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1.
M. Correale A. Totaro T. Passero S. Abruzzese F. Musaico A. Ferraretti R. Ieva M. Di Biase N. D. Brunetti 《Netherlands heart journal》2013,21(9):408-416
Background
Few works have evaluated the effect of statins on left ventricular dysfunction in patients with chronic heart failure (CHF), by using tissue Doppler imaging (TDI). We therefore aimed to investigate whether atorvastatin treatment may influence prognosis and myocardial performance evaluated by TDI in subjects with CHF.Methods
Five hundred thirty-two consecutive CHF outpatients enrolled in a local registry, the Daunia Heart Failure Registry, were prospectively analysed. 195 patients with CHF and left ventricular ejection fraction (LVEF) ≤40 %, either in treatment with atorvastatin (N: 114) or without statins (N: 81), underwent TDI examination. Adverse events were evaluated during follow-up.Results
The atorvastatin group showed a lower incidence of adverse events (cardiac death: 0 % vs 7 %, p < 0.01), and better TDI performance (E/E’ 15 ± 5.7 vs 18 ± 8.3, p < 001) than controls. Ischaemic CHF patients in treatment with atorvastatin also showed a lower incidence of adverse events (death: 10 % vs 26 %, p < 0.05; sustained ventricular arrhythmias: 5 % vs 19 %, p < 0.05, cardiac death: 0 vs 8 %, p < 0.05) and better TDI performance (E/E’ ratio: 15.00 ± 5.68 vs 19.72 ± 9.14, p < 0.01; St: 353.70 ± 48.96 vs 303.33 ± 68.52 msec, p < 0.01) than controls. The association between atorvastatin and lower rates of cardiac death remained statistically significant even after correction in a multivariable analysis (RR 0.83, 95 % CI 0.71–0.96, p < 0.05 in CHF with LVEF ≤40 %; RR 0.77, 95 % CI 0.62–0.95, p < 0.05 in ischaemic CHF with LVEF ≤40 %).Conclusions
Treatment with atorvastatin in outpatients with systolic CHF is associated with fewer cardiac deaths, and a better left ventricular performance, as assessed by TDI. 相似文献2.
Zhang Z Slobodianski A Ito WD Arnold A Nehlsen J Weng S Lund N Liu J Egaña JT Lohmeyer JA Müller DF Machens HG 《PloS one》2011,6(4):e19192
Background
Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy.Methods and Results
Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48±0.05 vs. 0.57±0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41±0.10 vs. 0.50±0.11; p<0.05; soleus ratio: soleus: 0.42±0.08 vs. 0.60±0.08; p<0.01) in the lower hindlimb were also observed.Conclusions
These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases. 相似文献3.
Background
No selection criteria for helical tomotherapy (HT) based stereotactic ablative radiotherapy (SABR) to treat early stage non-small cell lung cancer (NSCLC) or solitary lung metastases has been established. In this study, we investigate the dosimetric selection criteria for HT based SABR delivering 70 Gy in 10 fractions to avoid severe toxicity in the treatment of centrally located lesions when adequate target dose coverage is desired.Materials and Methods
78 HT-SABR plans for solitary lung lesions were created to prescribe 70 Gy in 10 fractions to the planning target volume (PTV). The PTV was set to have ≥95% PTV receiving 70 Gy in each case. The cases for which dose constraints for ≥1 OAR could not be met without compromising the target dose coverage were compared with cases for which all target and OAR dose constraints were met.Results
There were 23 central lesions for which OAR dose constraints could not be met without compromising PTV dose coverage. Comparing to cases for which optimal HT-based SABR plans were generated, they were associated with larger tumor size (5.72±1.96 cm vs. 3.74±1.49 cm, p<0.0001), higher lung dose, increased number of immediately adjacent OARs ( 3.45±1.34 vs. 1.66±0.81, p<0.0001), and shorter distance to the closest OARs (GTV: 0.26±0.22 cm vs. 0.88±0.54 cm, p<0.0001; PTV 0.19±0.18 cm vs. 0.48±0.36 cm, p = 0.0001).Conclusion
Delivery of 70 Gy in 10 fractions with HT to meet all the given OAR and PTV dose constraints are most likely when the following parameters are met: lung lesions ≤3.78 cm (11.98 cc), ≤2 immediately adjacent OARs which are ≥0.45 cm from the gross lesion and ≥0.21 cm from the PTV. 相似文献4.
