Cardiac assist devices (CAD) cause endothelial dysfunction with considerable morbidity. Employment of pulsatile CAD remains controversial due to inadequate perfusion curves and costs. Alternatively, we are proposing a new concept of pulsatile CAD based on a fundamental revision of the entire circulatory system in correspondence with the physiopathology and law of physics. It concerns a double lumen disposable tube device that could be adapted to conventional cardiopulmonary bypass (CPB) and/or CAD, for inducing a homogenous, downstream pulsatile perfusion mode with lower energy losses. In this study, the device's prototypes were tested in a simulated conventional pediatric CPB circuit for energy losses and as a left ventricular assist device (LVAD) in ischemic piglets model for endothelial shear stress (ESS) evaluations. In conclusion and according to the study results the pulsatile tube was successfully capable of transforming a conventional CPB and/or CAD steady flow into a pulsatile perfusion mode, with nearly physiologic pulse pressure and lower energy losses. This represents a cost-effective promising method with low mortality and morbidity, especially in fragile cardiac patients. Mechanical cardiac assist devices (CAD) disturb endothelial function and hemodynamics , 2. ThesShear stress-mediated endothelial function controls vascular tone with plenty of mediators , 5 as wedevices that increase coronary blood flow during diastole in order to improve the oxygenation and thus the performance of the myocardium, that is, the intra-aortic balloon pump (IABP) and the enhanced external counterpulsation pump (EECP) [devices that unload and bypass the heart pump either partially as achieved by left ventricular assist devices (LVAD), right ventricular assist devices (RVAD), and extracorporeal membrane oxygenation (ECMO) or completely like with biventricular assist devices, cardiopulmonary bypass (CPB) [In general, present CAD can be identified in two categories: p (EECP) , 9; thesss (CPB) –12.Conceptually, these devices are lumped models, designed for driving Newtonian compressible fluids inside closed pressurized hydraulic circuits implementing rigid tubes with fixed diameters , 14. Mea2), sex (95% men), and age  [Finally, permanent replacement of the heart with an artificial heart option is still a work in progress with short life expectancy, which limits its applications in specific categories, regarding body surface area (1.9 ± 0.22 mhildren) , 17.pharmacological supports [normothermia [pulsatile CPB [In a matter to overrule these side effects, different therapeutic strategies are currently applied, particularly with CPB such as supports , normothothermia , and pultile CPB . Howevertile CPB . Benefittile CPB , remain tile CPB , as the tile CPB . Besidestile CPB . On the tile CPB –28.off-bypass technique, which is still restricted to small groups of patients [These side effects may explain current popularity of conventional CPB , in addipatients .Therefore, an optimum cardiovascular perfusion device is still missing, because we cannot simulate properly a type-III passive ventricular pump with type-I  or type-II  pumps , 32.Alternatively, we are proposing a new concept of pulsatile CAD based on a fundamental revision of the entire circulatory system in correspondence with the physiopathology and law of physics.As shown in , it concIn this study, device prototypes were tested in a simulated conventional pediatric CPB circuit for energy losses and as a LVAD in ischemic piglets model for ESS evaluations.The goals of this study were to evaluate the feasibility of the proposed device to transform a steady-flow of conventional CAD into a pulsatile mode of perfusion with preservation of physiological ESS and minimum energy losses. This represents a cost-effective method with low morbidity and mortality.Device Prototype. A double lumen tube  and positioned at remote spots on the circuit as follows: pre/post-oxygenator ; pre/post-tube , and post-simulated resistance (P5), which represents the arterial perfusion curve in patients  and fixed pulsatile frequency (110 bpm) in group P.Circuit I: the tube was positioned downstream to the oxygenator at 6 cm distance from the aortic cannula.Circuit II: the tube was positioned downstream to the oxygenator at 150 cm distance from the aortic cannula.Circuit III: the tube was positioned upstream between the roller pump and oxygenator.Momentum energy losses were roughly calculated according to differences of flow pressures between the spots (P1–P5) and compared with tube position in 3 different mock circuits as follows.This study was approved by the Animal Research Facility at Sun Yat-sen University and conformed to the Guide for the Care and Use of Laboratory Animals .Ten domestic piglets of both sexes were randomly designated to either pulsatile group  or the nonpulsatile group . Animals were premedicated and maintained on general anesthesia according to our previously published protocols [rotocols . After aCardiac Catheterizations/Hemodynamic Monitoring. A (5 Fr.) double-lumen central venous line  was introduced through the RA purse-string for drug administration and RA pressure monitoring. An intrapulmonary catheter (5 Fr. Swan-Ganz) was introduced through the infundibular purse-string for pulmonary artery pressure (PAP). Left atrium (LA) pressure was obtained by direct needle puncture at predetermined time points. Cardiac output (CO) was measured with a TRANSONIC transit-time flowmeter temporarily positioned around the aortic root at predetermined time points.Total time (T) of the experiment was 3 h, divided into  in correspondence to data collection: T1 = baseline; T2 = nearly 1 h of myocardial ischemia, just before severe hemodynamic deterioration; and T3 = by the end of experiment after 2 h of treatment.Induction of Acute Myocardial Ischemia. After surgical preparation, and data collection for T1, the left anterior descending coronary artery (LAD) was encircled with a 4/0 polypropylene stitch, distal to the 2nd diagonal bifurcation and tightly obstructed with a snugger for 2 h period.During the first 1 h of ischemia, ventricular fibrillation (VF) and cardiac arrest were frequent after 20–30 min of ischemia. Animals were assisted with classical cardiopulmonary resuscitation (CPR) and DC shocks (20–30 J), without any further IHD pharmacological supports.After 30 min, heparin was given (250 UI/kg) intravenously, followed by LVAD installation as follows.In P group, a modified aortic cannula  was inserted at the aortic root and a short piece of PVC tube  was introduced into the LV apex. Both aortic cannula and LV vent were shortly cut in a matter to avoid energy losses caused by unnecessary length. A pulsatile tube prototype was connected at its distal end to a conventional roller pump (Cobe Cardiovascular Inc.) and to the aortic cannula at its proximal end. The LV vent was connected to the other end of the roller pump.In NP group, the aorta was cannulated using a standard aortic cannula  and an apical LV vent . Both aortic and LV vent were connected to a centrifugal pump (Sorin group Revolution).The LVAD circuit in both P and NP groups was primed with heparinized saline, then deaired, clamped, and kept on standby until T2. Animals that did not survive T2 were excluded. Hemodynamics data were collected from both groups at T1, T2, and T3 including AP, PAP, LA, and RA pressures, heart rate, and CO. The vascular resistance index was calculated with the flowing formula:pulmonary vascular resistance index (PVRI) = 80 ∗ (MPAP – PCWP) / CO ∗ Wt,systemic vascular resistance index (SVRI) = 80 ∗ (MAP – CVP) / CO ∗ Wt,where MPAP is the mean pulmonary arterial pressure, PCWP is the pulmonary capillary wedge pressure, substituted for LA pressure, MAP is the mean arterial pressure, CVP is the central venous pressure, substituted for RA pressure, CO is the cardiac output, and Wt is the body weight.Therapeutic Phase. During the second hour of ischemia in P group, the pulsatile tube generator was switched on at a fixed frequency (90 bpm) and irrespective of heart rate (93.755.25 bpm). The flow rate of the roller pump was kept around 0.3 L/min (150 mL/Kg). In the NP group, the centrifugal pump flow rate was fixed around 0.8 L/min.After 1 h of LV mechanical assist, the LAD snugger was released, allowing coronary reperfusion during the second hour of assistance .The ischemic zone was measured and evaluated macroscopically until the end of the experiment (T3).Animals were euthanized with a 10 mL injection of saturated potassium chloride (KCl) upon completion of 3 h of LVAD or just before severe hemodynamic deterioration.Statistics. Continuous variables are expressed as the mean SEM. Comparisons between groups of independent samples were performed with students t-test hemodynamic data in vitro and a 2-way ANOVA for the in vivo data. P with a value less than 0.05 was considered statistically significant. GraphPad Prism software was applied for all the statistical analyses in this study.In vitro, as resumed in P < 0.001).Reduction of the pulsatile perfusion curve amplitude was directly proportional to distance between aortic cannula and tube position; that is, I > II > III.The collected pulse pressure data from each circuit were as follows.≈ 7 mmHg.Circuit I = P4  − P5  ≈ 44 mmHg.Circuit II = P3  − P5  ≈ 26 mmHg. In circuit III, there were significant increased flow pressures in a retrograde manner; that is, P1 > P2 and P5 > P1 (P < 0.001).Circuit III = P2  − P5  In vivo, as resumed in (P < 0.05). Hemodynamic (P > 0.05), respectively. There was significant vasodilatation in the P group compared with NP; mean AP in the P group was 46.830.52 versus 79.881.65 in NP group ; mean PAP in P was 24.832.88 versus 34.537.68 in NP group ; SVRI was 451.7224.01 versus 1309.88 ± 151.93; and PVRI was 210.6616.02 versus 566.9897.98 , respectively.sumed in , apparensumed in . Clearansumed in . In P grodynamic  was betthttp://dx.doi.org/10.1155/2013/651769.For further details please refer to the supplementary attached operative movies available online at In this study, conventional steady-flows of a simulated CPB circuit and LVAD were transformed successfully into a pulsatile mode of perfusion, using a double lumens tube device.In vitro, there were significant pressure losses with tube position in circuits III and II compared with I. In vivo, the induced pulsatile perfusion curve was efficient to improve hemodynamic and restore endothelial function in the P group compared with NP group.Normally, fluid movement in hydraulic circuits, which means momentum transfers with frictional losses, depends on driving forces, resistances, viscosity, and conduits geometries .in vitro remain controversial due to different cardiovascular criteria [Nevertheless, quantifications of lumped models that could be achieved with accuracy according to the Bernoulli's principles of energy losses criteria , 38.Endothelial shear stress (ESS) that control vascular resistances could be influenced by hemorheological changes, particularly, pulse pressure and/or shear rate , 40.For example, under normal hemorheological conditions, microcirculation behavior approaches that of Newton's second law, such as seen in athletics; that is, a high physical performance (ESS) can be induced by increasing the pulse pressure and slowing the heart rate (shear rate). In contrast, in any abnormal hemorheological state, microcirculation presents behavior that approaches that of Bernoulli's 3rd equation, which is interpreted by the Fahraeus-Lindqvist effect , in whicTherefore, delivery of ESS with pulsatile CAD should be induced according to the biophysics and pathophysiological conditions of each heart circuit .Physiologically, the left heart side has specific morphological particularities that must be considered.The left ventricle (LV) and peristaltic arteries represent the main circulatory driving forces at the left heart circuit, which deliver almost constant shear rate and pulse pressure. Flow dynamics inside the valsalva sinuses determines coronary ostia morphogenesis  and may The main target at the left heart side is maintenance organs microcirculation with adequate ESS. And this may explain common phenomena like postoperative or postpartum depression syndrome , 44, by Contrarily