsider the use of molecular-targeted drugs and TACE with advances in immunotherapy.

Background Patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) who receive systemic chemotherapy have a poor prognosis. This study aimed to determine if one-shot cisplatin (CDDP) chemotherapy via hepatic arterial infusion (HAI) combined with radiation therapy (RT) prior to systemic chemotherapy could improve the outcomes of these patients. Methods This study consisted of 32 HCC patients with the following eligibility criteria: (i) portal vein invasion 3/4 and/or hepatic vein invasion 2/3; (ii) received one-shot CDDP via HAI; (iii) received RT for MVI, (iv) a Child–Pugh score ≤ 7; and (v) an Eastern Clinical Oncology Group Performance Status score of 0 or 1. To determine the therapeutic effect, we collected information on patient characteristics and took contrast-enhanced computed tomography at the start of the therapy and every 2 to 4 months after the start of therapy. We evaluated the overall response of the tumor and tumor thrombosis according to modified Response Evaluation Criteria in Solid Tumors. We assessed patient data using the Mann–Whitney U and Fisher exact tests and evaluated overall survival and progression-free survival using the log-rank test. Results The overall response rate at the first evaluation performed a median of 1.4 weeks after HAI was 16% for the main intrahepatic tumor and 59% for the MVI. The best responses were the same as those of the first-time responses. The duration of median survival was 8.6 months, and progression-free survival of the main intrahepatic tumor was 3.2 months. Predictive factors for overall survival were the relative tumor volume in the liver and the first therapeutic response of MVI. There were no severe adverse events or radiation-induced hepatic complications. Conclusions One-shot CDDP via HAI and RT were well tolerated and showed immediate and favorable control of MVI. Thus, this combination shows potential as a bridging therapy to systemic chemotherapy.

Rationale: Various treatments are available for treating hepatocellular carcinoma (HCC). The immune checkpoint inhibitor combination of atezolizumab plus bevacizumab was recently approved for the treatment of unresectable HCC, but there are few reports on the failure of the combination treatment. Here, we present a case of unresectable HCC with adrenal metastasis that was eventually operated on after lenvatinib (LEN) treatment that followed failed treatment with atezolizumab plus bevacizumab. Patient concerns: A 68-year-old man was diagnosed with non-alcoholic steatohepatitis-based HCC with adrenal metastasis. Diagnosis: Cirrhosis was classified as Child-Pugh score of 5. HCC was diagnosed as Barcelona Clinic Liver Cancer stage C. Interventions: We initiated treatment with atezolizumab plus bevacizumab. Liver dysfunction appeared 2 days after the first administration but was improved by intravenous rehydration and did not appear after the second course. The HCC shrank, but the adrenal metastasis grew bigger after the fourth course, so we changed the therapy to LEN. After HCC and adrenal metastasis were necrotic by LEN, conversion surgery was performed. Outcomes: After successful conversion therapy, the general condition of the patient was good, and has been carefully followed for 4 months to date without any evidence of further recurrences. Lessons: This case showed that even if atezolizumab plus bevacizumab is not effective, multidisciplinary treatment such as LEN and conversion surgery is possible. Given the efficacy of LEN after atezolizumab plus bevacizumab, it is important to consider that there is a possibility of cure even when first-line treatment is not effective for a patient with unresectable HCC.

Summary Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c 1c 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p vs 283 [22%] in the conventional therapy group, p vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Aim To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis. Methods A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child–Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events. Results All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm3 (range, 0.18–16.63) and 0.37 cm3 (range, 0–5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18–100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD

Background and Aim To assess the short- and long-term outcome of patients with gastric varices (GV) after balloon-occluded retrograde transvenous obliteration (B-RTO) by comparing bleeding cases with prophylactic cases. Methods Consecutive 100 patients with GV treated by B-RTO were enrolled in this retrospective cohort study. We compared the technical success, complications, and survival rates between bleeding and prophylactic cases. Results Of 100 patients, 61 patients were bleeding cases and 39 patients were prophylactic cases. Technical success was achieved in 95% of bleeding case and in 100% of prophylactic case, with no significant difference between these groups (overall technical success rate, 97%). The survival rates at 5 and 10 years were 50% and 22% in bleeding case, and 49% and 36% in prophylactic case, respectively. There was also no significant difference (P = 0.420). By multivariate analysis, survival rates correlated significantly with liver function (hazard ratio 2.371, 95% CI 1.457–3.860, P = 0.001) and hepatocellular carcinoma development (HR 4.782, 95% CI 2.331–9.810, P