Background
AKAP12/Gravin (A kinase anchor protein 12) is one of the A-kinase scaffold proteins and a potential tumor suppressor gene in human primary cancers. Our recent study demonstrated the highly recurrent loss of AKAP12 in colorectal cancer and AKAP12 reexpression inhibited proliferation and anchorage-independent growth in colorectal cancer cells, implicating AKAP12 in colorectal cancer pathogenesis.Methods
To evaluate the effect of this gene on the progression and metastasis of colorectal cancer, we examined the impact of overexpressing AKAP12 in the AKAP12-negative human colorectal cancer cell line LoVo, the single clone (LoVo-AKAP12) compared to mock-transfected cells (LoVo-CON).Results
pCMV6-AKAP12-mediated AKAP12 re-expression induced apoptosis (3% to 12.7%, p<0.01), migration (89.6±7.5 cells to 31.0±4.1 cells, p<0.01) and invasion (82.7±5.2 cells to 24.7±3.3 cells, p<0.01) of LoVo cells in vitro compared to control cells. Nude mice injected with LoVo-AKAP12 cells had both significantly reduced tumor volume (p<0.01) and increased apoptosis compared to mice given AKAP12-CON. The quantitative human-specific Alu PCR analysis showed overexpression of AKAP12 suppressed the number of intravasated cells in vivo (p<0.01).Conclusion
These results demonstrate that AKAP12 may play an important role in tumor growth suppression and the survival of human colorectal cancer. 相似文献5.
Schmidt C Wiener E Hoffmann J Klingebiel R Schmidt F Hofmann T Harms L Kunte H 《PloS one》2012,7(4):e35221
Background
Complications of idiopathic intracranial hypertension (IIH) are usually caused by elevated intracranial pressure (ICP). In a similar way as in the optic nerve, elevated ICP could also compromise the olfactory nerve system. On the other side, there is growing evidence that an extensive lymphatic network system around the olfactory nerves could be disturbed in cerebrospinal fluid disorders like IIH. The hypothesis that patients with IIH suffer from hyposmia has been suggested in the past. However, this has not been proven in clinical studies yet. This pilot study investigates whether structural changes of the olfactory nerve system can be detected in patients with IIH.Methodology/Principal Findings
Twenty-three patients with IIH and 23 matched controls were included. Olfactory bulb volume (OBV) and sulcus olfactorius (OS) depth were calculated by magnetic resonance techniques. While mean values of total OBV (128.7±38.4 vs. 130.0±32.6 mm3, p=0.90) and mean OS depth (8.5±1.2 vs. 8.6±1.1 mm, p=0.91) were similar in both groups, Pearson correlation showed that patients with a shorter medical history IIH revealed a smaller OBV (r=0.53, p<0.01). In untreated symptomatic patients (n=7), the effect was greater (r=0.76, p<0.05). Patients who suffered from IIH for less than one year (n=8), total OBV was significantly smaller than in matched controls (116.6±24.3 vs. 149.3±22.2 mm3, p=0.01). IIH patients with visual disturbances (n=21) revealed a lower OS depth than patients without (8.3±0.9 vs. 10.8±1.0 mm, p<0.01).Conclusions/Significance
The results suggest that morphological changes of the olfactory nerve system could be present in IIH patients at an early stage of disease. 相似文献6.
