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Are n-acetylglucosaminyltransferase V and beta1-6 branching N-linked oligosaccharides associated with good prognosis of patients with bladder cancer?
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N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. We examined the relationship between GnT-V expression and clinicopathologic features of the patients with bladder cancer. We immunohistochemically examined GnT-V expression in paraffin-embedded bladder cancer specimen using anti-GnT-V monoclonal antibody. We compared GnT-V expression with cause-specific survival of the patients with bladder cancer treated by radical cystectomy. Kaplan-Meier survival curves were generated to show the cause-specific survival. Univariate and multivariate analyses were carried out to compare GnT-V expression with other clinical and pathologic variables. We also evaluated mRNA expression of GnT-V and N-linked oligosaccharide structure in bladder cancer specimens. Immunohistochemistry revealed that GnT-V expression inversely correlated with tumor grade and stage. The incidence of positive GnT-V expression in bladder cancer was significantly higher in low-grade/superficial cancer than in high-grade/invasive cancer. The patients whose tumor was positive for GnT-V survived significantly longer than those whose tumor was negative for GnT-V. Univariate and multivariate analyses revealed that GnT-V expression was an independent predictor of prognosis of the patient. The expression of GnT-V mRNA determined by reverse transcription-PCR was consistent with the results with immunohistochemistry for tumor samples. Carbohydrate structural analysis revealed that superficial bladder cancer is rich in branched N-linked oligosaccharides, for which biosynthesis GnT-V is responsible.
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Abdominal obesity is associated with pro-thrombotic and inflammatory states. Therefore, the purpose of this study was to examine the expression of thrombin receptors (PAR1 and PAR4) human adipose tissue and whether thrombin stimulates an inflammatory cytokine and growth factor profile in human adipose tissue. Human adipose tissue, isolated preadipocytes and differentiated adipocytes were used in this study. PAR1 and PAR4 mRNA and protein were detected by RT-PCR and immunoblot analysis in both adipose tissue and adipose microvessels. In separate studies, IL-1beta, IL-6, MCP-1, TNF-alpha, IL-10, FGF-2, VEGF, and PDGF production were measured from adipose tissue (n = 5), adipocytes (n = 5), and preadipocytes (n = 3) supernatants with and without thrombin (1 or 10 U/ml; 24 hrs) treatment. Thrombin increased cytokine secretion of IL-1beta, IL-6, MCP-1 and TNF-alpha and growth factor secretion of VEGF from adipocytes along with MCP-1 and VEGF from preadipocytes. The direct thrombin inhibitor lepirudin given in conjunction with thrombin prevented the thrombin-mediated increase in cytokine and growth factor secretion.
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Does expression of polo-like kinase 1 ( PLK1 ) protein predict the survival of patients with gastric carcinoma?
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To assess the prognostic value of polo-like kinase 1 (PLK1), an important regulator of cell cycle progression, in patients with gastric carcinoma. PLK1 expression was determined in 160 gastric carcinoma patients by immunohistochemistry and compared with p53 expression and the proliferating cell nuclear antigen-labeling index (PCNA-LI) to evaluate the effect of PLK1 on tumor progression. Furthermore, PLK mRNA expression was determined in 26 advanced gastric cancer patients by reverse transcription-polymerase chain reaction (RT-PCR). PLK mRNA expression was detected in 25 (96.2%) patients by RT-PCR. Immunohistochemical staining revealed PLK1 expression in 84 (52.5%) patients. There were no significant relationships between PLK1 expression and various clinicopathological factors. PLK1 expression was significantly correlated with the PCNA-LI, but not p53 expression. The prognosis of patients with PLK1-positive tumors was significantly worse than that of patients with PLK1-negative tumors (p < 0.05). Moreover, multivariate analysis revealed that PLK1 expression was an independent prognostic factor. Patients with PLK1-positive and high PCNA-LI tumors showed a significantly poorer prognosis than patients with PLK1-negative and/or low PCNA-LI tumors. Furthermore, the prognosis of patients with PLK1- and p53-positive tumors was significantly worse than that of patients with PLK1- and p53-negative or PLK1-negative and p53-positive tumors.
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Enhanced activation of the mineralocorticoid receptors (MRs) in cardiovascular tissues increases oxidative stress, maladaptive immune responses, and inflammation with associated functional vascular abnormalities. We previously demonstrated that consumption of a Western diet (WD) for 16 weeks results in aortic stiffening, and that these abnormalities were prevented by systemic MR blockade in female mice. However, the cell-specific role of endothelial cell MR (ECMR) in these maladaptive vascular effects has not been explored. We hypothesized that specific deletion of the ECMR would prevent WD-induced increases in endothelial sodium channel activation, reductions in bioavailable nitric oxide, increased vascular remodeling, and associated increases in vascular stiffness in females. Four-week-old female ECMR knockout and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding resulted in aortic stiffness and endothelial dysfunction as determined in vivo by pulse wave velocity and ex vivo by atomic force microscopy, and wire and pressure myography. The WD-induced aortic stiffness was associated with enhanced endothelial sodium channel activation, attenuated endothelial nitric oxide synthase activation, increased oxidative stress, a proinflammatory immune response and fibrosis. Conversely, cell-specific ECMR deficiency prevented WD-induced aortic fibrosis and stiffness in conjunction with reductions in endothelial sodium channel activation, oxidative stress and macrophage proinflammatory polarization, restoration of endothelial nitric oxide synthase activation.
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Does surfactant protein D inhibit TNF-alpha production by macrophages and dendritic cells in mice?
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Surfactant protein (SP) D shares target cells with the proinflammatory cytokine TNF-alpha, an important autocrine stimulator of dendritic cells and macrophages in the airways. We sought to study the mechanisms by which TNF-alpha and SP-D can affect cellular components of the pulmonary innate immune system. Cytokine and SP-D protein and mRNA expression was assessed by means of ELISA, Western blotting, and real-time PCR, respectively, by using in vivo models of allergic airway sensitization. Macrophage and dendritic cell phenotypes were analyzed by means of FACS analysis. Maturation of bone marrow-derived dendritic cells was investigated in vitro. TNF-alpha, elicited either by allergen exposure or pulmonary overexpression, induced SP-D, IL-13, and mononuclear cell influx in the lung. Recombinant IL-13 by itself was also capable of enhancing SP-D in vivo and in vitro, and the SP-D response to allergen challenge was impaired in IL-13-deficient mice. Allergen-induced increase of SP-D in the airways coincided with resolution of TNF-alpha release and cell influx. SP-D-deficient mice had constitutively high numbers of alveolar mononuclear cells expressing TNF-alpha, MHC class II, CD86, and CD11b, characteristics of proinflammatory, myeloid dendritic cells. Recombinant SP-D significantly suppressed all of these molecules in bone marrow-derived dendritic cell cultures.
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The management of patients with recurrent colorectal liver metastases (RCLM) remains controversial. This study aimed to determine whether repeat liver resection for RCLM could be performed with acceptable morbidity, mortality and long-term survival. Of 1121 consecutive liver resections performed and prospectively analysed between 1987 and 2005, 852 'curative' resections were performed on patients with colorectal liver metastases. Single liver resection was performed in 718 patients, and 71 repeat hepatic resections for RCLM were performed in 66 patients. There were no postoperative deaths following repeat hepatic resection compared with a postoperative mortality rate of 1.4 per cent after single hepatic resection. Postoperative morbidity was comparable following single and repeat hepatectomy (26.1 versus 18 per cent; P = 0.172), although median blood loss was greater during repeat resection (450 versus 350 ml; P = 0.006). Actuarial 1-, 3- and 5-year survival rates were 94, 68 and 44 per cent after repeat hepatic resection for RCLM, compared with 89.3, 51.7 and 29.5 per cent respectively following single hepatectomy.
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Does serum glycated albumin predict the progression of diabetic retinopathy -- a five year retrospective longitudinal study?
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To assess the predictive value of glycated albumin (GA) and other risk factors on a progression of diabetic retinopathy (DR). In this retrospective longitudinal study, we enrolled the subjects with type 2 diabetes who had undergone fundus photography twice with a 5-years gap between January 2006 and December 2012, and had been measured consecutively for hemoglobin A1c (HbA1c) and GA levels every 3 or 6 months. The subjects were divided into two groups with or without a progression of DR. The mean HbA1c and mean GA were calculated separately by the sum of all measured values divided by the numbers of values throughout the study period. Of the 359 subjects, progression group showed significantly higher diabetes duration (8.41±5.72 vs. 6.46±5.77, P<0.01), baseline HbA1c (9.13±2.71 vs. 8.41±2.32, P<0.05), fasting plasma glucose (8.71±2.78 vs. 7.94±2.63, P<0.05), 2h-postprandial glucose (15.12±11.20 vs.13.14±4.72, P<0.05), eGFR (114.81±39.15 vs. 103.23±32.18, P<0.01), mean HbA1c (8.32±1.69 vs. 7.39±1.35, P<0.01) and mean GA (22.66±5.92 vs. 19.83±5.18, P<0.01) than non-progression group. The frequencies of subjects with DR progression increased obviously with the increment of baseline HbA1c, mean HbA1c and mean GA according to quartile stratification of the above three glucose parameters. Multivariable binary logistic regression analysis investigated that the factors affected the DR progression were the presence of DR at baseline (OR=0.391, P=0.005), mean HbA1c (OR=1.389, P=0.021), mean GA (OR=1.087, P=0.039) and eGFR (OR=1.008, P=0.045). The optimal cut-off values of mean HbA1c and GA to predict DR progression were 7.27% and 21.85%, respectively.
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Certain eukaryotic genomes, such as those of the amitochondriate parasites Giardia and Trichomonas, have very low intron densities, so low that canonical spliceosomal introns have only recently been discovered through genome sequencing. These organisms were formerly thought to be ancient eukaryotes that diverged before introns originated, or at least became common. Now however, they are thought to be members of a supergroup known as excavates, whose members generally appear to have low densities of canonical introns. Here we have used environmental expressed sequence tag (EST) sequencing to identify 17 genes from the uncultivable oxymonad Streblomastix strix, to survey intron densities in this most poorly studied excavate group. We find that Streblomastix genes contain an unexpectedly high intron density of about 1.1 introns per gene. Moreover, over 50% of these are at positions shared between a broad spectrum of eukaryotes, suggesting they are very ancient introns, potentially present in the last common ancestor of eukaryotes.
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Are novel mutations in the displacement loop of mitochondrial DNA associated with acute lymphoblastic leukemia : a genetic sequencing study?
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Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among those younger than 15 years of age. This study investigated alterations in the displacement loop (d-loop) region of mitochondrial DNA (mtDNA) as a risk factor and diagnostic biomarker for early detection and diagnosis of acute lymphoblastic leukemia. Using mtDNA from 23 subjects diagnosed with acute lymphoblastic leukemia, the first 450 bp of the d-loop region were amplified and successfully sequenced. This revealed 132 mutations at 25 positions in this region, with a mean of 6 alterations per subject. The d-loop alterations in mtDNA in subjects were all identified as single nucleotide polymorphisms in a homoplasmic distribution pattern. Mutant alleles were observed in all subjects with individual frequency rates of up to 95%. Thirteen mutant alleles in the d-loop region of mtDNA occurred with a high frequency. Novel alleles and locations were also identified in the d-loop of mtDNA as follows: 89 G insertions (40%), 95 G insertions (13%), 182 C/T substitutions (5%), 308 C insertions (19%), and 311 C insertions (80%). The findings of this study need to be replicated to be confirmed.
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Reflex bladder excitation has been demonstrated by stimulation of the pudendal nerve and several of its distal branches. However, excitation parameters have not been consistent and the relationship to anatomical locations within the urethra has not been fully investigated. An improved understanding of the lower urinary tract neurophysiology will improve human studies and neuroprosthetic device development. Intraurethral stimulation was performed in nine cats at near isovolumetric bladder volumes before and/or after spinalization. Bladder excitability profiles were obtained for lower (2 Hz) and higher (33 Hz) frequency stimuli along the urethra between the bladder neck and external meatus. Higher frequency stimuli were excitable at all urethral locations prior to spinalization but only excitable in the middle and distal urethra after spinalization. Lower frequency stimuli were excitable at proximal and middle locations before spinalization but not excitable at any location after spinalization. In most evaluations, bursting pulse stimulation patterns evoked greater bladder pressures than the dominant continuous frequency (2 or 33 Hz).
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Is higher fibrinogen level independently linked with the presence and severity of new-onset coronary atherosclerosis among Han Chinese population?
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Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size. We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082-1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889-1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383-2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833-1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155-2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L.
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To determine the effect of subthalamic stimulation on visually triggered eye and head movements in patients with Parkinson's disease (PD). We compared the gain and latency of visually triggered eye and head movements in 12 patients bilaterally implanted into the subthalamic nucleus (STN) for severe PD and six age-matched control subjects. Visually triggered movements of eye (head restrained), and of eye and head (head unrestrained) were recorded in the absence of dopaminergic medication. Bilateral stimulation was turned OFF and then turned ON with voltage and contact used in chronic setting. The latency was determined from the beginning of initial horizontal eye movements relative to the target onset, and the gain was defined as the ratio of the amplitude of the initial movement to the amplitude of the target movement. Without stimulation, the initiation of the head movement was significantly delayed in patients and the gain of head movement was reduced. Our patients also presented significantly prolonged latencies and hypometry of visually triggered saccades in the head-fixed condition and of gaze in head-free condition. Bilateral STN stimulation with therapeutic parameters improved performance of orienting gaze, eye and head movements towards the controls' level
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Does biventricular pacing have an advantage over left ventricular epicardial pacing alone to minimize proarrhythmic perturbation of repolarization?
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Cardiac resynchronization therapy (CRT) by simultaneous biventricular pacing is now widely accepted as a new therapeutic option for patients with severe congestive heart failure (CHF). Recent studies have shown comparable hemodynamic benefits of left ventricular (LV) pacing alone. The clinical usefulness of CRT, however, might be compromised by potential exaggeration of arrhythmogenic substrates through a modification of ventricular repolarization. We compared ECG parameters during sinus rhythm (SR), atrioventricular synchronous pacing at the right ventricular apex (RV(end)P), at LV epicardium (LV(epi)P), and at both sites (BiVP) in acute homodynamic studies of 14 CHF patients scheduled for CRT (QRS duration = 144 +/- 23 msec, LVEF = 27 +/- 10%). The maximum rate of increase in LV pressure (LVdp/dt(max)) was decreased significantly during RV(end)P, whereas it was increased similarly during LV(epi)P and BiVP compared with SR. QTc was increased during RV(end)P (by 10.2%) and LV(epi)P (by 26.1%). QTc dispersion (QTc(max)-QTc(min) in the six precordial leads) was also increased during LV(epi)P (by 66.5%). These parameters were unaffected during BiVP. JTc was unchanged, and the interval from the peak to the end of the T wave (Tc(peak-end)) was increased slightly (by 19.3%) during RV(end)P. Both JTc and Tc(peak-end) were increased dramatically during LV(epi)P (by 18.2% and 55.4%, respectively), but increased only modestly during BiVP (by 6.6% and 15.8%, respectively).
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Aggrecanase cleavage at the 392Glu-393Ala bond in the interglobular domain (IGD) of aggrecan, releasing N-terminal 393ARGS fragments, is an early key event in arthritis and joint injuries. Here, we use a quantitative immunoassay of aggrecan ARGS neoepitope fragments in human synovial fluid to determine if this cleavage-site specific method better identifies joint pathology than previously available less specific aggrecan assays. Synovial fluid (SF) from 26 people with healthy knees (reference) and 269 patients were analyzed in a cross-sectional study. Patient groups were acute inflammatory arthritis, acute knee injury, chronic knee injury and knee osteoarthritis (OA). Aggrecan ARGS fragments were assayed by ELISA using the monoclonal antibody OA-1. Total aggrecan content was analyzed by an ELISA using the monoclonal antibody 1-F21, and sulfated glycosaminoglycan by Alcian blue precipitation. Aggrecan ARGS fragment concentrations in all groups differed from the reference group (P < 0.001). The acute inflammatory arthritis group had the highest median level, 177-fold greater than that of the reference group. Median levels (in pmol ARGS/ml SF) were: reference 0.5, acute inflammatory arthritis 88.5, acute knee injury 53.9, chronic knee injury 0.5 and OA 4.6. In contrast, aggrecan and sulfated glycosaminoglycan concentrations varied much less between groups, and only acute inflammatory arthritis and acute knee injury were found to have a two-fold increase in median levels compared to the reference.
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Is testosterone production better preserved after 16 than 20 Gray irradiation treatment against testicular carcinoma in situ cells?
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To study the effect of 16 Gy radiotherapy (RT) vs. 20 Gy RT on Leydig cell function in men treated with radiotherapy against carcinoma in situ (CIS) of the testis. Fifty-one men who were treated between 1985 and 2005 were included. Fourteen men had been treated with 20 Gy and 37 with 16 Gy RT. Measurements of sex hormone-binding globulin and basic and stimulated testosterone, as well as luteinizing hormone levels were performed. The follow-up periods for the patients treated without additional chemotherapy were for the 20 Gy and 16 Gy group mean/median/min-max: 9.0/10.0/1.0-20.3 years and 4.0/3.1/0.4-14.1 years, respectively. During the follow-up period, men treated with 16 Gy RT had stable testosterone levels (-1.1%/year, p = 0.4), whereas men treated with 20 Gy had an annual decrease of 2.4% (p = 0.008). For the latter group, the testosterone decrease was most pronounced in the first 5 years, leveling off during the following 5 years. Additionally, more men treated with 20 Gy needed androgen substitution treatment. Our study showed an increased luteinizing hormone level for the men treated with 16 Gy, although this was not significant (p = 0.5). We anticipated a similar increase in the patients treated with 20 Gy but instead observed a decrease (-3.1%, p = 0.01).
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Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways.
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Is familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Associated with Succinate Dehydrogenase Defects?
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Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA, SDHB, SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA, SDHB, SDHC, and SDHD genes and familiar PTC in a large Brazilian family. Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single-stranded conformational polymorphism and direct sequencing. Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST.
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The purpose of our study was to evaluate the relationship between graft placement and in situ graft force after anterior cruciate ligament (ACL) reconstruction. Magnetic resonance imaging (MRI) was obtained for twelve human cadaveric knees. The knees, in intact and deficient-ACL states, were subjected to external loading conditions as follows: an anterior tibial load of 89 N at 0°, 15°, 30°, 45°, 60°, and 90° of flexion and a combined rotatory (simulated pivot-shift) load of 5 Nm of internal tibial torque and 7 Nm of valgus torque at 0°, 15°, and 30° of flexion. Three ACL reconstructions were performed in a randomized order: from the center of the tibial insertion site to the center of the femoral insertion site (Mid), the center of the tibial insertion site to a more vertical femoral position (S1), and the center of the tibial insertion site to an even more vertical femoral position (S2). The reconstructions were tested following the same protocol used for the intact state, and graft in situ force was calculated for the two loadings at each flexion angle. MRI was used to measure the graft inclination angle after each ACL reconstruction. The mean inclination angle (and standard deviation) was 51.7° ± 5.0° for the native ACL, 51.6° ± 4.1° for the Mid reconstruction (p = 0.85), 58.7° ± 5.4° for S1 (p < 0.001), and 64.7° ± 6.5° for S2 (p < 0.001). At 0°, 15°, and 30° of knee flexion, the Mid reconstruction showed in situ graft force that was closer to that of the native ACL during both anterior tibial loading and simulated pivot-shift loading than was the case for S1 and S2 reconstructions. At greater flexion angles, S1 and S2 had in situ graft force that was closer to that of the native ACL than was the case for the Mid reconstruction.
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Is reduced fronto-temporal connectivity associated with frontal gray matter density reduction and neuropsychological deficit in schizophrenia?
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A "disconnectivity model" of schizophrenia has been proposed, but it is still unclear if white matter abnormalities are associated with gray matter changes and if they may be the anatomic substrate of cognitive impairment, which is a core symptom of the disorder. The first objective was to detect if white matter microstructure alterations in schizophrenia are associated with or independent of gray matter change, using an optimized method for white matter (Tract-Based Spatial Statistics) and gray matter analyses (whole-brain voxel-wise approach). The second objective was to identify the neuropsychological correlates of white matter abnormalities in the schizophrenic group, using a comprehensive neuropsychological battery. In this case-control study 43 schizophrenic patients and 43 healthy volunteers were consecutively enrolled and matched for age and gender. Fractional anisotropy reduction was found in 6 fronto-temporal clusters (corrected p-values <0.05) in schizophrenic group in comparison with healthy volunteers, and 3 clusters showed fractional anisotropy increase (corrected p-values <0.05). Two of the clusters showing reduced fractional anisotropy were associated with reduced gray matter density in neuroanatomically-related regions in schizophrenic subjects (p-values ranging from 0.001 to 0.026). Executive, constructional-praxis, and working memory deficits were significant predictors of fractional anisotropy reduction in 4 clusters in the schizophrenic group (p-values ranging from <0.0001 to 0.0017).
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Duodenal reflux causes inflammation-related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, in preventing this carcinogenesis. A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux-related morphological changes, COX-2 expression, and its activity. At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P<.05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P<.01). COX-2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX-2 in the epithelium was up-regulated, reaching peak at an early stage of Week 20 in both groups (P<.005). The expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P<.005).
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Is adrenomedullin increased in the fetoplacental circulation in intrauterine growth restriction with abnormal umbilical artery waveforms?
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To examine whether adrenomedullin, a novel vasoactive peptide produced by the placenta, participates in the uteroplacental hemodynamic alterations in intrauterine growth restriction, we studied the correlation between adrenomedullin levels and fetoplacental blood flow. Maternal and umbilical blood samples were collected in pregnancies complicated by intrauterine growth restriction with abnormal umbilical artery Doppler findings and in control pregnancies. Adrenomedullin levels were measured by means of a specific radioimmunoassay, and flow velocimetry waveforms were recorded from uterine, umbilical, and fetal middle cerebral arteries. Mean adrenomedullin values in umbilical plasma were higher (P <.05) in patients with intrauterine growth restriction (63.7 +/- 34.2 pg/mL; n = 16) than in control subjects (38.1 +/- 14.8 pg/mL; n = 16). A significant correlation was found between maternal adrenomedullin levels and umbilical artery pulsatility index. Moreover, fetal adrenomedullin concentrations correlated negatively with middle cerebral artery pulsatility index and positively with umbilical artery pulsatility index/middle cerebral artery pulsatility index ratio.
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Substance use and crime/recidivism are irrevocably linked. We explore the nuances of this association by highlighting the prevalence, trends, and correlates of substance use dsorders in a large group of probationers/parolees. We examined SUDs among probationers and parolees in the United States using data from the National Study on Drug Use and Health (NSDUH). Logistic regression models were computed to examine eight distinct outcomes: alcohol abuse, illicit drug abuse, marijuana/hashish abuse, comorbid alcohol and illicit drug abuse, alcohol dependence, illicit drug dependence, marijuana/hashish dependence, and comorbid alcohol and illicit drug dependence. Probationers/parolees have high prevalence rates across all SUDs categories and these trends have been relatively constant. Prevalence rates for alcohol abuse and dependence are two to six times higher than for marijuana and other illicit drug abuse and dependence. Key correlates of substance abuse for probationers/parolees include: age, gender, race/ethnicity, education, income, risk propensity, crime/violence measures, and comorbid substance abuse. Similar correlates were found for substance dependence, in addition to employment and mental health treatment.
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Are drug Transporter Genetic Variants Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection : A Pharmacogenetic Study?
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To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement. This study investigated the association between 3 SNPs (ABCC2-24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m2 decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m2) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5'-nuclease assays. 95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/μl, median baseline eGFR of 96ml/min/1.73m2 (IQR 84.6-109.2), and median exposure to TDF of 3.66 years (IQR 1.93-5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m2 and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m2: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.
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The necessity for general anesthesia represents an impediment to using a laparoscopic approach for some procedures that are otherwise performed with the patient under local anesthesia using a conventional open technique. Heating and humidifying the insufflation gas reportedly reduces perioperative pain associated with a CO2 pneumoperitoneum, thus enabling awake laparoscopy. Two cases are reported herein of laparoscopy performed with the patient under local anesthesia using heated, humidified CO2 gas for the pneumoperitoneum. Both patients experienced pain with insufflation of heated, humidified CO2 gas of sufficient magnitude that the procedure could not be performed. The CO2 gas was washed out and replaced with helium gas insufflation with complete resolution of pain. The laparoscopic procedures were accomplished without further discomfort with local anesthesia and using a helium gas pneumoperitoneum.
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Do [ Treatment of burn cicatricial foot drop with Ilizarov fixator ]?
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To investigate the efficacy of Ilizarov fixator on cicatricial foot drop after burn. Six patients with cicatricial foot drop after burn were treated with Ilizarov fixator during June 2004 approximately October 2007, the fixator was set on the leg and foot by fixed bone needles. Nuts on the threaded rod were turned from 3 post operation day, 2 approximately 4 rounds per time and 4 times per day in the first week, then 1 approximately 2 rounds per time and 4 times a day, which corrected the deformity of talipes equinus by shortening or lengthening the thread rod in the front and at the back. Ankle joint was maintained in neutral position for 2 approximately 3 months after effective correction. Weight carrying for patients was increased gradually after removal of fixator. Ankle joint was maintained in neutral position with fixator at least three months. Patients were followed up 5 approximately 10 months. Ankle joints from all patients were restored to neutral position after application with fixator for 4 approximately 6 weeks. All patients achieved 0 degrees dorsiflexion in weight carrying for whole planta pedis after use of fixator for 12 approximately 15 weeks with good locomotion function.
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Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. The purpose of the present study was to investigate the involvement of COX-2 protein in breast cancer biological behavior through its correlation with the well-known clinicopathological parameters and the expression of p53, c-erbB-2, topoisomerase IIalpha (topoIIalpha) and peroxisome proliferator-activated receptor (PPARgamma) proteins, as well as its effect on patients' survival. We performed immunohistochemistry to detect COX-2, estrogen receptor (ER), progesterone receptor (PR), p53, c-erbB-2, topoIIalpha and PPARgamma proteins in 175 cases of invasive breast carcinomas. The results were elaborated by statistic analysis. Cytoplasmic expression of COX-2 was detected in 66.9% of breast carcinoma samples and was inversely correlated with both nuclear and histological grade (p < 0.0001 and p = 0.039, respectively), whereas its association with PR was found to be positive (p = 0.016). COX-2 expression was inversely correlated with topoIIalpha and p53 (p = 0.033 and p = 0.002, respectively), whereas its association with PPARgamma was parallel (p < 0.0001). In addition, c-erbB-2 of tumor cells was inversely correlated with COX-2 in stromal cells of the tumor (p = 0.011). Neither univariate nor multivariate analysis demonstrated any association between COX-2 expression and patient overall or disease-free survival.
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Are high mean platelet volume , low-grade systemic coagulation and fibrinolytic activation associated with androgen and insulin levels in polycystic ovary syndrome?
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The present study was designed to determine (a) the coagulation parameters, WBC and MPV levels; (b) whether there was any association between androgen and mean platelet volume and low-grade systemic coagulation in PCOS patients. A total of 48 patients with non-diabetic PCOS were studied in order to evaluate and compare with a non-PCOS group of 30 subjects. D-dimer, homeostatic model assessment (HOMA-IR), insulin, androgens, glucose, WBC and MPV concentrations were higher in women with PCOS. No difference was observed in fibrinogen, activated partial thromboplastin time and prothrombin time values between the two groups. Free testosterone was positively correlated with D-dimer, insulin, DHEAS, and MPV levels. In multiple stepwise regression analyses, free testosterone positively associated with D-dimer and DHEAS. MPV was positively correlated with insulin levels, HOMA-IR values, DHEAS and free testosterone levels in PCOS patients. In multiple stepwise regression analyses, MPV positively associated with insulin and DHEAS.