to the left heart side, the right heart side can adjust blood volume and shear rates at five different anatomical zones according to its physiological demands . The PA These may explain insufficiency of current CAD employments in congestive heart (CHF) patients with severe RV failure that still exhibit a high mortality rate (65%–95%) . In pedileft heart. This promotes pulsatile tube applications with conventional CPB and LVAD or as biventricular-assist device in association with a pulsatile suit device for a right ventricular-assist device [The proposed pulsatile tube device adapts to biophysics and pathophysiological conditions of the t device .or pre-aortic cannula (Z3), aortic cannula (Z4), and cardiovascular system (Z5).Practically, and for better understanding of the pulsatile tube's function as a cardiovascular perfusion device, we propose a state of momentum energy losses that could be identified in 6 main zones  as folloNormally, pulsatile tube (Z2) receives steady-flow from Z1, then the propagated pulsatile impacts move the stagnant blood boundaries' layers at the inner flexible tube and push them towards the center according to the “Bernoulli” principles. These would promote fewer traumatic effects of blood components compared with current devices. In addition, the downstream position of the pulsatile tube, which avoids already two obstructive zones of energy losses, makes high cost accessories unnecessary , 51The present study results showed the importance of energy losses in correlation to circuits length. Particularly, the distance between the pulsatile tube and the pre-aortic cannula (Z3), was represented by P4 in position (I), P3 and P2 in positions II and III, respectively. Eventually, these constitutions of vortices in Z3 are the consequences of strong pulsatile impacts inside rigid tubes with fixed geometries. Thus, compromising this Z3 distance between patients and CAD is crucial.In contrast, energy losses were very important with tube position in circuit III, which simulates current pulsatile CPB and/or CAD. We have observed severe leakage after few minutes of pulsations (≤5 min) with circuit III. The increased pressure at P5 due to this retrograde turbulent flow was enhanced by the application of a nonocclusive pump . In addiEnergy losses inside the aortic cannula (Z4) are usually caused by unnecessary length and tapering end. We have attempted to diminish these drawbacks of unnecessary length by shortening the aortic cannula in the P group.At the cardiovascular side (Z5), turbulent flow of energy losses that starts from the tip of aortic cannula (divergent diffuser) will be absorbed by the arterial wall filter to be dependent on ESS that control organs microcirculations .According to the present study results, the induced pulsatile tube pulse pressure of the  improvedContrary to the NP group, the induced vasodilatation of the pulsatile group was most probably caused by endothelial vasodilators secretion (e.g. NO), which means maintenance of ESS with tube pulsations. By the end of the experiment (T3), heart rate was 76.255.12 bpm in group P compared with 99.25 ± 3.77 bpm in the group NP, which signifies better hemodynamics with less myocardial oxygen consumption.Interestingly, myocardial recoveries in the pulsatile group occurred in pediatric immature myocardium of animal model with poor coronary collaterals , 54. Thiin vivo studies, the tube pulsations were not synchronized with heart rate. This confirms our therapeutic policy based on similar observations with other pulsatile devices , proving that pulsatile CAD should not be synchronized with the heartbeat in case of heart failure [We should emphasize that in all our  failure .Interestingly, the pulsatile tube was tested as a stimulator of the LV subendocardium without association roller pump, in two ischemic piglets (please refer to the supplementary attached movies). There was rapid clearance of the ischemic zone and improved contractility, after few minutes of unsynchronized pulsations , followed by severe vasodilatation.This proved the hypersensitivity of the LV endocardium and heterogeneity of the left heart endothelium that may be an emerging concept regarding the endothelial impact of current devices , 57.Although these results proved that pulsatile tube was efficient to maintain ESS, some weak points must be improved. This includes microporosity of the inner tube (PTFE), which became almost collapsed by the external latex membrane cover. Accordingly, tube association with a hypersensitive sophisticated centrifugal pump was impossible. There were centrifugal pump failures in two excluded piglets from the NP group due to uncontrolled systemic hypertensive crises (≥140 mmHg). Therefore, the use of a nonocclusive roller pump increased the circuits' artifacts, particularly III and II, and disturbed the applications of more recent formulae for energy losses evaluations , 34. In The proposed study concept deserves further evaluations with more enlarged investigations. To overcome the current limits, we are developing a new device with an inner tube made of ChronoFelx AR, which is similar to PTFE hardness (65 A–75 A) but without micropores. These enabled us to continue our ongoing studies: (a) pulsatile versus nonpulsatile LVAD in ischemic piglet models; (b) biventricular assist device combining the pulsatile tube as a LVAD and the pulsatile trouser as right ventricular assist device (RVAD) . We are Pulsatile tube adaptable to conventional perfusion devices could induce homogenous, downstream, and nearly physiologic pulsatile perfusion flow, with lower energy losses. This represents a cost-effective promising method with low mortality and morbidity, especially in fragile cardiac patients.1st Movie "Pulsatile Tube tested in vitro and in vivo": first part of the movie (in vitro study) shows the pulsatile tube integrated the arterial perfusion line of a mock cardiopulmonary bypass circuit (Circuit I). The middle part of the movie shows the arterial pressure curve obtained by the tube connected as LVAD on an arrested heart. End of the movie shows the tube connected to conventional roller pump as LVAD.2nd Movie: shows a control group piglet assisted with a conventional LVAD using a continuous flow centrifugal pump. The dark infracted zone was present after ≥ 1 h of assistance.3rd Movie: shows the pulsatile tube tested as CAD per se (without to be connected to a perfusion pump). There were macroscopic clearance of the infarcted zone and improvement of myocardial contractility, to be followed by severe vasodilation occurred after 5 minutes of pulsations, most probably due to massive release of endothelial mediators.Click here for additional data file.


Plastic mulching with drip irrigation is a new water-saving rice cultivation technology, but little is known on its productivity and water-saving capacity. This study aimed to assess the production potential, performance, and water use efficiency (WUE) of rice under plastic mulching with drip irrigation. Field experiments were conducted over 2 years with two rice cultivars under different cultivation systems: conventional flooding (CF), non-flooded irrigation incorporating plastic mulching with furrow irrigation (FIM), non-mulching with furrow irrigation (FIN), and plastic mulching with drip irrigation (DI). Compared with the CF treatment, grain yields were reduced by 31.76–52.19% under the DI treatment, by 57.16–61.02% under the FIM treatment, by 74.40–75.73% under the FIN treatment, which were mainly from source limitation, especially a low dry matter accumulation during post-anthesis, in non-flooded irrigation. WUE was the highest in the DI treatment, being 1.52–2.12 times higher than with the CF treatment, 1.35–1.89 times higher than with the FIM treatment, and 2.37–3.78 times higher than with the FIN treatment. The yield contribution from tillers (YCFTs) was 50.65–62.47% for the CF treatment and 12.07–20.62% for the non-flooded irrigation treatments. These low YCFTs values were attributed to the poor performance in tiller panicles rather than the total tiller number. Under non-flooded irrigation, root length was significantly reduced with more roots distributed in deep soil layers compared with the CF treatment; the DI treatment had more roots in the topsoil layer than the FIM and FIN treatments. The experiment demonstrates that the DI treatment has greater water saving capacity and lower yield and economic benefit gaps than the FIM and FIN treatments compared with the CF treatment, and would therefore be a better water-saving technology in areas of water scarcity. Rice is a main staple food for many people in the world. In Asia, around 700 million people live in rice-growing areas and rice is their main source of calories . Rice crExisting water-saving technologies for rice cultivation can be divided into three groups according to their water-saving capacity. The first group includes the continuously saturated soil cultivation system , the ricStudies of water usage of many field crops, such as grapes, cotton, and tomatoes, suggest that different modes of irrigation significantly affect crops growth and WUE, with higher water productivity and higher crop yield obtained under plastic mulching with drip irrigation than under furrow irrigation and sprinkler irrigation –19. HoweUnder non-flooded irrigation, the root-zone environment changes from being anaerobic to aerobic. Compared with traditional flooding, fewer roots are distributed in the topsoil layer, while more roots tend to be distributed in deeper soil layers –23. It iThe number of productive tillers per plant plays an important role in the formation of grain yield in rice. Not all tillers are productive and the productivity of tillers mainly depends on cultivars, tillering time, water regime, and plant density ,27. JianMany studies have investigated existing rice water-saving technologies. The objectives of the present study were to (1) characterize rice productivity under plastic mulching with drip irrigation; (2) compare yield formation and WUE under different cultivation conditions including conventional flooding (CF), plastic mulching with furrow irrigation under non-flooded irrigation (FIM), non-mulching with furrow irrigation under non-flooded irrigation (FIN) and plastic mulching with drip irrigation under non-flooded irrigation (DI).1The Tianye Group Company was the cooperation research institutions of the project and gave us permission to conduct the study on this site. Therefore, no specific permissions were required for these locations.2The field studies did not involve endangered or protected species.3The planting density of flooding irrigation referred to field production in Xinjiang province. And the result was from our field investigation in 2010 and 2011 years. No specific permissions were required for this plant density.