R. J. Folkeringa R. G. Tieleman J. G. Maessen M. H. Prins R. Nieuwlaat H. J. G. M. Crijns 《Netherlands heart journal》2011,19(1):17-23
Introduction
Statins may theoretically reduce postoperative atrial fibrillation (AF) in patients after cardiac valvular surgery due to preservation of endothelial function and anti-ischaemic, anti-inflammatory and anti-remodelling effects.Methods
Two hundred seventy-two patients who underwent cardiac workup and subsequently cardiac valvular surgery without AF and concomitant coronary artery bypass grafting (CABG) at our hospital were selected. Preoperative drug use and postoperative AF were recorded. AF was defined as any episode of AF longer than 10 s. In addition, results from echocardiography and blood samples were retrieved.Results
Baseline characteristics were as follows: mean age was 65 ± 11 years, 142 (52%) patients were male, 189 (70%) had undergone aortic valve surgery and the mean left ventricular ejection fraction was 57 ± 12%. Statins were used by 79 patients (29%). Statin users, more often, had a prior percutaneous coronary intervention (25% vs 9%, p < 0.001) or CABG (24% vs 4%, p < 0.001), diabetes mellitus (22% vs 5%, p < 0.001) and more often used β-blockers (51% vs 24%, p < 0.001). Patients in the non-statin group more often had surgery on more than one valve (10% vs 3%, p = 0.043) and had a higher cholesterol level (222 ± 48 vs 190 ± 43 mg/dl, p < 0.001). Postoperative AF occurred in 54% (43/79) of the patients with and in 55% (106/193) of the patients without statins (p = 0.941). There was also no difference in the timing of onset of AF or duration of hospital stay.Conclusion
In this observational study, statin use was not associated with a reduced incidence of AF in patients after cardiac valvular surgery. 相似文献7.
Lo YL Lin TY Fang YF Wang TY Chen HC Chou CL Chung FT Kuo CH Feng PH Liu CY Kuo HP 《PloS one》2011,6(11):e27769
Objectives
There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.Methods
After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.Results
The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.Conclusions
BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.Trial Registration
ClinicalTrials. gov NCT00789815相似文献8.
M. Correale T. Passero A. Totaro C. A. Greco F. De Rosa M. Concilio S. Abbruzzese G. Acanfora R. Ieva M. Di Biase N. D. Brunetti 《Netherlands heart journal》2013,21(1):36-43
Background
The cardiopulmonary exercise test (CPX) is an affordable tool for risk prediction in patients with chronic heart failure (CHF). We aimed to determine the role of CPX parameters in predicting the risk of incidence of sustained ventricular arrhythmias (SVA) in CHF.Methods
Sixty-one consecutive patients with CHF enrolled in the Daunia Heart Failure Registry underwent CPX and were followed for 327 ± 247 days. Clinical follow-up was performed every month and anticipated in case of re-hospitalisation for cardiac disease. Incidence of SVA was evaluated by direct clinical examination (ECG, ambulatory ECG).Results
Patients with episodes of SVA (N 14) showed lower values of pVO2 and PetCO2, and higher values of VE/VCO2, VE/VCO2 slope, and VE%. After correction for age, gender, diabetes, ischaemic heart disease and left ventricular ejection fraction, peak VO2 (hazard ratio (HR) 0.68, 95 % confidence interval (CI) 0.51–0.91, p < 0.05), VE% (HR 1.38, 95 % CI 1.04–1.84, p < 0.05), VE/VCO2 (HR 1.38, 95 % CI 1.04–1.82, p < 0.05), VE/VCO2 slope (HR 1.77, 95 % CI 1.31–2.39, p < 0.01), PetCO2 (HR 0.66, 95 % CI 0.50–0.88, p < 0.01) were found as predictors of SVA. At Kaplan-Meier analysis, lower event-free rates were found in subjects with peak VO2 values below median (log rank p < 0.05), values of VE/VCO2 above mean (p < 0.05), higher VE/VCO2 slope tertiles (p <0.05), and values of PetCO2 below median (p < 0.05).Conclusions
CPX provides prognostic independent information for risk of SVA in subjects with CHF. 相似文献9.
