Anti-HIV Tigliane Diterpenoids from Wikstroemia scytophylla.

During a chemical investigation of Wikstroemia scytophylla, three new [wikstrocins A-C (1-3)] and three known tigliane diterpenoids (4-6) were isolated. The structures of the new compounds were elucidated from extensive physiochemical and spectroscopic analysis. The correlations between the ECD Cotton effects and B ring structures of tiglianes were also evaluated. The isolated compounds were assessed for their anti-HIV activity against HIV-1 infection of MT4 cells, and two compounds (4 and 6) showed potent anti-HIV activity with IC50 values of 3.8 and 12.8 nM, respectively.

Comparison of Mill Suss™-guided radial artery catheterization with the long-axis in-plane ultrasound-guided method under general anesthesia: a randomized controlled trial.

Continuous arterial blood pressure measurement is an effective perioperative monitoring method in patients with high-risk comorbidities. Recently, ultrasound guidance has been reported to facilitate radial artery catheterization. A new device, Mill Suss™, has also been developed for visualization of the radial artery and superficial veins using near-infrared laser light. In this study, we hypothesized that the Mill Suss-guided method might reduce the time and the number of attempts required for radial artery catheterization under general anesthesia, as compared to the long-axis in-plane ultrasound-guided method. Seventy-two adult patients aged 20-80 years, ASA physical status I or II, were randomly assigned to the Mill Suss-guided group (Group M: n = 36) or ultrasound-guided group (Group U: n = 36). Primary outcomes were the time required for successful radial artery catheterization and the number of cannulation attempts. There were no significant differences in the characteristics of patients between the two groups. The time required for successful radial artery catheterization was significantly shorter in Group M than in Group U. The number of attempts for successful cannulation was not statistically significantly different between the two groups. However, the results might be different among anesthesiologists well experienced in the ultrasound-guided method.

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles.

The function of ARHGEF10, a known guanine nucleotide exchange factor (GEF) for RhoA with proposed roles in various diseases, is poorly understood. To understand the precise function of this protein, we raised a monoclonal antibody against ARHGEF10 and determined its localization in HeLa cells. ARHGEF10 was found to localize to vesicles containing Rab6 (of which there are three isoforms, Rab6a, Rab6b and Rab6c), Rab8 (of which there are two isoforms, Rab8a and Rab8b), and/or the secretion marker neuropeptide Y (NPY)-Venus in a Rab6-dependent manner. These vesicles were known to originate from the Golgi and contain secreted or membrane proteins. Ectopic expression of an N-terminal-truncated ARHGEF10 mutant led to the generation of large vesicle-like structures containing both Rab6 and Rab8. Additionally, small interfering (si)RNA-mediated knockdown of ARHGEF10 impaired the localization of Rab8 to these exocytotic vesicles. Furthermore, the invasiveness of MDA-MB231 cells was markedly decreased by knockdown of ARHGEF10, as well as of Rab8. From these results, we propose that ARHGEF10 acts in exocytosis and tumor invasion in a Rab8-dependent manner.

The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling.

Various gut bacteria, including Lactobacillus plantarum, possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo-cis-6,trans-11-octadecadienoic acid (γKetoC), a γ-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with γKetoC significantly suppressed proliferation of CD4+ T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c+ cells isolated from the spleen. γKetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further in vitro experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of γKetoC on DCs. We also found that γKetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of γKetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in Nrf2-/- BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and Nrf2+/- mice with colitis. In contrast, the pathology of colitis was deteriorated in Nrf2-/- mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in γKetoC-mediated anti-inflammatory responses.

[Food-dependent exercise-induced anaphylaxis that was difficult to evoke by a provocation test].

