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Phosphine (PH3) and ethyl formate (EF), the two popular fumigant disinfectants of stored product insect pests, are primarily evaluated for their knock down effects without considering their post-fumigation sub-lethal activities. The sub-lethal activities (adult survivorship, fecundity, sterility and female sex pheromone production) of the fumigants were evaluated on a field-to-storage insect pest adzuki bean beetle, Callosobruchus chinensis (L.). The adults’ survivorship and female fecundity, both were dose-dependently affected by sub-lethal PH3 and EF fumigation exposures. Hatchability of the eggs laid by fumigated female adults were also significantly affected. Gas-chromatography mass-spectrometry analysis of solid-phase micro-extraction from virgin fumigated C. cinensis females revealed that the PH3 LC25 (the lethal concentration required to kill the 25% of the population) fumigated female C. chinensis released significantly less amount of the pheromone components. In contrast, EF LC25 exposure did not affect the pheromone release. This study unveils the facts that the EF and PH3 fumigation have detrimental bioactivities against C. chinensis. Notably, this suggests to consider the sub-lethal EF and PH3 fumigation rather than the dose required to instantly kill all the C. chinensis individuals for disinfestation of stored adzuki bean.

A non-neoplastic mass posterior to the dens is termed a retro-odontoid mass (R-OM). This retrospective study evaluated radiographic and clinical outcomes and R-OM changes after upper cervical spine surgery. This study included 69 patients who underwent upper cervical spine surgery, including atlantoaxial fusion, occipitocervical fusion, or decompression. All patients underwent preoperative magnetic resonance imaging (MRI). Six-month follow-up MRI examinations were performed in 30 patients who had preoperative R-OMs. Radiographic outcomes of the anterior and posterior atlantodental intervals were measured using X-rays and computed tomography. The R-OM and space available for the cord (SAC) were measured using MRI. Clinical outcomes were evaluated using neck and arm pain visual analog scales, the Japanese Orthopedic Association score, the neck disability index, and the patient-reported subjective improvement rate. The anterior atlantodental interval decreased, while the posterior atlantodental interval and SAC increased postoperatively. Among the clinical outcomes, the neck and arm pain and the neck disability index decreased postoperatively, while the Japanese Orthopedic Association score increased. All clinical and radiographic outcomes improved postoperatively. The R-OM either decreased in size or disappeared after fusion surgery in all cases, except in one patient who underwent decompression surgery. In conclusion, stabilization through fusion surgery is essential for treating R-OM.

The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk. It is unclear whether subsequent fractures or a certain location and sequence of subsequent fractures are associated with mortality risk in the elderly. We aimed to investigate the relationship between subsequent fractures and mortality risk. Using the Korean National Health Insurance Research Database, we analyzed the cohort data of 24,756 patients aged > 60 years who sustained fractures between 2002 and 2013. Cox regression was used to assess the mortality risk associated with the number, locations, and sequences of subsequent fractures. Mortality hazard ratios (HRs) for women and men were shown to be associated with the number of subsequent fractures (one, 1.63 (95% confidence interval [CI], 1.48–1.80) and 1.42 (95% CI, 1.28–1.58); two, 1.75 (95% CI, 1.47–2.08) and 2.03 (95% CI, 1.69–2.43); three or more, 2.46(95% CI, 1.92–3.15) and 1.92 (95% CI, 1.34–2.74), respectively). For women, the mortality risk was high when hip (HR, 2.49; 95% CI, 1.80–3.44) or vertebral (HR, 1.40; 95% CI, 1.03–1.90) fracture occurred as a second fracture. Compared with a single hip fracture, there was a high mortality risk in the group with hip fracture after the first vertebral fracture (HR, 2.90; 95% CI, 1.86–4.54), followed by vertebral fracture after the first hip fracture (HR, 1.90; 95% CI, 1.12–3.22). The mortality risk showed a positive correlation as the number of subsequent fractures increased. Hip fracture showed the greatest association with mortality risk, followed by vertebral fracture. For the combination of hip and vertebral fracture, a hip fracture after a vertebral fracture showed the highest mortality risk.