Aim Steatosis is a common histological feature of chronic liver disease, especially alcoholic and non-alcoholic fatty liver disease, as well as chronic hepatitis C. A recent study showed that evaluating the controlled attenuation parameter (CAP) with transient elastography was an efficient way of non-invasively determining the severity of hepatic steatosis. The objective of this study was to prospectively evaluate the utility of CAP for diagnosing steatosis in patients with chronic liver disease. Methods One hundred and fifty-five consecutive patients with suspected chronic liver disease underwent steatosis diagnosis using CAP, blood sample analyses, computed tomography for assessing the liver/spleen ratio and liver biopsy. Steatosis was graded according to the percentage of fat-containing hepatocytes: S0, less than 5%; S1, 5–33%; S2, 34–66%; and S3: more than 66%. Results The CAP was significantly correlated with steatosis grade, and there were significant differences between the CAP value of the S0 patients and those of the patients with other grades of steatosis. S0 and S1–3 hepatic steatosis were considered to represent mild and significant steatosis, respectively. The CAP values of the patients with mild and significant steatosis were significantly different (P

Pain is a complex experience involving sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been extensively studied, those underlying its affective component have yet to be elucidated. Recently, we reported that corticotrophin-releasing factor (CRF)-induced depolarization in type II neurons within the dorsolateral bed nucleus of the stria terminalis (dlBNST) is critical for pain-induced aversive responses in rats. However, the intracellular signaling underlying the excitatory effects of CRF and the contribution of such signaling to the induction of pain-induced aversion remain unclear. In the present study, we addressed these issues by conducting whole-cell patch-clamp recordings in rat brain slices and by undertaking behavioral pharmacological analyses. Intracellular perfusion of protein kinase A (PKA) inhibitor Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS) or KT5720 suppressed the excitatory effects of CRF in type II dlBNST neurons, and bath application of Rp-cAMPS also suppressed it. In addition, bath application of forskolin, an adenylate cyclase (AC) activator, mimicked the effects of CRF, and pretreatment with forskolin diminished the excitatory effects of CRF. Furthermore, a conditioned place aversion (CPA) test showed that co-administration of Rp-cAMPS with CRF into the dlBNST suppressed CRF-induced CPA. Intra-dlBNST injection of Rp-cAMPS also suppressed pain-induced CPA. These results suggest that CRF increases excitability of type II dlBNST neurons through activation of the AC-cAMP-PKA pathway, thereby causing pain-induced aversive responses. The present findings shed light on the neuronal mechanisms underlying the negative affective component of pain and may provide therapeutic targets for treating intractable pain accompanied by psychological factors.

The Goto station of the Japan Sea-Farming Association conducted marine ranching experiments with striped jack Pseudocaranx dentex from 1988 to 1999 in the Goto Islands, Nagasaki, Japan. Marine ranching is a stocking method where released fish are fed for some period after release in order to decrease initial mortality from starvation. Ranched fish were fed for 0, 90, and 15 days after stocking in 1997, 1998, and 1999, respectively. During the experiment, herons (grey heron Ardea cinerea, black-crowned night heron Nycticorax nycticorax, and great egret Egretta alba) were often observed preying on released fish in the ranching area. The present study estimated the number of fish preyed upon by herons during observation periods in 1997, 1998, and 1999 from the number of herons that flew into the ranching area and the predation rate on ranched fish by herons. The former was counted during sightings. The latter was estimated from the sighting observations and heron regurgitations. The number of herons that flew into the ranching area increased with the feeding period. The numbers of fish lost to predation by herons in 1997, 1998, and 1999 were estimated to be 0, 5,741, and 829, respectively.

The surface composition of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM] [PF 6 ]) and 1-butyl-3-methylimidazolium dicyanamide ([BMIM] [DCA]) are studied by high-resolution Rutherford backscattering spectroscopy. Although [BMIM] [PF 6 ] is almost stoichiometric up to the topmost molecular layer, considerable deviation from the theoretical stoichiometry is observed for [BMIM] [DCA] in a surface layer of ∼1.5 nm thickness. Nitrogen is almost completely depleted in this layer while carbon is enhanced. In addition, there are oxygen impurities of ∼3 × 10 14 atoms/cm 2 in this surface layer. With the help of X-ray photoelectron spectroscopy measurements it is concluded that the surface of [BMIM] [DCA] is covered by ∼1.7 × 10 14 molecules/cm 2 of esters and/or carboxylic acids. These contaminant molecules have a preferred orientation, i.e. the carbonyl groups are on the surface of [BMIM] [DCA] and the alkyl chains are pointing towards vacuum. The origin of the contamination layer could be the surface segregation of bulk impurities.