–1, 60.83 mg kg–1, 25.46 mg kg–1, 342.54 mg kg–1, 7.30, and 33.71%, respectively.Field experiments were conducted from April to October in 2011 and 2012 at the Agricultural Drought Research Institute of the Tianye Group Company, Xinjiang province, China . The experimental ﬁeld of non-flooded irrigation in 2012 was adjacent to the ﬁeld used in 2011. The site of the conventional flooding treatments was about 150 m away from the non-flooded irrigation plots in both years. The physicochemical properties of the soil used for conventional flooding treatments were consistent with those of non-flooded irrigation treatments in both years . The soil was heavy loamy (U.S. taxonomy), with 21% clay, 36% silt, and 43 % sand on average over both years, with organic matter, Alkeline-N, Olsen-P, available potassium, pH and soil saturation volume moisture content in the 0–60 cm soil layer being 26.35 mg kgOryza sativa. L. cv. Xindao17), which is a high-yielding cultivar when cultivated with flooding irrigation under the local ecological conditions. The experiment was laid out in a split-plot design with three replicates, with the cultivation systems set as sub-factors and the varieties as the main factor. All plots in 2011 and 2012 had an area of 54 m2 (10 m × 5.40 m). To prevent water exchange between the plots, waterproof membranes were buried to a depth of 60 cm below the soil surface among the plots used for non-flooded irrigation. Dams of 20 cm height were built and covered by plastic ﬁlm for the FIM and FIN treatments to minimize water surface runoff. Each plot in the non-flooded irrigation treatments was covered with a 160 cm wide plastic film before sowing, and eight rows of rice were planted. Then holes were opened on the membrane surface when the rice was sown. Ten seeds were sown on each hill by artificial hand dibbled at a depth of 3 cm on 28 April 2011 and 23 April 2012. Strong seedlings were thinned to six plants per hill after seedling establishment. The planting density was 45.71 hills m–2 across cultivars and years under non-flooded irrigation, which the hill spacing in rows was 10 cm and the row spacing configurations were 10-30-10-30-10-30-10-45 cm  with five plants per hill (the planting density referred to field production in Xinjiang province). The CF treatment was arranged in small pools established in 2009 using a randomized complete block design with three replications across cultivars and years, and the area of the each pool was also same with the plot size of the non-flooding irrigation treatments. Because direct-seeded rice has a poor tillering capacity, a bit more seed rate or plant density than the CF system are necessary in field production [In 2011, field experiments were conducted using cultivar Ninggeng28 (japonica), which had a good performance under drip irrigation according to our preliminary testing results in 2009 and 2010. Three non-flooded irrigation cultivation treatments were investigated, including the DI, FIM, and FIN treatments, with the experimental treatments arranged in a randomized complete block design with three replicates. In 2012, we added a japonica variety  buried at 0–20 cm depth below the soil surface between narrow rows . The grain weight is expressed at 14% moisture content. Finally, matter translocation (MT), matter translocation efficiency (MTE), and contribution of pre-anthesis assimilates to grain weight (CPATG) were calculated: MT = Dry weight of stems and sheaths at anthesis – Dry weight of stems and sheaths at maturity. MTE (%) =MT / Dry weight of stems and sheaths at anthesis × 100. CPATG (%) = Matter translocation / grain weight at maturity × 100. To measure the aboveground biomass and leaf area index (LAI), plant samples were taken every 14 days from 23 May to 20 September in 2011, and from 20 May to 16 September in 2012 for all treatments. Twelve hills were harvested from each treatment for the CF, FIM, and FIN plots. However, because of non-uniform distribution of water in a horizontal direction in the DI plots, plant performance differences could exist between the near row and far row , so twelAt the three-leaf stage (37 days after sowing in 2011 and 39 days after sowing in 2012), thirty hills carrying strong seedlings (sixty hills for the DI treatment) were tagged to investigate dynamic tiller characteristics every seven days for all treatments in both years. Meanwhile, the main stem was labeled by marking it with red paint from the three-leaf stage to heading to distinguish the main stems from tillers. At maturity, nine hills rice (eighteen for the DI treatment) were randomly selected from labeled hills and divided into main stem panicles and tiller panicles for all treatments to determine the yield components of the main stem panicles and tiller panicles. An effective panicle was defined as one having more than five filled grains per panicle. The percentage of ﬁlled grains was deﬁned as a percentage of the number of grains that sink to the bottom of a beaker filled with specific gravity of 1.06 to total spikelets. Spikelets per panicle were the sum of filled and unfilled spikelets. The dry weight (14% moisture content) of one thousand filled spikelets was expressed as the 1000-grain weight. At flowering (1 August in 2011 and 3 August in 2012), the roots of three hills (six hills for the DI treatment) in 0–60 cm soil depth, which was averagely divided into three layer, were collected by core sampling for all treatments in both years . The roots washed with tap water on a 0.50 mm mesh screen were scanned on a ﬂat-bed image scanner  and the image was saved in TIF format according to the detailed method described by Kato –23. ThenN) and transpiration rate (E) of five flag leaves were measured using a portable open-flow gas exchange system LI–6400  under 1200 μmol m–2 s–1 light intensity from a red/blue LED light source during 10:30–12:30 h on four consecutive days during the grain filling stage (16–19 August in 2011 and 19–22 August in 2012). The canopy temperature and humidity were monitored with HOBO dataloggers  during anthesis. The dataloggers were installed in the top layer of the canopy in the center of the plot, and were located in the middle position of panicles [The net photosynthetic rate (P–1) was also roughly assessed; the output was grain yield (kg ha–1), and the investments mainly consisted of water consumption (m3 ha–1), seed rate (kg ha–1), consumption of plastic film (kg ha–1), and equipment consumption of drip irrigation system (US$ ha–1). Economic benefit (US$ ha–1) = grain yield (kg ha–1) × 0.52 US$ kg–1 – water consumption (m3 ha–1) × 0.07 US$ m3 – seed rate (kg ha–1) × 1.31 US$ kg–1 – 120 US$ ha–1 (consumption of plastic film) – 250 US$ ha–1 (equipment consumption of drip irrigation system) Economic benefit  procedure (SPSS16.0). Differences between means were compared by Fisher’s least-signiﬁcant-difference (LSD) test at the 5% probability level. -2, and 105.53 mm, respectively, in 2011; and 21.14 °C, 3594.35 MJ m–2, and 63.91 mm, respectively, in 2012  in terms of root length per unit soil volume decreased significantly with increasing depth of the soil layers across cultivars and years . For the-1 in the CF treatment, 3334.57–5901.61 kg ha-1 in the DI treatment, 2523.83–3576.42 kg ha-1 in the FIM treatment, and 2076.51–2313.52 kg ha-1 in the FIN treatment for both cultivars in two years. In generally, cultivar Ninggeng28 had higher yield and its components than cultivar Xindao17 . The bad performance of the non-flooded irrigation treatments in grain yield and its components could be relevant to a higher plant density which had significantly affected source-sink relationship and population structure compared with the CF treatment (In this study, the plant density in the non-flooded irrigation treatments was 1.37 times higher than that in the CF treatment across cultivars and years (274.26 plants mreatment , Table 4Under the non-flooded irrigation treatments, water consumption was reduced by 57.44–67.91% compared with the CF treatment . The redAlthough grain yield in the DI treatment was significantly lower than that in the CF treatment, WUE was 1.52-2.12 times greater in the DI treatment than in the CF treatment. Grain yield production mainly depended on tiller panicles in the CF treatment, but mainly on main stems in the non-flooded irrigation treatments, suggesting that the main reason was the poor performance in tiller panicles. More roots gathered in deep-soil layer in the non-flooded irrigation treatments than in the CF treatment. On the other hand, the DI treatment had a higher grain yield and HI, and more effective tillers, more roots in topsoil, higher WUE, and greater economic benefit compared with the FIM and FIN treatments. Therefore, the DI treatment could be considered a better water-saving cultivation technique in areas of arid and semiarid region.


Legionella pneumophila is a common cause of community-acquired pneumonia. Central nervous system dysfunction is common, and diagnosis in the absence of pulmonary symptoms can be challenging. Here we describe an atypical clinical presentation of Legionella infection in a patient with HIV who was found to have an unusual neuroradiologic lesion that further served to obscure the diagnosis. This is the first such description in a patient with Legionellosis and HIV coinfection.Legionella pneumonia and treated with complete symptom resolution.A 43 year-old HIV positive man presented to our hospital with dysarthria, fevers, headache, and altered mental status. Initial work-up revealed pneumonia and a lesion of the splenium of the corpus callosum on magnetic resonance imaging. He was subsequently diagnosed with Legionella infection and HIV.Neurologic abnormalities are frequent in Legionellosis, but the diagnosis may be difficult in the absence of overt respiratory symptoms and in the presence of HIV coinfection. A high index of suspicion and early initiation of empiric antibiotics is imperative since early treatment may help prevent long-term sequelae. Neuroimaging abnormalities, though rare, can help the physician narrow down the diagnosis and avoid unnecessary invasive testing. Future studies should aim to elucidate the as yet unknown role of neuroimaging in the diagnoses and prognostication of Legionellosis, as well as the interaction between  Legionella pneumophila is now recognized as a major cause of both community-acquired pneumonia, hemoglobin of 15.7 g/dL [lab range 14.0–18.0], platelet count of 135 × 103/mm3 [lab range 150–350]. Automated differential showed 87.5% segmented cells (lab range 30-85%), 9.3% lymphocytes (lab range 15-55%), 2.4% monocytes (lab range 0-10%), 0.8% eosinophils (lab range 0-5%), and 0% basophils. No manual differential was performed. A basic metabolic panel showed serum sodium of 134 mmol/L [lab range 137–145], serum potassium of 4.2 mmol/L (lab range 3.5-5.1), serum chloride of 100 mmol/L (lab range 98–107), and CO2 of 19 mmol/L [lab range 22.0–30.0]. Blood urea nitrogen, serum creatinine, and serum glucose were elevated at 33 mg/dL [lab range 9–20], 1.8 mg/dL [lab range 0.7–1.3] and 159 mg/dL [lab range 70–99], respectively. C-reactive protein (CRP) was high at 581 mg/dL [lab range 0–10]. Liver function studies showed an albumin level of 4.4 g/dL (lab range 3.5-5.0), total protein of 7.6 g/dL (lab range 6.3-8.2), total bilirubin of 0.7 mg/dL (lab range 0.2-1.3), direct bilirubin of 0.5 mg/dL (lab range 0–0.3), alkaline phosphatase of 62 U/L (lab range 38–126), alanine aminotransferase (ALT) of 49 U/L (lab range 13–69), and aspartate aminotransferase (AST) of 89 U/L (lab range 15–46). Urinalysis showed 2+ albumin, 3+ blood, trace WBC esterase, negative nitrite, 5–10 WBC, 0–5 red blood cells (RBC), 5–10 epithelial cells, 5–10 hyaline casts, 3+ amorphous cells, and 1+ mucous. A non-contrast computed tomography (CT) scan of the head did not reveal any abnormalities. Nasopharyngeal influenza assay was negative.Initial laboratory evaluation was notable for a white blood cell (WBC) count of 10.1 × 10Due to the combination of altered mental status, headache, and fever, a lumbar puncture was performed. The results demonstrated an elevated cerebrospinal fluid (CSF) glucose of 97 mg/dL [normal 40–70], CSF protein of 37 mg/dL [normal 12–60], and normal cell count and gram stain. Blood cultures were sent.). This chest CT demonstrated a left lower lobe consolidation with air bronchograms suggesting a diagnosis of pneumonia. Based upon the aforementioned findings, the patient was started on azithromycin and ceftriaxone for community-acquired pneumonia, as well as empiric acyclovir for herpes encephalitis.A chest x-ray was done and was read as a left hilar mass extending down towards the left lower lobe [Legionella or the other entities listed above, but clearly more research is needed in order to understand the utility of this radiologic abnormality in diagnosing and prognosticating encephalopathy.Splenial lesions on MRI, if symptomatic, are most commonly associated with delirium, ataxia, recent seizure, hemispheric disconnection syndrome, dysarthria, increased tone, or headache. These nonspecific findings do not easily localize anatomically. Becauseng (DWI). It remaLegionella pneumonia has been observed but not well-studied in HIV + individuals[Legionella infection in this context is unclear. At the least, HIV seropositivity and the predominance of neurologic symptomatology in this case distracted the clinicians from making a prompt diagnosis, highlighting the importance of early empiric antibiotic therapy.Coinfection with HIV confused timely diagnosis in this patient with Legionellosis. ividuals,39, and ividuals, so the Legionella pneumonia in a patient with HIV infection