Mushroom fly, Lycoriella mali (Diptera: Sciaridae), is the primary pest in imported mushrooms. The amount of Tricholoma matsutake imported from China increases every fall when it is harvested. When importing T. matsutake, disinfestation using methyl bromide (MB) or phosphine (PH3) is performed to prevent the introduction of L. mali. However, MB will be phased out due to ozone-depletion, chronic toxicity to workers, and residual issues. PH3 fumigation in mushroom disinfestation requires a long exposure time (24 h). In this study, we used ethyl formate (EF), which can replace MB and reduce exposure time. The efficacy of EF, PH3 and EF + PH3 on L. mali was evaluated. Using 4-h EF fumigation at 5 °C, the 3rd and 4th instar was the most tolerant stage in terms of 99% killed lethal concentration × time products (LCt99%). When 4-h EF fumigation at 5 °C was applied on all stages of L. mali, the LCt99% values of EF were 73.1 g h/m3 to the 1st and 2nd instar, 112.9 g h/m3 to the 3rd and 4th instar, 68.9 g h/m3 to pupae, and 20.1 g h/m3 to adult. It was confirmed that combination treatment with EF + PH3 had a synergistic effect on L. mali. The LCt99% of EF + 0.5 g/m3 of PH3 to the 3rd and 4th instar was 48.3 g h/m3. When only 140 g/m3 of EF was applied for 4 h at > 5 °C and 35 g/m3 of EF + 0.5 g/m3 of PH3 for 4 h at > 5 °C in commercial trials containing T. matsutake, proven efficacy (100%) on L. mali was confirmed. In the case of EF treatment only, phytotoxic damage occurred due to high Ct products, and there was no phytotoxic damage in combination treatment with EF + PH3. This study provides a new guideline for EF + PH3 combination treatment within a shorter exposure time (4 h) than existing PH3 treatment (24 h) and replacement of MB use.

Organic–inorganic hybrid perovskite solar cells (PSCs) are considered as one of the most promising emerging photovoltaics with outstanding performance. However, the commonly used organic hole transport materials (HTMs) suffer from heat-, light-, and bias-induced degradation along with defect diffusion and hygroscopic properties. To resolve these issues in conventional HTMs, inorganic materials with superior chemical stability, high carrier mobility, and low cost have been developed, demonstrating improved stability under rigorous conditions such as high temperature and long-term illumination. Understanding the properties of alternative inorganic HTMs is of prominent importance to realize more stable and efficient PSCs. This review summarizes the recent progresses in inorganic HTMs adopted in various device architectures, with their remarkable achievements in efficiency and long-term stability.

Herein, we synthesized uniform Cs2SnI6 films by two kinds of hybrid deposition methods by considering volume expansion involved during phase transformations. First, oblique thermal evaporation for CsI followed by SnI4 spin-coating resulted in uniform Cs2SnI6 films free of impurity phases. The rapid expansion (within 10 s of spin-coating) from CsI to Cs2SnI6 $$(\Delta V = 106\% )$$ was accommodated by porous CsI films inhibiting crack formation. Excess SnI4 on the Cs2SnI6 after spin-coating was effectively removed by toluene washing without any damages to Cs2SnI6, and optimum deposition parameters were suggested in terms of carrier mobility. Second, annealing CsI with SnI4 vapor at 250 °C and post-annealing in the SnI4 and I2 vapor at 300 °C produced Cs2SnI6 film with complete coverage. The slow reaction (70 min for a complete conversion) provided sufficient time for complete diffusion of SnI4 into CsI without crack formation even with compact CsI. The nonradiative recombination path in Cs2SnI6 was suppressed by post-annealing in the SnI4- and I2-atmosphere, as confirmed from the enhanced photoluminescence.