The surface of an ionic liquid, 1-hexyl-3-methyl-imidazolium bis(trifluoromethanesulfonyl) imide ([HMIM] [TFSI]), is observed by high-resolution Rutherford backscattering spectroscopy (HRBS). The composition depth profiles are derived from the observed HRBS spectrum through spectrum simulation. Although the overall composition is in good agreement with the stoichiometric composition the profiles have some structures at the surface. The concentrations of fluorine and carbon are enhanced while those of oxygen and nitrogen are reduced at the surface. These results indicate that both [HMIM] cation and [TFSI] anion show preferred orientations at the surface. The hexyl group of [HMIM] and CF3 groups of [TFSI] point toward the vacuum in the outermost molecular layer.

The surface of an ionic liquid, trimethylpropylammonium bis(trifluoromethanesulfonyl)imide ([TMPA] [TFSI]), is observed by high-resolution Rutherford backscattering spectroscopy (HRBS). The composition depth profiles are derived from the observed HRBS spectra through spectrum simulation. The observed composition is in good agreement with the stoichiometric composition at depths larger than ∼1 nm. The observed composition profiles, however, show pronounced structures at the surface. Fluorine profile has a sharp peak at ∼0.1 nm and a broad peak at ∼1.0 nm. The sulfur profile also has a peak at ∼0.35 nm. These results indicate that the molecules show preferred orientations at the surface. From the observed profiles, it was concluded that the C 1 conformer of the [TFSI] anion is dominant over the C 2 conformer at the surface in contrast to bulk, where the C 2 conformer is known to be dominant. It was also found that C 1 conformers are oriented with their CF 3 groups pointing toward the vacuum in the outermost molecular layer.

Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying its affective component. The bed nucleus of the stria terminalis (BNST) has been implicated in stress responses and negative affective states, such as anxiety, fear, and aversion. Recently, we demonstrated the crucial role of the BNST in the negative affective component of pain using the conditioned place aversion (CPA) test. In the present study, we investigated the involvement of the β-adrenoceptor–protein kinase A (PKA) signaling pathway within the BNST, in particular, within the ventral part of the BNST (vBNST), in pain-induced aversion in male Sprague Dawley rats.In vivomicrodialysis showed that extracellular noradrenaline levels within the vBNST were significantly increased by intraplantar formalin injection. Using the CPA test, we found that intra-vBNST injection of timolol, a β-adrenoceptor antagonist, dose-dependently attenuated the intraplantar-formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. Experiments with subtype-selective antagonists demonstrated the essential role of β2-adrenoceptors in F-CPA. Intra-vBNST injection of isoproterenol, a β-adrenoceptor agonist, dose-dependently produced CPA even in the absence of noxious stimulation. This isoproterenol-induced CPA was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. Together, these results suggest that PKA activation within the vBNST via the enhancement of β-adrenergic transmission is important for the negative affective component of pain.

Caulerpa lentillifera is a kind of edible seaweed, known as 'sea grape' or 'green caviar'. It is used in fresh salads. However, it is sensitive to low temperature and osmotic pressure, and is easily spoilt by storage in a refrigerator or washing with tap water. That is the reason why it is difficult to prevent food poisoning, especially due to Vibrio parahaemolyticus. In this study we investigated of marine bacteria and V. parahaemolyticus in C. lentillifera and cultured them in order to develop effective control of bacteria in commercial farms. The sixteen farms in the Okinawa Islands were investigated from August to September in 2006. A total of 176 samples were collected from eleven points during the cultivation processes and from the products. About 10(3) cfu/mL of marine bacteria were detected in the seawater used in the tank culture, but after cultivation of C. lentillifera the number had increased to about 10(6) cfu/mL. The number of marine bacteria in C. lentillifera did not change significantly through the process of planting to the final product (about 10(7) cfu/g). V. parahaemolyticus was detected in seawater from all processes and C. lentillifera was isolated from 56% of seawater, 25% of seed-stocks, and 18.8% of product samples, though but thermostable direct hemolysin gene was not detected from enrichment cultures or isolated V. parahaemolyticus strains. These results indicate that for prevention of food poisoning by V. parahaemolyticus in C. lentillifera, it is important to establish a suitable sterilization procedure for each process.