Nils Schallner Carlos C. Rom?o Julia Biermann Wolf A. Lagrèze Leo E. Otterbein Hartmut Buerkle Torsten Loop Ulrich Goebel 《PloS one》2013,8(4)
Purpose
Carbon monoxide (CO) is an accepted cytoprotective molecule. The extent and mechanisms of protection in neuronal systems have not been well studied. We hypothesized that delivery of CO via a novel releasing molecule (CORM) would impart neuroprotection in vivo against ischemia-reperfusion injury (IRI)-induced apoptosis of retinal ganglion cells (RGC) and in vitro of neuronal SH-SY5Y-cells via activation of soluble guanylate-cyclase (sGC).Methods
To mimic ischemic respiratory arrest, SH-SY5Y-cells were incubated with rotenone (100 nmol/L, 4 h) ± CORM ALF186 (10–100 µmol/L) or inactivated ALF186 lacking the potential of releasing CO. Apoptosis and reactive oxygen species (ROS) production were analyzed using flow-cytometry (Annexin V, mitochondrial membrane potential, CM-H2DCFDA) and Western blot (Caspase-3). The impact of ALF186± respiratory arrest on cell signaling was assessed by measuring expression of nitric oxide synthase (NOS) and soluble guanylate-cyclase (sGC) and by analyzing cellular cGMP levels. The effect of ALF186 (10 mg/kg iv) on retinal IRI in Sprague-Dawley rats was assessed by measuring densities of fluorogold-labeled RGC after IRI and by analysis of apoptosis-related genes in retinal tissue.Results
ALF186 but not inactivated ALF186 inhibited rotenone-induced apoptosis (Annexin V positive cells: 25±2% rotenone vs. 14±1% ALF186+rotenone, p<0.001; relative mitochondrial membrane potential: 17±4% rotenone vs. 55±3% ALF186+rotenone, p<0.05). ALF186 increased cellular cGMP levels (33±5 nmol/L vs. 23±3 nmol/L; p<0.05) and sGC expression. sGC-inhibition attenuated ALF186-mediated protection (relative mitochondrial membrane potential: 55±3% ALF186+rotenone vs. 20±1% ODQ+ALF186+rotenone, p<0.05). ALF186 protected RGC in vivo (IRI 1255±327 RGC/mm2 vs. ALF186+IRI 2036±83; p<0.05) while sGC inhibition abolished the protective effects of ALF186 (ALF186+IRI 2036±83 RGC/mm2 vs. NS-2028+ALF186+IRI 1263±170, p<0.05).Conclusions
The CORM ALF186 inhibits IRI-induced neuronal cell death via activation of sGC and may be a useful treatment option for acute ischemic insults to the retina and the brain. 相似文献10.
Borralho PM Simões AE Gomes SE Lima RT Carvalho T Ferreira DM Vasconcelos MH Castro RE Rodrigues CM 《PloS one》2011,6(8):e23787
Background
MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys)regulation of cell survival, proliferation, differentiation and death. Specifically, miRNA-143 (miR-143) is down-regulated in human colon cancer. In the present study, we evaluated the role of miR-143 overexpression on the growth of human colon carcinoma cells xenografted in nude mice (immunodeficient mouse strain: N: NIH(s) II-nu/nu).Methodology/Principal Findings
HCT116 cells with stable miR-143 overexpression (Over-143) and control (Empty) cells were subcutaneously injected into the flanks of nude mice, and tumor growth was evaluated over time. Tumors arose ∼ 14 days after tumor cell implantation, and the experiment was ended at 40 days after implantation. miR-143 was confirmed to be significantly overexpressed in Over-143 versus Empty xenografts, by TaqMan® Real-time PCR (p<0.05). Importantly, Over-143 xenografts displayed slower tumor growth compared to Empty xenografts from 23 until 40 days in vivo (p<0.05), with final volumes of 928±338 and 2512±387 mm3, respectively. Evaluation of apoptotic proteins showed that Over-143 versus Empty xenografts displayed reduced Bcl-2 levels, and increased caspase-3 activation and PARP cleavage (p<0.05). In addition, the incidence of apoptotic tumor cells, assessed by TUNEL, was increased in Over-143 versus Empty xenografts (p<0.01). Finally, Over-143 versus Empty xenografts displayed significantly reduced NF-κB activation and ERK5 levels and activation (p<0.05), as well as reduced proliferative index, evaluated by Ki-67 immunohistochemistry (p<0.01).Conclusions
Our results suggest that reduced tumor volume in Over-143 versus Empty xenografts may result from increased apoptosis and decreased proliferation induced by miR-143. This reinforces the relevance of miR-143 in colon cancer, indicating an important role in the control of in vivo tumor progression, and suggesting that miR-143 may constitute a putative novel therapeutic tool for colon cancer treatment that warrants further investigation. 相似文献11.