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Clinical use of doxorubicin is greatly limited by its severe cardiotoxic side effects. L-carnitine is a vitamin-like substance which has been successfully used in many cardiomyopathies, however, the intracellular mechanism(s) remain unclear. The objective of this study was set to evaluate the protective effect of L-carnitine on doxorubicin-induced cardiomyocyte apoptosis, and to explore its intracellular mechanism(s). Primary cultured neonatal rat cardiomyocytes were treated with doxorubicin (1 µM) with or without pretreatment with L-carnitine (1-30 mM). Lactate dehydrogenase assay, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, and flow cytometry measurement were used to assess cytotoxicity and apoptosis. Fluorescent probes 2',7'-dichlorofluorescein diacetate and chemiluminescence assay of superoxide production were used to detect the production of reactive oxygen species. Western blotting was used to evaluate the quantity of cleaved caspase-3, cytosol cytochrome c, and Bcl-x(L) expression. L-carnitine inhibited doxorubicin-induced reactive oxygen species generation and NADPH oxidase activation, reduced the quantity of cleaved caspase-3 and cytosol cytochrome c, and increased Bcl-x(L) expression, resulting in protecting cardiomyocytes from doxorubicin-induced apoptosis. In addition, L-carnitine was found to increase the prostacyclin (PGI(2)) generation in cardiomyocytes. The siRNA transfection for PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and L-carnitine's protective effect. Furthermore, blockade the potential PGI(2) receptors, including PGI(2) receptors (IP receptors), and peroxisome proliferator-activated receptors alpha and delta (PPARα and PPARδ), revealed that the siRNA-mediated blockage of PPARα considerably reduced the anti-apoptotic effect of L-carnitine.
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Are platelet monocyte aggregates and monocyte chemoattractant protein-1 inhibited by aspirin in critical limb ischaemia?
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Platelet monocyte aggregates (PMA) and monocyte chemoattractant protein-1 (MCP-1) play a significant role in atherosclerotic disease but the effect of aspirin and their role in peripheral arterial disease (PAD) requires further investigation. We have compared p-selectin, PMA and MCP-1 in patients with PAD treated with aspirin (75 mgs daily), with age matched controls not treated with aspirin. Using flow cytometry and ELISA, P-selectin, PMA and MCP-1 were compared in 3 populations; healthy controls (n=12), intermittent claudication (n=19) and critical limb ischaemia (CLI), (n=10). P-selectin was significantly higher in CLI patients (3.48% positive) compared to the claudicants (1. 36% positive) and the controls (1.76% positive). PMA levels were significantly higher for CLI population (44.5% positive) compared to the claudicants (20.48% positive) and the controls (28.33% positive). MCP-1 levels expression was significantly higher for the CLI patients (175.4 pg/mL) compared to the claudicants (76.1 pg/mL) and the controls (117.0 pg/mL).
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The aim of this study was to determine the effects of exogenous expression of the catalytic subunit of telomerase (hTERT) on the lifespan, growth characteristics, and tumorigenicity of normal human ovarian surface epithelial (OSE) cells. Low-passage primary cultures of normal human OSE cells were transfected with hTERT and the resulting cell lines were characterized. The ectopic expression of hTERT stabilized the telomeres of the OSE cultures above 8 kb. The hTERT-transfected OSE cell lines grew beyond the normal lifespan seen in OSE cells and propagated in culture for more than 40 passages before senescing. Moreover, the hTERT-transfected cells demonstrated extensive proliferative capacity as evidenced by their ability to continuously grow even when seeded at low dilutions. The morphologic features and normal differentiation patterns seen in normal OSE cells were likewise retained by the hTERT-transfected cells. In addition, the cultures remained responsive to physiologic concentrations of epidermal growth factor and transforming growth factor-beta. Changes associated with neoplastic transformation like anchorage-independent growth, tumorigencity and karyotypic instability were not observed.
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Do cytotoxic amounts of cisplatin induce either checkpoint adaptation or apoptosis in a concentration-dependent manner in cancer cells?
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Checkpoint adaptation (entry into mitosis with damaged DNA) is a process that links arrest at the G2/M cell cycle checkpoint and cell death in cancer cells. It is not known, however, whether cells treated with the genotoxic agent, cisplatin, undergo checkpoint adaptation or if checkpoint adaptation is a major pathway leading to cell death or not. Therefore, we investigated the relationship between treatment with cisplatin and cytotoxicity in cancer cells. Treatment of HT-29 human colorectal adenocarcinoma cells with cisplatin can induce cell death by one of two different mechanisms. Cells treated with a cytotoxic 30 μM amount of cisplatin died after undergoing checkpoint adaptation. Before dying, however, almost all treated cells were positive for histone γH2AX staining and contained high levels of cyclin B1. Rounded cells appeared that were positive for phospho-Ser10 histone H3, with low levels of phospho-Tyr15 cyclin-dependent kinase 1, high levels of cyclin-dependent kinase 1 activity, and checkpoint kinase 1 that was not phosphorylated on Ser345. These cells were in mitosis with damaged DNA. Strikingly, with 30 μM cisplatin, 81% of cells had entered mitosis before dying. By contrast, after treatment with 100 μM cisplatin, nearly all cells died but only 7% of cells had entered mitosis. Instead, these cells died by apoptosis; they were positive for annexin-V staining, contained cleaved caspase 3, cleaved caspase 9 and cleaved PARP and did not contain Mcl-1.
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The objective of this study was to examine the relationship of obstructive sleep apnea (OSA), body weight (BMI percentage [BMI%]), and monosymptomatic nocturnal enuresis (MNE) in children. A case-control study design was used. All children were 5 to 15 years of age; case patients were recruited from a comprehensive sleep disorders center (n = 149), and control subjects were recruited from a general pediatric practice in the same catchment area (n = 139). Case patients were subject to overnight polysomnograms and grouped into apnea severity categories (minimal, mild, moderate, or severe) on the basis of respiratory disturbance index and minimum arterial oxygen saturation levels. Data for all children included age; gender; height; weight; and history of MNE, snoring, diabetes, nasal allergies, and/or enlarged tonsils. BMI% was used to group children into weight categories as suggested by the Centers for Disease Control and Prevention (underweight, normal weight, at risk for overweight, and overweight). Two age groupings were created (5-10 years and 11-15 years). Descriptive statistics provided the prevalence of OSA, weight category, and MNE among case patients and control subjects. Cross-tabulations examined the relationship of severity of OSA with weight categories and MNE, stratified by age and gender. A series of logistic regression models explored the interrelationship of the grouping variables. A large majority (79.9%) of control subjects were at risk for overweight, and a large majority (80.0%) of children with MNE also had some degree of OSA. Logistic regression demonstrated that both MNE (odds ratio: 5.29) and overweight (odds ratio 4.16) were significantly associated with OSA but not with each other.
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Is diffusion tensor imaging of the posterior cingulate a useful biomarker of mild cognitive impairment?
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Mild cognitive impairment (MCI) is recognized as a predementia state, but its definition is inconsistent and only 20%-30% develop dementia after 2 years. Biomarkers may help identify individuals at greatest risk of progressive decline. The authors examine a novel neuroimaging technique, diffusion tensor imaging (DTI) as a potential biomarker of MCI. Cross-sectional prospective study. Subjects were recruited randomly using the electoral roll from two electorates in East Sydney, Australia. A community-dwelling sample (N = 249) and age 70-90 years. Screening to exclude dementia, comprehensive neuropsychiatric assessment, cognitive test battery, structural magnetic resonance imaging and DTI to obtain measures of fractional anisotropy (FA) and mean diffusivity (MD). MCI was diagnosed by standard criteria. After controlling for age, sex, and years of education, the amnestic MCI (aMCI) group demonstrated microstructural pathology in the parahippocampal white matter, frontal white matter, splenium of corpus callosum, and posterior cingulate region. The nonamnestic MCI (naMCI) group demonstrated microstructural pathology in the frontal white matter, internal capsule, occipital white matter, and the posterior cingulate region. A binary logistic regression model showed that DTI of the left posterior cingulate was significant in identifying persons with aMCI to an accuracy of 85.1%. Receiver operating characteristics curve analysis yielded a sensitivity of 80% and specificity of 60.3% in distinguishing aMCI from naMCI and the normal comparison group.
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The ability to achieve significant donor engraftment without fully myeloablative conditioning has revolutionized allogeneic stem cell transplantation. These nonmyeloablative approaches may allow extension of this potentially curative modality to an increasing number of patients including those with non-malignant diseases. Although a number of regimens have been explored, the optimal means of conditioning has not been determined. We previously demonstrated that rapamycin (RAPA) has the ability to promote T-cell tolerance even in the presence of costimulation. In the current study, we examine the ability of rapamycin or the calcineurin inhibitor cyclosporine A (CSA) to promote chimerism in a murine haploidentical bone marrow transplantation model. Mice were conditioned with 300 cGy and received either RAPA at 3 mg/kg/day IP, CSA at 20 mg/kg/day IP, or no immunosuppression starting on the day before the transplant and continued for 4 weeks. There was no apparent toxicity, and animals maintained normal blood counts throughout. More importantly, long-term macrochimerism was observed only in the RAPA-treated group.
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Does two Hours of Teamwork Training improve Teamwork in Simulated Cardiopulmonary Arrest Events?
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Teamwork during cardiopulmonary arrest events is important for resuscitation. Teamwork improvement programs are usually lengthy. This study assessed the effectiveness of a 2-hour teamwork training program. A prospective, pretest/posttest, quasi-experimental design assessed the teamwork training program targeted to resident physicians, nurses, and respiratory therapists. Participants took part in a simulated cardiac arrest. After the simulation, participants and trained observers assessed perceptions of teamwork using the Team Emergency Assessment Measure (TEAM) tool (ratings of 0 [low] to 4 [high]). A debriefing and 45 minutes of teamwork education followed. Participants then took part in a second simulated cardiac arrest scenario. Afterward, participants and observers assessed teamwork. Seventy-three team members participated-resident physicians (25%), registered nurses (32%), and respiratory therapists (41%). The physicians had significantly less experience on code teams (P < .001). Baseline teamwork scores were 2.57 to 2.72. Participants' mean (SD) scores on the TEAM tool for the first and second simulations were 3.2 (0.5) and 3.7 (0.4), respectively (P < .001). Observers' mean (SD) TEAM scores for the first and second simulations were 3.0 (0.5) and 3.7 (0.3), respectively (P < .001). Program evaluations by participants were positive.
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To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-beta deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD). Retinas of transgenic mice harboring a mutant presenilin (PS1) and a mutant APP gene were processed for TUNEL and immunohistochemistry with antibodies against APP, amyloid-beta, monocyte chemotactic protein (MCP)-1, and F4/80. Comparisons were made between age groups and between transgenic and wild-type congeners. The neuroretina demonstrated age-dependent increases in APP in the ganglion cells (RGCs) and in neurons of the inner nuclear layer (INL). Amyloid-beta demonstrated significant age-dependent deposition in the nerve fiber layer (NFL). TUNEL-positive RGC increased in an age-dependent fashion and in transgenic compared with wild-type congeners. Concomitant overexpression of MCP-1 and intense immunoreactivity for F4/80 suggested that RGCs upregulate MCP-1 in response to amyloid-beta. Activated microglia proliferated in response to MCP-1. In the outer retina, retinal pigment epithelium (RPE) demonstrated moderate age-dependent APP immunoreactivity, but nearby drusenlike deposits were not present. Amyloid-beta was observed in the choriocapillaris of the older animals.
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Is visual acuity related to parafoveal retinal thickness in patients with retinitis pigmentosa and macular cysts?
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To quantify the prevalence and effect on visual acuity of macular cysts in a large cohort of patients with retinitis pigmentosa. In 316 patients with typical forms of retinitis pigmentosa, visual acuity was measured with Early Treatment Diabetic Retinopathy Study (ETDRS) charts, macular cysts were detected with optical coherence tomography (OCT), and retinal thicknesses was quantified by OCT. The FREQ, LOGISTIC, and GENMOD procedures of SAS (SAS Institute, Cary, NC) were used to evaluate possible risk factors for cyst prevalence, and the MIXED procedure was used to quantify the relationships of visual acuity to retinal thickness measured at different locations within the macula. Macular cysts were found in 28% of the patients, 40% of whom had cysts in only one eye. Macular cysts were seen most often in patients with dominant disease and not at all in patients with X-linked disease (P = 0.006). In eyes with macular cysts, multiple regression analysis revealed that visual acuity was inversely and independently related to retinal thickness at the foveal center (P = 0.038) and within a parafoveal ring spanning an eccentricity of 5 degrees to 10 degrees from the foveal center (P = 0.004).
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Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung.
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Are levels of circulating endothelial cells and colony-forming units influenced by age and dyslipidemia?
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The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults, and in children with familial hypercholesterolemia (FH). Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony-forming units (CFUs), also known as endothelial progenitor cells. CEC number increased with age. Children with FH had elevated CECs as compared with healthy children, with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium-dependent vascular function, measured by flow-mediated dilatations, was positively associated with CFU number, even after adjustment for confounding risk variables.
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To determine whether intratrigonal Onabotulinum toxin A (OnabotA) injection produces a different symptomatic outcome and duration of effect on ulcerative (Ulc) and nonulcerative (NUlc) bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to compare the urinary levels of neurotrophines (NGF, BDNF, and GDNF) in response to OnabotA. Ten Ulc and 14 NUlc bladder pain syndrome/interstitial cystitis patients were included in this study. OnabotA (100 U) was injected in 10 trigonal sites, each receiving 10 U in 1 mL of saline. Outcome measures included pain visual analog scale (0-10), a 3-day voiding chart, O'Leary-Sant Score (OSS), and quality of life (QoL) from International Prostate Symptoms Score assessed before treatment, 1 month after injection, and every 3 months afterwards. Urinary NGF, BDNF, and GDNF were accessed using ELISA, at same time points. Treatment duration was determined at the time patients requested another injection. Patients had a mean age of 40 ± 12 years in the Ulc and 47 ± 13 years in the NUlc group (ns). Mean values at baseline of pain intensity, frequency, nocturia, OSS, QoL, and urinary NGF, BDNF, GDNF were identical in the 2 groups. Patients with the Ulc phenotype had a longer duration of symptoms (28.8 ± 11 vs 19.2 ± 8 months, P = .018). Both groups responded equally to OnabotA, with significant improvements in pain intensity, frequency, nocturia, OSS, QoL, and urinary NGF, BDNF, GDNF. The effect lasted for 9 ± 2.8 (Ulc) and 10.5 ± 2 (NUlc) months.
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Does biologically variable pulsation improve jugular venous oxygen saturation during rewarming?
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Conventional pulsatile (CP) roller pump cardiopulmonary bypass (CPB) was compared to computer controlled biologically variable pulsatile (BVP) bypass designed to return beat-to-beat variability in rate and pressure with superimposed respiratory rhythms. Jugular venous O2 saturation (SjvO2) below 50% during rewarming from hypothermia was compared for the two bypass techniques. A SjvO2 less than 50% during rewarming is correlated with cognitive dysfunction in humans. Pigs were placed on CPB for 3 hours using a membrane oxygenator with alpha-stat acid base management and arterial filtration. After apulsatile normothermic CPB was initiated, animals were randomized to CP (n = 8) or BVP (roller pump speed adjusted by an average of 2.9 voltage output modulations/second; n = 8), then cooled to a nasopharyngeal temperature of 28 degrees C. During rewarming to stable normothermia, SjvO2 was measured at 5 minute intervals. The mean and cumulative area for SjvO2 less than 50% was determined. No between group difference in temperature existed during hypothermic CPB or during rewarming. Mean arterial pressure, arterial partial pressure O2, and arterial partial pressure CO2 did not differ between groups. The hemoglobin concentration was within 0.4 g/dL between groups at all time periods. The range of systolic pressure was greater with BVP (41 +/- 18 mm Hg) than with CP (12 +/- 4 mm Hg). A greater mean and cumulative area under the curve for SjvO2 less than 50% was seen with CP (82 +/- 96 versus 3.6% +/- 7.3% x min, p = 0.004; and 983 +/- 1158 versus 42% +/- 87% x min; p = 0.004, Wilcoxon 2-sample test).
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Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin. A substantial portion of these tumors exhibits complex karyotypes and lack characterized chromosomal aberrations. Owing to such properties, both histopathologic and molecular classification of these tumors has been a significant challenge. This study examines the protein expression of a large number of human STS, including subtype heterogeneity, using two-dimensional gel proteomics. In addition, detailed proteome profiles of a subset of pleomorphic STS specimens using an in-depth mass-spectrometry approach identified subgroups within the leiomyosarcomas with distinct protein expression patterns. Pathways analysis indicates that key biologic nodes like apoptosis, cytoskeleton remodeling, and telomere regulation are differentially regulated among these subgroups. Finally, investigating the similarities between protein expression of leiomyosarcomas and undifferentiated pleomorphic sarcomas (UPS) revealed similar protein expression profiles for these tumors, in comparison with pleomorphic leiomyosarcomas.
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Are progression of radiographic joint damage in different eras : trends towards milder disease in rheumatoid arthritis attributable to improved treatment?
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Severity of rheumatoid arthritis and progression of radiographic joint damage have decreased over the last decades. To examine whether this trend is attributable to an underlying trend towards milder disease or to improved treatment. The study used an inception cohort of patients with early rheumatoid arthritis seen at the Wichita Arthritis Center, Wichita, Kansas, USA, since 1973 and monitored prospectively since their first clinic visit through clinical, radiographic, laboratory, demographic and self-reported data. The radiographic disease progression in patients with disease onset in the 1970s, 1980s and 1990s was compared using a multivariate regression model for longitudinal data. The analysis was adjusted for differences in baseline predictors, type of disease-modifying antirheumatic drugs (DMARDs) and steroid use. 418 patients with rheumatoid arthritis with radiographic follow-up were included. Patients in earlier decades used fewer DMARDs, had longer disease durations and higher tender joint counts at their first visit. Other important predictors of disease progression did not differ significantly between decades of disease onset. The unadjusted rates of radiographic progression differed between decades (analysis of variance, p = 0.01), with a significant trend towards less radiographic progression in more recent times (trend, p<0.001). However, after adjusting for DMARD use, steroid use and baseline predictors, differences between decades vanished (analysis of variance, p = 0.40) and the trend towards less radiographic progression disappeared (trend, p = 0.45).
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Non-shockable rhythms represent an increasing proportion of reported cases of out-of-hospital cardiac arrest but with an associated poor prognosis. In the present study, we investigated the effects of hydrogen inhalation on cardiac and neurological function after cardiopulmonary resuscitation and compared the therapeutic benefit with hypothermia in an asphyxial rat model of cardiac arrest. Cardiopulmonary resuscitation was initiated after 5 min of untreated asphyxial cardiac arrest. Animals were randomly assigned to three experimental groups immediately after successful resuscitation: ventilation with 2% hydrogen/98% oxygen under normothermia (H2 inhalation), ventilation with 2% nitrogen/98% oxygen under normothermia (Control), and ventilation with 2% nitrogen/98% oxygen under hypothermia (TH). Mixed gas inhalation continued for 1 h while hypothermia continued for 2 h. Animals were observed up to 96 h for assessment of survival and neurologic recovery. No statistical differences in baseline measurements were observed among groups and all the animals were successfully resuscitated. Serum cardiac troponin T and S100B measured during earlier post-resuscitation period were markedly reduced in both H2 inhalation and hypothermic groups. However, significantly better left ventricular ejection fraction, cardiac work, and neurological deficit score were observed in the H2 inhalation group. Ninety-six hours survival rate was significantly higher in the H2 inhalation group (75.0%), either compared with TH (45.8%) or compared with Control (33.3%). But there was no statistical difference between TH and Control.
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Does gestational age correlate with immunosuppressive properties of hydatidiform mole pregnancies?
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Soluble trophoblast extracts (HME) from some human hydatidiform mole pregnancies suppress IL-2-dependent T-cell proliferation, while others express no immunosuppressive bioactivity. This study was designed to determine if suppression by HME was correlated with gestational age, uterine size, or hCG secretion. Soluble extracts were prepared from nine hydatidiform mole trophoblast samples and screened for immunosuppressive activity using a murine cytotoxic T-cell proliferation assay (CTLL-2). Gestational ages were determined from last menstrual cycle and uterine size was estimated at the time of surgery. Serum samples were collected prior to uterine evacuation and were assayed for human chorionic gonadotropin (hCG). Four of nine HME samples significantly (P < 0.05) suppressed CTLL2 proliferation, while five exhibited no suppressive activity. A strong positive correlation (r = 0.639) was noted for the relationship between gestational age of the molar pregnancies and interleukin-2 (IL-2)-stimulated CTLL2 proliferation (expressed as % of control) in the presence of HME (500 micrograms/mL). This indicates that HME suppression of CTLL2 proliferation is highest in early gestation and then declines with increasing gestational age. A similar correlation was observed between estimated uterine size at surgery and CTLL2 proliferation with added HME, although the association was not as strong (r = 0.359). No association was noted between hCG levels and CTLL2 proliferative responses (r = -0.091).
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The purpose of this study was to examine the association between the frequency of alcohol consumption and stroke mortality among eastern Finnish men. This study is a population-based sample of men with an average follow-up of 20.2 years. A total of 2609 men with no history of stroke at baseline participated in the study. During the follow-up, 66 deaths from stroke occurred. After adjustment for systolic blood pressure, smoking, BMI, diabetes, and socioeconomic status, the relative risk (RR) among men who consumed alcohol <0.5 times per week was 0.70 (95% CI, 0.30-1.66; P = 0.419) compared with nondrinkers. Respective RR was 1.08 (95% CI, 0.51-2.27; P = 0.846) for men with alcohol consumption of 0.5-2.5 times per week and 2.44 (95% CI, 1.11-5.40; P = 0.027) for men who consumed alcohol >2.5 times per week after adjustment for risk factors. When the total amount of alcohol consumption (g/week) was taken into account with other covariates, RR was 0.71 (95% CI, 0.30-1.68; P = 0.437) for men with alcohol consumption <0.5 times per week and 1.16 (95% CI, 0.54-2.50; P = 0.704) among men who consumed alcohol 0.5-2.5 times per week. Among men who consumed alcohol >2.5 times per week compared with nondrinkers, RR was 3.03 (95% CI, 1.19-7.72; P = 0.020).
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Does resistance training contribute to improving the metabolic profile after a 6-month weight loss program in overweight and obese postmenopausal women?
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Limited data are available regarding the impact of caloric restriction (CR) in combination with resistance training (RT) on the metabolic profile of postmenopausal women. The objective of the study was to determine whether RT adds to CR in improving body composition and the metabolic profile. This was a 6-month, randomized, clinical trial. Patients included 107 postmenopausal women (body mass index >27 kg/m(2)). The intervention was a 6-month CR alone or in combination with a RT program. Fat mass (FM), lean body mass (LBM), abdominal sc fat and visceral fat, fasting lipids, insulin sensitivity, resting blood pressure, and inflammation markers were measured. Both groups were similar at baseline and significantly decreased body weight, body mass index, FM, percent FM, abdominal sc fat, and visceral fat after the study (P < 0.001), with greater losses of percent FM and trunk FM in the CR + RT group (P < 0.05). LMB significantly decreased in the CR (-0.9 +/- 2.4 kg) and the CR+RT (-0.4 +/- 2.2 kg) groups (P < 0.005), with no difference between them. Both groups significantly improved plasma triglycerides, fasting insulin level, glucose disposal, and markers of the inflammation profile after weight loss (P < 0.05), with no difference between groups. No improvements were observed for the other variables of interest in both groups.
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To explore the effect of intravenous injection rate and site of fentanyl on the incidence and onset time of fentanyl-induced cough. Seventy-five ASA class I or II patients were randomized into 3 groups and received intravenous fentanyl administration at 4 microg/kg in different manners. In group A, fentanyl was injected within 2 s into the forearm veins; in group B, fentanyl was injected in 2 s through the dorsal foot veins or the great saphenous vein anterior to the ankle; in group C, fentanyl was injected in 15 s by the same route as in group A. The incidence of cough was 44%, 52% and 8%, with cough onset time of 16.1-/+2.7 s, 21.9-/+3.7 s and 23.3-/+3.2 s in groups A, B and C, respectively. Compared with group A, group B had a delayed onset of cough (P<0.05), and group C had both a lowered incidence of cough (P<0.05) and delayed onset of cough (P<0.05).
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Is muscular dystrophy in the mdx mouse a severe myopathy compounded by hypotrophy , hypertrophy and hyperplasia?
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Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD. Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity. We confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks. Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei.
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Infections in cirrhosis are frequently complicated by kidney dysfunction that entails a poor prognosis. Urinary biomarkers may be of potential clinical usefulness in this setting. We aimed at assessing the value of urinary neutrophil gelatinase-associated lipocalin (uNGAL), a biomarker overexpressed in kidney tubules during kidney injury, in predicting clinical outcomes in cirrhosis with infections. One-hundred and thirty-two consecutive patients hospitalized with infections were evaluated prospectively. Acute kidney injury (AKI) was defined according to AKIN criteria. uNGAL was measured at infection diagnosis and at days 3 and 7 (ELISA, Bioporto, DK). Patients with AKI (n=65) had significantly higher levels of uNGAL compared to patients without AKI (203 ± 390 vs. 79 ± 126 μg/g creatinine, p<0.001). Moreover, uNGAL levels were significantly higher in patients who developed persistent AKI (n=40), compared to those with transient AKI (n=25) (281 ± 477 vs. 85 ± 79 μg/g creatinine, p<0.001). Among patients with persistent AKI, uNGAL was able to discriminate type-1 HRS from other causes of AKI (59 ± 46 vs. 429 ± 572 μg/g creatinine, respectively; p<0.001). Moreover, the time course of uNGAL was markedly different between the two groups. Interestingly, baseline uNGAL levels also predicted the development of a second infection during hospitalization. Overall, 3-month mortality was 34%. Independent predictive factors of 3-month mortality were MELD score, serum sodium, and uNGAL levels at diagnosis, but not presence or stage of AKI.
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Does exercise training restore abnormal myocardial glucose utilization and cardiac function in diabetes?
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Clinical and experimental studies have shown that a reduction in myocardial glucose utilization is a factor contributing to diabetic cardiomyopathy. This study determined whether exercise training could prevent the depression in glucose utilization observed in the diabetic rat heart. Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). After 10 weeks of treadmill running, exogenous myocardial glucose utilization and cardiac function were determined in isolated working hearts perfused under aerobic conditions and then subjected to a 60-min period of low-flow ischemia followed by reperfusion. Compared to aerobically perfused sedentary control hearts, rates of myocardial glucose oxidation and glycolysis were lower in diabetic hearts. Diabetes was also characterized by a pronounced decrease in cardiac function. Following exercise training, rates of myocardial glucose oxidation and glycolysis were restored and cardiac performance was improved compared to sedentary diabetic hearts. During low-flow ischemia, the decrease in glycolysis observed in hearts of sedentary diabetic rats was attenuated following exercise training. Following ischemia, glucose oxidation and glycolysis returned to preischemic levels in all groups. However, hearts from trained diabetic animals had higher rates of glucose oxidation compared to their respective sedentary group. This was accompanied by an enhanced recovery of heart function following ischemia.