who presented with altered mental status, dysarthria, and neuroimaging abnormalities that cleared with clinical improvement. In this case, appropriate antibiotic therapy was started immediately upon presentation, even though the diagnosis of Legionellosis was not made until urinary antigens came back four days later. The patient did indeed make a complete recovery, and we presume early antibiotic therapy helped in this convalescence to some extent.We describe an unusual case of This patient underwent brain MRI because he presented acutely ill with confusion and dysarthria in the setting of HIV infection without an obvious diagnosis. MRI revealed an isolated defect of the SCC. The significance of this lesion and the utility of advanced imaging techniques in encephalopathy in general and Legionellosis specifically is not known, since to date no prospective studies have evaluated the utility of either MRI or SPECT in the work-up of altered mental status or other neurologic signs in Legionellosis. Though cost is currently a significant barrier, these imaging modalities may be useful to assess prognosis, determine optimal treatment length, and possibly even diagnose Legionellosis when CNS symptoms predominate. Further research in this area is required. Regardless, clinicians need to be aware of this nonspecific finding so as to avoid unnecessary invasive procedures in the setting of encephalopathy.Legionella and HIV, additional investigation is warranted in order to better understand the immunologic interplay.The other challenging aspect of this patient’s presentation was his coinfection with HIV. Given the limited research into the relationship between Legionella infection in patients who present with altered mental status or neurologic symptoms, even when few respiratory symptoms are reported. Failure to send Legionella urinary antigens on presentation in this case led to a delay in diagnosis, though fortunately this patient was initially placed on adequate empiric therapy anyway. In the absence of overt respiratory symptoms, clinicians need to maintain a high index of suspicion as early therapy may help prevent permanent neurologic sequelae.In summary, clinicians should consider Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.ADEM: Acute disseminated encephalomyelitis; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CD4: Cluster of differentiation; CNS: Central nervous system; CRP: C-reactive protein; CSF: Cerebrospinal fluid; CT: Computed tomography; DWI: Diffusion-weighted imaging; ED: Emergency department; EEG: Electroencephalogram; HIV: Human immunodefiency virus; IgG: Immunoglobulin G; MRI: Magnetic resonance imaging; SCC: Splenium of the corpus callosum; SPECT: Single photon emission CT.The authors declare that they have no competing interests.All authors were involved in the clinical care of the patient. All authors participated equally in writing and editing this manuscript. All authors read and approved the final manuscript.NMR is a Resident in Neurology at the University of California at San Francisco. AK is a Resident in Internal Medicine at Mount Auburn Hospital, a teaching hospital of Harvard University, and a Clinical Fellow in Medicine at Harvard Medical School. BMB is an Instructor in Medicine in the Division of Infectious Disease at Mount Auburn Hospital and Harvard Medical School.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/12/225/prepub


In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial’s 12 week treatment induction period.The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 ; gp100 vaccine + placebo ; or ipilimumab + placebo . The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized “no change” (0–5), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20).In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated “no change” or “a little” impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p < 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain.Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients.Clinicaltrials.gov identification number NCT00094653 Advanced melanoma is a serious and life threatening cancer which has an impact on health-related quality of life (HRQL). According to the American Cancer Society, there were an estimated 68,130 new cases of melanoma and 8,700 deaths in the US in 2010, which accounts for almost three-fourths of all skin cancer deaths [Until the recent approvals for vemurafenib and ipilimumab, none of the currently approved treatments for advanced melanoma have shown overall survival benefit ,8-18. ThSeveral clinical trials comparing treatments for advanced melanoma have included HRQL measures ,20,26-36Ipilimumab is an anti-CTLA-4 monoclonal antibody with anti-tumor activity and has demonstrated statistically significant improvement in overall survival in a Phase III study (MDX010-20) in patients with previously treated unresectable stage III or IV melanoma . EfficacStudy MDX010-20 was conducted in accordance with International Conference on Harmonisation-Good Clinical Practices and the Declaration of Helsinki. The study was approved by local regulatory authorities and institutional review boards and Ethics Committees at the participating sites, and all subjects provided written consent. The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated patients with advanced stage III or IV melanoma . PatientIpilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every three weeks for up to four treatments (induction) . In the Treatment was started on day 1 of Week 1, and additional treatment was received at Weeks 4, 7, and 10 if there was no intolerable toxicity, no rapidly progressive disease, and no significant decline in performance status. This included patients who developed new lesions and/or experienced growth in baseline lesions. Patients were offered additional courses of therapy (reinduction) if they had stable disease after Week 12 or a confirmed partial or complete response and no dose-limiting toxicity, or if they had disease progression with their assigned treatment regimen .HRQL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) ,42. The Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status and symptom scores were calculated. Analysis of variance models were used to compare treatment differences for the HRQL outcomes. Since there is clinical interest in effectiveness and risks in older oncology patients, post hoc subgroup analysis of EORTC QLQ-C30 data by age (<65 years versus ≥65 years) was also conducted, and these analyses were compared to the results from the total sample . Descriptive analyses are reported for the data, and no statistical tests were performed due to the ad hoc nature and relatively small sample sizes. Interpretations of the mean change in scores were categorized as “no change” (0–5 points), “a little” (5–10 points), “moderate” (10–20 points), and “very much” (>20 points), based on Osoba et al. . When fuPatients were randomly assigned to either the ipilimumab plus gp100 (n = 403), ipilimumab alone (n = 137), and gp100 alone (n = 136) treatment arms. Participants from all three arms  had a mean age of 56.2 ± 57.0 years and 59% were male (Table In the Phase III study (MDX010-20), 95% had baseline HRQL assessments and Week 12 assessments were available for 236 (62%), 85 (65%), and 80 (61%) of the patients treated with ipilimumab plus gp100, ipilimumab alone, and gp100 alone, respectively. Missing HRQL data at baseline were due to administrative errors. Reasons for missing Week 12 data were primarily due to disease progression, adverse events, or death [When HRQL outcomes were evaluated, most observed baseline to Week 12 changes were no greater than minimal in the “a little” impairment category  advanced melanoma patients ,47. AlthThe HRQL results from the current ipilimumab study should be interpreted considering the following limitations. HRQL endpoint data were available for only 61% to 65% of patients randomized into the clinical trial. Disease progression was the most common reason for discontinuation of study drug . Rates of discontinuation of study drug due to adverse events were greatest for ipilimumab alone (13%) compared with ipilimumab plus gp100 (9%) and gp100 alone (4%). However, there were comparable completion rates of the EORTC QLQ-C30 across treatment arms in the current study (MDX010-20), so these missing data may not impact the interpretation of the HRQL results. Missing HRQL data is a significant problem for oncology studies, and patients who complete follow-up assessments are less likely to experience severe toxicity and are more likely to have better response to treatment . FinallyIn conclusion, ipilimumab at 3 mg/kg with and without gp100 vaccine does not have a significant negative impact on HRQL in patients completing the baseline and Week 12 follow-up, during the treatment induction phase compared with gp100 alone. Ipilimumab treatment results in little to no impairment in HRQL outcomes in advanced melanoma patients. The improved survival observed in the ipilimumab treated groups does not come with a significant burden on HRQL for patients in this analysis. Further research is needed to determine the long term impact of ipilimumab treatment on HRQL outcomes. In addition, further analyses are needed to better understand the impact of serious adverse events on HRQL in ipilimumab treated patients.CNS, Central Nervous System; DTIC, Dacarbazine; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire; FACT, Functional Assessment of Cancer Therapy; HRQL, Health-Related Quality of Life; I.V., Intravenous.DAR and SS are employees of United BioSource Corporation and have research support from Bristol-Myers Squibb (BMS). AJMV is on the BMS advisory board and has been paid honoraria by BMS. PL is a consultant to BMS, has been a member of BMS Speakers Bureau, and has received honoraria from BMS to attend international conferences. PL has undertaken a number of unpaid academic projects with BMS around treatment of melanoma and also this study; which have been or are being submitted for publication. CL has received honoraria from BMS for ipilimumab development. GL is a consultant for GlaxoSmithKline, Genentech, and BMS and has received honoraria from BMS. CHO has consulted for BMS, received honoraria from BMS, and has received an unrestricted grant from BMS for a clinical trial using ipilimumab. MM declares that she has no competing interests. AH is an employee with BMS, holds a leadership position with the Cancer Immunotherapy Consortium, and owns stocks in BMS. SW is an employee with and owns stock in BMS. SK is an employee with, owns stock in, and has research funding from BMS.DAR participated in data analysis and interpretation and manuscript writing. AJMV participated in data analysis and interpretation and manuscript writing. PL participated in the collection and assembly of data, data analysis and interpretation, and manuscript writing. CL participated in the conception and design and manuscript writing. GL participated in data analysis and interpretation and manuscript writing. CHO participated in the conception and design and manuscript writing. SS participated in manuscript writing and provided project management and administrative support. MM participated in data analysis and interpretation and manuscript writing. AH participated in data analysis and interpretation and manuscript writing. SW participated in conception and design and manuscript writing. SK participated in the conception and design, collection and assembly of data and manuscript writing. All authors read and approved the final manuscript.Methodology for comparison with other melanoma clinical trials. A systematic search of review articles and clinical trial articles was conducted in order to compare the HRQL findings from the ipilimumab studies to other published clinical trials in advanced melanoma that included the EORTC QLQ-C30. Microsoft Word document file name: HRQL Melanoma Manuscript Appendix_HQLO_final.doc.Click here for fileFigure A1. Baseline to endpoint changes in EORTC QLQ-C30 function and global health scores for advanced melanoma studies.Click here for fileFigure A2. Baseline to endpoint changes in EORTC QLQ-C30 symptom scores for advanced melanoma studies.Click here for file