JD Coso C González-Millán JJ Salinero J Abián-Vicén L Soriano S Garde B Pérez-González 《PloS one》2012,7(8):e43280
Background
To investigate the cause/s of muscle fatigue experienced during a half-iron distance triathlon.Methodology/Principal Findings
We recruited 25 trained triathletes (36±7 yr; 75.1±9.8 kg) for the study. Before and just after the race, jump height and leg muscle power output were measured during a countermovement jump on a force platform to determine leg muscle fatigue. Body weight, handgrip maximal force and blood and urine samples were also obtained before and after the race. Blood myoglobin and creatine kinase concentrations were determined as markers of muscle damage.Results
Jump height (from 30.3±5.0 to 23.4±6.4 cm; P<0.05) and leg power output (from 25.6±2.9 to 20.7±4.6 W · kg−1; P<0.05) were significantly reduced after the race. However, handgrip maximal force was unaffected by the race (430±59 to 430±62 N). Mean dehydration after the race was 2.3±1.2% with high inter-individual variability in the responses. Blood myoglobin and creatine kinase concentration increased to 516±248 µg · L−1 and 442±204 U · L−1, respectively (P<0.05) after the race. Pre- to post-race jump change did not correlate with dehydration (r = 0.16; P>0.05) but significantly correlated with myoglobin concentration (r = 0.65; P<0.001) and creatine kinase concentration (r = 0.54; P<0.001).Conclusions/significance
During a half-iron distance triathlon, the capacity of leg muscles to produce force was notably diminished while arm muscle force output remained unaffected. Leg muscle fatigue was correlated with blood markers of muscle damage suggesting that muscle breakdown is one of the most relevant sources of muscle fatigue during a triathlon. 相似文献12.
Objectives
To quantitatively analyze placental perfusion in a rat model at different gestation time and different portions of placenta by real-time contrast-enhanced ultrasound (CEUS) and parametric imaging analysis.Materials and Methods
Sixty pregnant rats at different gestation time (15 dys,17 days and 20 days) were injected intravenously with microbubbles (5×105 microbubbles /ml, 1.0 ml/kg), and cadence contrast pulse sequencing (transmission frequency of 7 MHz, mechanical index 0.18) was performed. Dynamic enhancement changes in placenta at different gestation time and different portions of placenta were measured and enhancement parameters analyzed with software. Correlation between enhancement parameters and average area densities of placenta vascular compartment was compared.Results
The pattern and real-time sequence of enhancement in uterus and placenta were clearly depicted by CEUS. The time-to-peak enhancement was earlier in central portion than that in peripheral portion (12.30±6.33s vs 36.26±10.65 s, p = 0.005), and peak intensity of enhancement is much higher in central portion than that in peripheral portion (30.20±2.85 dB vs 20.95±6.25 dB, p = 0.000). The peak intensity of enhancement at day 15 (27.70±4.47 dB) was lower than that at day 17 (30.20±2.85 dB, p = 0.042) and at day 20 (31.85±4.41 dB, p = 0.015) of gestation. Significant correlation between average area densities of vascular compartment and the peak intensity of enhancement was identified in placenta at different gestation time (p<0.05). The average area densities of vascular compartment was higher in central portion than that in peripheral portion and has significant correlation with peak intensity of enhancement of the two potions (p<0.01).Conclusion
CEUS is feasible to depict real-time sequence and quantitative parameters of perfusion in different portion of placenta at different gestational time in a rat model. 相似文献13.