To investigate the epidemiology of congenital scoliosis (CS) and treatment trends. An age-matched, nationwide, population-based study was conducted using the National Health Insurance and Health Insurance Review and Assessment databases from 2010 to 2015. Data regarding the diagnosis and treatment of scoliosis were extracted using International Classifications of Diseases, 10th revision codes. The age-matched normal population was determined from the Korean Statistical Information Service database. We analyzed the incidence rate of CS according to age and sex, as well as the proportion of surgically treated patients. A total of 1664 patients (aged 0–19 years) were diagnosed with CS. The overall average incidence rate of CS over the 5-year period was 3.08 per 100,000 persons, with the highest and second highest rates at 0 years and 12–16 years of age, respectively. The incidence rate stratified by age ranged from 1.5 to 20.1 per 100,000 persons among the age-matched normal population, with peaks at 0 years of age and the second growth spurt in adolescence (12–16 years for males; 10–14 years for females). Anterior surgery was rarely performed; posterior surgery was performed in 92 patients (5.5% of all patients), with the highest prevalence (56.5%) in patients diagnosed at 10–14 years of age. The overall average incidence rate of CS over a 5-year period was 3.08 per 100,000 persons. Only 5.5% of patients underwent surgery within 5 years after the initial diagnosis.

There are a few studies on the postoperative changes in sagittal alignment and corresponding factors, including hand grip strength (HGS) and muscle performance tests for lumbar spinal stenosis (LSS). Thus, we aimed to determine whether HGS can be a surrogate marker for global sagittal alignment changes after decompression with fusion surgery for LSS. This retrospective observational study included 91 patients who underwent spine fusion surgery for LSS. Radiological spinopelvic parameters, including sagittal vertical axis (SVA), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), global tilt (GT), and T1 pelvic angle (T1PA), were analyzed preoperatively and 1 year after posterior decompression and fusion surgery. To assess muscle performance, the 6-m walk (SMT), timed up and go (TUGT), and sit-to-stand (STS) tests were conducted. The relationship between HGS and postoperative SVA was examined through multiple linear regression analysis. Additionally, the relationship between HGS and preoperative/postoperative radiologic spinopelvic parameters and muscle performance test results was analyzed through Pearson's correlation. HGS was significantly correlated with age, preoperative and postoperative SVA, and the muscle performance tests. Furthermore, HGS was a factor that can significantly influence postoperative SVA changes in multiple linear regression analyses. Therefore, HGS may be a good predictor of postoperative SVA change.

Antifungal effects of ethanedinitrile (EDN) and ethyl formate (EF) on Aspergillus flavus were investigated using radial growth bioassay. A. flavus was inoculated in the center of potato dextrose agar plate and treated with 1, 5, and 10 g/m3 of EDN, or 5, 35, and 70 g/m3 of EF. EDN strongly inhibited fungal growth. At 1 g/m3 of EDN, the fungal growth reduced by 22.2% by the final days of culture. The growth was completely inhibited by EDN at the concentration of 5 g/m3. Antiaflatoxigenic activity of both the fumigants was also assessed. Aflatoxin formation was determined using high-performance liquid chromatography with a fluorescence detector. A. flavus did not produce aflatoxin B1 and aflatoxin B2 at EDN concentrations >5 g. EF had no inhibitory effect on A. flavus growth and the formation of aflatoxin. These results suggest that EDN can be an alternative for currently used antifungal agents to control fungal and aflatoxin contamination of stored grains.

Infestation of phosphine (PH3) resistant insects threatens global grain reserves. PH3 fumigation controls rice weevil (Sitophilus oryzae) but not highly resistant insect pests. Here, we investigated naturally occurring strains of S. oryzae that were moderately resistant (MR), strongly resistant (SR), or susceptible (wild-type; WT) to PH3 using global proteome analysis and mitochondrial DNA sequencing. Both PH3 resistant (PH3–R) strains exhibited higher susceptibility to ethyl formate-mediated inhibition of cytochrome c oxidase than the WT strain, whereas the disinfectant PH3 concentration time of the SR strain was much longer than that of the MR strain. Unlike the MR strain, which showed altered expression levels of genes encoding metabolic enzymes involved in catabolic pathways that minimize metabolic burden, the SR strain showed changes in the mitochondrial respiratory chain. Our results suggest that the acquisition of strong PH3 resistance necessitates the avoidance of oxidative phosphorylation through the accumulation of a few non-synonymous mutations in mitochondrial genes encoding complex I subunits as well as nuclear genes encoding dihydrolipoamide dehydrogenase, concomitant with metabolic reprogramming, a recognized hallmark of cancer metabolism. Taken together, our data suggest that reprogrammed metabolism represents a survival strategy of SR insect pests for the compensation of minimized energy transduction under anoxic conditions. Therefore, understanding the resistance mechanism of PH3–R strains will support the development of new strategies to control insect pests.