The effect of neoadjuvant chemotherapy (NAC) on Gastric carcinoma (GC) has been extensively studied, while its survival and surgical benefits remain controversial. This study aims to perform a meta-analysis of high-quality randomized controlled trials (RCTs), comparing efficacy, safety and other outcomes of NAC followed by surgery with surgery alone (SA) for GC.We systematically searched databases of MEDLINE, EMBASE, The Cochrane Library and Springer for RCTs comparing NAC with SA when treating GC. Reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases were also searched. Primary outcomes were 3-year and 5-year survival rates, survival time, and total and perioperative mortalities. Secondary outcomes included down-staging effects, R0 resection rate, and postoperative complications. Meta-analysis was conducted where possible comparing items using relative risks (RRs) and weighted mean differences (WMDs) according to type of data. NAC-related objective response, safety and toxicity were also specifically analyzed.P = 0.14). Significantly, higher incidence of cases without regional lymph node metastasis observed upon resection were achieved among patients receiving NAC than those undergoing SA . All other parameters were comparable. Of the evaluable patients, 43.0% demonstrated either complete or partial response. The comprehensive NAC-related side-effect rate was 18.2% among patients available for safety assessment.A total of 9 RCTs comparing NAC (n = 511) with SA (n = 545) published from 1995 to 2010 were identified. SA tended to be accompanied with higher overall mortality rate than NAC (46.03% vs 40.61%, RR: 0.83, 95% CI: 0.65–1.06, NAC contributes to lowering nodal stages, and potentially reduces overall mortality. Response rate may be an important influential factor impacting advantages, with chemotherapy-related adverse effects as a drawback. This level 1a evidence doesn't support NAC to outweigh SA in terms of survival and surgical benefits when dealing with GC. Although the incidence and cancer-related mortality have been decreasing steadily during the past century, gastric carcinoma (GC) remains one of the most common malignancies, and the second leading cause of cancer death worldwide For locally advanced lesion, adjuvant chemoradiotherapy is preferred in the US and Canada Adjuvant therapy for GC has been extensively studied, and a recently published meta-analysis demonstrated a small but statistically significant, affirmative and absolute 7% benefit in overall survival for patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy versus SA for locally advanced GC Neoadjuvant chemotherapy (NAC) has gained increasing attention as a treatment for GC since Wilke Up till now, pooled analyses on effectiveness of NAC for only GC patients have been conducted by Liao In our study, potential benefits of two managements were quantified using the meta-analytical method. Meta-analysis reaches the highest level of evidence when pooling data only from randomized trials th, 2013.A systematic literature search with search terms “neoadjuvant/preoperative chemotherapy”, “surgery” and “gastric/stomach cancer/carcinoma/adenocarcinoma”, and their combinations as key words was performed in MEDLINE, EMBASE, the Cochrane Library and Springer databases, and Google Scholar . SpecialTitles and abstracts of all identified articles were screened and we selected studies according to the following criteria: population-patients with GC  was included and referred as the NAC group, regardless of specific regimen, dosage and administration. As SA we considered all procedures as “surgery alone” or “primary surgery” and performed merely through gastrectomy. Processes in which further adjuvant postsurgical chemotherapy comparable between two groups were used to guarantee the efficacy were not excluded. Studies that included other types of malignancies or operation , or those that contained multivisceral resections were excluded unless the data were presented separatively.th edition of the Union for International Cancer Control (UICC) tumor node metastatic (TNM) classification of malignant tumors and the Japanese Gastric Cancer Classification Primary outcomes were 3-year and 5-year survival rates, overall survival time, perioperative mortality, and deaths due to recurrence/progression at the end of follow up. Secondary outcomes included down-staging effects namely tumor (ypT0-2) and nodal stages (ypN0) upon resection, R0 resection rate, and postoperative complications. Safety and toxity analysis focused on adverse effects of NAC was also conducted. As described in the included trials, survival time was recorded as the time from the date of randomization to death. Tumor and nodal stages at resection were recorded according to the 14Titles and abstracts of all retrieved records, and subsequently full-text articles were examined independently by 2 authors (A.M.X. and L.H.) according to PRISMA Missing data were handled by the following methods. Missing SDs were imputed on the basis of ranges when available Risk of bias was assessed for all articles by individual components using both The Cochrane Collaboration's tool for assessing risk of bias and the Jadad scoring system This study was carried out in line with the recommendations of the PRISMA 2χ test 2I values 2Pχ>0.100 and 2I<50%). If excessive heterogeneity was present, data were first rechecked and the DerSimonian random-effects model was used when heterogeneity persisted Dichotomous and continuous outcomes were presented as risk ratios (RRs) and weighted mean differences (WMDs), respectively. Data were pooled using the Mantel-Haenszel and the inverse-variance methods for dichotomous and continuous outcomes, respectively. Trials with zero events in both arms were excluded from meta-analysis. For all analyses, the 95% confidence interval (CI) was calculated. Heterogeneity was calculated using Higgins A total of 347 potential relevant publications were identified . We thenZ = 1.55, P = 0.12) or gender .The 9 included RCTs were published between 1995 and 2010, with 36 to 83 months of follow-up. A total of 1056 patients were included in our analysis with 511 recieving NAC (48.4%) and 545 (51.6%) undergoing SA. Patients' characteristics are listed in The trials had fair methodological quality with a mean Jadad score of 2.33 . They mostly suffer from methodological drawbacks frequently seen in clinical RCTs in general, mainly difficulties in concealing the allocation of patients, the inherent complexity of blinding between two procedures and small number of patients included in part of the researches. All trials had adequate sequence generation. Seven trials did not report double allocation concealment and 2 did not report loss to follow-up. Seven trials reported a sample size calculation . ParticuDetailed data and analyses by categories are available in 2χ = 23.06, P = 0.0003, 2I = 78%; 2χ = 20.34, P = 0.002, 2I = 71%) between two groups, so random-effects model was chosen. No significant difference was observed for both parameters between NAC and SA when treating GC  without significant heterogeneity, with a small number of patients analyzed though. Kobayashi P = 0.98) with random-effects model applied due to significant heterogeneity . Shchepotin P = 0.20).2χ = 20.53, P = 0.005, 2I = 66%), random-effects model chosen showed that there tended to be higher rate of mortality among patients undergoing SA than those receiving NAC at the end of follow-up .There being significant heterogeneity  for tumor stage upon resection (ypT0-2), random-effects model was applied. The combined data from 6 trials demonstrated comparable results between two groups .Since there was significant heterogeneity  or 5-year survival rate , total  or perioperative mortality , or postsurgical complication . NAC tended to result in more ypT0-2 status upon resection  and R0 resection , and significantly contributed to higher incidence of ypN0 upon resection  when compared to SA.Hartgrink's Kobayashi The overall NAC response rate (CR+PR) was calculated to be 43.0% (105/244), as was show in Safety analysis included both NAC-induced adverse effects . Hartgrink P = 0.04, There were significantly lower total mortality rates for patients receiving NAC than those undergoing SA when Hartgrink's study 2 gastrectomy is effective and safe, and D2 plus postoperative adjuvant chemotherapy with capecitabine and oxaliplatin for around 6 months in Korea Chemotherapy is an adjuvant treatment modality in the form of adjuvant chemotherapy, NAC and concomitant chemoradiotherapy NAC has several advantages including good toleration, better control of micrometastasis, and potentiality to downstage tumor and increase the probability of R0 resection so as to facilitate surgery The results of RCTs on NAC versus SA for GC vary in aspects of efficacy and safety. Four systematic reviews with considerable defects also made discrepant conclusions This study summarizes the highest quality data comparing NAC with SA. In our analysis, RCTs were all published after 1995, and those published after 2000 constitute most of the studies included. Some of the individual trials were inconclusive as they were underpowered and hence too small to identify the important determinants of ideal NAC. This meta-analysis aims to provide this evidence. The methodological quality of the 9 RCTs included in this meta-analysis was fair. Regimens of the included trials were standardized. Study population was similar between trials in all mentioned aspects.Ge's NAC, which is brought about to improve resection condition, is under heated discussion about its definite role in improving cure rate for GC patients Lack of response to NAC may delay curative surgery, and chemotherapy-induced toxicity may lead to increased surgical complications Number of courses administered may be another great impact factor. In ACCORD 07 Recently, a number of novel trials have been registered to examine the role of NAC in treatment of advanced GC, such as S-1 plus DDP or S-1 and DDP plus Taxanes Therefore, NAC should not be recommended as a regular and routine treatment for GC before obtaining abundant evidences of its certain efficacy on GC, and should be applied under the framework of clinical trials. Adequate surgery  without delay may remain the appropriate management for operable GC, until further large multicenter randomized studies sustaining NAC occurs. However, with joint efforts of clinicians, enterprises and academic centers, improvements in regimen like SP or PC, and maturation and modification of courses and administration, it's reasonable to believe that conducting NAC may benefit more and more GC patients with lower NAC-related adverse effects. This treatment modality is worthy of further investigation. Besides, individuality should be focused on during comprehensive treatment of GC patients, and systematic chemotherapy would be necessary among patients with micrometastatic disease already at diagnosis.The internal validity of this study is fair, mainly affected by the quality of RCTs available, with low risk of bias though. This analysis is limited by the diverse regimens, intervals between randomization and surgery, and follow-up period and the fact that not all outcomes of interest are reported by all enrolled studies.In conclusion, NAC doesn't contribute to significant survival benefits during the treatment of GC, and compares favorably with SA in tumor-free resection rates and postoperative complications. This may be due to regimens and courses issues. NAC definitely reduces nodal stage upon resection, and may result in a lower incidence of total mortality at the end of follow-up. All other indexes are similar. Response rate may be an important influential factor impacting possible advantages, and chemotherapy-related adverse effects can be a drawback. This level 1a evidence doesn't support NAC to outweigh SA in terms of efficacy and safety when dealing with GC. Still, further high-quality RCTs are needed to to update our finding with advancement of regimens, and future researches should be conducted in patients suffering from GC of discrepant stages and grades, and in those at diverse period of ages, separately.Checklist S1PRISMA checklist for this study.(DOC)Click here for additional data file.