Lise MC Sparsa A Marie I Lalloué F Ly K Martel C Bezanahary H Gondran G Loustaud-Ratti V Bonnetblanc JM Vidal E Jauberteau MO Fauchais AL 《PloS one》2010,5(11):e13918
Background
Neurotrophins (NTs) are able to activate lymphocytes and fibroblasts; they can modulate angiogenesis and sympathic vascular function. Thus, they can be implicated in the three pathogenic processes of systemic sclerosis (SSc). The aims of this study are to determine blood levels of Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT-3) in SSc and to correlate them with clinical and biological data.Methods
Serum samples were obtained from 55 SSc patients and 32 control subjects to measure NTs levels by ELISA and to determine their relationships with SSc profiles.Findings
Serum NGF levels were higher in SSc patients (288.26±170.34 pg/mL) than in control subjects (170.34±50.8 pg/mL, p<0.001) and correlated with gammaglobulins levels and the presence of both anti-cardiolipin and anti-Scl-70 antibodies (p<0.05). In contrast, BDNF levels were lower in SSc patients than in controls (1121.9±158.1 vs 1372.9±190.9 pg/mL, p<0.0001), especially in pulmonary arterial hypertension and diffuse SSc as compared to limited forms (all p<0.05). NT-3 levels were similar in SSc and in the control group (2657.2±2296 vs 2959.3±2555 pg/mL, NS). BDNF levels correlated negatively with increased NGF levels in the SSc group (and not in controls).Conclusion
Low BDNF serum levels were not previously documented in SSc, particularly in the diffuse SSc subset and in patients with pulmonary hypertension or anti-Scl-70 antibodies. The negative correlation between NGF and BDNF levels observed in SSc and not in healthy controls could be implicated in sympathic vascular dysfunction in SSc. 相似文献14.
Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle 总被引:1,自引:0,他引:1
Masharani UB Maddux BA Li X Sakkas GK Mulligan K Schambelan M Goldfine ID Youngren JF 《PloS one》2011,6(5):e19878
Background
The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.Methodology/Principal Findings
To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and 1H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H2O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.Conclusions
This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population. 相似文献15.
Background
It is controversial whether microRNA-126 is a tumor suppressive or oncogenic miRNA. More experiments are needed to determine whether microRNA-126 is associated with non-small cell lung cancer risk and prognosis.Methods
Over-expression of microRNA-126 was performed to evaluate the cell invasion and tumor growth in non-small cell lung cancer (NSCLC) cell lines and nude mouse xenograft model. Gain-of-function experiments and luciferase assays were performed to reveal the relationship between microRNA-126 and PI3K-Akt signal pathway in A549 cells. We analyzed the associations of the microRNA-126 expression between genetic variants within microRNA-126 and clinical information including smoking status, sex, age, and histological type and the tumor stage.Results
Over-expression of microRNA-126 in NSCLC cell lines decreased cell proliferation in vitro and tumor growth in the nude mouse xenograft model. And microRNA-126 repressed the activity of PI3K-Akt pathway by targeting binding sites in the 3′-untranslated region of PI3KR2 mRNA. The expression level of microRNA-126 was decreased in NSCLC lines and tumor tissues. The patients with low microRNA-126 expression had significantly poorer survival time than those with high microRNA-126 expression (means for survival time (month): 24.392±1.055 vs. 29.282±1.140, P = 0.005). However, there was no significant difference in the genotype and allele frequencies of the microRNA-126 variant (G>A, rs4636297) between cases and controls (P = 0.366). In addition, there was no association between SNP rs4636297 and survival time in NSCLC patients (P = 0.992). And microRNA-126 expression had no significant difference among the three genotype groups (P = 0.972).Conclusions
Our data indicate that microRNA-126 is a tumor-suppressor gene in NSCLC and low microRNA-126 expression is a unfavorable prognostic factor in NSCLC patients. However, the regulatory mechanism of microRNA-126 remains to be elucidated in different normal and malignant tissues. Therefore, further research is needed to explore the tumor suppressive functions of microRNA-126 in NSCLC. 相似文献16.