Marine ranching of striped jack Pseudocaranx dentex was undertaken at the Goto Station of the Japan Sea-Farming Association between 1988 and 1999. This stocking method aimed at protecting the released fish from predators and preventing dispersion by feeding for a certain period. The present study examined the reduction process in the number of ranched striped jack and the conditions required to keep the fish in the ranched area. We estimated the sighting rate and the dispersion coefficient from the ranched area per day from 1993 to 1999, on the assumption that natural mortality can be ignored, using the observed number of fish from the sighting observation. The number of fish that remained was represented by a decreasing exponential function of day. This decreasing process was divided into six phases at most. We found two phases when the number of fish that remained markedly decreased in 1993 and 1995. In the first phase, the dispersion was caused by lack of food due to an increased food demand caused by the growth of fish. In the second phase, the ranched fish moved out from the ranched area due to the cessation of feeding. This dispersion was also observed in other years when feeding was stopped.

Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs. A total of 85 surgically resected nodules (≤30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB-MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared. Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95 % confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682–0.890): CEUS, 0.784 (0.679–0.889), in combination, 0.876 (0.792–0.959). The sensitivity, specificity, and accuracy were 64.1 %, 95.7 %, and 81.2 % in EOB-MRI, 56.4 %, 97.8 %, and 78.8 % in CEUS, and 84.6 %, 95.7 %, and 90.6 % in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS. Combined diagnosis by EOB-MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs. • Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. • Macroscopic classification is useful to choose the treatment strategy for small HCCs. • Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. • The diagnosis of macroscopic findings by individual modality has limitations. • Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability.

The age and growth of turbot Psetta maxima in the Black Sea were examined from specimens caught by both coastal fisheries in Trabzon and a trawl net survey of the Trabzon Fisheries Research Institute from December 1997 to July 1999. The number of otoliths available for examination was 641 pairs of otoliths. We counted the number of otolith opaque and hyaline zones and measured the otolith and ring radii. Monthly changes in the ratio of the number of opaque edges and marginal growth rate indicated that a single ring was formed once a year for both sexes. The relations of back-calculated standard length(cm) L(t) to age t(years old) expressed using the Bertalanffy growth equation were represented as L(t)=54.8{1-e- 0.481(t + 0.011)} and L(t)=45.0{1-e- 0.597(t+0.011)} for female and male, respectively. The estimate of growth coefficient did not differ from those of turbot in the Gulf of Lion and in a release-recapture experiment in the Black Sea, but were nearly twice as large as that in the Gulf of Pomerania.

To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis.A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child-Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events.All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm(3) (range, 0.18-16.63) and 0.37 cm(3) (range, 0-5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18-100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD,50%) were observed in four (15%), 16 (62%) and six patients (23%), respectively. The median volume of PVT before treatment was significantly different between CR + PR and SD (2.09 vs 4.35 cm(3) , P = 0.045). No severe adverse events such as bleeding symptoms (e.g. gastrointestinal bleeding and cerebral hemorrhage) and thrombocytopenia were encountered.Danaparoid sodium for the treatment of PVT in patients with liver cirrhosis was safe and effective. Therefore, anticoagulation therapy with danaparoid sodium could have potential as one of the treatment options in PVT accompanied by cirrhosis.

Background— Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results— The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A 1c , hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11–1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88–0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16–1.31) with triglycerides and decreased by 0.86 (0.82–0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Conclusions— Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

5-Carbamoyl-3-pyridyl alkanols with low e.e. act as asymmetric autocatalysts in the consecutive asymmetric autocatalytic addition of diisopropylzinc to 5-carbamoyl-3-pyridinecarbaldehydes. The e.e. of pyridyl alkanol amplified up to 88% e.e. without the need for any other chiral auxiliary.

The surface structure of trimethylpropylammonium bis(trifluoromethanesulfonyl)imide ([TMPA] [TFSI]) is studied by high-resolution Rutherford backscattering spectroscopy at room temperature. The results provide direct evidence of the molecular ordering at the surface. The C1 conformer of the [TFSI] anion is dominant among two stable conformers, and the anions are oriented with their CF3 groups pointing toward the vacuum in the outermost molecular layer. The anions in the second molecular layer also show preferred orientation although it is rather weak.