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Evaluation of anal intraepithelial neoplasia (AIN) is subjective. Previous studies have shown p16 and Ki-67 expressions to correlate with AIN grade. Biomarkers like p16 and Ki-67 may improve interobserver agreement. The objectives were (1) to determine the extent of interobserver agreement in evaluating AIN on routine hematoxylin and eosin (H&E) sections and (2) to test whether p16 and/or Ki-67 staining improve interobserver diagnostic agreement. Seventy-seven anal specimens were retrieved. Sections were stained with monoclonal antibodies against p16 and Ki-67. Blind to the original diagnoses, 4 pathologists assessed H&E alone, p16 alone, Ki-67 alone, and all 3 simultaneously. Diagnoses were normal/reactive, AIN I/HPV, AIN II, and AIN III. Agreement was calculated using kappa and S statistics. Pathologists were board certified and had 2 to 25 years (mean = 13.6 years) of experience. Fair agreement was observed using H&E diagnosis alone (kappa = 0.38, S = 0.56). The p16 diagnostic evaluation demonstrated the highest agreement (kappa = 0.57, S = 0.73). Interobserver agreement for Ki-67 alone and for H&E/p16/Ki-67 combined were comparable to that of H&E alone (kappa = 0.4, S = 0.54 and kappa = 0.44, S = 0.62, respectively). When the pathologists' diagnoses for all diagnostic evaluations were compared with consensus diagnoses, the lowest average magnitude of disagreement was seen with Ki-67 alone, followed by p16 alone, H&E/p16/Ki-67 combined, and H&E alone.
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Do sleep spindle and slow wave frequency reflect motor skill performance in primary school-age children?
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The role of sleep in the enhancement of motor skills has been studied extensively in adults. We aimed to determine involvement of sleep and characteristics of spindles and slow waves in a motor skill in children. We hypothesized sleep-dependence of skill enhancement and an association of interindividual differences in skill and sleep characteristics. 30 children (19 females, 10.7 ± 0.8 years of age; mean ± SD) performed finger sequence tapping tasks in a repeated-measures design spanning 4 days including 1 polysomnography (PSG) night. Initial and delayed performance were assessed over 12 h of wake; 12 h with sleep; and 24 h with wake and sleep. For the 12 h with sleep, children were assigned to one of three conditions: modulation of slow waves and spindles was attempted using acoustic perturbation, and compared to yoked and no-sound control conditions. Mixed effect regression models evaluated the association of sleep, its macrostructure and spindles and slow wave parameters with initial and delayed speed and accuracy.
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Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient.
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Does monitoring breathing rate at home allow early identification of COPD exacerbations?
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Respiratory frequency increases during exacerbations of COPD (ECOPD). We hypothesized that this increase can be detected at home before ECOPD hospitalization. To test this hypothesis, respiratory frequency was monitored at home daily for 3 months in 89 patients with COPD (FEV₁, 42.3% ± 14.0%; reference) who were receiving domiciliary oxygen therapy (9.6 ± 4.0 h/d). During follow-up, 30 patients (33.7%) required hospitalization because of ECOPD. In 21 of them (70%), mean respiratory frequency increased (vs baseline) during the 5 days that preceded it (from 15.2 ± 4.3/min to 19.1 ± 5.9/min, P < .05). This was not the case in patients without ECOPD (16.1 ± 4.8/min vs 15.9 ± 4.9/min). Receiver operating characteristic analysis showed that 24 h before hospitalization, a mean increase of 4.4/min (30% from baseline) provided the best combination of sensitivity (66%) and specificity (93%) (area under the curve [AUC] = 0.79, P < .05). Two days before hospitalization, a mean increase of 2.3/min (15% change from baseline) was associated with a sensitivity of 72% and a specificity of 77% (AUC = 0.76, P < .05).
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To investigate the inhibition of amyloid beta-protein 42 (Abeta42) production in M146L cells by gamma-schisandrin. M146L cells which can produce considerable Abeta42 in vitro were treated with gamma-schisandrin (1.67, 5.00 and 15.00 microg x mL(-1)), beta-secretase inhibitor (S4562, 100.00 microg x mL(-1)) and gamma-secretase inhibitor (S2188, 13.68 microg x mL(-1)), separately. Cell counting kit-8 (CCK-8) was used to assess cell viability. Enzyme-linked immunosorbent assay (ELISA) was carried out to determine the amount of Abeta42. Western blotting was used to examine C99, an intermediary product of APP cleaved by beta-secretase. beta-Secretase and gamma-secretase activities were assayed by commercial kits. The CCK-8 assay indicated that different concentrations of gamma-schisandrin had no neurotoxicity on the cultured M146L. And the ELISA test showed that the amount of Abeta42 secreted by M146L cells treated with gamma-schisandrin (5.00 and 15.00 microg x mL(-1)) decreased obviously as compared with solvent control. The results of Western blotting test indicated that there was no change of C99 contents and beta-secretase activity in gamma-schisandrin treated cells, while gamma-secretase activity decreased obviously.
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Is fungal infection but not type of bacterial infection associated with a high mortality in primary and secondary infected pancreatic necrosis?
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Knowledge of microbiology in the prognosis of patients with necrotizing pancreatitis is incomplete. This study compared outcomes based on primary and secondary infection after surgery for pancreatic necrosis. From a limited prospective database of pancreatic necrosectomy, a retrospective case note review was performed (October 1996 to April 2003). 55 of 73 patients had infected pancreatic necrosis at the first necrosectomy. 25 of 47 patients had resistant bacteria to prophylactic antibiotics (n = 21) or did not receive prophylactic antibiotics (n = 4), but this was not associated with a higher mortality (9 of 25) compared to those with sensitive organisms (4 of 22). Patients with fungal infection (n = 6) had a higher initial median (95% CI) APACHE II score compared to those without (11 (9-13) verus 8.5 (7-10), p = 0.027). Five of six patients with fungal infection died compared to 13 of 47 who did not (p = 0.014). With the inclusion of secondary infections 21 (32%) of 66 patients had fungal infection with 10 (48%) deaths compared to 11 (24%) of 45 patients without fungal infection (p = 0.047).
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Results of the Women's Health Initiative Memory Study (WHIMS) raised concerns regarding the timing and formulation of hormone interventions. Conjugated equine estrogens (CEE), used as the estrogen therapy in the WHIMS trial, is a complex formulation containing multiple estrogens, including several not secreted by human ovaries, as well as other biologically active steroids. Although the full spectrum of estrogenic components present in CEE has not yet been resolved, 10 estrogens have been identified. In the present study, we sought to determine which estrogenic components, at concentrations commensurate with their plasma levels achieved following a single oral dose of 0.625 mg CEE (the dose used in the WHIMS trial) in women, are neuroprotective and whether combinations of those neuroprotective estrogens provide added benefit. Further, we sought, through computer-aided modeling analyses, to investigate the potential correlation of the molecular mechanisms that conferred estrogen neuroprotection with estrogen interactions with the estrogen receptor (ER). Cultured basal forebrain neurons were exposed to either beta-amyloid(25-35) or excitotoxic glutamate with or without pretreatment with estrogens followed by neuroprotection analyses. Three indicators of neuroprotection that rely on different aspects of neuronal damage and viability, LDH release, intracellular ATP level and MTT formazan formation, were used to assess neuroprotective efficacy. Results of these analyses indicate that the estrogens, 17alpha-estradiol, 17beta-estradiol, equilin, 17alpha-dihydroequilin, equilinen, 17alpha-dihydroequilenin, 17beta-dihydroequilenin, and Delta8,9-dehydroestrone were each significantly neuroprotective in reducing neuronal plasma membrane damage induced by glutamate excitotoxicity. Of these estrogens, 17beta-estradiol and Delta8,9-dehydroestrone were effective in protecting neurons against beta-amyloid25-35-induced intracellular ATP decline. Coadministration of two out of three neuroprotective estrogens, 17beta-estradiol, equilin and Delta8,9-dehydroestrone, exerted greater neuroprotective efficacy than individual estrogens. Computer-aided analyses to determine structure/function relationships between the estrogenic structures and their neuroprotective activity revealed that the predicted intermolecular interactions of estrogen analogues with ER correlate to their overall neuroprotective efficacy.
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Does the herbicide flamprop-M-methyl have a new antimicrotubule mechanism of action?
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The herbicidal mode of action of flamprop-M-methyl [methyl N-benzoyl-N-(3-chloro-4-fluorophenyl)-D-alaninate] was investigated. For initial characterization, a series of bioassays was used, which indicated a mode of action similar to that of mitotic disrupter herbicides. Cytochemical fluorescence studies, which included monoclonal antibodies against polymerized tubulin, were applied to elucidate effects on mitosis and microtubule assembly in maize roots. When seedlings were root treated with 50 microM of flamprop-M-methyl, cell division activity in meristematic root tip cells ceased within 4 h. The compound severely disturbed the orientation of spindle and phragmoblast microtubules, leading to defective spindle and phragmoblast structures. Cortical microtubules were only slightly affected. In late anaphase and early telophase cells, phragmoblast microtubules were disorganized in multiple arrays that hampered regular cell plate deposition in cytokinesis. Microtubules of the spindle apparatus were found attached to chromosomal kinetochores, but did not show regular organization associated with a zone of microtubule-organizing centres at the opposite ends of the cell. On account of this loss of spindle organization, chromosomes remained in a condensed state of prometaphase or metaphase. Unlike known microtubule disrupter herbicides, flamprop-M-methyl and its biologically active metabolite flamprop did not inhibit soybean tubulin polymerization to microtubules in vitro at 50 microM. In contrast, soybean plants responded sensitively to the compounds.
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Acute nonvariceal upper-GI hemorrhage (NVUGIH) is associated with significant morbidity and mortality. To examine the relationship between hospital volume and outcomes of NVUGIH. A cross-sectional study. Participating hospitals from the Nationwide Inpatient Sample 2004. All discharged patients with a primary discharge diagnosis of NVUGIH based on the International Classification of Diseases, Clinical Modification, ninth edition codes. Patients were divided into 3 groups based on discharge from hospitals with annual discharge volumes of 1 to 125 (low), 126 to 250 (medium), and >250 (high). In-hospital mortality, length of stay, and hospitalization charges. The study included a total of 135,366, 132,746, and 123,007 discharges with NVUGIH occurred from low-volume, medium-volume, and high-volume hospitals, respectively. On multivariate analysis, when adjusting for age, comorbidity, and the presence of complications, patients at high-volume hospitals had significantly lower in-hospital mortality (odds ratio [OR] 0.85 [95% CI, 0.74-0.98]) than patients at low-volume hospitals. Patients at high-volume hospitals were also more likely to undergo upper-GI endoscopy (OR 1.52 [95% CI, 1.36-1.69]) or early endoscopy within 1 day of hospitalization compared with low-volume hospitals (60.5% vs 53.8%, adjusted OR 1.28 [95% CI, 1.02-1.61]). Undergoing endoscopy within day 1 was associated with shorter hospital stays (-1.08 days [95% CI, -1.24 to -0.92 days]) and lower hospitalization charges (-$1958 [95% CI, -$3227 to -$688]).
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Is radiological review of specimen radiographs after breast localisation biopsy always necessary?
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The use of specimen radiographs to confirm the presence of the radiological abnormality in a breast specimen after localisation biopsy is standard practice. This study aims to show that a trained surgeon may assess breast specimen radiographs with similar efficacy as a radiologist. This retrospective study assessed all patients who had localisation breast surgery using wire or ultrasound (US) techniques between January 2002 and March 2003. Histopathological records and mammographic details were recorded from the hospital notes. A consultant radiologist and surgeon reviewed the specimen radiographs, identifying mammographic abnormalities and assessing margins. Localisation surgery was performed on 101 patients with US used to localize 68. The median specimen weight was 64g. A malignant diagnosis was made in 86 patients. In 23, the histological resection margins were considered to be close or involved by tumour and re-excision was performed in eight patients. Sixty-one specimen radiographs were reviewed. The radiologist identified every mammographic abnormality, and the surgeon identified the lesion in 58. The positive predictive value of specimen radiographs to identify histologically involved margins was 75 and 74% by the radiologist and the surgeon, respectively. Where good radiograph margins were reported in 40 and 35 patients by the radiologist and surgeon, respectively, 11 and 7 had histologically involved margins.
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Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II (Ang II) induces hypertension and is associated with proinflammatory immune responses. Our goal was to define the innate immune response in a model of genetic hypertension and the influences of cholinergic stimulation and Ang II. Studies were conducted on 4- to 5-week-old prehypertensive spontaneously hypertensive rats (SHRs) and age-matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were preexposed to nicotine or Ang II before Toll-like receptor (TLR) activation. Culture supernatants were tested for cytokines (tumor necrosis factor-α, interleukin [IL]-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY rats and SHRs. Nicotine and Ang II enhanced this TLR-mediated IL-6 response in prehypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR-mediated IL-6 response in WKY rats, whereas Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8-mediated IL-6 and IL-1β responses in prehypertensive SHRs but suppressed these responses in WKY rats. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the prehypertensive SHR spleen but not in WKY.
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Do ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain?
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Morphine consumption can vary widely between individuals even for identical surgical procedures. As mu-opioid receptor (OPRM1) is known to modulate pain perception and mediate the analgesic effects of opioid compounds in the central nervous system, we examined the influence of two OPRM polymorphisms on acute post-operative pain and morphine usage in women undergoing elective caesarean delivery. Data on self-reported pain scores and amount of total morphine use according to patient-controlled analgesia were collected from 994 women from the three main ethnic groups in Singapore. We found statistically significant association of the OPRM 118A>G with self-administered morphine during the first 24-hour postoperative period both in terms of total morphine (p = 1.7 x 10(-5)) and weight-adjusted morphine (p = 6.6 x 10(-5)). There was also significant association of this OPRM variant and time-averaged self-rated pain scores (p = 0.024). OPRM 118G homozygotes used more morphine and reported higher pain scores than 118A carriers. Other factors which influenced pain score and morphine usage include ethnicity, age and paying class.
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The effects of plasterboard composition on Streptomyces californicus growth and bioactivity of spores were studied. Streptomyces californicus was grown on 13 modified plasterboards under saturated humidity conditions. The total content of fatty acid methyl esters was used for quantifying S. californicus biomass, while the spore-induced cytotoxicity and production of nitric oxide (NO), tumour necrosis factor-alpha, and interleukine-6 (IL-6) in mouse macrophages was used to assess the bioactivity of spores. Removal of starch completely from the plasterboard or only from the core reduced significantly the biomass production and the biological activity of spores in comparison with reference board. The biocide added into the core or on the liner decreased the growth markedly and inhibited the sporulation totally. The biomass production correlated positively with the spore number, cytotoxicity, and production of NO and IL-6.
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Are the metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea influenced by ethanol?
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Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids also containing a carboxylic acid moiety are capable of undergoing an ethyl esterification with the metabolic formation of more lipophilic compounds with a much longer terminal half-life. To determine if isotretinoin (13-cis-RA), its main metabolite 4-oxo-isotretinoin (4-oxo-13-cis-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined. Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple self-administered questionnaire and by measuring serum ethanol levels during treatment. The concentrations of isotretinoin, 4-oxo-isotretinoin and possible ethylated and nonethylated metabolites were measured by reverse-phase high-performance liquid chromatography. Although seven of 11 patients had a considerable weekly alcohol intake, no endogenous synthesis of ethyl derivatives of isotretinoin, the main 4-oxo metabolite or the all-trans compounds was chromatographically detectable in any of the patients' plasma samples during the treatment period. Multiple dose pharmacokinetic data for the parent drug and its main metabolite were comparable to previous studies.
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We examined whether the presence and extent of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) predict adverse outcomes in nonischemic cardiomyopathy (NICM) patients. Morbidity and mortality is high in NICM patients. However, the clinical course of an individual patient is unpredictable and current risk stratification approaches are limited. Cardiovascular magnetic resonance detects myocardial fibrosis, which appears as LGE after contrast administration and may convey prognostic importance. In a prospective cohort study, 65 NICM patients with left ventricular (LV) ejection fraction < or =35% underwent CMR before placement of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death. The CMR images were analyzed for the presence and extent of LGE and for LV function, volumes, and mass. Patients were followed for an index composite end point of 3 cardiac events: hospitalization for heart failure, appropriate ICD firing, and cardiac death. A total of 42% (n = 27) of patients had CMR LGE, averaging 10 +/- 13% of LV mass. During a 17-month median follow-up, 44% (n = 12) of patients with LGE had an index composite outcome event versus only 8% (n = 3) of those without LGE (p < 0.001 for Kaplan-Meier survival curves). After adjustment for LV volume index and functional class, patients with LGE had an 8-fold higher risk of experiencing the primary outcome (hazard ratio 8.2, 95% confidence interval 2.2 to 30.9; p = 0.002).
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Do the HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro?
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Nucleoside analogues are suspected of playing a role in peripheral fat loss in patients during long-term treatment with antiretroviral drugs. We compared the long-term effects of stavudine (10 microM), zidovudine (1 muM), didanosine (10 microM), abacavir (4 microM), lamivudine (10 microM), and tenofovir (1 microM), near their maximum concentration values, on the differentiation, lipid accumulation, survival and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3-L1 adipocytes. None of the nucleoside reverse transcriptase inhibitors (NRTI) markedly altered the differentiation of 3T3-F442A cells, as shown by the unmodified percentage of cells with lipid droplets on day 7 and the expression of the early differentiation markers CCAAT/enhancer binding protein (C/EBP) beta (on day 2) and sterol regulatory element-binding protein. However, stavudine and zidovudine altered the lipid phenotype, decreasing the lipid content and expression of markers involved in lipid metabolism, namely C/EBPalpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid binding protein 2, fatty acid synthase and acetyl-coenzyme A carboxylase. Stavudine and zidovudine, contrary to the other NRTI, drove 5-10% of 3T3-F442A cells towards apoptosis, and reduced the lipid content and survival of differentiated 3T3-L1 adipocytes. Stavudine and zidovudine increased mitochondrial mass by two to fourfold, and lowered the mitochondrial membrane potential (JC-1 stain) as did zalcitabine (0.2 microM). Co-treatment with zidovudine plus lamivudine, or zidovudine plus lamivudine and abacavir, did not increase the effect of zidovudine on cell viability or apoptosis.
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There are limited and conflicting data available concerning the incidence of inadvertent splenectomy and its impact on the outcome in patients who have undergone oesophagectomy. The aim of this study is to identify the factors associated with a likelihood of inadvertent splenectomy and its influence on early and long-term outcome in patients having oesophagectomy for oesophageal carcinoma. A consecutive series of 738 oesophagectomies performed between 1991 and 2004 was analysed. In our practice, the spleen was removed only if damaged intraoperatively. Routine chemo- and immunoprophylaxis would subsequently be used. Multivariate analysis with logistic and Cox models determined significant variables. Of the 738 oesophagectomies, 48 (6.5%) had splenectomy. Neoadjuvant chemotherapy was administered to a minority of patients; none subsequently had splenectomy. There were significant differences between types of operation (Ivor-Lewis 18 (9.0%), left thoracolaparotomy 14 (9.9%) and left thoracophrenotomy 15 (3.9%), p=0.01). Splenectomy was more common with advanced N stage disease (OR=0.44 [0.20-0.95]; p=0.04). Splenectomy resulted in more blood transfusions (median, 2 units vs 0 units; p=0.03) more anastomotic leaks (7 [14.6%] vs 42 [6.1%]; p=0.02) but not an increase in pulmonary complications (p=0.64) or in-hospital mortality (1 [4.6%] vs 37 [5.4%]; p=0.30). Splenectomy did not significantly affect median survival (551 [332-770] days vs 627 [554-700] days; p=0.63).
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Does up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlate with poor prognosis?
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CD40 and its ligand, CD154, play a regulatory role in several signaling pathways among lymphocytes. Recently, it was reported that CD40 is expressed in several malignant tumors. However, the clinical impact of CD40 expression in nonsmall cell lung cancer has not been studied widely. One hundred twenty-nine surgical specimens of nonsmall cell lung cancer were assessed immunohistochemically for CD40 and CD154 expression, and that expression was correlated with patients' clinicopathologic parameters and outcome. Subsequently, in vitro analysis of CD40-CD154 signaling was performed. Immunohistochemical staining of tumor cells confirmed that 67 patients (51.9%) were positive for CD40, and 76 patients (58.9%) were positive for CD154. The survival of patients who had tumors that were negative for CD40 was significantly better than the survival of patients who had tumors that were positive for CD40 (P = .0004). Multivariate analysis using a Cox regression model indicated that CD40 expression in cancer cells is an independent, unfavorable prognostic factor (risk ratio, 1.855; P = .0403). By using an in vitro juxtacrine growth factor assay, the growth of LK2 cells (CD40-positive/CD154-negative) was accelerated by CD154-positive cancer cells, such as PC10 cells (CD40-negative/CD154-positive), by a juxtacrine mechanism.
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Lower urinary tract symptoms (LUTS) occur in 5-20% of women after antiincontinence procedures. Symptoms include complete urinary retention or storage, voiding, and postmicturition symptoms. The goal of this study was to determine the effect of time from sling placement to midline sling lysis on overall improvement in LUTS. After institutional review board approval, we conducted a retrospective cohort analysis of 112 subjects undergoing midline sling lysis from January 1997-September 2007. The inclusion criteria were women with a vaginal midline sling lysis for LUTS after a prior pubovaginal or midurethral sling. We excluded any subject with sling erosion without LUTS and those who underwent a repeated sling at the time of lysis. We compared subjects who had an early sling lysis (< or = 1 year from sling to lysis) to a late sling lysis (> 1 year). The primary outcome was based on the subject's report of overall improvement in symptoms. We abstracted data on demographics, presenting symptoms, physical examination, date of antiincontinence procedure, date of midline sling lysis, and postoperative symptoms. Statistical analysis consisted of Student t test, chi(2) test, Fisher exact test, and multivariate logistic regression. Of 112 subjects, 74 (66%) had an early sling lysis and 38 (34%) had a late sling lysis. These 2 groups were similar in age, menopausal status, presence of preoperative LUTS, anterior colporrhaphy at the time of lysis, and presence of an eroded sling. The early lysis group had a higher percentage of midurethral slings (36% vs 8%; P = .001), a lower rate of preoperative complete retention (70% vs 89%; P = .001), and a lower rate of prior urethrolysis (16% vs 45%; P = .003). No significant difference in follow-up time was found between early lysis compared with late lysis (49 +/- 89 months vs 43 +/- 71 months; P = .73). Ten (8.9%) subjects developed recurrent stress urinary incontinence after sling lysis, which was independent of time to lysis. In all, 94 (84%) subjects had improvement in their LUTS after midline sling lysis. Overall improvement occurred more often in the early sling lysis group compared with the late sling lysis group (91% vs 71%; P = .01). This finding retained significance in a multivariate logistic regression model, which included age, prior urethrolysis, preoperative complete retention, and type of sling (odds ratio, 4.0; 95% confidence interval, 1.2-13.2).
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Does mDM2SNP309 associate with elevated MDM2 protein expression or breast cancer risk?
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SNP309 polymorphism (T-G) at the promoter region of MDM2 has been reported to cause increased binding affinity of transcriptional activator Sp1 followed by increased MDM2 both in mRNA and protein level. This model was proposed in vitro in the small panel of cell lines that indicated an on average 8-fold higher level of MDM2 mRNA in cells bearing the GG genotype. The incidence of SNP309 was determined in a cohort of 158 breast, 17 endometrium, 13 cervix and 45 ovarian cancer tissues by PCR-RFLP. The expression of p53 and MDM2 protein levels in the cohort was immunohistochemically investigated and statistically correlated with SNP309 polymorphism using Pearson chi(2) and t test. No significant difference was observed in the G allele incidence in breast cancer specimens compared to 149 noncancer controls. Furthermore, no statistically significant association of the G allele frequencies and p53 and MDM2 protein expression levels was observed.
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The goal after open abdomen treatment is to reach primary fascial closure. Modern negative pressure wound therapy systems are sometimes inefficient for this purpose. This retrospective chart analysis describes the use of the 'components separation' method in facilitating primary fascial closure after open abdomen. A total of 16 consecutive critically ill surgical patients treated with components separation during open abdomen management were analyzed. No patients were excluded. Primary fascial closure was achieved in 75% (12/16). Components separation was performed during ongoing open abdomen treatment in 7 patients and at the time of delayed primary fascial closure in 9 patients. Of the former, 3/7 (43%) patients reached primary fascial closure, whereas all 9 patients in the latter group had successful fascial closure without major complications (p = 0.019).
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Does constant ocular infection with Chlamydia trachomatis predict risk of scarring in children in Tanzania?
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Clinically, constant severe trachoma predicts an increased risk of scarring in children. There are no data on the risk of scarring associated with constant infection with Chlamydia trachomatis, regardless of clinical manifestation. We propose to determine the 5-year incidence of scarring in children with a history of constant severe trachoma, constant infection, or both compared with children who had a history of neither. A 5-year, longitudinal observational study. Children aged less than 10 years with data on trachoma and infection for 3 of the 5 visits in the first 18 months, and follow-up 5-year data on scarring. Data were collected on clinical trachoma, and ocular swabs were taken to determine the presence of C. trachomatis in children in a hyperendemic village in Tanzania. Images were graded for scarring. Data were collected at baseline; 2, 6, 12, and 18 months; and 5 years from baseline. Severe trachoma was defined as the presence of 10 or more follicles, or trachoma intense. A child had constant infection (severe trachoma) if infection (severe trachoma) was present on at least 3 visits before the 5-year survey. Five-year risk of scarring. Of the 189 children, 22 (11.6%) had constant severe trachoma, but not constant infection. Nine children (4.8%) had constant infection but not constant severe trachoma. Both constant severe trachoma and constant infection were present in 16 children (8.5%). The 5-year incidence of scarring was similar in all 3 groups; children with constant severe trachoma only, with constant infection only, and with both were most likely to develop scars (35.0%, 44.4%, 31.2%, respectively) compared with those with sporadic trachoma or infection (15.2%) or neither (6.8%) (P = 0.0002).
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The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.
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Are stress and inflammatory biomarkers and symptoms associated with bioimpedance measures?
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This large cross-sectional, multi-centre study evaluated the association of body composition measurements by a novel dual frequency bioimpedance device (BIA-ACC) with chronic stress/inflammation biomarkers and the presence of medically unexplained symptoms (MUS). Participants were adult Caucasians of both sexes and included 10,416 lean subjects with no MUS (Group A), 58,710 lean subjects with MUS (Group B) and 30,445 overweight/obese subjects with no MUS and excessive fat mass (FM) (Group C). Total body extracellular water (ECW) was higher, while intracellular water (ICW) was lower in Group B than both other groups (P < 0.01). Group A had significantly lower FM and higher skeletal mass (SK) and phase angle (PA) than Group B and lower circulating high sensitivity (hs) CRP levels than both other groups. hsCRP was higher in Group C than Group A though (P < 0.01). Salivary cortisol in Group B was lower in the morning and higher in the evening than both other groups (P < 0.001), indicating circadian rhythm obliteration or reversal in this group. ECW correlated positively with serum hsCRP and 8 p.m. salivary cortisol, but negatively with 8 a.m. salivary cortisol, while PA correlated positively with 8 a.m. and negatively with 8 p.m. salivary cortisol and serum hsCRP. Both 8 a.m. and 8 p.m. salivary cortisol and serum hsCRP were associated with the presence of MUS and BIA-ACC measurements, including ECW, ICW, FM, SK and PA.
