Induction of nitric oxide synthase in Anopheles stephensi by Plasmodium falciparum: mechanism of signaling and the role of parasite glycosylphosphatidylinositols

Malaria parasite (Plasmodium spp.) infection in the mosquito Anopheles stephensi induces significant expression of A. stephensi nitric oxide synthase (AsNOS) in the midgut epithelium as early as 6 h postinfection and intermittently thereafter. This induction results in the synthesis of inflammatory levels of nitric oxide (NO) in the blood-filled midgut that adversely impact parasite development. In mammals, P. falciparum glycosylphosphatidylinositols (PfGPIs) can induce NOS expression in immune and endothelial cells and are sufficient to reproduce the major effects of parasite infection. These effects are mediated in part by mimicry of insulin signaling by PfGPIs. In this study, we demonstrate that PfGPIs can induce AsNOS expression in A. stephensi cells in vitro and in the midgut epithelium in vivo. Signaling by P. falciparum merozoites and PfGPIs is mediated through A. stephensi Akt/protein kinase B and a pathway involving DSOR1, a mitogen-activated protein kinase kinase, and an extracellular signal-regulated kinase. However, despite the involvement of kinases that are also associated with insulin signaling in A. stephensi cells, signaling by P. falciparum and by PfGPIs is distinctively different from signaling by insulin. Therefore, although mimicry of insulin by PfGPIs appears to be restricted to mammalian hosts of P. falciparum, the conservation of PfGPIs as a prominent parasite-derived signal of innate immunity can now be extended to include Anopheles mosquitoes, indicating that parasite signaling of innate immunity is conserved in mosquito and mammalian cells.     

Two notable features in PM<Subscript>10</Subscript> data and analysis of their causes

Hourly PM₁₀ mass concentrations were collected from 25 air quality monitoring stations in Seoul, Korea. Sixteen years of data, from 2000 to 2015, were analyzed. During that time, the annual average PM₁₀ concentrations declined almost linearly at a rate of ?1.98 μg m^?3 year^?1. The number of high PM₁₀ days declined faster than did the number of low PM₁₀ days. This indicates that the bulk of the annual average PM₁₀ mass concentration reduction was high-level PM₁₀ concentrations. Further analysis of this data revealed two interesting points. First, though the annual average PM₁₀ concentrations clearly lowered for period 1 (from 2000 to 2012; ?2.28 μg m^?3 year^?1), they remained almost unchanged at a virtually constant value for period 2 (from 2012 to 2015; ?0.02 μg m^?3 year^?1). Second, annual average PM₁₀ concentrations showed a large spatial concentration gradient among all monitoring stations in the early 2000s. However, the spatial concentration gradient got gradually smaller until reaching a nearly no-gradient, uniform concentration among all monitoring stations from 2010 onward. Clear PM₁₀ concentration reduction in period 1 was driven by local emission reduction. However, its reduction was not enough in period 2. The reduction of local emissions was negated by the increase of local activities and transported particulates, as well as the formation of secondary aerosol in Seoul from emissions transported from upwind regional sources. This resulted in PM₁₀ concentrations becoming stagnant in period 2. PM₁₀ reduction rate in the downwind area was faster than that in the upwind area. For the first 5 years, the reduction rate in the downwind area was great. Between all the stations observed, nearly all of the concentration difference was a result of more reduction in secondary aerosol. After 2005, coarse particles and primary elemental carbon (EC) played a key role in reducing the PM₁₀ concentration. Our findings on these two data features, and their causes, will help people to understand the most recent characteristics of particulate matters, in turn helping to update the control strategy for the continued improvement of particulate air quality in Seoul.     

Pharmacokinetic Comparison of 2 Fixed-Dose Combination Tablets of Amlodipine and Valsartan in Healthy Male Korean Volunteers: A Randomized,Open-Label, 2-Period,Single-Dose,Crossover Study

Background

Amlodipine and valsartan have different mechanisms of action, and it is known that the combination therapy with the 2 drugs increases treatment effects compared with the monotherapy with each drug. A fixed-dose combination (FDC) drug is a formulation including fixed amounts of active drug ingredients combined in a single dosage form that is expected to improve medication compliance.