Two spotted spider mite, Tetranychus urticae, is a polyphagous pest to a variety of plants and they are hard to be controlled due to occurrence of resistance to acaricides. In this study, biochemical evaluation after ethyl formate (EF) and phosphine (PH3) fumigation towards T. urticae might help officials to control them in quarantine purposes. PH3 fumigation controlled eggs (LC50; 0.158 mg/L), nymphs (LC50; 0.030 mg/L), and adults (LC50; 0.059 mg/L) of T. urticae, and EF effectively affected nymphs (LC50; 2.826 mg/L) rather than eggs (LC50; 6.797 mg/L) and adults (LC50; 5.836 mg/L). In a longer exposure time of 20 h, PH3 fumigation was 94.2-fold more effective tool for control of T. urticae than EF fumigant. EF and PH3 inhibited cytochrome c oxidase (COX) activity differently in both nymphs and adults of T. urticae. It confirmed COX is one of target sites of these fumigants in T. urticae and COX is involved in the respiratory chain as complex IV. Molecular approaches showed that EF fumigation completely down-regulated the expression of cox11 gene at the concentration of LC10 value, while PH3 up-regulated several genes greater than twofold in T. urticae nymphs treated with the concentration of LC50 value. These increased genes by PH3 fumigation are ndufv1, atpB, para, and ace, responsible for the expression of NADH dehydrogenase [ubiquinone] flavoprotein 1, ATP synthase, and acetylcholinesterase in insects, respectively. Lipidomic analyses exhibited a significant difference between two fumigants-exposed groups and the control, especially an ion with 815.46 m/z was analyzed less than twofold in the fumigants-treated group. It was identified as PI(15:1/18:3) and it may be used as a biomarker to EF and PH3 toxicity. These findings may contribute to set an effective control strategy on T. urticae by methyl bromide alternatives such as EF and PH3 because they have shared target sites on the respiratory chain in the pest.

Drug candidates often cause an unwanted blockage of the potassium ion channel of the human ether-a-go-go-related gene (hERG). The blockage leads to long QT syndrome (LQTS), which is a severe life-threatening cardiac side effect. Therefore, a virtual screening method to predict drug-induced hERG-related cardiotoxicity could facilitate drug discovery by filtering out toxic drug candidates. In this study, we generated a reliable hERG-related cardiotoxicity dataset composed of 2130 compounds, which were carried out under constant conditions. Based on our dataset, we developed a computational hERG-related cardiotoxicity prediction model. The neural network model achieved an area under the receiver operating characteristic curve (AUC) of 0.764, with an accuracy of 90.1%, a Matthews correlation coefficient (MCC) of 0.368, a sensitivity of 0.321, and a specificity of 0.967, when ten-fold cross-validation was performed. The model was further evaluated using ten drug compounds tested on guinea pigs and showed an accuracy of 80.0%, an MCC of 0.655, a sensitivity of 0.600, and a specificity of 1.000, which were better than the performances of existing hERG-toxicity prediction models. The neural network model can predict hERG-related cardiotoxicity of chemical compounds with a high accuracy. Therefore, the model can be applied to virtual high-throughput screening for drug candidates that do not cause cardiotoxicity. The prediction tool is available as a web-tool at http://ssbio.cau.ac.kr/CardPred .

Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor κB (NF-κB) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-κB in H9c2 cells overexpressing the urotensin II receptor (H9c2UT). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2UT cells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2UT cells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-κB signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3α/β were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2UT cells. Furthermore, UII-mediated cellular hypertrophy was inhibited by amlexanox, a selective GRK5 inhibitor, in H9c2UT cells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-κB and HDAC5 at least in part by ERK1/2 and GSK3α/β-independent pathways.

A carbon nanofluid was adapted to examine the characteristics of its cooling performance in an exhaust gas recirculation (EGR) cooler, compared with that of the usual working fluid water. After steady state, the heat transfer rate of water became nearly constant; however, that of the nanofluid showed a slight increase, suggesting that something happened to the nanofluid. The result shows that the cooling performance of the carbon nanofluid was a little better than that of water; however, its performance data improved with time while those of water were stable. It shows that assembly of the carbon nanoparticles changed with its circulation through the EGR cooler and the shape of the particle assembly depended on the dispersion method employed.