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Inside the cell, the HIV Tat protein is mainly found in the nucleus and nucleolus. The nucleolus, the site of ribosome biogenesis, is a highly organized, non-membrane-bound sub-compartment where proteins with a high affinity for nucleolar components are found. While it is well known that Tat accumulates in the nucleolus via a specific nucleolar targeting sequence, its function in this compartment it still unknown. To clarify the significance of the Tat nucleolar localization, we induced the expression of the protein during oogenesis in Drosophila melanogaster strain transgenic for HIV-tat gene. Here we show that Tat localizes in the nucleoli of Drosophila oocyte nurse cells, where it specifically co-localizes with fibrillarin. Tat expression is accompanied by a significant decrease of cytoplasmic ribosomes, which is apparently related to an impairment of ribosomal rRNA precursor processing. Such an event is accounted for by the interaction of Tat with fibrillarin and U3 snoRNA, which are both required for pre-rRNA maturation.
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Does aminoguanidine impede human pancreatic tumor growth and metastasis development in nude mice?
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To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization. Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression. Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change.
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Our purpose was to evaluate fetal fibronectin, interleukin-6, and C-reactive protein from patients with preterm labor to establish prognostic subcategories. Thirty-seven patients with preterm labor had cervical fetal fibronectin and plasma C-reactive protein sampled. Eighteen of these patients had amniotic fluid interleukin-6 levels measured. Outcome variables were (1) delivery before 34 weeks and (2) delivery within 48 hours. Detectable cervical fetal fibronectin identified 89% of patients who were delivered before 34 weeks' gestation. Interleukin-6 > 1500 pg/ml identified 88% of patients who were delivered within 48 hours. C-reactive protein > 1.5 mg/dl correlated with elevated interleukin-6 levels (p < 0.001).
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Does tranexamic acid prevent rebleeding in an uncontrolled hemorrhage porcine model?
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Fluid resuscitation after uncontrolled hemorrhage might promote rebleeding and irreversible shock. Tranexamic acid is a procoagulant drug that limits blood loss after surgery of the hip, knee, and heart. We hypothesized that pretreatment with tranexamic acid reduces the rebleeding in uncontrolled hemorrhage and thereby allows safe administration of crystalloid fluid resuscitation. A 120-minute intravenous infusion of 100 mL/kg of Ringer's solution was given to 24 pigs (mean weight, 20 kg) 10 minutes after lacerating the infrarenal aorta. The animals were randomized to receive an intravenous injection of 15 mg/kg of tranexamic acid or placebo just before starting the resuscitation. Rebleeding events were monitored by two ultrasonic probes positioned proximal and distal to the laceration. Tranexamic acid had no effect on the number of rebleeding events, bled volume, or mortality. The initial bleeding stopped within 4 minutes after the injury. The five animals that died suffered from 4.4 rebleeding events on average, which tripled the total blood loss, whereas the survivors had only 1.3 such events during fluid resuscitation (p < 0.02). At autopsy, death was associated with a larger total hemorrhage; the blood recovered from the abdomen weighed 1.4 kg (median) in nonsurvivors and 0.6 kg in survivors (p < 0.001), with the difference being attributable to rebleeding.
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Nasopharyngeal carcinoma (NPC) poses one of the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100,000. In our previously linkage analysis, a locus on 3p21 was identified to link to NPC. In this study, family-based association analysis was performed to test the transmission disequilibrium of chromosome 3p in 18 high-risk nasopharyngeal carcinoma families of Hunan province in southern China. Single locus and multi-point of transmission disequilibrium test was performed by Genehunter program package with 15 microsatellite markers on chromosome 3p in 18 nasopharyngeal carcinoma pedigrees. A major transmission disequilibrium peak was observed near D3S1568, which possessed 20 alleles or haplotypes of 6 loci, spanning a 12.4 cM region from D3S1298 to D3S1289 on chromosome 3p21.31-3p21.2, and 3 alleles or haplotypes reached high significantly difference (P < 0.01).
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Does in vivo imaging of mice infected with bioluminescent Trypanosoma cruzi unveil novel sites of infection?
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The development of techniques that allow the imaging of animals infected with parasites expressing luciferase opens up new possibilities for following the fate of parasites in infected mammals. D-luciferin potassium salt stock solution was prepared in phosphate-buffered saline (PBS) at 15 mg/ml. To produce bioluminescence, infected and control mice received an intraperitoneal injection of luciferin stock solution (150 mg/kg). All mice were immediately anesthetized with 2% isofluorane, and after 10 minutes were imaged. Ex vivo evaluation of infected tissues and organs was evaluated in a 24-well plate in 150 μg/ml D-luciferin diluted in PBS. Images were captured using the IVIS Lumina image system (Xenogen). Dissected organs were also evaluated by microscopy of hematoxylin-eosin stained sections. Here we describe the results obtained using a genetically modified Dm28c strain of T. cruzi expressing the firefly luciferase to keep track of infection by bioluminescence imaging. Progression of infection was observed in vivo in BALB/c mice at various intervals after infection with transgenic Dm28c-luc. The bioluminescent signal was immediately observed at the site of T. cruzi inoculation, and one day post infection (dpi) it was disseminated in the peritoneal cavity. A similar pattern in the cavity was observed on 7 dpi, but the bioluminescence was more intense in the terminal region of the large intestine, rectum, and gonads. On 14 and 21 dpi, bioluminescent parasites were also observed in the heart, snout, paws, hind limbs, and forelimbs. From 28 dpi to 180 dpi in chronically infected mice, bioluminescence declined in regions of the body but was concentrated in the gonad region. Ex vivo evaluation of dissected organs and tissues by bioluminescent imaging confirmed the in vivo bioluminescent foci. Histopathological analysis of dissected organs demonstrated parasite nests at the rectum and snout, in muscle fibers of mice infected with Dm28c-WT and with Dm28c-luc, corroborating the bioluminescent imaging.
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Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients. RA patients participating in the CARRE investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients. In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA.
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Does stent design favorably influence the vascular response in normal porcine coronary arteries?
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The purpose of this study was to compare the arterial response following implantation of a stainless-steel, balloon-expandable, tubular slotted stent with that of a novel computer-designed, multi-cellular stent in normal porcine coronary arteries. Intracoronary stent placement has evolved into the primary strategy for percutaneous revascularization of symptomatic coronary arterial lesions. Presently there is intense interest in developing new stent designs to improve stent delivery and biocompatability. Computer-assisted design was utilized to develop a balloon-expandable stent with symmetric expansion properties, uniform arterial wall coverage, longitudinal flexibility and radial strength. Quantitative coronary angiography and histological assessment of the stented arteries was used to evaluate the acute and chronic vascular responses to a stainless-steel, balloon-expandable, tubular slotted stent as compared to the computer-designed BX stent in the normolipemic swine. Forty stents (24 BX, 16 tubular slotted) were implanted in 19 miniature swine at a mean inflation pressure of 9 atm using identical delivery systems. Eight of the BX and none of the tubular slotted stents were post-dilated with a non-compliant balloon at 12-14 atm. The mean stent-to-artery ratio was similar for the BX (1.03 +/- 0.06) and tubular slotted (1.04 +/- 0.11; p = 0.59) designs. Protrusion or asymmetric radial flaring of a strut at the stent margin was present in 1 of 23 BX stents (4.3%) and 10 of 15 tubular slotted stents (66.7%; p < 0.0001). The mean arterial injury score was significantly less for the BX stent (0.2 +/- 0.2) as compared with the tubular slotted stents (0.4 +/- 0.4; p = 0.025). At 3 days, thrombus area was similar for the BX and tubular slotted designs (0.42 +/- 0.16 mm2 versus 0.44 +/- 0.18 mm2, respectively; p = 0.88). The mean neointimal area was significantly less for the BX at 2 months (1.09 +/- 0.25 mm2 versus 2.93 +/- 2.26 mm2 in the tubular slotted stent) and at 6 months (1.10 +/- 0.26 mm2 versus 2.07 +/- 0.65 mm2 in the tubular slotted stent; p = 0.01), resulting in approximately 50% less in-stent stenosis.
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Learning and memory deficits are commonly reported in children with heavy prenatal alcohol exposure. Our recent work suggested that children with heavy prenatal alcohol exposure retained information as well as controls on a verbal learning test but not on a test of nonverbal learning and memory. To better understand the cause of this differential pattern of performance, the current study re-analyzed data from our previous study to determine if the presence of an implicit learning strategy may account, at least in part, for the finding of spared retention. The current study examined verbal learning and memory abilities in 35 children with Fetal Alcohol Spectrum Disorders (FASD) and 34 nonexposed controls (CON) matched for age (9-16 years), sex, ethnicity, handedness, and socioeconomic status. Groups were compared on two measures of verbal learning, one with an implicit strategy (California Verbal Learning Test-Children's Version; CVLT-C) and one without (Verbal Learning subtest of the Wide Range Assessment of Memory and Learning; VL-WRAML). Children with FASD learned less information overall than children in the CON group. Both groups learned a greater percentage of information and reached a learning plateau earlier on the CVLT-C compared with the VL-WRAML. Groups also showed comparable rates of retention after a delay on the CVLT-C. In contrast, on the VL-WRAML, children with FASD showed poorer retention rates than children in the CON group. Interestingly, children with FASD did not differ from children in the CON group on CVLT-C semantic clustering scores for learning trials 1 through 3, and greater utilization of semantic clustering was correlated with better learning and memory performance in both groups. This overall pattern of results was not related to overall intellectual level.
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Do central retinal artery Doppler flow parameters reflect the severity of cerebral small-vessel disease?
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We investigated the usefulness of central retinal artery (CRA) Doppler flowmetry in patients with cerebral small-vessel disease (SVD). CRA Doppler flowmetry was performed in 103 SVD patients who underwent MRI. Sixty-four adjusted control subjects were also registered. We assessed average CRA flow parameter values for both eyes with the clinical and MRI findings. Each Doppler flowmetry was performed within 5 minutes. Patients with SVD had significantly lower end-diastolic and mean velocities of the CRA than control subjects; they also had higher pulsatility and resistive indexes. Multivariate analysis showed that the number of small infarcts was an independent predictor of peak systolic and mean velocities. Grade of periventricular hyperintensities was an additional independent predictor of peak systolic and mean velocities, whereas the number of small infarcts was predictive of end-diastolic velocity.
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Immune responses are tempered in immunologically privileged sites including the testis. Previous studies have shown that islet transplantation in the testis significantly prolongs islet allograft survival. However, mechanisms underlying testicular immune privilege and intratesticular allograft survival remain unclear. Allogeneic murine islets were transplanted in the testis. Programmed death-1 ligand-1 (PD-L1) expression was detected by immunohistochemstry and real-time polymerase chain reaction. Infiltrating T-cell proliferation was measured by bromodeoxyuridine uptakes, whereas their apoptosis was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling methods. Transgenic T cells were used to track allospecific memory T-cell generation. We found that programmed death-1 (PD-1):PD-L1 negative costimulation is essential for prolonged survival of intratesticular islet allografts, as blocking PD-L1 or PD-1, but not PD-L2 and cytotoxic T-lymphocyte antigen 4, abrogated long-term survival of intratesticular islet allografts. As controls, blocking PD-1 or PD-L1 did not significantly accelerate the acute rejection of islet allografts transplanted under the renal capsule, a conventional islet-grafting site. We also found for the first time that PD-L1 is constitutively expressed mainly by spermatocytes and spermatids in seminiferous tubules of the testis. Moreover, infiltrating T cells underwent less vigorous proliferation but faster apoptosis in the testis than in the kidney. Blocking PD-1:PD-L1 costimulation largely abolished the suppression of T-cell proliferation and acceleration of T-cell apoptosis. Importantly, testicular immune privilege significantly suppressed the generation and proliferation of donor-specific memory CD8 T cells.
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Is maternal protein intake associated with infant blood pressure?
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Animal data show that low protein intake in pregnancy programs higher offspring blood pressure, but similar data in humans are limited. We examined the associations of first and second trimester maternal protein intake with offspring blood pressure (BP) at the age of six months. In a prospective US cohort study, called Project Viva, pregnant women completed validated semi-quantitative food-frequency questionnaires (FFQ) to measure gestational protein intake. Among 947 mother-offspring pairs with first trimester dietary data and 910 pairs with second trimester data, we measured systolic blood pressure (SBP) up to five times with an automated device in the offspring at the age of six months. Controlling for blood pressure measurement conditions, maternal and infant characteristics, we examined the effect of energy-adjusted maternal protein intake on infant SBP using multivariable mixed effects models. Mean daily second trimester maternal protein intake was 17.6% of energy (mean 2111 kcal/day). First trimester nutrient intakes were similar. Mean SBP at age 6 months was 90.0 mm Hg (SD 12.9). Consistent with prior reports, adjusted SBP was 1.94 mm Hg lower [95% confidence interval (CI) -3.45 to -0.42] for each kg increase in birth weight. However, we did not find an association between maternal protein intake and infant SBP. After adjusting for covariates, the effect estimates were 0.14 mm Hg (95% CI 20.12 to 20.40) for a 1% increase in energy from protein during the second trimester, and 20.01 mm Hg (95% CI 20.24 to -0.23) for a 1% increase in energy from protein in the first trimester.
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To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area.
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Is bordetella pertussis an uncommon pathogen in children hospitalized with bronchiolitis during the winter season?
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In the United States (U.S.), Bordetella pertussis incidence has increased. Cough and apnea are common findings in pertussis and also in bronchiolitis, the most common cause of hospitalization in U.S. infants. The objective was to determine the prevalence of B. pertussis infection in children hospitalized with bronchiolitis and to describe its clinical course. Children hospitalized with bronchiolitis and age <2 years were eligible for a prospective, multicenter cohort study during 3 consecutive winter seasons (November-March) from 2007 to 2010. Sixteen sites in 12 states participated using a standardized enrollment protocol. Families were asked the 2010 Centers for Disease Control and Prevention pertussis classification questions. Nasopharyngeal aspirates were obtained and tested by real-time polymerase chain reaction for 16 viruses, Mycoplasma pneumoniae and B. pertussis. Two thousand sixty-eight (94%) of 2207 children had 1 or more respiratory pathogens. B. pertussis was identified in 4 children [0.2%; 95% confidence interval (CI): 0.1-0.5%] with 3 having a viral co-infection. All 4 were younger than 4 months; 2 met the Centers for Disease Control and Prevention definition of probable pertussis; and 3 had received at least 1 dose of an acellular pertussis vaccine. During the hospitalization, 2 had paroxysmal cough, 1 required intensive care unit care and the median length of stay was 13 days.
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Hypercholesterolemia is a well-established risk factor for the development of kidney injury. Considering that female sex hormones may play a preventative role in both cardiovascular and renal diseases, the aim of the present study was to evaluate the effects of female sex hormones on hypercholesterolemia-induced renal dysfunction. Apolipoprotein E-deficient (ApoE) and C57 control female mice underwent an ovariectomy (OVX) or sham surgery and after 2 months, creatinine clearance, uremia and proteinuria were determined. Renal oxidative stress and lipid deposition were also quantified. Values are presented as mean ± SEM. Statistical analyses were performed using Two-way ANOVA followed by Tukey's post hoc test. Creatinine clearance (μL/min) was similar between C57 (171 ± 17) and ApoE (140 ± 26) mice underwent sham surgery. OVX resulted in a reduced glomerular filtration rate in both C57 (112 ± 8, ~ - 35%, p < 0.05) and ApoE (61 ± 10, ~ - 56%, p < 0.05) animals. Plasma levels of urea (mg/dL) were higher in both ApoE groups (Sham: 73 ± 7; OVX: 73 ± 8, p < 0.05) when compared to C57 animals (Sham: 49 ± 3; OVX: 60 ± 4), with no changes among ovariectomized groups. Proteinuria levels (mg/24 h) were similar between C57 (Sham: 25.1 ± 5.7; OVX: 33.7 ± 4.7) and ApoE sham animals (26.4 ± 3.5), however, 24-h urine protein excretion was augmented in ApoE OVX animals (49.6 ± 5.8, p < 0.05). Histological kidney analysis demonstrated that the absence of female sex hormones resulted in increased oxidative stress, which was more severe in ApoE mice (C57 Sham: 9.2 ± 0.4; C57 OVX: 22.9 ± 1.0; ApoE Sham: 13.9 ± 0.7; ApoE OVX: 34.0 ± 1.4 au x 103, p < 0.05). As expected, ApoE mice presented higher lipid deposition, which was not affected by OVX (C57 Sham: 0 ± 0; C57 OVX: 0 ± 0; ApoE Sham: 6.8 ± 1.6; ApoE OVX: 5.2 ± 0.8% x 10-2, p < 0.05). Ovariectomy resulted in a similar reduction in ER-α protein expression in the renal cortex (C57: 0.78 ± 0.04; ApoE: 0.81 ± 0.04 au, p < 0.05) when compared to sham animals (C57:1.00 ± 0.04; ApoE: 1.03 ± 0.03 au).
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Is the protein tyrosine phosphatase non-receptor type 22 C1858T polymorphism a joint susceptibility locus for immunthyroiditis and autoimmune diabetes?
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The lymphoid tyrosine phosphatase (LYP) encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is a strong inhibitor of T cells. The single nucleotide polymorphism (SNP) C1858T within the PTPN22 gene was recently associated with autoimmune thyroid disease (AITD) and type I diabetes (T1D). The purpose of this study was to examine the joint association of this polymorphism with the co-occurrence of AITD and T1D. In this association study, 310 white subjects were genotyped for the C1858T polymorphism. The study population included 70 patients with both AITD and T1D (AITD+T1D), 70 patients with AITD only, 70 patients with T1D only, and 100 healthy controls. Patients with both AITD and T1D, and controls were also typed for HLA-DRB1. PTPN22 C1858T genotyping was performed by minisequencing. For HLA-DRB1 typing, polymerase chain reaction (PCR) sequence-specific oligonucleotide probes were used. The PTPN22 1858 minor T-allele frequency was strongly increased in patients with AITD+T1D (23.6%) compared with controls (8.0%, pc<0.001), with patients with AITD only (8.6%, pc=0.006), or with T1D only (10.7%, pc=0.028). T-allele carriers were also more frequently present in the group with AITD+T1D versus controls (41.4% vs. 14.0%, OR=4.35, 95% CI=2.08-9.09), AITD (17.1%, OR=3.42, 95% CI=1.56-7.48), and T1D (21.4%, OR=2.59, 95% CI=1.23-5.45). Especially in subjects with Hashimoto's thyroiditis (HT)+T1D, T-allele carriers were mostly frequent (50% vs. 14%, OR=6.14, 95% CI=2.62-14.38, pc<0.001). Considering all included patients with AITD, T-allele carriers were 29.3% vs. 14.0% in controls (p=0.008, OR=2.54, 95% CI=1.30-4.98). Patients carrying the PTPN22 1858 T allele had a twofold increased frequency of the HLA-DRB1*03 allele (64.7% vs. 37.3%, pc=0.034).
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To study the effects of centrophenoxine (CPH, meclofenoxate) on chronic cerebral hypoperfusion induced deficits in rats. Chronic hypoperfusion in rats was performed by permanent bilateral ligation of the common carotid arteries. Morris water maze was used to measure spatial memory performance. Spectrophotometrical techniques were used to assay SOD, GPx activities, MDA content, TXB2, and 6-keto-PGF1alpha levels. Morphological change was examined by HE staining. The expression of Bax and p53 protein were assayed by immunohistochemistry analysis. Chronic hypoperfusion in rats resulted in spatial memory impairments shown by longer escape latency and shorter time spent in the target quadrant. These behavioral dysfunction were accompanied by increase in SOD and GPx activities, the content of MDA, the levels of pro-inflammatory mediators (TXB2, 6-keto-PGF1alpha), overexpression of Bax and P53 protein, and delayed degeneration of neurons in cortex and hippocampus. Oral administration of CPH (100 mg/kg, once per day for 37 d) markedly improved the memory impairment, reduced the increase in antioxidant enzyme activities, MDA content and the levels of pro-inflammatory mediators to their normal levels, and attenuated neuronal damage.
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Are membrane-bound estrogen receptor-α expression and epidermal growth factor receptor mutation associated with a poor prognosis in lung adenocarcinoma patients?
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The purpose of this study is to clarify the correlations between the expression of membrane-bound estrogen receptor-α (mERα) and epidermal growth factor receptor (EGFR) mutation and clinicopathological factors, especially in relation to the prognosis, in patients with lung adenocarcinoma. We conducted a retrospective review of the data of 51 lung adenocarcinoma patients with tumors measuring less than 3 cm in diameter. Immunohistochemical staining for mERα expression and detection of the EGFR mutation status were performed. Among the 51 patients, the tumors in 15 showed both mERα expression and EGFR mutation. ("double positive") Significant associations between "double positive" and vascular invasion, vascular endothelial growth factor expression, and Ki-67 expression were observed. A multivariate analysis revealed that only "double positive" was an independent risk factor influencing the recurrence-free survival.
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Exogenous GLP-1 slows gastric emptying in health and diabetes leading to diminished glycemic excursions. Gastric emptying is markedly accelerated by hypoglycemia. The primary objective was to determine whether GLP-1 attenuates the acceleration of gastric emptying induced by hypoglycemia. Ten healthy volunteers were studied on four separate days in a randomized double-blind fashion. Blood glucose was stabilized using a glucose/insulin clamp at hypoglycemia (2.6 mmol/L on two occasions [hypo]) or euglycemia (6.0 mmol/L on two occasions [eu]) between T = -15 and 45 min before clamping at 6.0 mmol/L until 180 min. During hypoglycemia and euglycemia, subjects received intravenous GLP-1 (1.2 pmol/kg/min) or placebo. At T = 0 min, subjects ingested 100 g beef mince labeled with 20 MBq (99m)Tc-sulfur-colloid and 3 g of 3-O-methyl-glucose (3-OMG), a marker of glucose absorption. Gastric emptying was measured scintigraphically from T = 0 to 180 min and serum 3-OMG taken at 15-min intervals. The areas under the curve for gastric emptying and 3-OMG concentration were analyzed using one-way repeated-measures ANOVA with Bonferroni-Holm adjusted post hoc tests. Gastric emptying was accelerated during hypoglycemia (hypo/placebo vs. eu/placebo; P < 0.001), as was glucose absorption (P < 0.03). GLP-1 slowed emptying during euglycemia (eu/placebo vs. eu/GLP-1; P < 0.001). However, hypoglycemia-induced acceleration of gastric emptying on placebo was markedly diminished by GLP-1 (hypo/placebo vs. hypo/GLP-1; P < 0.008), as was glucose absorption (P < 0.01).
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Is lipoprotein internalisation induced by oncogenic AMPK activation essential to maintain glioblastoma cell growth?
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Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer. To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients. We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting 'de novo' fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells.
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Evidence-based fall prevention programs primarily attract older women, who are increasingly burdened by fall-related injuries. However, little is known about the relationship between older female participants' baseline health status and self-reported falls over the course of fall prevention interventions. Using data from A Matter of Balance/Volunteer Lay Leader Model (AMOB/VLL) workshops, this study examines female participants' sociodemographics and health indicators associated with self-reported falls at baseline and postintervention. Data were analyzed from 837 older women (M = 76.2 years) collected during the statewide AMOB/VLL dissemination in Texas. Longitudinal Poisson regression models, using the generalized estimating equation method, were used to investigate the associations of personal characteristics and health indicators with and reductions in the number of self-reported falls from baseline to postintervention. Approximately 21% of participants reported falling at baseline, and the number of reported falls significantly decreased from baseline to postintervention (β = -0.443). At baseline, more unhealthy physical days (β = 0.022), more unhealthy mental days (β = 0.018), and lower Falls Efficacy Scale scores (β = -0.052) were significantly associated with more falls reported at baseline. More falls at baseline was also associated with worse program attendance (β = -0.069). Greater improvements in Falls Efficacy Scale Scores (β = -0.069) and decreases in unhealthy physical health days (β = 0.026) over the course of the intervention were significantly associated with greater reductions in reported falls at postintervention, respectively.
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Does [ New compound NL-608 ( a nutlin analog ) induce apoptosis in human breast cancer MCF-7 cells ]?
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To observe the effect of NL-608 (a nutlin analog) on apoptosis induction in human breast cancer MCF-7 cells in vitro, and investigate the relevant molecular mechanism. The effect of NL-608 on proliferation of MCF-7 cells was determined by MTT assay. The apoptosis in MCF-7 cells was determined by flow cytometry with annexin V-FITC and PI. The activity of caspase 3, caspase 8 and caspase 9 was determined with caspase activity assay kit and Western blot, and the proteins of Fas and FasL were determined by Western blot. NL-608 showed a dose-dependent inhibitory effect on the proliferation of MCF-7 cells. It induced apoptosis in MCF-7 cells in a dose-dependent manner. The activity of caspase 3 and caspase 8 in MCF-7 cells was increased with the increasing concentration of NL-608, but caspase 9 had no changes. The proteins of Fas and FasL were increased in a dose-dependent manner.
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Arterial blood pressure (BP) is a reliable marker of circulatory dysfunction in cirrhotic patients. There are no prospective studies evaluating the association between different levels of arterial BP and ascites development in compensated cirrhotic patients. Therefore, we evaluated the relationship between arterial BP and ascites development in compensated cirrhotic patients. A total of 402 patients with compensated HCV-related cirrhosis were prospectively followed during 6 years to identify ascites development. At baseline, patients underwent systolic, diastolic and mean arterial pressure (MAP) measurements. Any history of arterial hypertension was also recorded. The occurrence of events such as bleeding, hepatocellular carcinoma, death and liver transplantation prior to ascites development were considered as competing risk events. Over a median of 156 weeks, ascites occurred in 54 patients (13%). At baseline, MAP was significantly lower in patients with ascites development (75.9 mm/Hg [95%CI, 70.3-84.3]) than those without ascites (93.6 mm/Hg [95% CI: 86.6-102.3]). After adjusting for covariates, the 6-year cumulative incidence of ascites was 40% (95%CI, 34%-48%) for patients with MAP<83.32 mm/Hg. In contrast, cumulative incidences of ascites were almost similar among patients with MAP values between 83.32 mm/Hg and 93.32 mm/Hg (7% [95% CI: 4%-12%]), between 93.32 mm/Hg and 100.31 mm/Hg (5% [95% CI: 4%-11%]) or higher than 100.31 mm/Hg (3% [95% CI: 1%-6%]). The MAP was an independent predictor of ascites development.
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Is low relative skeletal muscle mass indicative of sarcopenia associated with elevations in serum uric acid levels : findings from NHANES III?
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Sarcopenia may be related to increases in reactive oxygen species formation and inflammation, both of which are associated with elevations in serum uric acid. To test the hypothesis that a reduced skeletal muscle mass index, indicative of sarcopenia, is related to elevations in uric acid. Cross-sectional analysis of nationally representative data. Third National Health and Nutrition Examination Survey, 1988-1994. 7544 men and women 40 years of age and older who had uric acid, skeletal muscle mass, and select covariate information. Skeletal muscle mass assessment was based on a previously published equation including height, BIA-resistance, gender, and age. Absolute skeletal muscle mass was calculated for all study population individuals and compared against the sex-specific mean for younger adults. Serum uric acid data were gathered from the NHANES laboratory file. A logistic regression analysis revealed that elevations in serum uric acid are significantly related to sarcopenia status. For every unit (mg/dL) increase in uric acid, the odds ratio of manifesting a skeletal muscle mass index at least one standard deviation below the reference mean was 1.12. Participants in the highest grouping (> 8 mg/dL) of serum uric acid concentration had 2.0 times the odds of manifesting sarcopenia compared to the lowest grouping (< 6 mg/dL) (p < 0.01) after adjusting for the additional covariates.