We studied a cohort of 56 CTx patients with chronic kidney disease receiving 0.75 mg bid EVL to maintain blood levels of 5–8 ug/L (designated RD group) and a cohort of 51 CTx patients with chronic kidney disease receiving 0.5 mg bid to maintain blood levels of 3–5 ug/L (designated LD group). The primary endpoint was a composite of death, rejection and premature EVL discontinuation up to 1 year after introduction of EVL. The primary endpoint was reached by 32% of patients in the LD group and by 41.1% of patients in the RD group (P = 0.361). Biochemical safety parameters were comparable in both groups. Our results indicate that low-dose EVL may be as effective and safe as regular dose EVL.For cardiac transplant (CTx) recipients, the recommended everolimus (EVL) dose is 0.75 mg bid or 1.5 mg bid and the target trough blood level is 3–8  The use of calcineurin inhibitors (CNIs) such as cyclosporine (CSA) and tacrolimus (TAC) has dramatically increased medium-term life expectancy after heart transplantation but has had only limited impact on long-term outcomes for heart transplant recipients . One of The mammalian target of rapamycin (TOR) inhibitor everolimus (EVL) potentially reduces CAV, while maintaining the low cellular rejection rates seen with standard therapy . In addiμg/L, with 6 to 8 μg/L considered as the optimal range for most patients [The EVL dosage is according to trough blood levels 0.75 or 1.5 mg twice daily. Target blood levels are 3 to 8 patients . Approxipatients , 10.It is currently not known whether patients would benefit from a low EVL dose. It was therefore the aim of this cohort study to compare efficacy and safety of low-dose EVL with regular dose administration in cardiac transplant recipients.n = 104), neurotoxicity of CNI inhibitors (n = 2), and a tumour diagnosis (n = 1). Of the 107 patients, a cohort of 56 patients received a regular EVL dose  to maintain blood levels to 5–8 ug/L. The RD group was switched over to EVL between January 2004 and December 2004. Due to concerns about potential side effects of EVL (8), a cohort of 51 patients who changed to EVL between January 2005 and June 2006 received low doses  to maintain blood levels to 3–5 ug/l. After conversion to EVL, the CSA or TAC dose was reduced gradually in both groups: on the first day of converting to EVL, for safety reasons CSA or TAC dose was reduced only by 20%. During the next 4 days, the CSA or TAC dose was further reduced to achieve an overall reduction of 40%. Purine inhibitors and methylprednisone were stopped after changing patients to EVL. All procedures of this investigation were in accordance with the Helsinki declaration of 1975.This investigation is based on patients who were changed from immunosuppressive therapy with CNI, purine antagonist, and methylprednisolone to EVL plus low-dose CNI therapy at our clinic between January 2004 and June 2006. Of 1054 eligible cardiac transplant recipients, 173 received EVL plus low-dose CNI therapy . After eIn the RD and LD groups, we assessed patients' data for up to one year after converting to EVL. The primary endpoint was a composite endpoint of death, graft loss, premature EVL discontinuation due to adverse events, and any event of rejection. Secondary endpoints were safety parameters determined on the basis of laboratory evaluations. In detail, we recorded serum concentrations of triglycerides, total cholesterol, HDL- and LDL-cholesterol, creatinine, blood urea nitrogen (BUN), white blood cells, red blood cells, and platelets before converting to EVL (t0) and at six (t6) and twelve months (t12) after conversion. Blood trough levels of immunosuppressives were recorded before conversion , and at t1, t3, t6, t9, and t12 . Immunosuppressives were determined by liquid chromatography tandem mass spectrometry . Hematological parameters were analyzed by the Cell-Dyn 3700 , whereas the other biochemical parameters were measured by the Architect ci8000 . Glomerular filtration rate was assessed by the MDRD formula .2 (low output syndrome).Generally, we do not perform myocardial biopsies routinely after discharge. We assume a clinically proven rejection that needs a daily cortisone bolus of 1000 mg for three days when at least two of the following five criteria are present: an echocardiography assessed ejection fraction <50%, a left ventricular ejection time <200 ms, an isovolumetric relaxation time >60 ms, occurrence of septic hypokinesia and pericardial effusion, and a mean arterial pressure <65 mmHg in parallel with nausea, weakness, and abdominal or thoracic pain. We assume a clinically proven severe rejection which needs OKT therapy when cardiac index is <1.6 L/min/mP values < 0.05 (two-tailed test) were considered statistically significant. We used the statistical software package PASW, version 18 , to perform the analyses. This analysis was designed by the authors, who had full access to the data, analysed the data, and controlled all decisions regarding publication.Categorical variables are reported using the percent of observations. Continuous variables are expressed as mean and standard deviation (SD). For comparisons of categorical variables, the two-sided Fisher exact test or the chi-square were used when appropriate. Comparisons of continuous variables at baseline and at specific time points were performed with the Mann-Whitney test. Time effects were evaluated using the Friedman test. The Wilcoxon test was used to assess differences between groups at specific time points. Complication rates were calculated with the Kaplan-Meier product-limit estimator. The log-rank test was used in order to test for potential differences in complication rates between the study groups. μg/L;.TAC: 6–10 μg/L). After reduction of the CNI-dose, blood trough levels of CSA and TAC decreased to a similar degree in both study groups (P < 0.001). The corresponding values at t12 were 8.8 mg  and 13.3 mg , respectively (P < 0.001). Thus, weekly EVL dose was 50% higher in the RD group than that in the LD group.Baseline characteristics are listed in y groups . As one y groups . In the P = 0.361). Thus, results did not differ significantly between the two groups. Moreover, the rates of death, premature EVL discontinuation, and episodes of rejection were similar in both groups (P = 0.166). Eight clinically proven cardiac rejections occurred during follow-up. The prevalence did not differ between the LD and RD group (h groups . In detaRD group . Of the P = 0.340). In detail, in the LD group 3 patients had died, 1 patient was retransplanted, 5 had developed a cardiac rejection, and 14 had to discontinue EVL. The corresponding values for the RD group were death (n = 5), cardiac rejection (n = 3), and EVL discontinuation (n = 23).Three years after converting to EVL, the composite endpoint was reached by 45.1% of the patients in the LD group and by 53.6% of the patients in the RD group (P = 0.054). Whereas infections were prevalent in the LD group, edema/dyspnoe and cytopenia were the most prevalent adverse events in the RD group . Our target EVL blood level is now 4.0−6.5 μg/L.The percentage of patients with cardiac rejection was in the range observed in earlier studies in maintenance cardiac transplant recipients receiving EVL –15. AlthDue to the inclusion criteria, the vast majority of our patients had already had poor kidney function when they changed over to EVL. Recent data indicate only a modest improvement in kidney function in patients with already existing renal dysfunction , 20. In Our results of unchanged LDL-cholesterol levels and higher triglyceride levels during follow-up are in line with earlier results . The larOur study has some limitations. Besides the aforementioned fact that it was a nonrandomized investigation, some may criticize that we excluded from our study a large number of patients who were switched over to EVL. However, the vast majority of these patients were at high risk of insufficient immunosuppression due to poor adherence or recurrent rejection. In these patients, it would have been unethical to administer a low EVL dose. Instead, all 56 patients with regular EVL dose who were included in our data analysis would have had the theoretical chance to receive the low EVL dose if they would have been switched over at another point of time. Some may also argue that the follow-up was restricted to one year only. However, even at 3 years of follow-up, the two groups did not differ with respect to major clinical results.The results of our cohort study indicate that low-dose EVL may be as effective and safe as regular dose EVL.