Del Coso J Muñoz-Fernández VE Muñoz G Fernández-Elías VE Ortega JF Hamouti N Barbero JC Muñoz-Guerra J 《PloS one》2012,7(2):e31380
Background
To investigate the effects of a caffeine-containing energy drink on soccer performance during a simulated game. A second purpose was to assess the post-exercise urine caffeine concentration derived from the energy drink intake.Methodology/Principal Findings
Nineteen semiprofessional soccer players ingested 630±52 mL of a commercially available energy drink (sugar-free Red Bull®) to provide 3 mg of caffeine per kg of body mass, or a decaffeinated control drink (0 mg/kg). After sixty minutes they performed a 15-s maximal jump test, a repeated sprint test (7×30 m; 30 s of active recovery) and played a simulated soccer game. Individual running distance and speed during the game were measured using global positioning satellite (GPS) devices. In comparison to the control drink, the ingestion of the energy drink increased mean jump height in the jump test (34.7±4.7 v 35.8±5.5 cm; P<0.05), mean running speed during the sprint test (25.6±2.1 v 26.3±1.8 km · h−1; P<0.05) and total distance covered at a speed higher than 13 km · h−1 during the game (1205±289 v 1436±326 m; P<0.05). In addition, the energy drink increased the number of sprints during the whole game (30±10 v 24±8; P<0.05). Post-exercise urine caffeine concentration was higher after the energy drink than after the control drink (4.1±1.0 v 0.1±0.1 µg · mL−1; P<0.05).Conclusions/significance
A caffeine-containing energy drink in a dose equivalent to 3 mg/kg increased the ability to repeatedly sprint and the distance covered at high intensity during a simulated soccer game. In addition, the caffeinated energy drink increased jump height which may represent a meaningful improvement for headers or when players are competing for a ball. 相似文献17.
Background
This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.Methodology/Principal Findings
One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65±.13) as compared to the fifth day during treatment (1.26±.19, p<0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89±.13, 1.00±.21, 1.13±.23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32±2.34 branches/mm3, p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29±3.51 branches/mm3). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45±1.36 µm2) as compared to saline treated tumor regions (30.83±4.31 µm2, p<0.001) and non-tumor regions (22.80±1.11 µm2, p<0.01).Conclusions/Significance
Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment. 相似文献18.
Background
Gastric carcinoma and primary gastric lymphoma (PGL) are the two most common malignancies in stomach. The purpose of this study was to screen and validate a biomarker of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for distinguishing advanced gastric carcinoma (AGC) from PGL for clinical applications.Methodology/Principal Findings
We reviewed PET/CT scans collected from January 2008 to April 2012 of 69 AGC and 38 PGL (14 low-grade mucosa-associated lymphoid tissue [MALT], 24 non-MALT aggressive non-Hodgkin lymphoma [ANHL]) with a focus on FDG intensity (maximum standardized uptake value [SUVmax]) of primary lesions and its CT-detected abnormalities, including maximal gastrointestinal wall thickness (THKmax) and mucosal ulcerations. Gastric FDG uptake was found in 69 (100%) patients with AGC and 36 (95%, 12 MALT vs. 24 ANHL)with PGL. The presence of CT-detected abnormalities of AGC and PGL were 97% (67/69) and 89% (12 MALT vs. 22 ANHL), respectively. After controlling for THKmax, SUVmax was higher with ANHL than AGC (17.10±8.08 vs. 9.65±5.24, p<0.05) and MALT (6.20±3.60, p<0.05). THKmax did not differ among MALT, ANHL and AGC. Mucosal ulceration was more common with AGC (n = 9) than PGL (n = 2),but the difference was not statistically significant (p>0.05). Cross-validation analysis showed that for distinguishing ANHL from AGC, the classifier with SUVmax as a feature achieved a correct classification rate of 81% with thresholds 13.40±1.12 and the classifier with SUVmax/THKmax as a feature achieved a correct classification rate of 83% with thresholds 7.51±0.63.Conclusions/Significance
SUVmax/THKmax may be as a promising biomarker of FDG-PET/CT for distinguishing ANHL from AGC. Structural CT abnormalities alone may not be reliable but can help with PET assessment of gastric malignancies. 18F-FDG PET/CT have potential for distinguishing AGC from PGL at the individual level. 相似文献19.
M Lang B Kojonazarov X Tian A Kalymbetov N Weissmann F Grimminger A Kretschmer JP Stasch W Seeger HA Ghofrani RT Schermuly 《PloS one》2012,7(8):e43433
Background
The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63–2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO–sGC–cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.Methods and Results
Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55±0.02, p<0.05), increased cardiac output (60.8±.8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03±0.3 mmHg min−1 ml−1 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05).Conclusion
Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil. 相似文献20.
Quantifying the impact of soil compaction on root system architecture in tomato (Solanum lycopersicum) by X-ray micro-computed tomography 总被引:2,自引:0,他引:2
Tracy SR Black CR Roberts JA Sturrock C Mairhofer S Craigon J Mooney SJ 《Annals of botany》2012,110(2):511-519