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This study investigated two approaches, short hairpin RNA (shRNA) and the potent ABL inhibitor, dasatinib, alone and together, to achieve complete inhibition of BCR-ABL activity in Philadelphia-positive (Ph(+)) cells. shRNA specific for BCR-ABL b3a2 were delivered, by lentiviral transduction or electroporation, to K562 cells, with or without dasatinib. mRNA and protein knockdown were measured by quantitative reverse transcriptase polymerase chain reaction, flow cytometry, and Western blotting. BCR-ABL activity was assessed by intracellular flow cytometry for pCrkL. Cell death and apoptosis were assayed using trypan blue exclusion, Annexin-V, and active caspase-3 staining. Forty-eight hours after transduction or electroporation of shRNA, BCR-ABL mRNA, and protein were reduced by 75% and >90%, respectively, and sustained for 5 days. Lentiviral delivery and electroporation were equally effective. pCrkL was inhibited in association with cell death. By 5 days after transduction or electroporation, viable cells represented 50% of input, with a 12-fold reduction vs control, which expanded 6-fold. When shRNA, titrated by green fluorescent protein into low and high, was combined with dasatinib (concentration range, 0-10 nM), low shRNA was additive with low dasatinib (0.6 and 1 nM), leading to inhibition of pCrkL, induction of activated caspase-3, expression of Annexin-V, and marked reduction in viable cells.
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Are aging-related renal injury and inflammation associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice?
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The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls.
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Dextran-40 is effective in reducing postoperative Doppler-detectable embolization in patients undergoing carotid endarterectomy (CEA). Dextrans are thought to have antithrombotic and antiplatelet effects. The mode of action is unclear. In rats, dextran blocks uptake of tissue plasminogen activator (tPA) by mannose-binding receptors. Because this would have the effect of enhancing endogenous fibrinolysis, we explored this effect of dextran-40 on fibrinolysis in man. Twenty patients undergoing endovascular stenting for abdominal aortic aneurysm were randomized to receive 100 mL of 10% dextran-40 or saline, over 1 hour, during their operation in addition to heparin. Blood samples were taken preoperatively, intraoperatively (immediately after operative procedure), and 24 hours postoperatively. Thrombi were formed in a Chandler loop and used to assess endogenous fibrinolysis over 24 hours, measured as the fall in thrombus weight, and the release of fluorescently labelled fibrinogen from the thrombus. Plasma samples were analyzed for markers of fibrinolysis; plasmin-antiplasmin (PAP), PAI-1, and t-PA, and for functional von Willebrand factor (vWF). Platelet response to thrombin and other agonists was measured by flow cytometry. Thrombi formed ex vivo from the intraoperative blood samples from the dextran-treated patients exhibited significantly greater fibrinolysis vs preoperative samples, seen both as a significantly greater percentage reduction in thrombus weight (from 34.7% to 70.6% reduction) and as an 175% increase in the release of fluorescence (P < .05). Fibrinolysis returned to baseline levels the next day. No change was seen in the saline-treated group. Plasma levels of PAP and PAI-1 increased significantly postoperatively in the dextran-treated group vs the saline group (P < .05). The postoperative level of functional VWF was significantly lower in the dextran-treated group vs controls. A specific reduction occurred in the platelet response to thrombin, but not to other agonists, in the intraoperative samples from the dextran-treated group (11.1% vs 37.1%; P = .022), which was not seen in the controls.
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Are interactions between CB ( 1 ) receptors and TRPV1 channels mediated by 12-HPETE cytotoxic to mesencephalic dopaminergic neurons?
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We recently proposed the existence of neurotoxic interactions between the cannabinoid type 1 (CB(1)) receptor and transient receptor potential vanilloid 1 (TRPV1) channels in rat mesencephalic cultures. This study seeks evidence for the mediator(s) and mechanisms underlying the neurotoxic interactions between CB(1) receptors and TRPV1 in vitro and in vivo. The mediator(s) and mechanism(s) for the interactions between CB(1) receptors and TRPV1 were evaluated by cell viability assays, immunocytochemistry, Fura-2 calcium imaging, mitochondrial morphology assay, ELISA and Western blot assay in vitro in neuron-enriched mesencephalic cultures. Injections into the substantia nigra and subsequent cell counts were also used to confirm these interactions in vivo. The neurotoxic interactions were mediated by 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), an endogenous TRPV1 agonist. CB(1) receptor agonists (HU210 and WIN55,212-2) increased the level of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a downstream metabolite of 12(S)-HPETE, which stimulates TRPV1-mediated death of mesencephalic neurons, both in vitro and in vivo. The neurotoxicity was mediated by increased intracellular Ca(2+) concentration ([Ca(2+)](i)) through TRPV1, consequently leading to mitochondrial damage and was attenuated by baicalein, a 12-lipoxygenase inhibitor.
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Several reports have indicated the benefits of the acute care surgery (ACS) model in surgical outcomes. We tried to delineate the impact of the ACS model on surgical efficiency and quality. Before the ACS model was implemented, abdominal surgical emergencies were evaluated by an on-call nontrauma general surgeon (pre-ACS model). An in-house trauma surgeon treated all patients with trauma or nontrauma abdominal surgical emergencies after the ACS model. Patients with acute appendicitis who underwent appendectomies were included. We conducted a pre- and poststudy to compare the time patients were in the emergency department and surgical qualities. There were 146 and 159 patients enrolled in the pre-ACS model and ACS model, respectively. The overall ED length of stay in the ACS model was significantly shorter than that in the pre-ACS model (300.3 ± 61.7 vs 719.1 ± 339.0 minutes, P < .001). Hospital LOS was also significantly shorter in the ACS model than in the pre-ACS model (2.44 ± 1.39 vs 3.83 ± 2.21 days, P = .022).
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Do perinatal androgens and adult behavior vary with nestling social system in siblicidal boobies?
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Exposure to androgens early in development, while activating adaptive aggressive behavior, may also exert long-lasting effects on non-target components of phenotype. Here we compare these organizational effects of perinatal androgens in closely related Nazca (Sula granti) and blue-footed (S. nebouxii) boobies that differ in neonatal social system. The older of two Nazca booby hatchlings unconditionally attacks and ejects the younger from the nest within days of hatching, while blue-footed booby neonates lack lethal aggression. Both Nazca booby chicks facultatively upregulate testosterone (T) during fights, motivating the prediction that baseline androgen levels differ between obligately siblicidal and other species. We show that obligately siblicidal Nazca boobies hatch with higher circulating androgen levels than do facultatively siblicidal blue-footed boobies, providing comparative evidence of the role of androgens in sociality. Although androgens confer a short-term benefit of increased aggression to Nazca booby neonates, exposure to elevated androgen levels during this sensitive period in development can also induce long-term organizational effects on behavior or morphology. Adult Nazca boobies show evidence of organizational effects of early androgen exposure in aberrant adult behavior: they visit unattended non-familial chicks in the colony and direct mixtures of aggression, affiliative, and sexual behavior toward them. In a longitudinal analysis, we found that the most active Non-parental Adult Visitors (NAVs) were those with a history of siblicidal behavior as a neonate, suggesting that the tendency to show social interest in chicks is programmed, in part, by the high perinatal androgens associated with obligate siblicide. Data from closely related blue-footed boobies provide comparative support for this interpretation. Lacking obligate siblicide, they hatch with a corresponding low androgen level, and blue-footed booby adults show a much lower frequency of NAV behavior and a lower probability of behaving aggressively during NAV interactions. This species difference in adult social behavior appears to have roots in both pleiotropic and experiential effects of nestling social system.
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Surgery has been the gold standard in the treatment of adult pyloric stenosis (APS). The introduction of proton pump inhibitors (PPIs) in 1989 revolutionised the treatment of peptic ulcer disease and its complications. We carried out a prospective study to evaluate the effectiveness of PPIs as an alternative to surgery for treatment of APS. Six consecutive patients admitted with a diagnosis of adult peptic pyloric stenosis between November 1999 and August 2002 were studied. The diagnosis was confirmed with endoscopy. All patients were commenced on a twice-daily dose of intravenous PPI. This was changed to oral treatment after 2 days. Main outcome measures evaluated were resolution of symptoms on PPIs and failure of medical therapy. There were five females and one male. Median age at diagnosis was 72 years (range, 30-90 years). Median duration of symptoms was 2 weeks (range, 1-5 weeks). Of the patients, five had a history of peptic ulcer disease. Complete resolution was achieved in 5 patients (83%). Median duration for resolution of symptoms was 9 days (range, 5-14 days). All patients were changed to oral PPIs after 2 days. One patient did not respond to oral therapy and required surgical intervention (pyloroplasty). Median follow-up was 26 months (range, 6-48 months). There was no recurrence of symptoms. All patients were discharged on low-dose PPI.
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Is the performance of prostate specific antigen for predicting prostate cancer maintained after a prior negative prostate biopsy?
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It has been suggested that prostate specific antigen has no predictive value for prostate cancer after a first negative biopsy has been performed. We compared the performance operating characteristics of prostate specific antigen for prostate cancer between a first and subsequent prostate biopsy in a group of men with complete verification of cancer status. From the 18,882 participants in the Prostate Cancer Prevention Trial we examined men in the placebo group who had only a first biopsy or a first and second prostate biopsy with a prostate specific antigen and digital rectal examination within 1 year before each biopsy. The receiver operating characteristic curve was estimated for prostate specific antigen for detection of prostate cancer on the first biopsy compared to the second, and the C-statistics were compared. Of this group 5,608 men had a first biopsy and 687 of those with a negative first biopsy underwent a second biopsy. The C-statistic was 0.650 (95% CI 0.632, 0.668) for the first biopsy and 0.664 (95% CI 0.607, 0.721) for the second biopsy. The C-statistic for the second biopsy was statistically significantly greater than 0.5 (p <0.001) and overlapped with that from the first biopsy.
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Intracerebral hemorrhage (ICH) induces microglial activation and the release of inflammatory cytokines, leading to inflammation in the brain. IRAK4, an essential component of the MyD88-dependent pathway, activates subsets of divergent signaling pathways in inflammation. In the experiment, microglia were stimulated with erythrocyte lysates, and then miR-367, IRAK4, NF-ĸB activation and downstream proinflammatory mediator production were analyzed. In addition, inflammation, brain edema, and neurological functions in ICH mice were also assessed. Here, we report that ICH downregulated miR-367 expression but upregulated IRAK4 expression in primary microglia. We also demonstrate that miR-367 suppressed IRAK4 expression by directly binding its 3'-untranslated region. MiR-367 inhibited NF-ĸB activation and downstream proinflammatory mediator production. Knocking down IRAK4 in microglia significantly decreased the IRAK4 expression and inhibited the NF-ĸB activation and the downstream production of proinflammatory mediators. In addition, our results indicate that miR-367 could inhibit expression of proinflammatory cytokines, reduce brain edema, and improve neurological functions in ICH mice.
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Is mortality in patients with non-functioning pituitary adenoma increased : systematic analysis of 546 cases with long follow-up?
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Non-functioning pituitary adenomas (NFAs) have a prevalence of 7-22/100,000 people. A significant number of patients suffer from morbidities related to the tumor, possible recurrence(s), and treatments utilized. Our aim was to assess mortality of patients with macroNFA and predictive factors. Retrospective cohort study in a tertiary referral center in the UK. A total of 546 patients operated for a macroNFA between 1963 and 2011 were studied. Mortality data were retrieved through the National Health Service Central Register and hospital records and recorded as standardized mortality ratio (SMR). Mortality was estimated for the total and various subgroups with clinical follow-up data. Median follow-up was 8 years (range: 1 month-48.5 years). SMR was 3.6 (95% CI, 2.9-4.5), for those operated before 1990, 4.7 (95% CI, 2.7-7.6) and for those after 1990, 3.5 (95% CI, 2.8-4.4). Main causes of death were cardio/cerebrovascular (33.7%), infections (30.1%), and malignancy (28.9%). Cox regression analysis demonstrated that only age at diagnosis remained an independent predictor of mortality (hazard ratio 1.10; 95% CI, 1.07-1.13, P<0.001), whereas sex, presentation with acute apoplexy, extent of tumor removal, radiotherapy, recurrence, untreated GH deficiency, FSH/LH deficiency, ACTH deficiency, TSH deficiency, and treatment with desmopressin had no impact.
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IL-17 is an important cytokine signature of the TH differentiation pathway TH17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. We set out to determine the frequency of TH17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. Explanted lungs from patients undergoing transplantation or organ donors (CF samples=18; non-CF, nonbronchiectatic samples=10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for TH17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen-responsive CD4+IL-17+ cells. There were double-positive IL-17+IL-22+ cells [TH17(22)], and the IL-22+ population had a higher proportion of memory characteristics. Antigen-specific TH17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs.
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Does surgery for spontaneous intracerebral hemorrhage have greater remedial value than conservative therapy?
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The aim of this study was to compare the efficacy of surgery for spontaneous intracerebral hemorrhage with that of medical treatment, based on data from the Japan Stroke Registry Study. From 1999 to 2001, 1010 patients with spontaneous intracerebral hemorrhage were registered in the Japan Standard Stroke Registry Study from 45 stroke center hospitals in Japan. The National Institutes of Health Stroke Scale (NIHSS), Japan Stroke Scale (JSS), and modified Rankin Scale scores were used to compare severity and improvement in patients given surgical and medical treatment.
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Endogenous glucocorticoids (GCs) modulate numerous biologic systems involved in the initiation and maintenance of arthritis. Bone cells play a critical role in the progression of arthritis, and some of the effects of GCs on inflammation may be mediated via these cells. The aim of this study was to investigate the impact of osteoblast-targeted disruption of GC signaling on joint inflammation, cartilage damage, and bone metabolism in the K/BxN mouse serum transfer model of autoimmune arthritis. Intracellular GC signaling was disrupted in osteoblasts through transgenic overexpression of 11beta-hydroxysteroid dehydrogenase type 2 under the control of a type I collagen promoter. Arthritis was induced in 5-week-old male transgenic mice and their wild-type (WT) littermates, and paw swelling was assessed daily until the mice were killed. The mice were examined by histology, histomorphometry, and microfocal computed tomography, and serum was analyzed for cytokines, adrenocorticotropic hormone, and corticosterone. Acute arthritis developed in both transgenic and WT mice treated with K/BxN mouse serum. However, the arthritis and local inflammatory activity were significantly attenuated in transgenic mice, as judged by clinical and histologic indices of inflammation and cartilage damage. Bone turnover and bone volume remained unchanged in arthritic transgenic mice, while WT mice exhibited stimulated bone resorption, suppressed osteoblast activity, and significantly reduced bone volume, compatible with the known effects of active inflammation on bone. Circulating levels of proinflammatory cytokines tended to be lower in arthritic transgenic mice than in control transgenic mice.
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Is interferon lambda-3 associated with clinical outcome in patients with HCV-induced compensated cirrhosis : a long-term cohort study?
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Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression.
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The herbicidal mode of action of flamprop-M-methyl [methyl N-benzoyl-N-(3-chloro-4-fluorophenyl)-D-alaninate] was investigated. For initial characterization, a series of bioassays was used, which indicated a mode of action similar to that of mitotic disrupter herbicides. Cytochemical fluorescence studies, which included monoclonal antibodies against polymerized tubulin, were applied to elucidate effects on mitosis and microtubule assembly in maize roots. When seedlings were root treated with 50 microM of flamprop-M-methyl, cell division activity in meristematic root tip cells ceased within 4 h. The compound severely disturbed the orientation of spindle and phragmoblast microtubules, leading to defective spindle and phragmoblast structures. Cortical microtubules were only slightly affected. In late anaphase and early telophase cells, phragmoblast microtubules were disorganized in multiple arrays that hampered regular cell plate deposition in cytokinesis. Microtubules of the spindle apparatus were found attached to chromosomal kinetochores, but did not show regular organization associated with a zone of microtubule-organizing centres at the opposite ends of the cell. On account of this loss of spindle organization, chromosomes remained in a condensed state of prometaphase or metaphase. Unlike known microtubule disrupter herbicides, flamprop-M-methyl and its biologically active metabolite flamprop did not inhibit soybean tubulin polymerization to microtubules in vitro at 50 microM. In contrast, soybean plants responded sensitively to the compounds.
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Do cD56+ T cells inhibit hepatitis C virus replication in human hepatocytes?
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CD56(+) T cells are abundant in liver and play an important role in defense against viral infections. However, the role of CD56(+) T cells in control of hepatitis C virus (HCV) infection remains to be determined. We investigated the noncytolytic anti-HCV activity of primary CD56(+) T cells in human hepatocytes. When HCV Japanese fulminant hepatitis-1 (JFH-1)-infected hepatocytes were co-cultured with CD56(+) T cells or incubated in media conditioned with CD56(+) T cell culture supernatants (SN), HCV infectivity and replication were significantly inhibited. The antibodies to interferon (IFN)-gamma or IFN-gamma receptor could largely block CD56(+) T cell-mediated anti-HCV activity. Investigation of mechanism(s) responsible for CD56(+) T cell-mediated noncytolytic anti-HCV activity showed that CD56(+) T SN activated the multiple elements of janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and enhanced the expression of IFN regulatory factors (IRFs) 1, 3, 7, 8, and 9, resulting in the induction of endogenous IFN-alpha/beta expression in hepatocytes. Moreover, CD56(+) T SN treatment inhibited the expression of HCV-supportive micro RNA (miRNA)-122 and enhanced the levels of anti-HCV miRNA-196a in human hepatocytes.
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Growth factor therapy provides a therapeutic alternative for "no option" patients with coronary disease. Fibroblast Growth Factor-2 (FGF-2) predominantly stimulates angiogenesis, the growth of new capillaries, whereas Monocyte Chemoattractant Protein-1 (MCP-1) is considered an arteriogenic agent. We hypothesised a synergetic effect of FGF-2 and MCP-1 in ischemic myocardium. A severe coronary stenosis was created in pigs. After one week, chronic ischemia was confirmed by angiography, echocardiography, reduced ejection fraction, and increase of marker enzymes. FGF-2, MCP-1, both, or vector only were then injected intramyocardially as plasmid DNA in the impaired area. Regional contractility and number of capillaries and arterial vessels were evaluated after three months. FGF-2, FGF-2+MCP-1, and vector, but not MCP-1 alone improved regional contractility at rest, whereas only FGF-2 alone ameliorated function under stress conditions. Angiogenesis in the ischemic area was stimulated by FGF-2 compared to MCP-1. In contrast, MCP-1 induced arteriogenesis relative to FGF-2.
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Is eD bedside point-of-care lactate in patients with suspected sepsis associated with reduced time to iv fluids and mortality?
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Early recognition and treatment of sepsis improves outcomes. We determined the effects of bedside point-of-care (POC) lactate measurement on test turnaround time, time to administration of IV fluids and antibiotics, mortality, and ICU admissions in adult ED patients with suspected sepsis. We hypothesized that bedside lactate POC testing would reduce time to IV fluids and antibiotics. We compared 80 ED patients with suspected sepsis and a lactate level of 2 mmol/L or greater before and 80 similar patients after introduction of POC lactate measurements. Groups were compared with Χ(2) and Mann Whitney U tests. A sample size of 80 patients in each group had 85% power to detect a 30-minute difference in time to IV fluids or antibiotics. Study groups were similar in age, gender, baseline lactate levels, sepsis severity, and Sequential Organ Failure Assessment (SOFA) scores. Introduction of POC lactate was associated with significant reductions in test turnaround time (34 [26-55] vs. 122 [82-149] minutes; P < 0.001), time to IV fluids (55 [34-83] vs. 71 [42-110] minutes; P = 0.03), mortality (6% vs. 19%; P = 0.02), and ICU admissions (33% vs. 51%, P = 0.02), but not time to IV antibiotics (89 [54-156] vs. 88 [60-177] minutes; P = 0.35).
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Different classes of small RNAs (sRNAs) refine the expression of numerous genes in higher eukaryotes by directing protein partners to complementary nucleic acids, where they mediate gene silencing. Plants encode a unique class of sRNAs, called trans-acting small interfering RNAs (tasiRNAs), which post-transcriptionally regulate protein-coding transcripts, as do microRNAs (miRNAs), and both sRNA classes control development through their targets. TasiRNA biogenesis requires multiple components of the siRNA pathway and also miRNAs. But while 21mer siRNAs originating from transgenes can mediate silencing across several cell layers, miRNA action seems spatially restricted to the producing or closely surrounding cells. We have previously described the isolation of a genetrap reporter line for TAS3a, the major locus producing AUXIN RESPONS FACTOR (ARF)-regulating tasiRNAs in the Arabidopsis shoot. Its activity is limited to the adaxial (upper) side of leaf primordia, thus spatially isolated from ARF-activities, which are located in the abaxial (lower) side. We show here by in situ hybridization and reporter fusions that the silencing activities of ARF-regulating tasiRNAs are indeed manifested non-cell autonomously to spatially control ARF activities.
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Does [ Pitavastatin enhance angiogenesis and perfusion in a murine mode of limb ischemia ]?
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We investigated the effects of pitavastatin on angiogenesis and perfusion in C3H/He mice with unilateral hind limb ischemia. C3H/He mice treated with saline (n = 15) or pitavastatin (1 mg.kg(-1).d(-1), n = 15) per gavage for 1 week underwent unilateral hind limb ischemia surgery and were treated for another 5 weeks. Hind-limb blood flow was measured by Laser Doppler perfusion imager (LDPI, ischemic/nonischemic limb, %) at baseline, immediately after ischemia and weekly thereafter for 5 weeks. Endpoints included local vessel counts by immunofluorescence, phospho-Akt positive cell counts by immunoenzyme histochemical technique, vascular endothelial growth factors (VEGFs) expression in ischemic limbs by Western blot and serum nitric oxide metabolite (NOx) by chrome dioxide Griess method. Lower extremity perfusion was significantly improved in pitavastatin treated mice vs. controls as measured by LDPI% at 1 week post ischemia and thereafter (P < 0.05). Pitavastatin treatment was associated with significantly increased capillary count [(47 +/- 11) vs. (26 +/- 14)/per high-power field (x 200), P < 0.05] and greater percentage of phospho-Akt positive cells [(6 +/- 1) vs. (2 +/- 0)/per high-power field (x 200), P < 0.05] in ischemic limbs. Serum NOx [(77.3 +/- 21.8) vs. (52.1 +/- 11.2) mol/L, P < 0.05) and VEGF protein expression in ischemic limbs were also significantly increased in pitavastatin group than those in control group.
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Mutations of the caspase-activating recruitment domain 15 (CARD15) gene on chromosome 16 are associated with chronic inflammatory granulomatous bowel disease (Crohn's disease). Sarcoidosis is a systemic granulomatous disease with unknown etiology, which shares histological features with Crohn's disease. To evaluate whether ethnic Danes with sarcoidosis have an increased frequency of CARD15 mutations compared to healthy control subjects. Genotyping for CARD15 mutations R702W, G908R, and L1007fsinsC, also designated single nucleotide polymorphism (SNP) SNP8, SNP12 and SNP13, respectively, were performed by capillary electrophoresis single-strand confirmation polymorphism in 53 patients with histologically verified sarcoidosis and in 103 healthy controls. The frequencies of CARD15 mutations in sarcoidosis patients were: SNP8, 4/106 chromosomes (3.8%); SNP12, 2/106 chromosomes (1.9%); SNP13, 2/106 chromosomes (1.9%); SNP8+SNP12+SNP13, 8/106 chromosomes (7.6%). All 8 patients were heterozygous. The frequencies in controls were: SNP8, 9/206 chromosomes (4.4%); SNP12, 2/206 chromosomes (1.0%); SNP13, 4/206 chromosomes (1.9%); SNP8+SNP12+SNP13, 15/206 chromosomes (7.3%). All controls were heterozygous. The differences were not statistically significant (p>0.05). Furthermore, the course of disease was not significantly different in the 8 patients with CARD15 mutations and the 45 patients without mutations.
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Does nebivolol induce parallel improvement of left ventricular filling pressure and coronary flow reserve in uncomplicated arterial hypertension?
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Our aim was to analyze the effects of 3-month antihypertensive therapy by nebivolol, a beta-blocking agent with nitric oxide-mediated vasodilatory properties, on coronary flow reserve (CFR) and left ventricular filling pressure (LVFP) in uncomplicated arterial hypertension. Twenty newly diagnosed, never treated, uncomplicated hypertensive patients (14 male and six female patients, mean age = 49 years), I-II WHO grade, underwent single-blind nebivolol treatment. At baseline and at 3-month follow-up, patients underwent Doppler echocardiography including pulsed Tissue Doppler of septal mitral annulus: the ratio between transmitral E velocity and myocardial early diastolic velocity (E/Em ratio) was calculated as an index of LVFP degree. Transthoracic Doppler-derived CFR (high-dose dipyridamole coronary diastolic peak flow velocity to resting coronary peak flow velocity ratio) of distal left anterior descending artery was also determined. After 3-month nebivolol therapy, rate-pressure product decreased (P < 0.0001). No significant change of left ventricular mass index, relative wall thickness and midwall shortening was detected. Left ventricular end-diastolic diameter and stroke volume were both marginally increased. Nebivolol increased Em (P < 0.0001), reduced E/Em ratio (from 9.0 +/- 1.6 to 8.2 +/- 1.1, P < 0.0001) and enhanced CFR (from 2.07 +/- 0.2 to 2.20 +/- 0.2, P = 0.003), because of increased hyperemic coronary flow velocity (P < 0.001). CFR increase remained significant (P < 0.001) after normalizing resting and dipyridamole coronary velocities for the respective rate-pressure product. The increase of normalized CFR induced by nebivolol was related with E/Em ratio decrease (r = -0.65, P < 0.002).
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Mice heterozygous for the Del1 transgene locus with a short deletion mutation in the type II collagen gene develop early-onset degenerative changes in the knee joints that progress to end-stage osteoarthritis by the age of 12-15 months. This study focuses on the expression and distribution of syndecan-1, a cell-surface heparan sulfate proteoglycan, during the development of osteoarthritic cartilage degeneration, to better understand its role in this disease. Northern analyses of total RNA extracted from knee joints of transgenic Del1 mice and their nontransgenic controls were used to monitor changes in syndecan-1 mRNA levels during development, growth, ageing, and cartilage degeneration. Immunohistochemistry was used to study the distribution of syndecan-1 in the knee joints at different stages of cartilage degeneration. Syndecan-1 mRNA was present in knee joints throughout life, with the highest mRNA levels in ageing knee joints. In Del1 mice, a transient upregulation of syndecan-1 mRNA synthesis was observed at the age of 6 months coinciding with early stages of cartilage degeneration and a period of attempted repair. Immunostaining for syndecan-1 was most intense in chondrocytes of superficial and intermediate zones of articular cartilage adjacent to defect areas. Chondrocyte clusters also stained strongly for syndecan-1.
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Does the HIV Tat protein affect processing of ribosomal RNA precursor?
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Inside the cell, the HIV Tat protein is mainly found in the nucleus and nucleolus. The nucleolus, the site of ribosome biogenesis, is a highly organized, non-membrane-bound sub-compartment where proteins with a high affinity for nucleolar components are found. While it is well known that Tat accumulates in the nucleolus via a specific nucleolar targeting sequence, its function in this compartment it still unknown. To clarify the significance of the Tat nucleolar localization, we induced the expression of the protein during oogenesis in Drosophila melanogaster strain transgenic for HIV-tat gene. Here we show that Tat localizes in the nucleoli of Drosophila oocyte nurse cells, where it specifically co-localizes with fibrillarin. Tat expression is accompanied by a significant decrease of cytoplasmic ribosomes, which is apparently related to an impairment of ribosomal rRNA precursor processing. Such an event is accounted for by the interaction of Tat with fibrillarin and U3 snoRNA, which are both required for pre-rRNA maturation.