High power conversion efficiency and device stabilization are two major challenges for CH3NH3PbI3 (MAPbI3) perovskite solar cells to be commercialized. Herein, we demonstrate a diffusion-engineered perovskite synthesis method using MAI/ethanol dipping, and compared it to the conventional synthesis method from MAI/iso-propanol. Diffusion of MAI/C2H5OH into the PbCl2 film was observed to be more favorable than that of MAI/C3H7OH. Facile perovskite conversion from ethanol and highly-crystalline MAPbI3 with minimized impurities boosted the efficiency from 5.86% to 9.51%. Additionally, we further identified the intermediates and thereby the reaction mechanisms of PbCl2 converting into MAPbI3. Through straightforward engineering to enhance the surface morphology as well as the crystallinity of the perovskite with even faster conversion, an initial power conversion efficiency of 11.23% was obtained, in addition to superior stability after 30 days under an ambient condition.

To date, skillful medical management and advanced surgical techniques have provided increased quality of life with less postoperative morbidity in patients with spinal metastasis. We assessed the survival of patients with spinal metastasis according to two treatment modalities: surgery and conservative treatment. From 2005 to 2010, a total of 577 patients (200 surgery, 377 conservative treatment) who had spinal metastasis were enrolled. Prognostic factors and survival were assessed by Cox regression and Kaplan–Meier analyses in patients receiving either surgery or conservative treatment. The mean age was 59.7 (range 21–87) years in the surgery group and 59.9 (range 28–90) years in the conservative treatment group. The major primary cancers were of lung, liver, and colorectal origin in the surgery group and lung, liver, and breast in the conservative group. The mean ± SD Tokuhashi score in the surgery group was 8.12 ± 3.09 and in the conservative group was 8.0 ± 2.8 (not significant). The hazard ratio of the primary cancer group ranged from 1.870 to 3.217 compared to that of the most favorable primary cancer group in all patients. Survival was affected significantly by sex, adjuvant therapy, and postoperative survival in the surgery group and by clinical symptom, metastasis to major internal organ, and primary cancer origin in the conservative group. With this retrospective review of 577 cases of spinal metastasis, different prognostic factors depending on the treatment modality were discovered. Hence, consideration of these factors depending on the treatment modality could be helpful in treating patients with spinal metastasis.

Background: The objective of this study was to evaluate of prevalence of co-existing spine and hip disease using initial screening kidney-ureter-bladder (KUB) radiograph in patients over 50 who underwent spinal surgery. Materials and Methods: The study subjects were 388 patients (male: female=117:271; mean age 62.0 years) who underwent spinal surgery between 2008 and 2010. We retrospectively reviewed the initial KUB radiographs used to diagnose the spine and hip disease. Depending on the extent of acetabular and hip joint visualization in KUB, we divided the subjects into three groups: Acetabulum, hip joint, and femoral neck visualization. The hip visualization rate was also assessed with respect to patient height. χ 2 and logistic regression test were used for statistical analysis. Results: 126 (32.5%) cases had significant hip pathology including hip osteoarthritis (Kellgren/Lawrence grade 3 in 123 cases, grade 4 in 3 cases) and avascular necrosis (1 case each of Ficat stage IIA and IIB), and 8 cases had other morphologic abnormalities. Regarding acetabulum-hip visualization in KUB, 7 (1.8%) cases had acetabulum visualization only, 16 (4.1%) had hip joint visualization, and 365 (94.1%) had femoral neck including lesser trochanter visualization. Patients were categorized into four groups according to height (less than 150 cm, 150-159 cm, 160-169 cm, greater than 170 cm). The hip visualization rates differed significantly among these four groups ( P Conclusions: The prevalence of discernible hip pathology in patients who underwent spinal surgery was 32.5%. Hip joint visualization was excellent (98.2%) in KUB radiographs. Hence, spinal surgeons should pay attention to hip pathology in surgically indicated spinal patients.