Objective

The goal of this study was to compare the pharmacokinetic profiles of single administration of a newly developed FDC tablet containing amlodipine orotate 10 mg and valsartan 160 mg (test formulation) with the conventional FDC tablet of amlodipine besylate 10 mg and valsartan 160 mg (reference formulation) in healthy male Korean volunteers.

Methods

This was a randomized, open-label, single-dose, 2-way crossover study. Eligible subjects were between the ages of 20 and 50 years and within 20% of their ideal weight. Each subject received a single dose of the reference and the test formulations, with a 14-day washout period between formulations. Blood samples were collected up to 144 hours after the dose, and pharmacokinetic parameters were determined for amlodipine and valsartan. Adverse events were evaluated based on subject interviews and physical examinations.

Results

Forty-eight of the 50 enrolled subjects completed the study. For both amlodipine and valsartan, the primary pharmacokinetic parameters were included in the range for assumed bioequivalence, yielding 90% CI ratios of 0.9277 to 0.9903 for AUC_0–last and 0.9357 to 1.0068 for C_max in amlodipine, and 0.9784 to 1.1817 for AUC_0–last and 0.9738 to 1.2145 for C_max in valsartan. Dizziness was the most frequently noted adverse event, occurring in 4 subjects with the test formulation, followed by oropharyngeal pain occurring in 1 subject with the test formulation and 3 subjects with the reference formulation. All other adverse events occurred in <3 subjects.

Conclusions

These findings suggest that the pharmacokinetics of the newly developed FDC tablet of amlodipine and valsartan did not differ significantly from the conventional FDC tablet in these healthy Korean male subjects. Both formulations were well tolerated, with no serious adverse events observed. ClinicalTrials.gov identifier: NCT01823913.     

Complete mitochondrial genome sequence of the tiny dragonfly, <Emphasis Type="Italic">Nannophya pygmaea</Emphasis> (Odonata: Libellulidae)

The tiny dragonfly, Nannophya pygmaea (Odonata: Libellulidae), has been listed as an endangered insect in South Korea. We sequenced the complete 15,112-bp-long mitochondrial genome (mitogenome) of the species. The genome included a typical set of genes (13 protein-coding genes [PCGs], two rRNA genes, and 22 tRNA genes) and one non-coding region with an arrangement identical to that found in most insects. Among the 13 PCGs, only ND1 started with the atypical TTG. The 441-bp-long A+T-rich region possessed the highest A/T content (84.6%) in the genome. N. pygmaea was placed as the sister to Orthetrum species belonging to Libellulidae. Unlike conventional phylogenetic results, the suborders Anisozygoptera and Zygoptera formed a strong sister group in both Bayesian inference (BI) and maximum likelihood (ML) methods (BI, BPP?=?1 and ML, 88–94%), justifying the use of different types of molecular markers for phylogenetic analysis.     

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report.

PURPOSE: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m(2)/d and leucovorin 20 mg/m(2)/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v. 70% at 4 years; P =.043). Twenty-three recurrences occurred in arm I and 38 in arm II (P =.047). Overall survival was not significantly different between arms I and II (84% v. 82% at 4 years; P =.387). CONCLUSION: Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.     

The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling

Protein scaffolds play an important role in signal transduction, regulating the localization of signaling components and mediating key protein interactions. Here, we report that the major binding partners of the Connector Enhancer of KSR 1 (CNK1) scaffold are members of the cytohesin family of Arf guanine nucleotide exchange factors, and that the CNK1/cytohesin interaction is critical for activation of the PI3K/AKT cascade downstream from insulin and insulin-like growth factor 1 (IGF-1) receptors. We identified a domain located in the C-terminal region of CNK1 that interacts constitutively with the coiled-coil domain of the cytohesins, and found that CNK1 facilitates the membrane recruitment of cytohesin-2 following insulin stimulation. Moreover, through protein depletion and rescue experiments, we found that the CNK1/cytohesin interaction promotes signaling from plasma membrane-bound Arf GTPases to the phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) to generate a PIP₂-rich microenvironment that is critical for the membrane recruitment of insulin receptor substrate 1 (IRS1) and signal transmission to the PI3K/AKT cascade. These findings identify CNK1 as a new positive regulator of insulin signaling.     