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The objective of this study was to compare health-related quality of life (HR-QoL), disability/work productivity, and health care utilization in a variety of medical disorders with and without comorbid major depressive disorder (MDD) in the general population. Twelve-month MDD (Composite International Diagnostic Interview) diagnosis was determined among 4181 participants from a community sample. Medical diagnoses (respiratory, cardiovascular, allergic, endocrine/metabolic, gastrointestinal, and neurological diseases) were made after medical examination. HR-QoL was evaluated with the MOS-SF-36. Outpatient doctor visits and disability/work productivity were assessed by self-report. Comorbid MDD was associated with a lower SF-36 mental summary score in all medical diagnoses and with a lower physical summary score in comorbid allergic and neurological disorders. The number of coexisting medical disorders was strongly related to lower physical and mental summary scores in cases without comorbid depression. The number of outpatient doctor visits increased by 42% when any of the medical disorders without comorbid MDD was present, and comorbid MDD was associated with a further 24-42% increase, depending on the medical disorder. Comorbid MDD was strongly associated with lower full-time working status (37.1% with MDD vs. 51.0% without MDD) and with a significant increase in disability days (45%) in the presence of any medical disorder.
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Does ascorbic Acid ameliorate nicotine exposure induced impaired spatial memory performances in rats?
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The long lasting behavioural and cognitive impairments in offspring prenatally exposed to nicotine have been confirmed in animal models. In the present study, we investigated the effect of ascorbic acid on prenatal nicotine exposure induced behavioral deficits in male offspring of rats. The pregnant Wistar dams were divided into four groups of six rats: control, vehicle control, nicotine and nicotine+ascorbic acid groups. The nicotine group received daily dose of subcutaneous injections of 0.96 mg/kg body weight (bw) nicotine free base throughout gestation. Pregnant dams in nicotine+ascorbic acid group were first given nicotine free base (0.96 mg/kg bw/day; subcutaneous route) followed by ascorbic acid (50 mg/kg bw/day, orally) daily throughout gestation. The cognitive function of male offspring of all the experimental groups was studied using Morris water maze test at postnatal day 40. Prenatal nicotine exposure altered spatial learning and memory in male offspring. However, treatment with ascorbic acid ameliorated these changes in rats.
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"Virtual fracture clinics" have been reported as a safe and effective alternative to the traditional fracture clinic. Robust protocols are used to identify cases that do not require further review, with the remainder triaged to the most appropriate subspecialist at the optimum time for review. The objective of this study was to perform a "top-down" analysis of the cost effectiveness of this virtual fracture clinic pathway. National Health Service financial returns relating to our institution were examined for the time period 2009 to 2014 which spanned the service redesign. The total staffing costs rose by 4% over the time period (from £1 744 933 to £1 811 301) compared with a national increase of 16%. The total outpatient department rate of attendance fell by 15% compared with a national fall of 5%. Had our local costs increased in line with the national average, an excess expenditure of £212 705 would have been required for staffing costs.
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Does lactose enhance calcium bioavailability in lactose-tolerant , healthy adults?
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There is evidence from animal studies that lactose has a beneficial effect on intestinal calcium absorption. However, data concerning the effect of lactose on calcium absorption in lactose-tolerant adults are inconclusive. Our objective was to investigate the effect of lactose on calcium bioavailability in humans by the use of a stable-strontium test under controlled metabolic conditions. Eleven healthy, lactose-tolerant subjects (8 women, 3 men) randomly received a bolus of 2.27 mmol strontium alone (load A), the bolus with 35 g lactose (load B), or the bolus with 17.5 g glucose and 17.5 g galactose (load C). Blood samples were drawn at 0, 15, 30, 60, 90, 180, 240, and 300 min. Urine specimens were collected during the time intervals -2 to 0, 0-2, 2-4, 4-6, and 6-24 h. Pharmacokinetic parameters of strontium bioavailability were comparable for all 3 loads. In detail, fractional absorption at 240 min for loads A, B, and C was 12.1 +/- 0.7%, 13.0 +/- 1.1%, and 12.2 +/- 0.7%, respectively. Areas under the curve for 0-240 min were 70.8 +/- 6.3, 69.6 +/- 3.5, and 65.8 +/- 5.1 micromol*h/L for loads A, B, and C, respectively (NS). Moreover, fractional strontium excretion values of 5.1 +/- 0.8% (load A), 5.8 +/- 0.4% (load B), and 5.2 +/- 0.8% (load C) were not significantly different.
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Transcription of plastid-encoded genes requires two different DNA-dependent RNA polymerases, a nuclear-encoded polymerase (NEP) and plastid-encoded polymerase (PEP). Recent studies identified two related pfkB-type carbohydrate kinases, named FRUCTOKINASE-LIKE PROTEIN (FLN1 and FLN2), as components of the thylakoid bound PEP complex in both Arabidopsis thaliana and Sinapis alba (mustard). Additional work demonstrated that RNAi-mediated reduction in FLN expression specifically diminished transcription of PEP-dependent genes. Here, we report the characterization of Arabidopsis FLN knockout alleles to examine the contribution of each gene in plant growth, chloroplast development, and in mediating PEP-dependent transcription. We show that fln plants have severe phenotypes with fln1 resulting in an albino phenotype that is seedling lethal without a source of exogenous carbon. In contrast, fln2 plants display chlorosis prior to leaf expansion, but exhibit slow greening, remain autotrophic, can grow to maturity, and set viable seed. fln1 fln2 double mutant analysis reveals haplo-insufficiency, and fln1 fln2 plants have a similar, but more severe phenotype than either single mutant. Normal plastid development in both light and dark requires the FLNs, but surprisingly skotomorphogenesis is unaffected in fln seedlings. Seedlings genetically fln1-1 with dexamethasone-inducible FLN1-HA expression at germination are phenotypically indistinguishable from wild-type. Induction of FLN-HA after 24 hours of germination cannot rescue the mutant phenotype, indicating that the effects of loss of FLN are not always reversible. Examination of chloroplast gene expression in fln1-1 and fln2-1 by qRT-PCR reveals that transcripts of PEP-dependent genes were specifically reduced compared to NEP-dependent genes in both single mutants.
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Does combined use of etanercept and MTX restore CD4⁺/CD8⁺ ratio and Tregs in spleen and thymus in collagen-induced arthritis?
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To further explore the mechanism of etanercept (ENT, rhTNFR:Fc) and methotrexate (MTX) in the combined treatment of rheumatoid arthritis (RA), we investigated whether thymic and splenic T-cell subsets and their related cytokines imbalance could be restored by ETN/MTX treatment. The effect of ETN/MTX on collagen-induced arthritis (CIA) was evaluated by arthritis scores, joint and spleen histopathology, as well as indices of thymus and spleen. T lymphocytes proliferation was determined by [(3)H]-TdR incorporation. Levels of TNF-α, LT-α, IL-1β, RANKL, IL-10, IL-17, IFN-γ and IL-6 were detected by enzyme linked immunosorbent assay. The subsets of T lymphocytes including CD4(+), CD8(+), CD3(+)CD4(+), CD4(+)CD25(+), CD4(+)CD62L(+) and CD4(+)CD25(+)Foxp3(+) cells were quantified using flow cytometry. Combined administration of ETN/MTX significantly inhibited the proliferation of T lymphocytes, decreased serum IL-6, TNF-α, IL-1β, RANKL and macrophage supernatant IL-17, LT-α, increased serum IFN-γ and macrophage supernatant IL-10. Moreover, the combined administration could restore CD4(+)/CD8(+) ratio and Treg cells of CIA thymus and spleen.
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Vascular endothelial growth factor (VEGF) has been suggested to enhance glucose transport across the blood-brain barrier, thereby increasing brain glucose supply. Increased brain glucose concentration is known to suppress food intake and to decrease body mass via action on hypothalamic regulation centers. Based on the crucial role of VEGF on brain glucose supply, we hypothesized that higher VEGF concentrations are associated with lower food intake and body mass in humans. Intending to investigate subjects with high variance of blood glucose, we examined patients with type 2 diabetes mellitus. Our hypothesis was tested in a population-based cohort of 190 subjects with type 2 diabetes. Plasma VEGF levels in conjunction with other parameters known to modulate food intake were measured and subsequently correlated with food intake patterns at a breakfast buffet as well as with body mass. We found that subjects with higher concentrations of plasma VEGF had 17% less carbohydrate intake (P=0.003) and 4.8% lower body mass (P=0.017) than those with lower VEGF concentrations. Intake of protein and fat did not correlate with VEGF concentrations. These associations of plasma VEGF were confirmed in multiple linear regression analyses controlling for several parameters interacting with food intake.
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Does quantitative proteomics analysis reveal similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets?
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Platelets are a natural source of growth factors, cytokines and chemokines, that regulate angiogenesis and inflammation. It has been suggested that differential release of pro- and anti-angiogenic growth factors from platelet α-granules by protease-activated receptors (PAR) 1 and 4 may be important for the regulation of angiogenesis. We aimed to compare the releasates of unstimulated platelets with PAR-1- and PAR-4-stimulated platelets. The release of β-thromboglobulin, platelet factor (PF)-4, thrombospondin, platelet-derived growth factor (PDGF)-A/B, regulated and normal T-cell expressed and secreted (RANTES/CCL5), endostatin, CXCL12, and vascular endothelial growth factor (VEGF) was measured with enzyme-linked immunosorbent assay (ELISA). Mass spectrometry (MS)-based quantitative proteomics identified 93 proteins from platelets stimulated with PAR-1 and PAR-4. A strong correlation between the factors released after either stimulus was observed (Spearman's r 0.94, P < 0.001). Analysis with ELISA showed that stimulation with PAR-1 or PAR-4 lead to non-differential release of β-thromboglobulin, PF-4, thrombospondin, PDGF-A/B, RANTES/CCL5, endostatin, CXCL12, and VEGF. Release of thrombospondin was slightly lower after PAR-1 stimulation (7.2 μg/mL), compared with PAR-4 induced release (9.8 μg/mL; P < 0.05).
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This study was designed to characterize urinary isolates of Escherichia coli that produce extended-spectrum beta-lactamases (ESBLs) and to determine the prevalence of other antimicrobial resistance genes. A total of 264 non-duplicate clinical isolates of E. coli were recovered from urine specimens in a tertiary-care hospital in Busan in 2005. Antimicrobial susceptibility was determined by disk diffusion and agar dilution methods, ESBL production was confirmed using the double-disk synergy (DDS) test, and antimicrobial resistance genes were detected by direct sequencing of PCR amplification products. E. coli isolates were classified into four phylogenetic biotypes according to the presence of chuA, yjaA, and TSPE4. DDS testing detected ESBLs in 27 (10.2%) of the 264 isolates. The most common type of ESBL was CTX-M-15 (N=14), followed by CTX-M-3 (N=8) and CTX-M-14 (N=6). All of the ESBL-producing isolates were resistant to ciprofloxacin. PCR experiments detected genes encoding DHA-1 and CMY-10 AmpC beta-lactamases in one and two isolates, respectively. Also isolated were 5 isolates harboring 16S rRNA methylases, 2 isolates harboring Qnr, and 19 isolates harboring AAC(6')-Ib-cr. Most ESBL-producing isolates clustered within phylogenetic groups B2 (N=14) and D (N=7).
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Is colonoscopy performance stable during the course of an extended three-session working day?
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Three-session days were introduced in our endoscopy unit to accommodate the increased demand resulting from the introduction of the National Health Service Bowel Cancer Screening Programme (BCSP). Cecal intubation rate (CIR) and adenoma detection rate (ADR) may decline with time during a standard working day, but data are lacking for an extended three-session day. We assessed colonoscopy performance in an extended three-session day. Colonoscopies performed during the year 2011 were retrospectively analyzed. The CIR and ADR were analyzed according to the time of day when procedures were done: morning (AM), afternoon (PM), or evening (EVE). Because of an expected higher incidence of adenomas in the BCSP patients, ADR was analyzed according to indication (BCSP or non-BCSP). Of the 2574 colonoscopies, 1328 (51.7 %) were in male patients and 1239 (48.3 %) in female patients with a median age of 63 years (interquartile range [IQR], 51 - 70). Of the 2574 colonoscopies, 1091 (42.4 %) were performed in AM lists, 994 (38.6 %) in PM lists, and 489 (19 %) in EVE lists. Time of day did not affect the CIRs for the AM, PM, and EVE lists (90.5 %, 90.1 %, and 89.9 %, respectively; χ (2) [2, N = 2540] = 0.15, P = 0.927). The CIR was reduced in female patients and those with poor bowel preparation (P < 0.05). After exclusion of the BCSP patients, the ADR was lower in the EVE lists than in the AM and PM lists on univariate analysis, but on multivariate analysis, this difference was not significant (P > 0.05). The ADR was significantly higher in patients older than 60 years and in men (P < 0.001). Queue position did not independently influence the CIR or ADR.
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Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages. We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs. The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages.
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Do endogenous TasiRNAs mediate non-cell autonomous effects on gene regulation in Arabidopsis thaliana?
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Different classes of small RNAs (sRNAs) refine the expression of numerous genes in higher eukaryotes by directing protein partners to complementary nucleic acids, where they mediate gene silencing. Plants encode a unique class of sRNAs, called trans-acting small interfering RNAs (tasiRNAs), which post-transcriptionally regulate protein-coding transcripts, as do microRNAs (miRNAs), and both sRNA classes control development through their targets. TasiRNA biogenesis requires multiple components of the siRNA pathway and also miRNAs. But while 21mer siRNAs originating from transgenes can mediate silencing across several cell layers, miRNA action seems spatially restricted to the producing or closely surrounding cells. We have previously described the isolation of a genetrap reporter line for TAS3a, the major locus producing AUXIN RESPONS FACTOR (ARF)-regulating tasiRNAs in the Arabidopsis shoot. Its activity is limited to the adaxial (upper) side of leaf primordia, thus spatially isolated from ARF-activities, which are located in the abaxial (lower) side. We show here by in situ hybridization and reporter fusions that the silencing activities of ARF-regulating tasiRNAs are indeed manifested non-cell autonomously to spatially control ARF activities.
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To determine the relationship between preoperative catecholamine levels and intraoperative peak plasma lactate levels in patients who underwent adrenalectomy for pheochromocytoma. Retrospective observational study. Operating room in one university hospital. The records of 27 ASA physical status 1 and 2 patients who underwent adrenalectomy for pheochromocytoma were studied. Preoperative catecholamine levels and intraoperative plasma lactate levels were recorded. Twenty cases had high lactate levels (>2 mmol/L). Preoperative urine epinephrine levels and urine metanephrine levels showed a moderate correlation with intraoperative peak plasma lactate levels (rs = 0.475 and rs = 0.499, respectively; Spearman's rank correlation test). Receiver operating characteristic (ROC) curve analysis for preoperative urine epinephrine levels showed good performance for prediction of high lactate levels [>2 mmol/L, area under the curve (AUC) =0.800], whereas ROC for preoperative urine norepinephrine levels showed no predictive performance for high lactate levels.
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Are flow-dependent changes in Doppler-derived aortic valve effective orifice area real and not due to artifact?
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We sought to determine whether the flow-dependent changes in Doppler-derived valve effective orifice area (EOA) are real or due to artifact. It has frequently been reported that the EOA may vary with transvalvular flow in patients with aortic stenosis. However, the explanation of the flow dependence of EOA remains controversial and some studies have suggested that the EOA estimated by Doppler-echocardiography (EOA(Dop)) may underestimate the actual EOA at low flow rates. One bioprosthetic valve and three rigid orifices were tested in a mock flow circulation model over a wide range of flow rates. The EOA(Dop) was compared with reference values obtained using particle image velocimetry (EOA(PIV)). There was excellent agreement between EOA(Dop) and EOA(PIV) (r2 = 0.94). For rigid orifices of 0.5 and 1.0 cm2, no significant change in the EOA was observed with increasing flow rate. However, substantial increases of both EOA(Dop) and EOA(PIV) were observed when stroke volume increased from 20 to 70 ml both in the 1.5 cm2 rigid orifice (+52% for EOA(Dop) and +54% for EOA(PIV)) and the bioprosthetic valve (+62% for EOA(Dop) and +63% for EOA(PIV)); such changes are explained either by the presence of unsteady effects at low flow rates and/or by an increase in valve leaflet opening.
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This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines-interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)-were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy.
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Does protein phosphatase 2A regulate central sensitization in the spinal cord of rats following intradermal injection of capsaicin?
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Intradermal injection of capsaicin into the hind paw of rats induces spinal cord central sensititzation, a process in which the responsiveness of central nociceptive neurons is amplified. In central sensitization, many signal transduction pathways composed of several cascades of intracellular enzymes are involved. As the phosphorylation state of neuronal proteins is strictly controlled and balanced by the opposing activities of protein kinases and phosphatases, the involvement of phosphatases in these events needs to be investigated. This study is designed to determine the influence of serine/threonine protein phosphatase type 2A (PP2A) on the central nociceptive amplification process, which is induced by intradermal injection of capsaicin in rats. In experiment 1, the expression of PP2A protein in rat spinal cord at different time points following capsaicin or vehicle injection was examined using the Western blot method. In experiment 2, an inhibitor of PP2A (okadaic acid, 20 nM or fostriecin, 30 nM) was injected into the subarachnoid space of the spinal cord, and the spontaneous exploratory activity of the rats before and after capsaicin injection was recorded with an automated photobeam activity system. The results showed that PP2A protein expression in the spinal cord was significantly upregulated following intradermal injection of capsaicin in rats. Capsaicin injection caused a significant decrease in exploratory activity of the rats. Thirty minutes after the injection, this decrease in activity had partly recovered. Infusion of a phosphatase inhibitor into the spinal cord intrathecal space enhanced the central sensitization induced by capsaicin by making the decrease in movement last longer.
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Preclinical studies generated the hypothesis that older stored red blood cells (RBCs) can increase transfusion risks. To examine the most updated and complete clinical evidence and compare results between two trial designs, we assessed both observational studies and randomized controlled trials (RCTs) studying the effect of RBC storage age on mortality. Five databases were searched through December 2014 for studies comparing mortality using transfused RBCs having longer and shorter storage times. Analysis of six RCTs found no significant differences in survival comparing current practice (average storage age of 2 to 3 weeks) to transfusion of 1- to 10-day-old RBCs (OR 0·91, 95% CI 0·77-1·07). RBC storage age was lower in RCTs vs. observational studies (P = 0·01). The 31 observational studies found an increased risk of death (OR 1·13, 95% CI 1·03-1·24) (P = 0·01) with increasing age of RBCs, a different mortality effect than RCTs (P = 0·02).
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Does oral ingestion of streptococcus thermophilus diminish severity of small intestinal mucositis in methotrexate treated rats?
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Currently, there are no available effective preventative or adjunctive agents to alleviate symptoms of chemotherapy-induced mucositis. This is compounded by the absence of a recognized and validated noninvasive biomarker to assess gut function. This study investigated the effects of orally ingested Streptococcus thermophilus (TH-4) on chemotherapy-induced small intestinal damage in rats using the noninvasive (13)C-sucrose breath test (SBT). Gastrointestinal damage was induced in 27 female dark agouti rats (148 +/- 1g) with MTX (1.5 mg/kg; i.m.). Rats received MTX or saline at 0 h; with daily treatment of: TH-4 at doses of 10(9) (high), 10(8) (low) cfu/mL, or skim milk (vehicle), 48 h pre and 96 h post-MTX. The noninvasive (13)C-sucrose breath test (SBT) was conducted at -24, 24 and 96 h post-MTX to monitor gut function. At sacrifice, small intestinal tissues were collected for determinations of sucrase activity, myeloperoxidase (MPO) activity and histological assessment. MTX + vehicle and MTX + low TH-4-treated rats produced significantly lower SBT and sucrase activity results compared to saline controls (p < 0.001). In contrast, MTX + high TH-4 treatment showed no significant differences in the SBT compared to saline controls, and the SBT results were significantly higher compared to MTX + vehicle and MTX + low TH-4 (p < 0.05). MPO levels were significantly elevated (p < 0.05) in MTX + vehicle and MTX + low TH-4, but not following MTX + high TH-4 treatment, compared to saline controls. This was further confirmed by histological analyses.
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To investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, cyclin-dependent kinase inhibitor 2B (CDKN2B) gene, and methylthioadenosine phosphorylase (MTAP) gene and myocardial infarction (MI) in Chinese Hans. A total of 432 patients with MI and 430 controls were included in the study. Nine polymorphisms in the MTAP gene, two polymorphisms in the CDKN2A gene, and two polymorphisms in the CDKN2B gene were selected using a tagging single nucleotide polymorphism (tSNP) strategy. We observed that rs7027989 in the MTAP gene, and rs3217992 and rs1063192 in the CDKN2B gene were significantly associated with MI in male subjects. For rs7027989 and rs3217992, male subjects with the AA or AG genotypes had 1.26-fold and 1.24-fold increased risk of MI, respectively, compared with those with the GG genotype. For rs1063192, the G allele was associated with a reduced risk of MI with a per-allele OR of 0.71 in male subjects. The risk of rs7027989 and rs1063192 remained significant after adjusting for covariates.
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Is body mass index associated with higher Gleason score and biochemical recurrence risk following radical prostatectomy in Chinese men : a retrospective cohort study and meta-analysis?
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The aim of the study is to investigate whether body mass index (BMI) affected pathological characteristics and biochemical recurrence (BCR) of prostate cancer after radical prostatectomy in Chinese men. Medical records of 211 Chinese patients who underwent radical prostatectomy between 2006 and 2014 were retrospectively reviewed, with follow-up time of 24.5 ± 27.0 months. Multivariate logistic and Cox regression analyses were applied to address the impact of BMI on adverse pathological outcomes and BCR following prostatectomy. A meta-analysis of published studies from MEDLINE or EMBASE was conducted to determine the relationship between BMI and BCR following prostatectomy among Asian populations. Higher BMI was positively correlated with higher biopsy Gleason score (odds ratios (OR) 1.163, 95 % confidence interval (CI) 1.023-1.322, P = 0.021) and pathological Gleason score (OR 1.220, 95 % CI 1.056-1.410, P = 0.007) in multivariate analysis. BCR was detected in 48 patients (22.7 %). Multivariate Cox proportional hazards analysis revealed that higher BMI (hazard ratio (HR) 1.145, 95 % CI 1.029-1.273, P = 0.013) and prostate-specific antigen (HR 1.659, 95 % CI 1.102-2.497, P = 0.015) levels were independent predictors of BCR. The meta-analysis enrolled eight Asian studies of 4145 patients treated by radical prostatectomy. Based on random-effects approach, a 5 kg/m(2) increase in BMI was correlated with 28 % higher risk of BCR (HR 1.22, 95 % CI 0.86-1.72) without statistical significance.
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One of the most important tools against foot-and-mouth disease, a highly contagious and variable viral disease of cloven-hoofed animals, is vaccination. However, the effectiveness of foot-and-mouth disease vaccines on slowing the spread of the disease is questionable. In contrast, high potency vaccines providing early protection may solve issues with the spread of the disease, escaping mutants, and persistency. To increase the potency of the vaccine, additives such as saponin and aluminium hydroxide are used. However, the use of saponin with an oil adjuvant is not common and is sometimes linked to toxicity. QS-21, which is less toxic than Quil A, has been presented as an alternative for use with saponin. In this study, the addition of QS-21 to a commercially available foot-and-mouth disease water-in-oil-in-water emulsion vaccine was evaluated in cattle. After vaccination, serum samples were collected periodically over 3 months. Sera of the QS-21 and normal oil vaccine groups were compared via serum virus neutralization antibody titre and liquid phase blocking enzyme-linked immunosorbent assay antibody titre. The results showed that there was a significant early antibody increase in the QS-21 group.
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Does community-Based Multidisciplinary Computed Tomography Screening Program improve Lung Cancer Survival?
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Lung cancer is the most common cause of cancer deaths in the United States. Overall survival is less than 20%, with the majority of patients presenting with advanced disease. The National Lung Screening Trial, performed mainly in academic medical centers, showed that cancer mortality can be reduced with computed tomography (CT) screening compared with chest radiography in high-risk patients. To determine whether this survival advantage can be duplicated in a community-based multidisciplinary thoracic oncology program, we initiated a CT scan screening program for lung cancer within an established health care system. In 2008, we launched a lung cancer CT screening program within the WellStar Health System (WHS) consisting of five hospitals, three health parks, 140 outpatient medical offices, and 12 imaging centers that provide care in a five-county area of approximately 1.4 million people in Metro-Atlanta. Screening criteria incorporated were the International Early Lung Cancer Action Program (2008 to 2010) and National Comprehensive Cancer Network guidelines (2011 to 2013) for moderate- and high-risk patients. A total of 1,267 persons underwent CT lung cancer screening in WHS from 2008 through 2013; 53% were men, 87% were 50 years of age or older, and 83% were current or former smokers. Noncalcified indeterminate pulmonary nodules were found in 518 patients (41%). Thirty-six patients (2.8%) underwent a diagnostic procedure for positive findings on their CT scan; 30 proved to have cancer, 28 (2.2%) primary lung cancer and 2 metastatic cancer, and 6 had benign disease. Fourteen patients (50%) had their lung cancer discovered on their initial CT scan, 11 on subsequent scans associated with indeterminate pulmonary nodules growth and 3 patients who had a new indeterminate pulmonary nodules. Only 15 (54%) of these 28 patients would have qualified as a National Lung Screening Trial high-risk patient; 75% had stage I or II disease. Overall 5-year survival was 64% and 5-year cancer specific survival was 71% in the screened patients, whereas nonscreened lung cancer patients during that time in WHS had an overall survival of only 19% (p < 0.001).
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Glucagon-like peptide-2 (GLP-2) enhances intestinal absorption in adult animals. Glucocorticosteroids accelerate the ontogeny of the intestine and increase sugar uptake in adult animals. Modifying the maternal diet during lactation alters nutrient uptake in the offspring. The authors hypothesized that GLP-2 and dexamethasone, when administrated to lactating rat dams, enhance sugar uptake in the suckling and postweanling offspring. Rat dams were treated during lactation with GLP-2 (0.1 microg/g/day subcutaneously [SC], twice daily), dexamethasone (0.128 microg/g/day SC, once daily), GLP-2 + dexamethasone (same doses), or placebo. The suckling offspring were sacrificed at 19-21 days of age, and the postweanlings were sacrificed 4 weeks later. Intestinal glucose and fructose uptake was assessed using an in vitro ring technique. GLP-2 and dexamethasone resulted in lower body weights, and dexamethasone caused intestinal atrophy in sucklings. The jejunal atrophy in sucklings given dexamethasone was prevented by GLP-2 + dexamethasone. In sucklings, the maximal transport rate and the Michaelis affinity constant for ileal glucose uptake were both increased by GLP-2 and GLP-2 + dexamethasone. In contrast, in postweanlings, the maximal transport rate for jejunal glucose uptake was reduced by dexamethasone and GLP-2, as was ileal fructose uptake.
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Does removal of LDL from plasma by adsorption reduce adhesion molecules on mononuclear cells in patients with arteriosclerosis obliterans?