The objective of this study was to investigate atrial myocardial properties through two-dimensional (2D) myocardial imaging in patients with atrial fibrillation (AF) and its predictive role for recurrence after catheter ablation. Echocardiographic examinations were performed in 40 patients with paroxysmal AF before catheter ablation and 40 age- and gender-matched healthy control subjects. Using a software package, bidimensional acquisitions were analyzed to measure longitudinal strain and strain rate for the left atrium (LA). Systolic strain and strain rate in all eight segments, and its average values, were significantly reduced in AF patients compared to controls. During 9 months of follow-up after catheter ablation for AF, 11 of 40 AF patients had AF recurrence. AF recurrence was associated with gender, LA volume index, and average values of systolic strain and strain rate. By multivariate analysis, only average strain was an independent predictor of AF recurrence (OR = 0.88, 95% CI 0.79-0.98, p = 0.018). Lower systolic strain of LA was strongly associated with recurrence after catheter ablation. Thus, diverse adjunctive ablation strategies should be considered to reduce recurrence in patients with lower systolic strain.

The objective of this work was to assess the predictive value of pre-procedural N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients undergoing atrial fibrillation (AF) ablation. Seventy-three consecutive patients with AF (paroxysmal n = 49, persistent n = 24) and preserved left ventricular (LV) systolic function (LV ejection fraction > 45%) were prospectively enrolled in this study. All of the enrolled patients underwent catheter ablation after a measurement of their plasma NT-proBNP levels, and an echocardiographic examination with assessment of their LV diastolic function and left atrial(LA) volume. Patients with AF recurrence at 3 months had more persistent AF (P = 0.001), a higher LA volume index (P = 0.002), lesser decelerating times (DT) of mitral inflow (P = 0.014), and higher NT-proBNP levels (P < 0.001), when compared with patients with sinus rhythm restoration. The baseline log NT-proBNP correlated significantly with age (r = 0.26, P = 0.025), LA volume index (r = 0.41, P = 0.001), E/E’ (r = 0.34, P = 0.007), DT (r = −0.34, P = 0.007), and E (r = 0.25, P = 0.04). The log NT-proBNP (HR 7.76, 95% CI 2.95–20.39, P < 0.001) was an independent predictor of AF recurrence. The measurement of NT-proBNP added incremental predictive value to standard indexes of LA size or diastolic function, including LA volume index and DT (P = 0.02). This study suggests the clinical utility of the level of NT-proBNP as an integrating marker of various risk factors, and as an incremental predictive marker for AF catheter ablation.

Essential oils extracted fromEucalyptus blakelyi (1,8-cineole, 77.5%),Melaleuca fulgens (1,8-cineole, 56.9%) and 1,8-cineole were shown to have fumigant toxicity against different development stages ofSitophilus oryzae. The eggs ofS. oryzae were the most tolerant, followed by pupae, larvae and adults in that order.M. fulgens oil,E. blakelyi oil and 1,8-cineole at 100 µl per liter of air gave, respectively, LT50 values of 16.2, 17.4 and 9.1 h for adults, 31.1, 19.3 and 17.5 h for larvae, 55.6, 75.2 and 39.7 h for pupae, and required >7 days for eggs. Only 1,8-cineole (200 µl −1 air) gave a significant egg kill by 7 days and the LT95 was 134.5 h. 1,8-Cineole could be a useful new fumigant.

We investigated the interaction between nitric oxide and the renin angiotensin system in regulating isolated pulmonary arterial tension and pulmonary arterial pressure (PAP) in renal hypertensive rats (RHR) made by complete ligation of left renal artery. Losartan induced a depressor response that was smaller in RHR than in normotensive rats (NR) (3.3 and 7.0 mmHg, respectively, at 3.0 mg/kg, p0.05), and the response was significantly reduced by N(G)-nitro-L-arginine methyl ester (L-NAME). Angiotensin II elevated the PAP (7.6 and 10.8 mmHg at 0.1 mug/kg; 20.3 and 23.6 mmHg at 1.0 mug/kg, respectively) and contracted the isolated pulmonary artery (pD(2): 8.79 and 8.71, respectively) from both NR and RHR with similar magnitude, and these effects were significantly enhanced by L-NAME in NR, but not in HRR. Acetylcholine lowered the PAP slightly less effectively in RHR than in NR (3.8 and 6.0 mmHg at 10 mug/kg, respectively) and relaxed the pulmonary artery precontracted with norepinephrine in both rats with similar magnitude (E(max): 60.8 and 63.6%, respectively), and the effect being completely abolished after pretreatment with L-NAME or removal of endothelial cells. These results suggest that nitric oxide interacts with renin angiotensin system to control the pulmonary vascular tension and pulmonary arterial circulation of RHR.