東京水産大学

The osteological development of elements forming the oral cavity was examined in early stage larvae of the grouper,Epinephelus coioides, from hatching to 242.5 hours after hatching. By the time of initial mouth opening, at 54 hours after hatching, the fundamental elements, composed of the trabecula, some components of the lower branchial and hyoid arches, the quadrate and symplectic-hyomandibular cartilages, maxilla and Meckel's cartilage, had appeared. No further elements were observed until 165 hours after initial mouth opening, except some components in the lower branchial arch and head region. The appearance of new elements and initial ossification of existing cartilage occurred thereafter, but all elements related to feeding either had not appeared or had not started ossifying until 188.5 hours after initial mouth opening. Based on the morphology and developmental modes of these elements, the feeding mode of grouper larvae was considered to be “sucking/grasping.” However, the appearance and ossification of elements occurred slowly, with no transitional phase from sucking to grasping modes of feeding being observed during the study; such delayed development of the feeding-related bony elements was considered to be a cause of the difficulty in rearing early stage grouper larvae.

Larvae of red-spotted grouper, Epinephelus coioides, were reared in outdoor tanks with nauplii of copepods (mainly Pseudodiaptomus annandalei and Acartia tsuensis)and/or rotifers, Brachionus rotundiformis. Grouper larvae successfully started feeding on early stage nauplii even though their abundance was as low as approximately 100 individuals 1−1 and showed better survival and growth thereafter compared to those fed with rotifers only. Incidence of feeding reached 100% on day 4 when nauplii were available and only on day 9 when rotifers were given alone. Larvae seemed to be poor feeders at the onset of feeding, attempting to capture any food organisms in the tank water. Selective feeding ability of larvae started from day 4 and the larvae then preferred to feed on medium- and large-size nauplii rather than on rotifers as they grew. Larvae appeared to have a better chance at surviving in the presence of early stage nauplii, which were probably caught more easily than rotifers.

To assess the short- and long-term outcome of patients with gastric varices (GV) after balloon-occluded retrograde transvenous obliteration (B-RTO) by comparing bleeding cases with prophylactic cases.Consecutive 100 patients with GV treated by B-RTO were enrolled in this retrospective cohort study. We compared the technical success, complications, and survival rates between bleeding and prophylactic cases.Of 100 patients, 61 patients were bleeding cases and 39 patients were prophylactic cases. Technical success was achieved in 95% of bleeding case and in 100% of prophylactic case, with no significant difference between these groups (overall technical success rate, 97%). The survival rates at 5 and 10 years were 50% and 22% in bleeding case, and 49% and 36% in prophylactic case, respectively. There was also no significant difference (P = 0.420). By multivariate analysis, survival rates correlated significantly with liver function (hazard ratio 2.371, 95% CI 1.457-3.860, P = 0.001) and hepatocellular carcinoma development (HR 4.782, 95% CI 2.331-9.810, P 0.001). The aggravating rates of esophageal varices (EV) were 21%, 50%, and 54% at 12, 60, and 120 months after B-RTO. By multivariate analysis, aggravating rates significantly correlated with EV existing before B-RTO (HR 18.114, 95% CI 2.463-133.219, P = 0.004).B-RTO for GV could provide the high rate of complete obliteration and favorable long-term prognosis even in bleeding cases as well as prophylactic cases. Management of EV after B-RTO, especially in coexisting case of GV and EV, would be warranted.

Pain is a complex experience composed of sensory and affective components. Although the neural systems of the sensory component of pain have been studied extensively, those of its affective component remain to be determined. In the present study, we examined the effects of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) injected into the dorsolateral bed nucleus of the stria terminalis (dlBNST) on pain-induced aversion and nociceptive behaviors in rats to examine the roles of these peptides in affective and sensory components of pain, respectively.In vivomicrodialysis showed that formalin-evoked pain enhanced the release of CRF in this brain region. Using a conditioned place aversion (CPA) test, we found that intra-dlBNST injection of a CRF1or CRF2receptor antagonist suppressed pain-induced aversion. Intra-dlBNST CRF injection induced CPA even in the absence of pain stimulation. On the other hand, intra-dlBNST NPY injection suppressed pain-induced aversion. Coadministration of NPY inhibited CRF-induced CPA. This inhibitory effect of NPY was blocked by coadministration of a Y1or Y5receptor antagonist. Furthermore, whole-cell patch-clamp electrophysiology in dlBNST slices revealed that CRF increased neuronal excitability specifically in type II dlBNST neurons, whereas NPY decreased it in these neurons. Excitatory effects of CRF on type II dlBNST neurons were suppressed by NPY. These results have uncovered some of the neuronal mechanisms underlying the affective component of pain by showing opposing roles of intra-dlBNST CRF and NPY in pain-induced aversion and opposing actions of these peptides on neuronal excitability converging on the same target, type II neurons, within the dlBNST.