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There is increasing evidence that immune processes are important in the development of atherosclerosis. We investigated whether low density lipoprotein (LDL) adsorption therapy affected serum cytokine levels and the expression of adhesion molecules on peripheral blood mononuclear cells (lymphocytes and monocytes) in patients with arteriosclerotic obliterance (ASO). LDL adsorption therapy was repeated ten times over a period of three months in ten ASO patients. The total serum cholesterol and LDL cholesterol levels were significantly reduced at the end of therapy. This was associated with a significant improvement in Fontaine's classification and ankle pressure index. We also measured serum levels of inflammatory cytokines (interleukin-1 beta (IL-1 beta), IL-6 and tissue necrosis factor alpha (TNF-alpha)) and expression of adhesion molecules (lymphocyte function-associated antigen 1 alpha (LFA-1 alpha), LFA-1 beta, CD2, very late antigen (VLA)-4, VLA-5 and CD44) on mononuclear cells in the same patients and a group of healthy subjects. Serum levels of all inflammatory cytokines were markedly higher in ASO patients compared with healthy subjects, but there was no significant difference in the level before and after LDL adsorption. VLA-4 expression on CD3+ cells, but not of other adhesion molecules, was markedly higher in ASO patients compared with healthy subjects. LDL adsorption caused a significant reduction in CD2, VLA4 and VLA-5 expression on CD3+ cells. Furthermore, VLA-4 and VLA-5 expression on monocytes diminished significantly after LDL adsorption.
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In colorectal cancer, there are significant differences between synchronous and metachronous distant metastases. However in recent studies, synchronous and metachronous metastases were always lumped together, neglecting their clinical and molecular differences. The mechanism of the latency of metachronous metastases is still unclear. We conducted this study to reveal the relationship between EGFR pathways and metachronous metastases, and try to find efficient predictors. PCRs and pyrosequencing were used to detect KRAS, BRAF, PIK3CA and PTEN mutations in primary tumor tissues in a total of 281 patients from 2002 to 2008. Patients were identified into three groups: no-metastases group, synchronous-metastases group and metachronous-metastases group. Clinical and survival data were collected from a prospective database. KRAS codon 13 mutation was an independent predictor only for metachronous distant metastases (OR = 11.857, P < 0.001), but not for synchronous metastases. Male gender (OR = 2.233, P = 0.024), primary tumor located at rectum (OR = 0.404, P = 0.041), and primary pN2 stage (OR = 3.361, P = 0.01) were also independent predictors for metachronous distant metastases. Different SNPs in KRAS worked significantly different in determining synchronous or metachronous metastases. BRAF mutation (Univariate, OR = 11.5, P = 0.039) and > 200 ng/ml preoperative CEA (Univariate, OR = 41, P = 0.011) potentially predicted metastases within 6 months after primary tumor resection. After metachronous metastases, radical resection (HR = 0.280, P = 0.002) was the most important protective factor for long-term survival.
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Is serum paraoxonase-1 activity more closely related to HDL particle concentration and large HDL particles than to HDL cholesterol in Type 2 diabetic and non-diabetic subjects?
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We determined relationships of the anti-oxidative enzyme, paraoxonase-1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM). Serum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects. PON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p<0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p<0.05). PON-1 was more closely related to HDL cholesterol than to apoA-I (p=0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p<0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics.
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Substaging of T1 bladder tumors into T1a and T1b based on invasion of the tumor superficial to and beyond the muscularis mucosa has been assigned prognostic significance. We determined whether outcomes after intravesical bacillus Calmette-Guerin (BCG) differ between stage T1a and T1b subcategories. Retrospective pathological evaluation of the initial transurethral resection specimens of stage T1 bladder tumors was performed by 2 pathologists. Grade 1, 2 or 3 and stage T1a or T1b were assigned to each case. Followup was from the date of transurethral resection to date of death or the last visit. Kaplan-Meier probability and log rank test were used to evaluate recurrence and progression. Substaging was performed in 49 of the 55 patients (89%) with stage T1 disease. Disease was stage T1a in 32 (65%), stage T1b in 17 (35%), grade 3 in 45 (92%) and grade 2 in 4 (8%) cases. Maximum followup was 147 months (median 71) and 28 cases had a minimum of 5 years of followup. Recurrence was noted in 33 cases (67.3%), including 22 stage T1a (69%) and 11 stage T1b (65%), at a median followup of 11.3 and 8.6 months, respectively. Progression to a higher stage of disease was recorded in 12 cases (24.4%), including 7 (22%) stage T1a and 5 (29%) stage T1b, at a median followup of 108 and 120 months, respectively. The difference between T1a and T1b subcategories was not statistically significant in regard to recurrence-free (p = 0.7203) and progression-free (p = 0.574) outcomes.
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Is the metabolically healthy but obese phenotype associated with lower plasma levels of persistent organic pollutants as compared to the metabolically abnormal obese phenotype?
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Although obesity is strongly linked to insulin resistance and type 2 diabetes, a subset of obese individuals termed metabolically healthy but obese (MHO) appears relatively protected from the development of cardiometabolic complications. The origins of this metabolically healthy phenotype remain unclear. Recently, persistent organic pollutants (POPs) have emerged as potential endocrine disruptors. The aim of this study was to test the hypothesis that the MHO phenotype presents lower circulating levels of POPs as compared to the metabolically abnormal obese (MAO) phenotype. We conducted a cross-sectional study of 76 nondiabetic obese (body mass index ≥30 kg/m(2)) postmenopausal women. Plasma concentrations of 21 POPs as well as cardiometabolic risk factors were analyzed. For similar age, body mass index, and fat mass index, MHO women (n = 40) showed higher insulin sensitivity levels and a more favorable cardiometabolic profile than MAO women (n = 36), as evidenced by a 2-fold increase in glucose disposal rates measured by the hyperinsulinemic-euglycemic clamp (P = .001). Among 18 detectable pollutants measured, MAO women had higher plasma concentrations of 12 POPs (fold increase, 1.4-2.9; P < .001-.036). Logistic regression analyses showed that the prevalence of the MAO phenotype was significantly associated with higher levels of total dioxin- and non-dioxin-like polychlorinated biphenyls (odds ratio, 4.7; 95% confidence interval, 1.8-12.5; P = .002), as well as trans-nonachlor (odds ratio, 6.1; 95% CI, 2.2-16.4; P < .001).
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The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival. Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib. RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/-8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/-6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures.
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Do mR imaging findings of ovarian torsion correlate with pathological hemorrhagic infarction?
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The aim of this study was to clarify the magnetic resonance (MR) imaging findings, including diffusion-weighted imaging (DWI), of hemorrhagic infarction of ovarian torsion. Twelve patients presenting surgically confirmed ovarian masses with torsion were independently evaluated by two radiologists about the following MR findings: presence of ascites, uterine deviation, wall thickening on T2 weighted image (WI), recognition of twisted pedicle on T1/T2WI, and presence of wall enhancement of ovarian lesions on Gd-T1WI. The signal intensities on T1WI and DWI were compared with those of the iliopsoas muscle and the nerve root, respectively. These MR findings were statistically compared between cases of ovarian torsion with histopathologically proven hemorrhagic infarction and those without. Pathologically, hemorrhagic infarction of the wall was confirmed in six of twelve cases. Ascites, uterine deviation and twisted pedicle were detected in most cases whether with or without hemorrhagic infarction. The complete absence of wall enhancement was observed in only one case with necrosis. A higher signal intensity of the wall compared to controls was observed in 4/6 and 5/6 cases with infarction on T1WI/DWI, respectively. This was not observed in any cases without infarction. Three out of five cystic lesions with hemorrhagic infarction showed irregular wall thickening on T2WI, and no cystic lesion without hemorrhagic infarction did. Smooth wall thickening was observed in 2/6 cases without hemorrhagic infarction.
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Many trauma patients have been consuming alcohol at the time of injury. Although high concentrations of alcohol are correlated with poor outcome, few studies have examined the effects of low levels of alcohol. We examined the effects of low alcohol exposure after burn injury using a murine model. Three- and 18-month-old mice were given ethanol or saline 30 minutes before a 15% total body surface area burn injury. Twenty-four hours after injury, cellular immune responses, including delayed-type hypersensitivity response and splenocyte proliferation were examined, along with production of interferon-gamma, interleukin (IL)-2, and IL-4. Alcohol administration resulted in a significant increase in interferon-gamma in the aged, but not young, burn-injured mice. Likewise, slight increases in IL-2, IL-4, and the delayed-type hypersensitivity response were observed.
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Does dysfunction of reward processing correlate with alcohol craving in detoxified alcoholics?
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Alcohol dependence may be associated with dysfunction of mesolimbic circuitry, such that anticipation of nonalcoholic reward fails to activate the ventral striatum, while alcohol-associated cues continue to activate this region. This may lead alcoholics to crave the pharmacological effects of alcohol to a greater extent than other conventional rewards. The present study investigated neural mechanisms underlying these phenomena. 16 detoxified male alcoholics and 16 age-matched healthy volunteers participated in two fMRI paradigms. In the first paradigm, alcohol-associated and affectively neutral pictures were presented, whereas in the second paradigm, a monetary incentive delay task (MID) was performed, in which brain activation during anticipation of monetary gain and loss was examined. For both paradigms, we assessed the association of alcohol craving with neural activation to incentive cues. Detoxified alcoholics showed reduced activation of the ventral striatum during anticipation of monetary gain relative to healthy controls, despite similar performance. However, alcoholics showed increased ventral striatal activation in response to alcohol-associated cues. Reduced activation in the ventral striatum during expectation of monetary reward, and increased activation during presentation of alcohol cues were correlated with alcohol craving in alcoholics, but not healthy controls.
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The purpose of this study was to compare the smooth muscle content and apoptosis of the uterosacral ligament in women with and without uterine prolapse. Uterosacral ligaments were sampled in women with (n = 9) or without (n = 9) uterine prolapse undergoing hysterectomy. Smooth muscle of the uterosacral ligament was identified by immunohistochemistry. Digital image analysis was used to determine the fractional area of smooth muscle in the histologic cross sections. Apoptosis was assessed by terminal deoxynucelotidyl-transferase-mediated dUTP nick-end-labeling method. The fractional area of nonvascular smooth muscle in the uterosacral ligament of women with uterine prolapse was significantly decreased compared to women without prolapse (0.32 +/- 0.12 vs. 0.42 +/- 0.03, P = .02) and the apoptotic index was significantly higher compared to women without prolapse (0.20 +/- 0.06 vs. 0.08 +/- 0.04, P < .01).
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Are fascial closure after open abdomen : initial indication and early revisions decisive factors -- a retrospective cohort study?
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The surgical treatment method in which the peritoneal cavity is opened anteriorly and deliberately left open, hence often called "open abdomen" has become the standard of care in damage-control procedures as well as in the management of intra-abdominal hypertension and in severe intra-abdominal sepsis. Whereas open abdomen has been closed in two stages traditionally, a modern trend is to close the fascial layers within the initial hospitalization to avoid complications like enterocutaneous fistula and hernia formation. The aim of this study was to determine crucial factors influencing the possibility of fascial closure after open abdomen. Between 2003 and 2013, 355 adult patients were treated with open abdomen in our institution. Their data were collected and retrospectively analyzed. They were divided into two groups depending on fascial closure or not (fascial closure, n = 137 (39%) vs. non-fascial closure, n = 218 (61%)). The patients who reached fascial closure had a significantly higher rate of initially performed open abdomen (97 patients (71%) vs. 118 (54%), p = 0.002) and the periods of time until a second and a third look operation were significantly shorter (2.7 ± 2.5 vs. 4.2 ± 6.6 days, p = 0.021 and 5.6 ± 3.7 vs. 8.5 ± 8.6 days, p = 0.006). Furthermore, the presence of peritonitis (64 patients (47%) vs. 83 patients (38%), p = 0.023) and large bowel resection (74 patients (54%) vs. 90 patients (41%), p = 0.022) were significantly higher in this group. Rates of in-hospital mortality (97 patients (44%) vs. 38 patients (28%), p = 0.002) and the presence of pancreatitis (19 patients (9%) vs. 3 patients (2%), p = 0.013) were significantly higher in the non-fascial closure group.
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To better understand B-cell activation in MS by analyzing the immunoglobulin (Ig)G heavy chain variable region (VH) repertoire found in MS brains and comparing it with brain VH sequences in individuals with subacute sclerosing panencephalitis (SSPE)--a chronic encephalitis produced by measles virus (MV)-and characterized by an antigen-driven oligoclonal IgG response to MV antigens. The specificity of oligoclonal IgG in MS CSF and plaques, and their relevance to the pathogenesis of MS is unknown. Nested PCR was used to amplify and sequence the rearranged IgG heavy-chain VH repertoire in plaques of three acute MS brains and in three SSPE brains. A representative population of VH sequences from each tissue was aligned to the known 51 functional VH germline segments. From this the authors determined the closest VH family germline segment, and the degree and location of somatic mutations for each unique IgG. As expected for an antigen-driven response against MV antigens, most VH sequences from the SSPE brains were mutated extensively compared with their closest germline segments. Furthermore, SSPE VH sequences accumulated replacement mutations preferentially in the complementary-determining regions (CDRs) relative to framework regions-features normally observed during antigen-driven selection. A comparison of VH family and germline usage also demonstrated that each SSPE brain had its own unique IgG response. When the authors compared the VH response in MS plaques with SSPE, MS VH sequences were also mutated extensively, displayed a preferential accumulation of replacement mutations in CDRs, and were unique in each MS brain.
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Do specific oral medications decrease the need for surgery in adhesive partial small-bowel obstruction?
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Nothing by mouth (NPO) is the standard treatment for small-bowel obstruction. Whether oral medications should be prohibited during treatment of adhesive, partial small-bowel obstruction is unclear. The goal of this study was to determine whether a combination of specific oral medications in adhesive, partial small-bowel obstruction will decrease the need for operative intervention. Of 266 consecutive adult patients with partial small-bowel obstruction admitted at a tertiary medical center, 236 were randomized into 2 groups. Group I patients were treated with intravenous hydration, nasogastric tube decompression, and NPO. Group II patients were placed on intravenous hydration, nasogastric tube decompression, and oral fluids incorporating an oral laxative, a digestant, and a defoaming agent. We compared differences between the groups in (1) the number of patients having a successful nonoperative treatment, (2) complications, and (3) recurrence of symptoms. A total of 116 and 120 patients comprised groups I and II, respectively. The number of patients treated successfully by a nonoperative approach was less in group I than in group II (77% vs 90%, P < .01). The complications and recurrence rate for groups I and II did not differ (4% vs 5% and 5% vs 4%, respectively).
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Aging of the skin is affected by intrinsic and extrinsic factors. Especially important extrinsic factor is ultraviolet radiation, which causes premature aging of the skin. Intrinsic aging is influenced by genetic factors, and changes in hormones. In menopause, changes in hormonal balance have been suggested to enhance aging of the skin.
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Does inhibition of epidermal growth factor receptor signaling decrease p63 expression in head and neck squamous carcinoma cells?
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Both the epidermal growth factor receptor (EGFR) and the p53 homologue p63 are overexpressed in a significant number of cases of head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor and p63 both possess oncogenic properties, including the potential to increase cell proliferation and antagonize apoptosis. ZD1839 ("Iressa") is an adenosine triphosphate-competitive inhibitor specific to the EGFR tyrosine kinase currently under evaluation as a chemotherapeutic agent in HNSCC. The objective was to investigate whether p63 expression is decreased after treatment of HNSCC cells with ZD1839. Downregulation of p63 by ZD1839 would identify a potential molecular relationship between EGFR signaling and p63 and could provide insight into the mechanism of action of ZD1839. In vitro examination of p63 expression after ZD1839 treatment. A human HNSCC cell line, SCC-012, was treated with varying doses of ZD1839. p63 protein and messenger RNA levels were analyzed by Western and Northern blot analyses. The effect of ZD1839 on SCC-012 cell cycle was analyzed by flow cytometric analysis. In SCC-012 cells there was a dose-dependent decrease in p63 protein and messenger RNA levels over the course of ZD1839 treatment. Levels of phosphorylated MAPK decreased and p27KIP-1 levels increased after ZD1839 treatment. ZD1839 treatment induced a twofold increase in G1-phase cells and a 3.5-fold decrease in S-phase cells consistent with growth arrest.
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An increased risk of cerebral palsy in multiples has been reported. To determine the risk for the development of periventricular leukomalacia (PVL) of twin and triplet pregnancy. Retrospective single-centre study at a tertiary care university hospital. Infants ≤ 35 weeks gestational age born between 1988 and 2008. Risk of twin and triplet compared to singleton pregnancy regarding development of PVL in one offspring. Of 6195 infants 117 singletons and 39 multiples were diagnosed as having cystic PVL. Perinatal data did not differ as did not ultrasonographic findings and neurologic outcome. The relative risk (RR) of a twin pregnancy resulting in at least one infant with PVL when born prior to 36 weeks was 2.181 (CI 95% 1.474-3.228, p < .0001), and 6.793 (CI 95% 2.470-13.108, p < .0001) of a triplet pregnancy. In-vitro fertilisation was present in 3% of affected twins compared to 100% in triplets (p < .001).
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Is dopamine Administration a Risk Factor for Delirium in Patients Undergoing Coronary Artery Bypass Surgery?
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Delirium is an important morbidity following heart surgery. We sought to determine whether dopamine infusion is associated with increased risk of delirium in patients undergoing coronary artery bypass grafting. A total of 137 patients (mean age; 61.02±7.83, 105 males) were included in the study. Patients undergoing isolated coronary artery bypass grafting were considered eligible and those with preoperative neurological deficit or significant neurocognitive disorders, dementia or psychiatric disorders were excluded. Primary outcome measure was occurrence of delirium within 72 hours after operation. The diagnosis of delirium was made using confusion assessment method for the intensive care unit questionnaire. Both administration of dopamine as a dichotomised variable and the total amount of dopamine per kg body-weight were included in two different logistic regression models. Delirium occurred in 18 (13.1%) patients. Age adjusted Mantel-Haenszel relative risk for delirium with receiving dopamine was 4.62. Relative risk was 2.37 (0.18 to 31.28, 95% CI, p=0.51) in total doses over 10mg whereas it was 3.55 (1.16 to 10.89 95% CI, p=0.02) in total doses over 30 mg per kg body-weight. Older age (p=0.03), dopamine administration (OR: 9.227 95% CI, 2.688-32.022, p<0.001) and the amount of dopamine administered (OR: 1.072, 95% CI, 1.032-1.115, p<0.001) were independent predictors for delirium 72 hours after surgery.
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Atopy and systemic onset juvenile idiopathic arthritis (SoJIA) are two potential outcomes of a dysregulated immune system. Although rare, SoJIA causes 60% of the morbidity of JIA patients which exhibit a wide heterogeneity of prognosis and treatment. Co-morbidities can complicate the responses to therapy. To study the influence of co-existing atopy on the prognosis of SoJIA. Patients diagnosed with SoJIA between Jan 2006 and Sep 2010 were screened, enrolled in this prospective cohort study, and followed for 2 years. Management of SoJIA patients was assessed by ACR Pedi30/50/70 criteria, laboratory variables, and systemic feature score. At disease onset, 61 SoJIA patients (34 male and 27 female) were enrolled and were divided into SoJIA patients with atopy (n = 27) or those without atopy (n = 34). Atopic group at disease onset had significantly higher numbers of affected joints, ferritin levels and IgE serum levels than the non-atopic group. At 3 and 6 months, fewer SoJIA patients with atopy reached the ACR Pedi50 criteria (p < 0.02). During the 2 years of follow-up time, the number of infections and the number of flares were significantly higher in the SoJIA with atopy group (p < 0.01).
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Is small Intestinal Bacterial Overgrowth Associated with Intestinal Inflammation in the Irritable Bowel Syndrome?
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Small intestinal bacterial overgrowth is encountered in bowel disorders, including irritable bowel symptoms. Low degrees of inflammation have been recently reported in the irritable bowel syndrome. We looked for the association between intestinal inflammation and small intestinal bacterial overgrowth in irritable bowel syndrome. Small intestinal bacterial overgrowth was assessed by the H2 glucose breath test in 90 consecutive patients with irritable bowel syndrome. A check-up of the oral cavity was carried out before the breath testing. Further on, the patients were classified into two groups, positive and negative, at the breath test. Then they were tested for intestinal inflammation with a fecal test for calprotectin. We used a semiquantitative test for this study. Both groups were compared for the association of intestinal inflammation with small intestinal bacterial overgrowth. A number of 24/90 (26.7%) patients with irritable bowel syndrome had small intestinal bacterial overgrowth. A positive test for intestinal inflammation was significantly more frequent in patients with irritable bowel syndrome and small intestinal bacterial overgrowth (chi(2): p<0.05).
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Time to achieve target temperature varies substantially for patients who undergo targeted temperature management (TTM) after cardiac arrest. The association between arrival at target temperature and neurologic outcome is poorly understood. We hypothesized that shorter time from initiation of cooling to target temperature ("induction") will be associated with worse neurologic outcome, reflecting more profound underlying brain injury and impaired thermoregulatory control. This was a multicenter retrospective study analyzing data from the Penn Alliance for Therapeutic Hypothermia (PATH) Registry. We examined the association between time from arrest to return of spontaneous circulation (ROSC) ("downtime"), ROSC to initiation of TTM ("pre-induction") and "induction" with cerebral performance category (CPC). A total of 321 patients were analyzed, of whom 30.8% (99/321) had a good neurologic outcome. Downtime for survivors with good outcome was 11 (IQR 6-27) min vs. 21 (IQR 10-36) min (p=0.002) for those with poor outcome. Pre-induction did not vary between good and poor outcomes (98 (IQR 36-230) min vs. 114 (IQR 34-260) (p=ns)). Induction time in the good outcome cohort was 237 (IQR 142-361) min compared to 180 (IQR 100-276) min (p=0.004). Patients were categorized by induction time (<120min, 120-300min, >300min). Using multivariable logistic regression adjusted for age, initial rhythm, and downtime, induction time >300min was associated with good neurologic outcome when compared to those with an induction time <120min.
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Is effective intra-esophageal acid control associated with improved radiofrequency ablation outcomes in Barrett 's esophagus?
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Endoscopic radiofrequency ablation (RFA) is a promising new treatment of Barrett's esophagus (BE). Adjunctive intra-esophageal pH control with proton pump inhibitors and/or anti-reflux surgery is generally recommended to optimize squamous re-epithelialization after ablation. The aims of this study were to examine the association between intra-esophageal pH control and RFA outcomes and to identify predictive factors to achieve complete elimination (CE) of BE following RFA. We retrospectively studied the outcomes of BE patients treated with RFA. Esophageal acid exposure (EAE) was assessed utilizing 24-h pH monitoring on therapy. CE was endoscopically defined as no area suspicious for residual metaplasia following RFA. Of 45 patients (33 men; mean age 61.6, mean BE length C4.1 M4.6) examined for EAE, 29 % exhibited moderate-severe EAE despite therapy. Reduction in BE surface area and CE rate were higher in the normal-mild EAE group compared with the moderate-severe EAE group (99 vs. 95 %, p = 0.02; 44 vs. 15 %, p = 0.09, respectively). Using univariate analysis, age, gender, race, aspirin/NSAIDs use, baseline worst histology, baseline BE surface area, and the number or types of RFA had no correlation with CE. By multivariate multiple logistic regression analysis, normal-mild EAE and smaller hiatal hernia were independent factors associated with CE.
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It is well documented that oxidized low-density lipoproteins (LDLs) can stimulate human vascular endothelial cells to produce monocyte chemoattractant protein-1 (MCP-1). Vitamin C is known to be an important antioxidant for vasodilatation. The purpose of this study was to determine whether pretreatment with vitamin C could protect against oxidized-LDL-induced expression of MCP-1 in cultured human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were used for desired experiments before passage 4. Lysophosphatidylcholine (lysoPC), an oxidized component of LDL, was designated as the stimulator for MCP-1 synthesis from cultured HUVECs. MCP-1 concentrations in the cultured media were determined by enzyme-linked immunosorbent assay. MCP-1 RNA was evaluated by a semi-quantitative reverse transcriptase-polymerase chain reaction. HUVECs secreted MCP-1 within 30 minutes after exposure to 50 microM lysoPC. Compared with samples treated with lysoPC alone, pretreatment with vitamin C in concentrations of 50, 100, 150, and 200 microM, reduced levels of MCP-1 in the culture medium by 44%, 51%, 60%, and 67%, respectively, while levels of MCP-1 mRNA decreased by 15%, 18%, 80%, and 82%, respectively.
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Are variants in TNFAIP3 , STAT4 , and C12orf30 loci associated with multiple autoimmune diseases also associated with juvenile idiopathic arthritis?
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Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA.
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Many patients require temporary inotropic support after cardiac surgery, and dobutamine is one of the commonly used drugs for this purpose. However, dobutamine infusion is frequently associated with unwanted sinus tachycardia. Selective sinus node electrical vagal stimulation through a discrete epicardial ganglionic plexus (fat pad) approach can achieve sinus rate slowing. Because sinus node fat pad vagal stimulation (SNFP-VS) can easily be applied during or after cardiac surgery, we hypothesized that combining selective SNFP-VS with dobutamine could produce desired hemodynamic improvement while avoiding sinus tachycardia in patients when inotropic drug support is needed. This exploratory experimental study was performed in 7 open-chest dogs. Dobutamine (2.5 to 10 microg x kg(-1) x min(-1)) was infused at a rate producing at least 30% increase in sinus rate and cardiac output. Then electrical SNFP-VS was applied in the epicardial ganglionic plexus located at the right pulmonary vein-atrial junction, to slow the sinus rate back to control level. Hemodynamic data during control, with steady-state dobutamine infusion, and with dobutamine plus SNFP-VS were collected and compared. Dobutamine significantly increased heart rate, systolic and diastolic blood pressures, peak left ventricular systolic pressure, positive and negative maximal derivatives of left ventricular pressure, and cardiac output. Combining SNFP-VS with dobutamine eliminated sinus rate increase while preserving all major hemodynamic benefits. Selective SNFP-VS itself had no direct effect on cardiac contractility during atrial pacing.
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Is small artery elasticity assessed by pulse wave analysis no measure of endothelial dysfunction?
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Determination of endothelial function has emerged as a crucial factor in the assessment of individual cardiovascular risk. Sonographic measurement of flow-mediated dilation (FMD) is the most widespread technique to assess endothelial function, but analysis is very time-consuming and requires an experienced examiner. Recently, it was speculated that a reduction of small artery compliance (C2) measured by pulse wave analysis might be an indicator of endothelial dysfunction. In the present study, we investigated the correlation of pulse wave analysis parameters and endothelial function with special regard to patients who are at increased risk for endothelial dysfunction. One hundred and thirty-six subjects (65 male, 71 female) were included in the study. One hundred and twenty-three probands were hypertensive. Endothelium-dependent vasodilation was assessed sonographically (flow-mediated dilation) using standard protocols and as a change of reflection index (deltaRI) after application of salbutamol by photoplethysmography. Small artery compliance, large artery compliance (C1), and systemic vascular resistance (SVR) were measured by computerized pulse wave analysis of the radial artery (CR-2000; Hypertension Diagnostics, Eagan, Minnesota, USA) and were tested for correlation with FMD. Mean FMD was 6.29 +/- 2.86%. Means of pulse wave analysis-derived vascular parameters were 4.91 +/- 2.86 ml/mmHg x 100 (C2), 13.35 +/- 5.41 ml/mmHg x 10 (C1) and 1611.6 +/- 348.5 dynes x s x cm(-5) (SVR). Regression analysis excluded a significant correlation between FMD, C2, C1 and SVR (r2 < 0.05 each) both in hypertensives and normotensives. There was no significant correlation between C2 and deltaRI (r2 = 0.023).