The changes in blood pressure may relate to the alterations of the responsiveness to vasoconstrictors and vasodilators, and these alterations can arise the modifications in the properties of angiotensin II (AII) receptor. In order to examine the changes of AII receptor in the hypertensive mechanism of renin-dependent hypertensive rats (RHRs; two-kidney, one-ligated type), we compared the equilibrium binding characteristics of [3H]All in adrenal cortex and medulla from RHRs and normotensive rats. The dissociation constants of All binding in both tissues of RHRs were very similar to those in the respective tissue of normotensive rats. However, the maximum binding was increased from 805 to 1050 fmole/mg protein in the adrenal cortex of RHRs, and decreased from 172 to 126 fmole/mg protein in the adrenal medulla of RHRs. These results imply that the up- and down-regulation of the All receptor population on the cell surface of adrenal glands from RHRs are consorted with the elevation of blood pressure and the activation of renin-angiotensin system.

IY-80843, N-[2-(2-Methoxyphenyl)ethyl]-N′-[4-(Imidazole-4-yl) phenyl] formamidine, is a new potent H2-receptor antagonist. The potential secondary pharmacologic effects of this agent, on the central nervous and cardiovascular systems were studied. IY-80843 caused ptosis, suppression of locomotion, hypothermia, prolongation of sleeping time and hypotensive effects in mice, rats and dogs. These results suggest that IY-80843 affects the function of the central nervous and cardiovascular systems in a dose-dependent manner.

This study was conducted to characterize thein vivo pharmacology of KR-30988, KR-30992 and losartan, new AT1 antagonists, given as i.v. cumulative doses, in two animal models of high renin, conscious renal artery-ligated hypertensinve rats (RHRs) and normotensive rats anesthetized with urethane (900 mg/kg, i.p.) and α-chloralose (90 mg/kg, i.p.), with a special emphasis on the pharmacological characterization of the latter model. In conscious RHRs, KR-30988, KR-30992, losartan and captopril caused a dose-dependent decrease in blood pressure, their relative potencies (ED20) being 0.057, 0.208, 0.164 and 0.018 mg/kg i.v., repectively. In anesthetized rats, 2 hours after anesthesia, plasma renin activity was increased from 7.31 to 34.07 ng/ml/h, the level approximately 1.5 times greater than the highest level in RHRs. In anesthtized rats, the ED20S for all four compounds were 0.011, 0.046, 0.035 and 0.004 mg/kg i.v., repectively. By comparison, ED20s from anesthetized rats were 4 to 5 times smaller than those from conscious RHRs, with a good correlation (r=0.999) noted between ED20s from two groups of rats. The data on ED20 may indicate the higher sensitivity of anesthetized rats to the hypotensive activity of the compounds and the same order of potencies in two models. These results suggest that, in addition to RHRs, the nomotensive rats anesthetized as above can serve as a suitable model for the rapid pharmacological evaluation of AT1 receptor antagonists.

Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality. We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11). In non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. ClinicalTrials.gov: NCT00940654

Oxidative stress is critical for causing cardiac injuries during ischemia-reperfusion (IR), yet the molecular mechanism for this remains unclear. In the present study, we observe that hypoxia and reoxygenation, a component of ischemia, effectively induces apoptosis in the cardiac myocytes from neonatal rats and it concomitantly leads to induction of GADD153, an apoptosis-related gene. Furthermore, IR injury of rat heart showed a GADD153 overexpression in the ischemic area where the TUNEL reaction was positive. A downregulation of cardiac ankyrin repeat protein (CARP) was also observed in this ischemic area. Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. Accordingly, the induction of GADD153 mRNA were followed by the CARP down-regulation in an in vivo rat coronary ischemia/reperfusion injury model. These results suggest that GADD153 over-expression and the resulting downregulation of CARP may have causative roles in apoptotic cell death during cardiac IR injury.