As a result of ingesting wheat- and soybean-based food products in school meals, an 8-year-old boy repeatedly experienced dyspnea and urticaria while exercising. Based on the symptoms, he was assumed to have been experiencing a food-dependent exercise-induced anaphylactic reaction. Based on the Japanese pediatric guideline for oral food challenge in food allergy 2009, examination using various combinations of food products (wheat and soybeans), medicine (aspirin), and exercise was performed. However, the examination failed to elicit any symptoms. Although we eliminated the food products from the examination, dyspnea caused by exercising after ingesting only wheat products was observed again. Thereafter, we performed a provocation test using wheat products, but symptoms were observed only on increasing the amount of ingested food and the momentum of exercise, without administering aspirin. The possibility that wheat is a more potent inducing factor than aspirin in increasing the momentum of exercise and amount of ingestion in food-dependent exercise-induced anaphylaxis was suggested.

Value signals guide abstraction during learning.

The human brain excels at constructing and using abstractions, such as rules, or concepts. Here, in two fMRI experiments, we demonstrate a mechanism of abstraction built upon the valuation of sensory features. Human volunteers learned novel association rules based on simple visual features. Reinforcement-learning algorithms revealed that, with learning, high-value abstract representations increasingly guided participant behaviour, resulting in better choices and higher subjective confidence. We also found that the brain area computing value signals - the ventromedial prefrontal cortex - prioritised and selected latent task elements during abstraction, both locally and through its connection to the visual cortex. Such a coding scheme predicts a causal role for valuation. Hence, in a second experiment, we used multivoxel neural reinforcement to test for the causality of feature valuation in the sensory cortex, as a mechanism of abstraction. Tagging the neural representation of a task feature with rewards evoked abstraction-based decisions. Together, these findings provide a novel interpretation of value as a goal-dependent, key factor in forging abstract representations.

Effects of cardiac rehabilitation on physical function and exercise capacity in elderly cardiovascular patients with frailty.

BACKGROUND: The effects of cardiac rehabilitation (CR) on long-term prognosis of cardiovascular disease (CVD) are well known. However, the effect of CR on frail CVD patients has not been fully addressed. METHODS: This study consisted of 89 CVD patients with their age ≥65 years old (68 males, 75 ± 6 years), who participated in the outpatient CR program for 3 months. All the patients underwent cardiopulmonary exercise testing and the physical frailty was assessed using the Japanese Version of the Cardiovascular Health Study Standard before and after CR. Based on the assessment of frailty before CR, the patients were divided into the following two groups: frailty group (n = 23) and non-frailty group (n = 66: robust in 10 and pre-frail in 56 patients). RESULTS: In the frailty group, 20 patients (87%) improved from frail status after CR, and usual walking speed, maximal grip strength, and lower extremity strength were significantly improved (1.06±0.20 vs. 1.20±0.18 m/sec, p<0.001; 21.7 ± 5.5 vs. 23.6 ± 6.3 kg, p<0.01; 0.37±0.09 vs. 0.43±0.11 kgf/kg, p = 0.001, respectively), but peak VO2 did not change after CR (15.9 ± 3.1 vs. 16.2 ± 3.8 ml/min/kg, NS). In the non-frailty group, all these parameters were significantly improved after CR (1.24±0.19 vs. 1.29±0.23 m/sec, p<0.05, 28.7 ± 7.0 vs. 30.2 ± 7.3 kg, p<0.001, 0.50±0.18 vs. 0.54±0.13 kgf/kg, p<0.05, 17.7 ± 4.7 vs 18.5 ± 4.2 ml/min/kg, p<0.01, respectively). CONCLUSION: Short-term CR could obtain the improvement of the physical function, providing the prerequisite step for possibly following improvement of exercise capacity in elderly CVD patients with frailty. It may be inferred that longer duration of CR would be needed to obtain the improvement of exercise capacity in these patients, being the future consideration to be determined.

Histone deacetylase inhibitors sensitize 5-fluorouracil-resistant MDA-MB-468 breast cancer cells to 5-fluorouracil.