Effects of a 4-Week Multimodal Rehabilitation Program on Quality of Life,Cardiopulmonary Function,and Fatigue in Breast Cancer Patients

Purpose

This study examines the effects of a rehabilitation program on quality of life (QoL), cardiopulmonary function, and fatigue in breast cancer patients. The program included aerobic exercises as well as stretching and strengthening exercises.

Methods

Breast cancer patients (n=62) who had completed chemotherapy were randomly assigned to an early exercise group (EEG; n=32) or a delayed exercise group (DEG; n=30). The EEG underwent 4 weeks of a multimodal rehabilitation program for 80 min/day, 5 times/wk for 4 weeks. The DEG completed the same program during the next 4 weeks. The European Organization for Research and Treatment of Cancer-Core Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23), predicted maximal volume of oxygen consumption (VO₂max), and fatigue severity scale (FSS) were used for assessment at baseline, and at 2, 4, 6, and 8 weeks.

Results

After 8 weeks, statistically significant differences were apparent in global health, physical, role, and emotional functions, and cancer-related symptoms such as fatigue and pain, nausea, and dyspnea on the EORTC QLQ-C30; cancer-related symptoms involving the arm and breast on the EORTC QLQ-BR23; the predicted VO₂max; muscular strength; and FSS (p<0.050), according to time, between the two groups.

Conclusion

The results of our study suggest that a supervised multimodal rehabilitation program may improve the physical symptoms, QoL, and fatigue in patients with breast cancer.     

The effects of an electronic medical record on the completeness of documentation in the anesthesia record

ObjectivesThe purpose of this study is to evaluate the completeness of anesthesia recording before and after the introduction of an electronic anesthesia record.MethodsThe study was conducted in a Korean teaching hospital where the EMR was implemented in October 2008. One hundred paper anesthesia records from July to September 2008 and 150 electronic anesthesia records during the same period in 2009 were randomly sampled. Thirty-four essential items were selected out of all the anesthesia items and grouped into automatically transferred items and manual entry items. 1, .5 and 0 points were given for each item of complete entry, incomplete entry and no entry respectively. The completeness of documentation was defined as the sum of the scores. The influencing factors on the completeness of documentation were evaluated in total and by the groups.ResultsThe average completeness score of the electronic anesthesia records was 3.15% higher than that of the paper records. A multiple regression model showed the type of the anesthesia record was a significant factor on the completeness of anesthesia records in all items (β = .98, p < .05) and automatically transferred items (β = .56, p < .01). The type of the anesthesia records had no influence on the completeness in manual entry items.ConclusionsThe completeness of an anesthesia record was improved after the implementation of the electronic anesthesia record. The reuse of the data from the EMR was the main contributor to the improved completeness.     

Endothelial progenitor cells from human dental pulp-derived iPS cells as a therapeutic target for ischemic vascular diseases

Human dental pulp cells (hDPCs) are a valuable source for the generation of patient-specific human induced pluripotent stem cells (hiPSCs). An advanced strategy for the safe and efficient reprogramming of hDPCs and subsequent lineage-specific differentiation is a critical step toward clinical application. In present research, we successfully generated hDPC-iPSCs using only two non-oncogenic factors: Oct4 and Sox2 (2F hDPC-hiPSCs) and evaluated the feasibility of hDPC-iPSCs as substrates for endothelial progenitor cells (EPCs), contributing to EPC-based therapies. Under conventional differentiation conditions, 2F hDPC-hiPSCs showed higher differentiation efficiency, compared to hiPSCs from other cell types, into multipotent CD34⁺ EPCs (2F-hEPCs) capable to differentiate into functional endothelial and smooth muscle cells. The angiogenic and neovasculogenic activities of 2F-hEPCs were confirmed using a Matrigel plug assay in mice. In addition, the therapeutic effects of 2F-hEPC transplantation were confirmed in mouse models of hind-limb ischemia and myocardial infarction. Importantly, 2F-EPCs effectively integrated into newly formed vascular structures and enhanced neovascularization via likely both direct and indirect paracrine mechanisms. 2F hDPC-hiPSCs have a robust capability for the generation of angiogenic and vasculogenic EPCs, representing a strategy for patient-specific EPC therapies and disease modeling, particularly for ischemic vascular diseases.