In order to clarify the nutritional conditions of larval milkfish in the surf zone, the following parameters were examined: 1) DNA and RNA content and RNA/DNA ratio of fed and unfed larvae collected from the surf zone and reared in the laboratory; 2) survival rate of the unfed larvae; and 3) total length, otolith increment counts and RNA/DNA ratio of wild larvae collected daily from the surf zone. The DNA and RNA content of the unfed larvae decreased, but increased in fed larvae. The RNA/DNA ratio decreased in unfed larvae, whereas in the fed larvae it decreased for the first three days after capture and increased thereafter. These results indicated that the values of DNA and RNA content and RNA/DNA ratio could be used as an indicator of nutritional condition of milkfish larvae after 6 days of starvation. Although total length of the wild-larvae did not show serial changes, their otolith increment counts showed continuous increases, indicating that the larvae sojourned in the surf zone for several days. In the same period, RNA/DNA ratios of the wild larvae decreased continuously, the ratios of larvae with fewer otolith increment counts being relatively higher than those of larvae with greater increment counts. Based on these results, the milkfish larvae remaining in the surf zone were concluded as being under insufficient nutritional conditions.

The osteological development of elements comprising the oral cavity and fins was examined in early stage larvae of laboratory-reared milkfish,Chanos chanos, from hatching to 200 hours after hatching. Fundamental elements of the oral cavity had developed by the time of initial mouth opening, 54 hours after hatching. The oral cavity was long and cylindrical, with a short, robust Meckel's cartilage, and robust quadrate and symplectic-hyomandibular cartilages. The initial ossification of existing elements and addition of new elements occurred between 120–146 hours after initial mouth opening (HAMO), whereas the cartilaginous basihyal and caudal fin-supports appeared at 37.5 and 61.5 HAMO, respectively. Based on the morphology and developmental patterns of characters examined in this study, the feeding mode of early stage larval milkfish was considered to be “straining,” with an improvement in feeding ability occurring between 120–146 HAMO.

The osteological development of the feeding apparatus was examined in early stage larvae of laboratory-reared seabass,Lates calcarifer. At initial mouth openings 40 hours after hatching, the larvae were equipped with the fundamental elements forming the oral cavity, such as the trabecular roof, the lower branchial and hyoid arches forming the floor, the quadrate and symplectic-hyomandibular cartilages making up the sides, and the maxilla and Meckel's cartilage bordering the jaws. The cleithrum appeared almost simultaneously. The mechanics of creating a negative pressure in the oral cavity, which results in a “sucking” mode of feeding, were elucidated from these elements. During a period from 50–60 to 100–110 hours after initial mouth opening (HAMO), new elements such as the premaxilla and jaw teeth appeared, and the ossification of existing elements started. The new elements apparently enabled the larvae to “grasp” food organisms, in addition to the already existing and increasing sucking ability, from 100–110 HAMO.

The temperature effect on the development of Calanoid copepod,Acartia tsuensis, was investigated in the laboratory.A. tsuensis could develop from eggs to adults within the water temperature range of 17.5–30.0°C. The relationship between the duration required to attain a developmental stagei (Di; days) and water temperature (T; °C) was expressed asDi=Ai(T−1)−2.05, whereAi is a coefficient obtained for the stagei. A. tsuensis developed isochronally at 20.0–27.5°C, while the instar duration of advanced nauplii and copepodids tended to be longer at 17.5°C and 30.0°C. Quadratic equations could be applied to express the relationship between stage-specific mortality coefficients and water temperature with the minimu mortality observed at 22.5°C from egg to nauplius stage 3 (N−3) and at 25.0°C from N−3 to copepodide stage 6. Fecundity at 22.5–30.0°C was larger (7.9–13.5 eggs/female/day) than that at 17.5–20.0°C (0–2.6 eggs/female/day). These observations indicate thatA. tsuensis adapts well physiologically in a warmwater environment with an optimal water temperature of about 25°C. The study includes morphological description ofA. tsuensis, because the species seems to have been often confused with otherAcartia species, such asA. omorii occurring in a similar locality, due largely to lack of the information on the morphological characters of the nauplii and early copepodids.