Resistance to 5-fluorouracil (5-FU) is a serious problem in cancer therapy and overcoming it is required in order to improve the efficacy of cancer chemotherapy. Histone deacetylase (HDAC) inhibitors are used in cancer treatments and, recently, it has been reported that HDAC inhibitors can overcome resistance to various anti-cancer drugs in vitro. In the present study, a 5-FU-resistant breast cancer cell line was established, and the effects of HDAC inhibitors in these cells were examined. The 5-FU-resistant cell line MDA-MB-468 (MDA468/FU) was established by continuous exposure of the parental cells to 5-FU. This subline was characterized by high resistance to 5-FU, higher mRNA expression levels of thymidylate synthetase and dihydropyrimidine dehydrogenase (DPD), and lower mRNA expression levels of uridine monophosphate synthetase (UMPS) than the parental cells. Gimeracil, a DPD inhibitor, did not affect the sensitivity of MDA468/FU cells to 5-FU. Oteracil, a UMPS inhibitor, decreased the cytotoxicity of 5-FU in MDA468 cells, but not in MDA468/FU cells. The HDAC inhibitors, valproic acid and suberanilohydroxamic acid sensitized the two cell lines to 5-FU in a concentration-dependent manner. In conclusion, the results of the present study revealed that HDAC inhibitors increase the sensitivity to 5-FU in 5-FU-sensitive and -resistant cells.

Relationship between PK/PD of Cefepime and Clinical Outcome in Febrile Neutropenic Patients with Normal Renal Function.

The efficacy of cefepime (CFPM) is known to depend on the ratio of the time that the serum levels exceed the minimum inhibitory concentration (MIC) to the dosing interval (%T>MIC). The objective of this study was to clarify the relation between %T>MIC and clinical outcome of CFPM, and to identify the optimal dosage regimen. We investigated the outcome of CFPM treatment for febrile neutropenia (FN) patients with normal renal function. Treatment success was defined as the completion of FN therapy with CFPM only. And we calculated %T>MIC for each case based on population pharmacokinetic parameters. The MIC value for simulation was set as 8 µg/mL. In logistic regression analysis, treatment success was significantly associated with the elevation of %T>MIC in the group with persistent neutropenia, yielding a receiver operating characteristic curve with an optimal cutoff value of 73.1%. Next, we simulated %T>MIC for each case under various dosing regimens. For patients whose creatinine clearance (CLcr) exceeded 100 mL/min, it was found to be difficult to attain the objective under the current regimen. In contrast, it was calculated that treatment with 2 g three times a day (t.i.d.) could attain the objective for most of the patients with 3 h of infusion. These results suggest that CFPM treatment under the current regimen is ineffective for FN patients with normal or augmented renal function, and that 2 g t.i.d. is necessary in quite a lot cases, although such use is off-label.

Clinical evaluation of pediatric anaphylaxis and the necessity for multiple doses of epinephrine.

BACKGROUND: Epinephrine administered intramuscularly is the treatment of choice for anaphylaxis, and more than 1 dose is occasionally required. OBJECTIVE: To determine clinical background of anaphylaxis for improving the treatment, management, and prognosis of anaphylaxis. METHODS: Children who had satisfied the diagnostic criteria for anaphylaxis according to the National Institute of Allergy and Infectious Disease Food Allergy and Anaphylaxis Network were selected from our hospital from April 1, 2009 to March 31, 2012. RESULTS: We analyzed 61 patients from the ages of 2 months to 14 years who satisfied the diagnostic criteria for anaphylaxis. Parents of 32 children (52.5%) reported that they had been administered single dose of epinephrine, and 3 children (4.9%) reported receiving multiple doses of epinephrine. The latter group experienced syncope more often (p = 0.049) than the former and suffered more often from comorbid allergic diseases (p = 0.043) that included either bronchial asthma, allergic rhinitis, or atopic dermatitis. Two (3.3%) children experienced biphasic reactions. Patients who experienced a biphasic reaction were more likely to have experienced syncope (p = 0.033), vomiting (p = 0.02), and administration of multiple doses of epinephrine (p = 0.0016). CONCLUSION: Our findings lead us to recommend that children receiving more than 1 injection of epinephrine should be observed for 24 hours, because it seems that children with requiring more than 1 injection of epinephrine might be have biphasic reactions.

A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers.

Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.