T3 or T4 increase with TSH decrease, and more compensation of thermogenic AUC decrease. Ghrelin played key roles in the actions of ALZ on the hypothermia with indigestion. The pharmacological mechanisms of ALZ involved the homeostasis of ghrelin expression and secretion.This study is aimed to investigate the Aconitum Lizhong pill (ALZ) pharmacological actions on hypothermia with indigestion, especially the ghrelin roles. The littermate-matched rats were randomly divided into four groups. Control did sham operation or standard diet, Model carried out interscapular brown adipose (IBA) removal with standard diet, Fat-diet did IBA removal with fat-diet, and ALZ did IBA removal and fat-diet with 4.536 g/kg/d ALZ. The potency of adaptive thermogenesis, ghrelin levels in plasma or gastric mucosa, thyroid hormones and metabolite in sera, expression of ghrelin mRNA, and protein in gastric mucous membrane were determined. ALZ relieved the hypothermia processes with indigestion, via inhibiting ghrelin expression and increasing ghrelin secretion; the dynamics from the therapy is supported with the energy changes as less body weight loss, less plasma lipid decrease, more plasma  Aconitum Lizhong pill (ALZ) is a classical herbal product for the patients with Spleen Yang Deficiency in traditional Chinese medicine (TCM) . This syGhrelin, a peptide hormone mainly secreted from gastric mucosa, regulates food intake, energy balance, and gut motility , 5. The In the present study, ghrelin is supposed to be a bridging signal between both processes, as the key effecter of ALZ actions for Spleen Yang Deficiency. Matched with rat littermates, IBA tissue is removed to induce hypothermia, high fatty diet was fed to replicate indigestion, and ALZ was administered intragastrically to moderate the processes of the syndrome –11. The Wistar rats  weighing 200–220 g were supplied by the Animal Centre of the Chinese Academy of Medical Sciences. Standard rodent pellets or Fat-diet pellets  for rats were prepared by Beijing Scientific Animal Feedstuff Company. Rats were housed in a SPF laboratory. All experiment procedures were performed in accordance with the guidelines of animal experiments from the Committee of Medical Ethics, National Health Department of China. Aconitum carmichaelii with aconitine, Codonopsis tangshen or Atractylodes macrocephala with atractylenolide III, Zingiber officinale with gingerol, and Glycyrrhiza uralensis with glycyrrhetic acid. According to Pharmacopoeia of the People's Republic of China (2010), the decoction was prepared and concentrated to 0.4536 (g/mL) by the pharmaceutical department, Beijing University of Chinese Medicine.Aconitum Lizhong pill is a thermogenesis-promoting prescription derived from TCM, consisting of five dried medical herbs (2 : 4 : 3 : 2 : 2 w/w) with representative molecules, such as The rats were randomly divided into 18 pairs with one male and one female in a cage (D650 cm × W450 cm × H200 cm). The male rat was taken out of the cage after the vaginal plug was found. The four littermates (8.12 ± 1.83 g) per litter were bred and randomly divided into four groups. With 18 litters, the weight was not significantly different among the groups .d42 after birth, fed with standard rodent pellets continuously from d56, and administrated intragastrically with saline (10 mL/kg) from d70. After anesthesia with anesthetic ether, rat thermogenesis was observed, and the plasma or gastric tissues were harvested at d98. Rats underwent sham operation to remove brown adipose tissue at d42 after birth; the others were the same as the Control group. Rats underwent surgery to remove brown adipose tissue at d56; the others were the same as the Model group.  Rats were fed with fat-diet from d70 to d98; the others were the same as the Fat-diet group. Rats were administrated intragastrically with ALZ (4.536 g/kg) from d42 after birth from all rats except Control rats. Briefly, rats were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg). The IBA was exposed through an incision from neck to the middle of the back with aid of binocular stereomicroscopy. A butterfly-shaped IBA was revealed and dissected with mechanical arms of stereomicroscope. Vessels and nerves were cut with electrothermal knife edge. The skin incision was sutured with some subcutaneous tissue.IBA was removed at d42 (W42) and d98 (W98). The growth ratio was calculated from the formula Gr = (W98 − W42) ÷ W42 × 100%. After fasting for 12 h, each rat was weighed at d98. The plasma was separated by centrifugation (1600 ×g for 15 min) and stored at −70°C. Levels of total protein (TP), total cholesterol (TC), triglycerides (TG), and glucose (Glu) in plasma were determined by the use of an AutoAnalyzer . Blood samples were taken after thermogenesis at d42, d70, and d98. Briefly, the rats were under ether anesthesia. Three thermometers were used to measure different sites of temperatures. The first one was fixed in the colon for core temperature, the second one was fixed on the skin of the left leg for skin temperature, and the third one was set in the air of the laboratory for controlled thermoneutral temperature. The thermometers were connected with PowerLab. Thirty minutes after rats awoke from anesthetization, the temperatures were recorded, isoproterenol hydrochloride  was given to rats through venepuncture in the tail vein, then the temperatures were recorded for 120 minutes continuously -1-propanesulfonate  and protease inhibitor cocktail Tablet Complete (Roche Diagnostics). The homogenate was then centrifuged at 12,000 g for 30 min at 4°C. The protein concentrations of supernatant were determined with the Bradford method. Equal amounts of protein (20 N = 72), excepting for biological molecule tests (ghrelin mRNA and protein) in 7 letters (N = 28).All data were standardized with data for rat partners in the same litter to control the variations due to heredity among the various litters. Make the average of 4 littermates in each litter equal to the total average of all rats in 18 letters . ALZ could slow down this decrease tendency (P < 0.01). Compared with Control , the groP < 0.01). ALZ could reverse the changes of TC, TG, and Glu (P < 0.01), but level of TP decreased (P < 0.01). Compared with Control , levels T3 was highest in Model (P < 0.01) and significantly reduced in Fat-diet and ALZ (P < 0.01). So did the similar changes of T4 and the reverse changes of TSH , and ALZ did not relive the hypothermia. At d98, ALZ promoted thermogenesis significantly (P < 0.01), so did the thermogenic AUC (Isoproterenol-induced thermogenesis  was demoenic AUC . P < 0.01) and Fat-diet (P < 0.05) showed significant increment of plasma ghrelin level compared with Control (P < 0.05).  Rats in Model ( Control . ALZ incP < 0.01). ALZ moderated this potency (P < 0.01).  The gastric ghrelin  detected In Control rats, the positive staining was located in the cytoplasm of typical gastric endocrine cells; positive-stained cells in the stomach were found from the neck to the base of the oxyntic gland . In ModeP < 0.01). ALZ increased that significantly. The amount of existed ghrelin in gastric mucosa  reduced P < 0.01). ALZ regulated down its expression (P < 0.01).  The levels of ghrelin mRNA  were higP < 0.01). ALZ could reverse the changes (P < 0.01).  Compared with Control , the amor = 0.664, P < 0.001, N = 72). In addition, an inverse relation was found between the plasma ghrelin content and the thermogenic AUC . The positive linear relation was found between gastric ghrelin level and the thermogenic AUC . An inverse relation was found between plasma ghrelin content and existing gastric ghrelin amount in all rats  with lower TSH, lower thermogenic peak or AUC, higher gastric ghrelin expression, less gastric ghrelin detected by IHC or IRA, and more plasma ghrelin. It suggested that IBA removal may upregulate ghrelin expression and ghrelin secretion. (2) Compared with Model rats, Fat-diet rats were characterized with further less weight, higher lipid metabolites , lower thyroid hormones  with higher TSH, higher thermogenic peak or AUC, lower gastric ghrelin expression, more gastric ghrelin content detected by IHC, less gastric, and plasma ghrelin level detected by IRA. It suggested that Fat-diet relieves the upregulation of ghrelin secretion, decreases acute cold tolerance, and increases chronic cold tolerance. (3) Compared with Fat-diet rats, ALZ-administrated rats were characterized with higher weight, higher plasma metabolites , lower thyroid hormones  with further higher TSH, higher thermogenic peak or AUC, lower gastric ghrelin expression, more gastric ghrelin content detected by IHC, higher gastric, and plasma ghrelin level detected by IRA. It suggested that ALZ downregulates ghrelin expression, promotes ghrelin secretion, and consequently increases cold tolerance. ALZ made an economical energy balance for maintaining a stable cold tolerance in the model of hypothermia with indigestion. In the present study, the hypothermia was induced by IBA removal, and the indigestion was replicated with fat-diet. The hypothermia with indigestion was significantly relived with ALZ . The resThe ghrelin secretion is close to energy balance and thermogenesis  19]. Pl. Pl19]. There are three conclusions that could be made from these data. (1) A rat model of the hypothermia with indigestion had been replicated with IBA removal following a fat-diet. The adaptive thermogenesis, thyroid-related hormones, plasma metabolites, and their related behaviors were in accordance with the features of Spleen Yang Deficiency in TCM. (2) ALZ downregulated ghrelin-mRNA expression and promoted ghrelin secretion into blood, at least, leading to the decrease of catabolism for energy storage and the improvement of gut motility. Some data supported ghrelin as one of the effective bimolecular for ALZ pharmacological actions, such as adaptive thermogenesis, thyroid-related hormones, plasma metabolites, and the related behaviors. (3) A special network for drug-NEI disease should be set up as a dry model of the hypothermia with indigestion, so that the detail actions of ALZ could delicately be analyzed in the multilayer . The rol


Aim. The present study was designed to investigate the cytotoxicity of a panel of 280 Korean medicinal plants belonging to 73 families and 198 species against human CCRF-CEM leukemia cells. Selected phytochemicals were investigated in more detail for their mode of action. Methods. The resazurin assay was used to determine cytotoxicity of the plant extracts. Microarray-based mRNA expression profiling, COMPARE, and hierarchical cluster analyses were applied to identify which genes correlate with sensitivity or resistance to selected phytochemicals of the Korean plants. Results. The results of the resazurin assay showed that cytotoxicity extracts tested at 10 μg/mL from 13 samples inhibited proliferation more than 50% (IC50 < 10 μg/mL) and the most active plants are Sedum middendorffianum (15.33%) and Lycoris radiata (17.61%). Out of 13 selected phytochemicals from these plants, hopeaphenol and deoxynarciclasine were the most cytotoxic ones. Genes from various functional groups  were significantly correlated with response of tumor cell lines to these two compounds. Conclusion. The results provide evidence on the possible use of selected Korean medicinal plants and chemical constituents derived from them for the treatment of tumors. Since ancient times, humans have derived many benefits from medicinal plants. A variety of different medicinal plants have traditionally been used in Asian cultures as medicinal plants to treat cancers . The phaTraditional Korean medicine is widely used in Korea and is the primary health care system for more than 20% of the population , 7. As pIn the pharmacopoeia of many countries worldwide including Korea, there is still a serious lack of information on the use of medicinal plants in the treatment of cancer. However, it has been recommended that ethnopharmacological usages such as for immune and skin disorders, inflammatory, infectious, parasitic, and viral diseases should be taken into account when selecting plants used to treat cancer, since these reflect disease states bearing relevance to cancer or cancer-like symptoms , 10. In http://dx.doi.org/10.1155/2013/341724). The extraction of the air-dried and powdered plant material was conducted using methanol (HPLC grade) with either ASE 300 (Dionex) or a sonicator (Branson Ultrasonics) at 50°C. The extracts were then conserved at 4°C until further use.Medicinal plants used in the present work were collected at different localities of the Republic of Korea and provided by Prof. Ik-Soo Lee . The plants were identified at the National herbarium, where voucher specimens were deposited under the references numbers  was used as a positive (cytotoxic) control. Human CCRF-CEM leukemia cells were obtained from Professor Axel Sauerbrey . Cells were maintained in RPMI 1640 