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Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and resistance to therapies. Recent studies have reported that HCC may be derived not only from adult hepatocytes and hepatoblasts but also hepatic stem/progenitors. In this context, HepaRG cells may represent a suitable cellular model to study stem/progenitor cancer cells and the retrodifferentiation of tumor-derived hepatocyte-like cells. Indeed, they differentiate into hepatocyte- and biliary-like cells. Moreover, tumor-derived HepaRG hepatocyte-like cells (HepaRG-tdHep) differentiate into both hepatocyte- and biliary-like cells through a hepatic progenitor. In this study we report the mechanisms and molecular effectors involved in the retrodifferentiation of HepaRG-tdHep into bipotent progenitors. Gene expression profiling was used to identify genomic changes during the retrodifferentiation of HepaRG-tdHep into progenitors. We demonstrated that gene expression signatures related to a poor-prognosis HCC subclass, proliferative progenitors, or embryonic stem cells were significantly enriched in HepaRG progenitors derived from HepaRG-tdHep. HepaRG-tdHep retrodifferentiation is mediated by crosstalk between transforming growth factor beta 1 (TGFβ1) and inflammatory cytokine pathways (e.g., tumor necrosis factor alpha [TNFα] and interleukin 6 [IL6]). Signatures related to TNFα, IL6, and TGFβ activation pathways are induced within the first hour of retrodifferentiation. Moreover, specific activation or inhibition of these signaling pathways allowed us to determine that TNFα and IL6 contribute to the loss of hepatic-specific marker expression and that TGFβ1 induces an epithelial-to-mesenchymal transition of HepaRG-tdHep. Interestingly, the retrodifferentiation process is blocked by the histone deacetylase inhibitor trichostatin A, opening new therapeutic opportunities.
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Are first-trimester screening markers altered in pregnancies conceived after IVF/ICSI?
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To determine the levels of first-trimester screening markers and to assess the false-positive rate for first-trimester combined screening for Down syndrome in a large national population of women pregnant after assisted reproductive technology (ART), in order to decide whether or not to correct risk calculation for mode of conception. A national prospective cohort study of 1000 pregnancies achieved after ART was compared with a control group of 2543 pregnancies conceived spontaneously. All women completed a first-trimester combined screening program. Risk calculation was performed retrospectively based on the screening parameters to avoid bias due to the use of different algorithms of risk calculation. In chromosomally normal pregnancies conceived after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), the pregnancy-associated plasma protein-A multiples of the median value was significantly decreased when compared with that of pregnancies conceived spontaneously (0.78 and 0.79 vs. 0.98), while there was no difference in the group treated by frozen embryo replacement. There was no difference in the level of free beta-human chorionic gonadotropin between groups. The median nuchal translucency thickness was smaller in the overall ART group compared with controls. The false-positive rate of first-trimester combined screening in the overall ART group, adjusted for maternal age, was significantly higher when compared with controls (9.0% vs. 6.0%).
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Gastrointestinal dysfunction is one of the major complications of diabetes. The roles of inflammation in diabetes and its associated complications are increasingly recognized. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of pro-inflammatory mediators. The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on delayed gastric emptying in diabetic rats and to elucidate its possible mechanism. SB203580 was administered in diabetic rats induced by intraperitoneal injection of streptozotocin. The gastric emptying rate of rats was measured by using phenol red solution, and blood glucose levels and body weights were observed. p38 MAPK activity and iNOS expression were assessed by Western blot analysis. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were determined by enzyme-linked immunosorbent assay. Gastric emptying was delayed significantly in diabetic rats and improved significantly with SB203580; high glucose significantly activated p38 MAPK and increased the expression of iNOS, TNF-α and IL-1β. The administration of SB203580 led to a significant decrease in the activation of p38 MAPK and the expression of iNOS, TNF-α and IL-1β.
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Does glutamine restore Tight Junction Protein Claudin-1 Expression in Colonic Mucosa of Patients With Diarrhea-Predominant Irritable Bowel Syndrome?
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Recent studies showed that patients with diarrhea-predominant irritable bowel syndrome (IBS-D) had an increased intestinal permeability as well as a decreased expression of tight junctions. Glutamine, the major substrate of rapidly dividing cells, is able to modulate intestinal permeability and tight junction expression in other diseases. We aimed to evaluate, ex vivo, glutamine effects on tight junction proteins, claudin-1 and occludin, in the colonic mucosa of patients with IBS-D. Twelve patients with IBS-D, diagnosed with the Rome III criteria, were included (8 women/4 men, aged 40.7 ± 6.9 years). Colonic biopsy specimens were collected and immediately incubated for 18 hours in culture media with increasing concentrations of glutamine from 0.6-10 mmol/L. Claudin-1 and occludin expression was then measured by immunoblot, and concentrations of cytokines were assessed by multiplex technology. Claudin-1 expression was affected by glutamine (P < .05, analysis of variance). In particularly, 10 mmol/L glutamine increased claudin-1 expression compared with 0.6 mmol/L glutamine (0.47 ± 0.04 vs 0.33 ± 0.03, P < .05). In contrast, occludin expression was not significantly modified by glutamine. Interestingly, glutamine effect was negatively correlated to claudin-1 (Pearson r = -0.83, P < .001) or occludin basal expression (Pearson r = -0.84, P < .001), suggesting that glutamine had more marked effects when tight junction protein expression was altered. Cytokine concentrations in culture media were not modified by glutamine treatment.
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Prostate cancer (PCa) is a leading cause of cancer-related death in men, which emphasizes the need for novel therapeutic approaches. Targeting microRNA (miRNA) has been considered as a therapeutic strategy against cancers. Human miR-204-5p potentially targeting BCL2 has been reported to be downregulated in various cancers. We hypothesized that miR-204-5p overexpression induces cancer cell apoptosis by repressing BCL2 expression. A vector harboring mature miR-204-5p was constructed and delivered into human PCa cells. The expression level of miR-204-5p was determined by miRNA quantitative polymerase chain reaction (QPCR). Luciferase reporter assays were performed to verify the function of mature miR-204-5p and its direct binding to BCL2 transcripts. The expression levels of BCL-2 messenger RNA (mRNA) and protein samples were measured by QPCR and Western blot, respectively. Cell viability was detected by WST-1 assays. Induction of apoptosis was determined by increased levels of cleavage caspase 3 and caspase 3/7 activity. The expression levels of miR-204-5p were downregulated in PCa cells compared with normal prostate epithelial cells. Transfection of pSM-204 resulted in up to 6.2-fold higher expression of miR-204-5p when compared with pSM control. The mRNA levels of several potential target genes of miR-204-5p were decreased in pSM-204-transfected PC3 and Rv1 cells. BCL2 mRNA and protein expression decreased in miR-204-5p-transfected cells, which led to cytochrome C release from mitochondria. It subsequently increased cleaved caspase 3 and caspase 3/7 activities and reduced cell viability. Cotransfection of a reporter vector harboring the BCL2 3'-untranslated region to compete with endogenous transcripts partially rescued miR-204-5p-induced apoptosis.
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Is magnetic resonance imaging superior to cardiac scintigraphy to identify nonresponders to cardiac resynchronization therapy?
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Left ventricular (LV) postero-lateral scar and total scar burden are factors responsible for a poor response to cardiac resynchronization therapy (CRT). Contrast-enhanced magnetic resonance imaging (CMR) and (99m)Tc-2-methoxy isobutyl isonitrile single photon emission computed tomography (SPECT) perfusion imaging are widely used to detect myocardial scar tissue; however, their ability to detect regional scars and predict a positive response to CRT has not been fully evaluated. CMR and SPECT were performed in 17 patients with dilated cardiomyopathy (DCM) and seven patients with ischemic cardiomyopathy (ICM) before CRT. All images were scored, using a 17-segment model. To analyze the LV scar regions by CMR, we assessed the transmural delayed enhancement extent as the transmural score in each segment (0 = no scar, 4 = transmural scar). Similarly, a perfusion defect score was assigned to each segment by SPECT (0 = normal uptake, 4 = defect). By both SPECT and CMR imaging, the total scar score was significantly higher in the ICM than in the DCM group. An LV postero-lateral wall scar region was detected using both imaging modes. By SPECT imaging, the percentage of regional scar score in the LV inferior wall was significantly higher in the DCM than in the ICM group.
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It is well known that cyclooxygenase-2 (COX-2) and its major derivative product prostaglandin E2 (PGE2) play key regulatory roles in the ovulation process. Animal studies have demonstrated that the inhibition of nitric oxide (NO) suppresses ovarian PGE2 production and ovulation. Although the expression of NO synthases has been detected in human granulosa cells, the effect of NO on COX-2 expression and PGE2 production in these cells remains unknown. The purpose of this article was to investigate the effects of NO on COX-2 expression and PGE2 production in human granulosa cells. SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with simian virus 40 large T antigen. SVOG cells were used to investigate the effects of NO on COX-2 expression and PGE2 production. The study was conducted in an academic research center. The levels of mRNA and protein were examined by RT-quantitative real-time PCR and Western blotting, respectively. The accumulation levels of PGE2 were measured by ELISA. Treatment with the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced COX-2 expression and PGE2 production. In addition, the stimulatory effect of SNAP on COX-2 and PGE2 was mimicked by treatment with the cGMP analog 8-bromo-cGMP (8-Br-cGMP). Interestingly, neither SNAP nor 8-Br-cGMP affected the expression of COX-1. Moreover, our results showed that either SNAP or 8-Br-cGMP activated cAMP response element-binding protein (CREB) signaling and that the knockdown of CREB attenuated SNAP- and 8-Br-cGMP-induced COX-2 expression and PGE2 production.
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Do cochlear implant surgery at 12 months of age or younger?
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Early presentation of congenitally deaf children for cochlear implantation is leading to surgery in younger candidates. The safety of cochlear implantation in children aged 12 months and younger is reviewed with radiologic assessment of mastoid bone anatomy and surgical outcome data. Analysis of case records and temporal bone computed tomography (CT) scans with description of surgical technique in infants. Chart analysis of children aged 12 months or younger at cochlear implantation. Mastoid bone anatomy was compared with older children (mean age 2 years) using CT scans. Twenty-five infants received implants at 7 to 12 months of age because of meningitis (n = 4) or early detection of deafness (n = 21). Mastoid marrow content on CT scan was significantly greater in this age group (P < .001 Mann-Whitney rank sum test), but pneumatization was always adequate for safe identification of surgical landmarks. The smaller size of the mastoid bone was not restrictive. An extended postauricular approach was used in the first 11 cases and a 2.5 cm hair-line incision in the remainder. Ligature tie-down of the device was completed in all cases. No complications occurred. All are full-time implant users, except one with other neurologic sequelae of preoperative meningitis.
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The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV.
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Is male breast cancer : the scenario changing?
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The overall incidence of male breast cancer is around 1% of all breast cancers and is on the rise. In this review we aim to present various aspects of male breast cancer with particular emphasis on incidence, risk factors, patho-physiology, treatment, prognostic factors, and outcome. Information on all aspects of male breast cancer was gathered from available relevant literature on male breast cancer from the MEDLINE database over the past 32 years from 1975 to 2007. Various reported studies were scrutinized for emerging evidence. Incidence data were also obtained from the IARC, Cancer Mondial database.
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Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001).
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Is elevated serum periostin associated with liver stiffness and clinical outcome in biliary atresia?
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To analyze serum periostin and liver stiffness in postoperative biliary atresia (BA). A total of 60 BA patients and 14 controls were enrolled. Serum periostin levels were analyzed by ELISA. Liver stiffness measurement was determined by transient elastography. Biliary atresia patients had significantly higher periostin and liver stiffness values than controls. Serum periostin levels were remarkably increased in BA patients with jaundice compared to those without jaundice. Moreover, serum periostin was correlated with liver stiffness.
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Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients. Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay. We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies.
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Are high levels of cathepsin D and cystatin B associated with increased risk of coronary events?
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The majority of acute coronary syndromes are caused by plaque ruptures. Proteases secreted by macrophages play an important role in plaque ruptures by degrading extracellular matrix proteins in the fibrous cap. Matrix metalloproteinases have been shown to be markers for cardiovascular disease whereas the members of the cathepsin protease family are less studied. Cathepsin D, cathepsin L and cystatin B were measured in plasma at baseline from 384 individuals who developed coronary events (CEs), and from 409 age-matched and sex-matched controls from the Malmö Diet and Cancer cardiovascular cohort. Cathepsin D (180 (142-238) vs 163 (128-210), p<0.001), cathepsin L (55 (44-73) vs 52 (43-67), p<0.05) and cystatin B levels (45 (36-57) vs 42 (33-52), p<0.001) were significantly increased in CE cases compared to controls. In addition, increased cathepsin D (220 (165-313) vs 167 (133-211), p<0.001), cathepsin L (61 (46-80) vs 53 (43-68), p<0.05) and cystatin B (46 (38-58) vs 43 (34-54), p<0.05) were associated with prevalent diabetes. Furthermore, cathepsin D and cystatin B were increased in smokers. The HRs for incident CE comparing the highest to the lowest tertile(s) of cathepsin D and cystatin B were 1.34 (95% CI 1.02 to 1.75) and 1.26 (95% CI 1.01 to 1.57), respectively, after adjusting for age, sex, low-density lipoprotein/high-density lipoprotein ratio, triglycerides, body mass index, hypertension and glucose, but these associations did not remain significant after further addition of smoking to the model. In addition, cathepsin D was increased in incident CE cases among smokers after adjusting for cardiovascular risk factors.
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To investigate the effect of recurrent laryngeal nerve (RLN) identification on the complications after total thyroidectomy and lobectomy. Total 134 consecutive patients undergoing total thyroidectomy or thyroid lobectomy from January 2003 to November 2004 were investigated retrospectively. Patients were divided into two groups: RLN identified (Group A) or not (Group B). The two groups were compared for RLN injury and hypocalcaemia. The numbers of patients and nerves at risk were 71 and 129 in Group A, and 63 and 121 in Group B, respectively. RLN injury in Group A (0) was significantly lower than that in Group B (5 [7.9%]) patients, 7 [5.8%] nerves) for the numbers of patients (P=0.016) and nerves at risk (P=0.006). Temporary hypocalcaemia was significantly higher in Group A than in Group B (14 [24.1%] vs 6 [10.3%], P=0.049). Permanent complications in Group B were significantly higher than those in Group A (13 [20.6%] vs 4 [5.6%], P=0.009).
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Are angiogenesis and dendritic cell density correlated with metachronous distant metastasis in curatively operated rectal cancer?
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Apart from surgery, treatment of rectal cancer increasingly involves the use of (neo-)adjuvant strategies. To optimize the selection process for these therapy regimens, especially in the field of cellular and molecular biology, new prognostic factors additional to the established TNM system are being investigated. Two groups of patients ( n=2x85) with rectal carcinoma curatively treated by surgery alone were studied retrospectively (median follow-up 6.1 years). To exclude the effect of the surgeon only patients free of locally recurrent disease were selected. Patient groups were matched for age, gender, UICC stage, and year of operation (1982-1991) and differed only in subsequent metachronous distant metastatic spread, i.e., the criterion to be studied. The factors investigated in uni- and multivariate analysis were angiogenesis, density of dendritic cells, grading, venous invasion, and lymphatic invasion. Grading invariably proved to be the only significant prognostic factor. In univariate analysis the absence of venous invasion was also correlated significantly with increased disease-free survival.
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We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy. Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking. The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness. The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 +/- 0.43 vs. 2.44 +/- 0.30; p < 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n = 24) and without (n = 7) LV hypertrophy.
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Is coexpression of IQ-domain GTPase-activating protein 1 ( IQGAP1 ) and Dishevelled ( Dvl ) correlated with poor prognosis in non-small cell lung cancer?
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IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear. We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed. The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five-year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705±3.355 vs 58.403±2.543 months, p<0.05).
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Pay-for-performance for patients is a cost-effective means of improving health behaviours. This study examined the association between the pay time for performance for patients and CHS use by chronic patients. A cross-sectional study was undertaken to estimate distribution characteristics of CHS use in 2011 and collect data of socio-demographic characteristics (sex, age, education level, occupation, disposable personal income in 2011, distance between home and community health agency), chronic disease number, and time of pay-for-performance for patients. Participants were 889 rural adults with hypertension or type II diabetes aged 35 and above. Standardized CHS use means chronic patients use CHS at least once per quarter. Patients who received incentives prior to services had 2.724 times greater odds of using standardized CHS than those who received incentives after services (95%CI, 1.986-3.736, P<0.001). For all subgroups (socio-demographic characteristics and chronic disease number), patients who received incentives prior to services were more likely to use standardized CHS than those receiving incentives after services.
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Does neamine inhibit prostate cancer growth by suppressing angiogenin-mediated rRNA transcription?
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Angiogenin (ANG) undergoes nuclear translocation and stimulates rRNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG. The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression. Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of ANG and inhibits rRNA transcription, cell proliferation, and angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in murine prostate-restricted AKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis and an increase in prostate epithelial cell apoptosis.
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Recent studies suggest that air pollution plays a role in type 2 diabetes (T2D) incidence and mortality. The underlying physiological mechanisms have yet to be established. We hypothesized that air pollution adversely affects insulin sensitivity and secretion and serum lipid levels. Participants were selected from BetaGene (n = 1,023), a study of insulin resistance and pancreatic β-cell function in Mexican Americans. All participants underwent DXA and oral and intravenous glucose tolerance tests and completed dietary and physical activity questionnaires. Ambient air pollutant concentrations (NO2, O3, and PM2.5) for short- and long-term periods were assigned by spatial interpolation (maximum interpolation radius of 50 km) of data from air quality monitors. Traffic-related air pollution from freeways (TRAP) was estimated using the dispersion model as NOx. Variance component models were used to analyze individual and multiple air pollutant associations with metabolic traits. Short-term (up to 58 days cumulative lagged averages) exposure to PM2.5 was associated with lower insulin sensitivity and HDL-to-LDL cholesterol ratio and higher fasting glucose and insulin, HOMA-IR, total cholesterol, and LDL cholesterol (LDL-C) (all P ≤ 0.036). Annual average PM2.5 was associated with higher fasting glucose, HOMA-IR, and LDL-C (P ≤ 0.043). The effects of short-term PM2.5 exposure on insulin sensitivity were largest among obese participants. No statistically significant associations were found between TRAP and metabolic outcomes.
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Are long-term safety and efficacy observed after implantation of Zotarolimus-Eluting stent in real-world clinical practice?
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Zotarolimus-eluting stents (ZESs) have been shown to be safe and effective in randomised trials. We sought to report the clinical outcomes after implantation of ZES in real-world clinical practice. ZES have been approved for clinical use in Singapore since April 2005. Until December 31, 2007, a total of 219 patients had undergone implantation of ZES. After excluding 11 foreign patients with whom contact was lost, 208 patients (246 lesions, 305 stents) formed the study cohort. A high-proportion of diabetic patients (n=90, 43.3%) was included. Recommended dual antiplatelet therapy was at least 3 months (n=147) for patients treated before or 12 months (n=61) after January 2007. As of January 2008, the median follow-up duration was 19 months (range: 1 to 33 months). There were 10 (4.8%) deaths, including 7 (3.4%) cardiac deaths. Myocardial infarction occurred in 11 (5.3%) patients. The numbers of patients requiring target vessel revascularisation and target lesion revascularisation were 10 (4.8%) and 5 (2.4%) respectively. Using the ARC definition, there were two cases of definite stent thrombosis on days 7 and 17, and one case of probable stent thrombosis on day 15.
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Crohn's Disease (CD), a chronic Inflammatory Bowel Disease, can occur in any part of the gastrointestinal tract, but most frequently in the ileum. Visceral hypersensitivity contributes for development of chronic abdominal pain in this disease. Currently, the understanding of the mechanism underlying hypersensitivity of Crohn's ileitis has been hindered by a lack of specific animal model. The present study is undertaken to investigate the visceral hypersensitivity provoked by 2,4,6-trinitrobenzene sulfonic (TNBS)-induced ileitis rats. Male Sprague-Dawley rats were anaesthetized and laparotomized for intraileal injection of TNBS (0.6 ml, 80 mg/kg body weight in 30% ethanol, n = 48), an equal volume of 30% Ethanol (n = 24), and Saline (n = 24), respectively. Visceral hypersensitivity was assessed by visceromotor responses (VMR) to 20, 40, 60, 80, and 100 mmHg colorectal distension pressure (CRD) at day 1, 3, 7, 14, 21, and 28. Immediately after CRD test, the rats were euthanized for collecting the terminal ileal segment for histopathological examinations and ELISA of myleoperoxidase and cytokines (TNF-α, IL-1β, IL-6), and dorsal root ganglia (T11) for determination of calcitonin gene-related peptide by immunohistochemistry, respectively. Among all groups, TNBS-treatment showed transmural inflammation initially at 3 days, reached maximum at 7 days and persisted up to 21 days. The rats with ileitis exhibited (P < 0.05) VMR to CRD at day 7 to day 21. The calcitonin gene-related peptide-immunoreactive positive cells increased (P < 0.05) in dorsal root ganglia at day 7 to 21, which was persistently consistent with visceral hypersensitivity in TNBS-treated rats.
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Are hLA-DR and HLA-DQ markers for rapid disease progression in primary sclerosing cholangitis?
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The association between primary sclerosing cholangitis (PSC) and the HLA haplotype A1, B8, DR3, DQ2 is well established. During the last few years, several additional HLA associations have been suggested in PSC. Furthermore, two different HLA-DR specificities have been reported to be markers for rapid disease progression. Our aim was to critically evaluate all of the current and as yet mostly unconfirmed HLA class II issues in PSC. Seventy-five Swedish patients with PSC were HLA-DR and HLA-DQ genotyped. Of the recently described HLA associations in PSC, the association with the DRB1*1301, DQA1*0103, DQB1*0603 haplotype was decisively confirmed, whereas the DRB1*04 specificity was only slightly under-represented and the frequency of DR2 was neutral. The association with codon 38 of DRB genes was secondary to the DRB3*0101 association. HLA-DR and HLA-DQ alleles were not found to be markers of disease progression.
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Ginsenoside Rg3 is one of the active ingredients isolated from Panax ginseng C.A. Meyer. Previous studies demonstrated that Rg3 has antioxidant and neuroprotective abilities. The purpose of this study was to evaluate the protective effect of Rg3 on erectile function in streptozotocin (STZ)-induced diabetic rats. Two-month-old Sprague-Dawley male rats received a one-time intraperitoneal (IP) STZ (60 mg/kg) or vehicle injection after a 16-hour fast. Three days later, rats were randomly divided into four groups and were treated with daily gavage feedings of a mix of distilled saline water and 0.5% carboxymethylcellulose or Rg3 dissolved in the mix at doses of 10 mg/kg and 100 mg/kg for 3 months. A sham group underwent IP injection of saline followed by daily gavage of the above mix for 3 months. Erectile function was assessed by cavernosal nerve electrostimulation at 3 months. The penis was then harvested and deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed. Western blot was performed to examine cleaved caspase-3, platelet endothelial cell adhesion molecule (PECAM)-1, and smooth muscle actin (SMA). Neural regeneration was measured by nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. In the negative control group, the functional evaluation showed a lower mean intracavernosal pressure (ICP) with cavernosal nerve stimulation than in the sham group; there was a significant change in the expression of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA, as well as in the SOD and MDA production in the corpus cavernosum. Histological analysis of specimens stained for NADPH showed a significant change in the staining quality of the neurons in the dorsal nerves; TUNEL showed a greater apoptotic index in corpus cavernosum cells. With daily oral gavage with 100 mg/kg Rg3, the ICP/mean arterial pressure value was significantly higher than in the controls. The level of cleaved caspase-3, bcl-2, bcl-xl, PECAM-1, and SMA and the number of positively stained nerve fibers tended to revert to normal after Rg3 treatment. The apoptotic index in corpus cavernosum cells was lowered.
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Is chronic thromboembolic pulmonary hypertension associated with iron overload?
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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized as the incomplete resolution of emboli after pulmonary embolism (PE) and the subsequent fibrotic organization and remodeling of pulmonary vascular bed. It has been reported that abnormal fibrin probably contributes to the incomplete resolution of emboli. And there is evidence that free iron could convert fibrinogen into fibrin which is remarkably resistant to lysis. Thus, we hypothesized that persistent iron overload might participate in the development of CTEPH. A case-control study was conducted. Forty-five CTEPH patients were enrolled as cases, and 36 age and sex frequency-matched chronic PE patients without pulmonary hypertension were selected as controls. Levels of free iron, soluble transferrin receptor (sTfR), ferritin, sTfR/ferritin ratio, hepcidin-25, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and malondialdehyde (MDA) were compared between the two groups. Logistic regression analysis was carried out to estimate odds ratios. There was no difference of the levels of free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, and MDA between CTEPH patients and the controls. Levels of sTfR and ferritin in both groups were within the normal limits. Levels of IL-6 in CTEPH patients were significantly higher than that in the controls. A negative correlation was observed between hepcidin-25 and sTfR (Spearman's r=-0.438, P<.001), and a positive correlation was observed between hepcidin-25 and ferritin (Spearman's r=0.503, P<.001). In the univariate logistic regression model, there was no association observed between CTEPH and free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, IL-6, and MDA.
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Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.
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Does insulin combined with Chinese medicine improve glycemic outcome through multiple pathways in patients with type 2 diabetes mellitus?
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Insufficient insulin secretion or inefficient insulin response are responsible for the clinical outcome of type 2 diabetes mellitus. Administration of insulin alone is prone to cause secondary effects, resulting in an unsatisfactory outcome. Shen-Qi-Formula (SQF), a well-known Chinese medicinal formula, has been used for diabetic treatment for a long time. The present study was designed to investigate whether SQF in combination with insulin improved the clinical outcome of type 2 diabetes mellitus, and what mechanisms were possibly involved in the treatment. A total of 219 patients were included in the study. Of these, 110 patients were treated with insulin monotherapy, and 109 with the combination therapy of SQF and insulin. Before and after 12-week treatment, the fasting blood glucose, postprandial blood glucose, β-cell function, insulin resistance and blood lipids were measured. The 12 weeks of SQF treatment in combination with insulin significantly decreased the fasting and postprandial blood glucose levels. Insulin secretion was not increased after the treatment, but β-cell function and insulin resistance were obviously improved. Furthermore, 12 weeks of treatment with SQF and insulin improved the levels of glucagon-like peptide-1, oxidative stress, blood lipids, coagulation function and bodyweight.
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To characterize the integron-harbouring Gram-negative bacteria in recreational lakes, with focus on the genetic content of integrons, antimicrobial resistance profiles and virulence-associated genes. The presence and structure of integrons in coliform bacteria isolated from the water of four recreational lakes located in Poznań, Poland, was determined by PCR method. Antimicrobial resistance testing was done by disc diffusion method. Virulence-associated genes in integron-bearing Escherichia coli isolates were detected by PCR. A total of 155 integron-bearing strains of coliform bacteria were cultured. Sequence analysis showed the presence of dfrA7, aadA1, dfrA1-aadA1, dfrA17-aadA5 and dfrA12-orfF-aadA2 gene cassette arrays in class 1 integrons and dfrA1-sat2-aadA1 in class 2 integrons. Higher frequency of integron-positive bacteria and higher antimicrobial resistance ranges were noted in colder months (January and November) compared with spring and summer months. The integron-harbouring E. coli carried up to nine virulence-associated genes, with the highest frequency of kpsMT (84.6%) and traT (783%), coding for group 2 capsule and determining human serum resistance respectively.
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