containing 100 units/mL penicillin and 100 mg/mL streptomycin and supplemented with heat-inactivated 10% fetal bovine serum (FBS), in a humidified environment at 37°C with 5% CO4 cells/mL were seeded in 96-well plates, and extracts were added immediately. After 24 h incubation, 20 μL resazurin 0.01% w/v solution was added to each well and the plates were incubated at 37°C for 1-2 h. Fluorescence was measured on an automated 96-well Infinite M2000 Pro plate reader  using an excitation wavelength of 544 nm and an emission wavelength of 590 nm. Doxorubicin was used as positive control. The concentration of DMSO was kept at or below 0.1% in all experiments. Each assay was done at least three times, with three replicates each. All samples were tested at a single concentration of 10 μg/mL.Alamar Blue or Resazurin  reduction assay  was usedhttp://dtp.nci.nih.gov/). For hierarchical cluster analysis, objects were classified by calculation of distances according to the closeness of between-individual distances by means of hierarchical cluster analysis. All objects were assembled into a cluster tree (dendrogram). The merging of objects with similar features leads to the formation of a cluster, where the length of the branch indicates the degree of relation. The distance of a subordinate cluster to a superior cluster represents a criterion for the closeness of clusters as well as for the affiliation of single objects to clusters. Thus, objects with tightly related features appear together, while the separation in the cluster tree increases with progressive dissimilarity. Previously, cluster models have been validated for gene expression profiling and for approaching molecular pharmacology of cancer , isolated from the bark of A. japonica, showed cytotoxic activities on human, B16 mouse melanoma cells and SNU-1 gastric cancer cell lines with IC50 values varying from 17.02 to 55.47 μM [μg/mL. In addition, Kim et al. [via Fas-mediated pathway was also reported in human MCF-7 breast adenocarcinoma cells by prodelphinidin B-2 3,3′-di-O-gallate, a constituent of M. rubra [A. japonica and M. rubra. Similarly, the presence of cytotoxic compounds such as quercetin or ferulic acid [R. corchorifolius and S. middendorffianum extracts [Sedum takesimense [50 value of 6 µM) [Caryopteris incana. But extract from Caryopteris incana did not show significant activities against CCRF-CEM leukemia cells in the present study. To the best of our knowledge, the cytotoxic effect of several active plants  against 55.47 μM . Interesm et al.  reportedm et al.  in the eM. rubra . The prelic acid , in R. cextracts , 25 and esimense  could alof 6 µM)  {active of 6 µM) } were rein vitro and in vivo [We screened the NCI database of the Developmental Therapeutics Program of the NCI for the constituents of our panel of Korean medicinal plants. The two most cytotoxic compounds were hopeaphenol and deoxynarciclasine. Both compounds have been previously reported to be cytotoxic –32. Whil in vivo , 32, the50 values for both compounds of 60 tumor cell lines with transcriptomic mRNA expression levels of this cell line panel [50 values for investigational drugs to identify candidate genes for drug resistance [To gain insight into possible modes of action of both phytochemicals, we investigated gene expression profiles of the NCI cell line panel. By microarray-based gene expression and COMPARE analyses, we correlated the ICne panel . This apne panel . Clustersistance , 35 and sistance , 37.R > 0.5 and R < −0.5 were identified to significantly correlate with sensitivity or resistance to hopeaphenol. Except for fibroblast growth factor 9 [Eleven genes passing the correlation thresholds of factor 9 , none ofThe genes correlating with the response of tumor cells to deoxynarciclasine were also not known to confer drug resistance as of yet, but many of them belong to functional groups, which are associated with response to chemotherapy. For example, transcriptional regulation, signal transduction, and cell proliferation are well-known processes influencing the success of cancer chemotherapy –42. ThisAdenophora racemosa, Cinnamomum japonicum, Eurya japonica, Sedum middendorffianum, and Vitis flexuosa. The identification of cytotoxic phytochemicals from these plants, for example, hopeaphenol, and deoxynarciclasine, and the investigation of their possible molecular modes of action may foster the development of novel treatment strategies against otherwise drug-resistant and refractory tumors. The present work provides evidence that some plants derived from Korean medicine could be useful in the treatment of leukemia and supports the advanced investigation of the most active plants extracts. It also provides first pharmacological data on the cytotoxicity of some plants, such as Extracts of medicinal plants used in traditional Korean medicine investigated for cytotoxic activity towards cancer cells.Click here for additional data file.


Background. Inflammation in the Brugada syndrome (BrS) and its clinical implication have been little studied. Aims. To assess the level of inflammation in BrS patients. Methods. All studied BrS patients underwent blood samples drawn for C-reactive protein (CRP) levels at admission, prior to any invasive intervention. Patients with a previous ICD placement were controlled to exclude those with a recent (<14 days) shock. We divided subjects into symptomatic (syncope or aborted sudden death) and asymptomatic groups. In a multivariable analysis, we adjusted for significant variables . Results. Fifty-four subjects were studied  male). Twenty (37%) were symptomatic. Baseline characteristics were similar in both groups. Mean CRP level was 1,4 ± 0,9 mg/L in asymptomatic and 2,4 ± 1,4 mg/L in symptomatic groups (P = .003). In the multivariate model, CRP concentrations ≥ 2 mg/L remained an independent marker for being symptomatic . Conclusion. Inflammation seems to be more active in symptomatic BrS. C-reactive protein concentrations ≥ 2 mg/L might be associated with the previous symptoms in BrS. The value of inflammation as a risk factor of arrhythmic events in BrS needs to be studied. The Brugada syndrome (BrS) is an inherited cardiac disorder occurring particularly in young, apparently healthy individuals and is associated with a variety of arrhythmias, mainly ventricular tachyarrhythmias that can induce syncope or sudden cardiac arrest (SCA) . Patientin vivo effects of fever and its various aspects,” including “inflammatory cells and cytokines” [Increased body of evidence links lethal ventricular arrhythmias with inflammatory states . It is ktokines” . C-reacttokines” . Serum lV1–V3) in conjunction with a documented ventricular fibrillation (VF), self-terminating polymorphic ventricular tachycardia (VT), agonal nocturnal respiration, syncope, aborted SCA, or family history (<45 years) of SCA. Asymptomatic patients were compared with symptomatic (syncope and aborted SCA). Study protocol was approved by the Institutional Review Board of Pitié-Salpêtrière Hospital, and informed consent was obtained from each participant.Patients of our BrS registry were carefully analyzed in terms of past medical history. They were referred for three main reasons: family screening of a BrS index case, unexplained syncope, or aborted SCA. At admission, a complete clinical history, including family antecedents with emphasis on SCA, was obtained. All patients underwent physical examination and cardiac work-up that included ECG, 2D echocardiography, signal averaged ECG (SAECG), ajmaline challenge (in the absence of spontaneous type 1 ECG pattern), and at least two of the following cardiac imaging studies: right ventricular angiography, cardiac MRI, or ventricular radionuclide imaging. The diagnosis of BrS was made if ECG displayed coved-type ST-segment elevation, either spontaneously or after a sodium channel blocker challenge, in at least one right precordial lead . For characterization of inflammatory state, only CRP measurements were performed. Data were collected retrospectively, and we verify that no recent arrhythmic event had occurred prior to blood sample testing. In those patients with established diagnosis of BrS and carriers of an ICD, a device interrogation was performed to exclude recent (<14 days) shock discharge.V1 through V3. Wide QRS was duration of QRS > 120 ms. Other covariates of interest were age, atrial fibrillation (AF), drug challenge by ajmaline test, family history of SCD, and ICD placement for high-risk status or for secondary prevention. Hypertension was defined as diastolic blood pressure ≥ 90 mmHg and/or systolic blood pressure ≥ 140 mmHg and/or a patient on antihypertensive medication. Diabetes mellitus was based on a fasting blood sugar ≥ 7 mmol/L and/or on insulin regimen or on any other antidiabetic treatment. Smoking was classified into ever and never smokers. Lipid lowering treatment was statin treatment with anti-inflammatory properties. Aspirin, even when a low dose is used, has the potential to influence CRP release . Brugadat-test for independent samples. Continuous variables that did not show a normal distribution were compared using the Mann-Whitney U test. Categorical variables were summarized as proportions and compared using the χ2  test or the Fischer exact test if cell counts were less than 5. For the multivariate model, only factors that attained statistical significance (P < .1) in the univariate analysis were included. A 2-tailed P value <.05 was considered statistically significant. Statistical analysis was performed with SPSS version 11.0.1 software (SPSS Inc). Continuous variables were expressed as mean ± SD if they demonstrated a normal distribution and as median (range) otherwise. Means of continuous variables that showed normal distribution were compared with the Student's P = 0.001, The study sample consisted of 54 patients, with a mean age of 45 ± 13 years old and 49 (91%) being male. Twenty (37%) were symptomatic (17 syncope and 3 aborted SCA) . BaselinP = .009, CI 95% 1.56–22.08, and P = .018, CI 95% 1.32–19.31, resp.). Asymptomatic and symptomatic patients were comparable in gender, cardiovascular risk factors, and main ECG features . Mean age and CRP levels were the only parameters significantly different in univariate analysis between both groups. In Implantation of an ICD started in our centre before current recommendations . TherefoP = .003). CRP concentration ≥ 2 mg/L was an independent marker for being symptomatic  (P = .022), syncope (P = .025), syncope and/or aborted SCA (P = .018), and the decision to implant an ICD (P = .003) in univariate analysis. After multivariate analysis, only overall symptoms (syncope and/or resuscitated SCA) remained significantly different   . A CRP c7–18,79) . The aim of this study was to assess the inflammatory profile measured by CRP in individuals with BrS. The study also looked at the association between past history of arrhythmic events and CRP level. This study shows that patients with BrS syndrome and life-threatening symptoms such as syncope or sudden death have more active inflammation than those without symptoms. Moreover, a CRP level ≥ 2 mg/L is more frequent in the presence of previous cardiac arrhythmic events. CRP is a biomarker of inflammation, and high levels have been associated with an increased risk of all-cause mortality . It predWe found that a single plasma value of CRP concentration is robustly associated with either syncope or SCA in BrS. Studies assessing inflammatory patterns in BrS have reported controversial findings. One did not detect inflammatory changes in cardiac biopsies . Others We consider this finding relevant for risk stratification in BrS. With an increasing number of patients being diagnosed with BrS, our knowledge has also grown in every single aspect of this disease. However, estimation of the likelihood to die suddenly remains difficult in the absence of resuscitated SCA . For exaSCN5A gene. Therefore, a correlation between genotype and inflammation could not be established. This is a very pertinent lack of information as there is a bunch of literature showing that loss-of-function SCN5A mutations lead to fibrosis and structural heart disease [The strength of the study is that it is the first to our knowledge to evaluate CRP as a marker of inflammation in BrS. This may help provide a better understanding of the large spectrum of the disease. However, there are some potential limitations which merit consideration. First, we did not use the nephelometric technique assessing high sensitivity C-reactive protein (hs-CRP) which is about a 10-fold more sensitive than the immunoturbidimetric assay used in this study. Secondly, few patients in our series (11 out of 54 (20%)) have been genotyped and only one displayed a mutation in  disease , 39, empCRP levels are increased in symptomatic patients with BrS. The causative role of inflammation in occurrence of arrhythmic events in this disease needs to be further studied.