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Does [ Vitamin C reverse benzo ( a ) pyrene-induced cell cycle changes by E2F pathway ]? | To study the role of E2F1/4 pathway in vitamin C reversing benzo (a) pyrene [B (a) P]-induced changes of cell cycle in human embryo lung fibroblasts (HELF) and the relationship between E2F1 and cyclin D1/CDK4. The stable transfectants, HELF transfected with antisense cyclin D1 and antisense CDK4, were established to detect the relationship of signaling pathway. Cells were cultured and pretreated with vitamin C before stimulation with B (a) P for 24 hours. The expression levels of cyclin D1, CDK4, E2F1 and E2F4 were determined by Western blot and the band intensity was analysed as the relative value to control by using the Gel-Pro 3.0 software. Flow Cytometric Analysis was employed to detect the distributions of cell cycle. B (a) P significantly elevated the expression levels of cyclin D1, CDK4, E2F1 and E2F4 in HELF cells. Vitamin C decreased the expression levels of above proteins in B (a) P-stimulated HELF cells. The expression levels of these proteins in B (a) P-treated above transfectants were lower than those in B (a) P-treated HELF cells. The expression levels of above proteins with vitamin C combined with antisense cyclin D1 were decreased as compared to those with antisense cyclin D1 alone. B (a) P increased the percentage of S phase as compared to the controls [(41.1 +/- 0.2)% vs (33.5 +/- 3.2)%, P < 0.05]. Both vitamin C [(33.2 +/- 0.6)% vs (41.1 +/- 0.2)%, P < 0.05] and antisense cyclin D1 [(31.2 +/- 1.3)% vs (41.1 +/- 0.2)%, P < 0.05] suppressed the changes of cell cycle induced by B (a) P. Vitamin C combined with antisense CDK4 markedly suppressed B (a) P-induced changes of cell cycle as compared to those with antisense CDK4 alone. | Peripheral arterial disease (PAD) is associated with poor prognosis in terms of cardiovascular (CV) morbidity and mortality. Matrix metalloproteinases (MMPs) contribute to vascular remodeling by degrading extracellular matrix components and play a role in atherosclerosis as demonstrated for MMP-10 (stromelysin-2). This study analyzed MMP-10 levels in PAD patients according to disease severity and CV risk factors and evaluated the prognostic value of MMP-10 for CV events and mortality in lower limb arterial disease after a follow-up period of 2 years. MMP-10 was measured by enzyme-linked immunosorbent assay in 187 PAD patients and 200 sex-matched controls. PAD patients presented with increased levels of MMP-10 (702 ± 326 pg/mL control vs 946 ± 473 pg/mL PAD; P < .001) and decreased levels of tissue inhibitor of matrix metalloproteinase 1 (312 ± 117 ng/mL control vs 235 ± 110 ng/mL PAD; P < .001) compared with controls. Among PAD patients, those with critical limb ischemia (n = 88) showed higher levels of MMP-10 (1086 ± 478 pg/mL vs 822 ± 436 pg/mL; P < .001) compared with those with intermittent claudication (n = 99), whereas the MMP-10/tissue inhibitor of matrix metalloproteinase 1 ratio remained similar. The univariate analysis showed an association between MMP-10, age (P = .015), hypertension (P = .021), and ankle-brachial index (P = .006) in PAD patients that remained significantly associated with PAD severity after adjustment for other CV risk factors. Patients with the highest MMP-10 tertile had an increased incidence of all-cause mortality and CV mortality (P < .03). |
Are genetic polymorphisms of the serotonin transporter , but not the 2a receptor or nitric oxide synthetase , associated with pulmonary hypertension in chronic obstructive pulmonary disease? | Pulmonary hypertension (PH) is prognosti- cally important in chronic obstructive pulmonary disease (COPD). Since PH only weakly correlates with hypoxemia, other factors must play a role. To investigate whether polymorphisms of the serotonin transporter (5HTT), serotonin-2a receptor (5HTR2a) and endothelial nitric oxide synthetase (eNOS) are related to PH in COPD. In 59 COPD patients who underwent right heart catheterization, 6-min walking distance, NYHA functional class, pulmonary function tests, blood gases and 5HTT, 5HTR2a and eNOS (4ab and T298C) polymorphisms were determined. Forty-nine COPD patients in NYHA functional class III-IV were included. Ten were excluded due to comorbid causes of PH (mainly chronic thromboembolic). PH (mPAP > or =25 mm Hg) was present in 55% and usually mild, but out of proportion (mPAP > or =40 mm Hg) in 12%. Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%), and LL homozygote patients had more severe PH. In patients with out-of-proportion PH, the L-allelic frequency was even 75%. We found no association of 5HTR2a and eNOS polymorphism with PH in COPD. | Skin grafting is needed for traditional auricular reconstruction. As the skin grafts contract, the postoperative framework is distorted. This leads to a decrease in the auriculocephalic angle. The objective of this study was to test a new method to cover the reconstructive framework by using three skin flaps and a larger tissue expander than that normally used. This may reduce the distortion of the reconstructed ear and create a well-shaped auriculocephalic angle. A large expander was inserted in the postauricular mastoid area. Three expanded flaps were then created to cover the anterior and posterior frameworks, with separate mastoid coverage. By measuring the height and angle at three different points on the reconstructed ear and comparing them with the contralateral normal ear, a system for measuring the auriculocephalic angle was established. The surface of the framework and the mastoid area were covered by three flaps developed from one large tissue expander. The appearance of the reconstructed ears was similar to that of the normal side by the patient's 6- to 12-month follow-up. The difference in the distance at the three points between the reconstructed and normal sides after the three-flap reconstruction was less than that following traditional reconstruction (p < 0.05). The variation in the angle measured at these three points in the three-flap group was also much smaller than that in the traditional group (p < 0.01). |
Is anxiety associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson 's disease patients? | Anxiety is a common non-motor symptom among patients with Parkinson's disease (PD). Although the etiology of anxiety in PD is likely to be multifactorial, a dysfunction in the dopaminergic system might be implicated in its pathogenesis. The aim of our study was to investigate a possible dopaminergic mechanism involved in anxiety in newly diagnosed never-medicated PD patients using SPECT and ¹²³I-FP-CIT as the dopamine transporter ligand. Thirty-four newly diagnosed, untreated PD patients with asymmetric motor symptoms were included in the study: 17 patients with right- and 17 with left-motor onset, matched for age, disease duration and motor disability constituted the group. They were all evaluated for anxiety and depression and underwent an SPECT with ¹²³I-FP-CIT. Dopamine transporter (DAT) availability values for right and left caudate and putamen were calculated and compared between patients with and without anxiety. Regression analyses were also performed in order to correlate DAT availability with the severity of the anxiety symptoms. Comparison between PD patients with and those without anxiety revealed significant differences of DAT availability in all the examined regions except the right putamen. In the group of patients considered as a whole, a significant correlation was found between increased anxiety severity and decreased DAT availability in right caudate. | The goal of this study was to investigate the expression of early growth response-1 (Egr-1), a vascular pathogenic transcription factor, and its potential relationship with tissue factor (TF), a key player during the thrombus formation in the abdominal aortic aneurysm (AAA) wall. Although intraluminal thrombus is a common finding in human AAA, the molecular mechanism of the thrombus formation has not been studied. During the elective AAA repair, specimens were taken from the thrombus-covered and thrombus-free portions of the aneurysmal wall in each of 16 patients with AAA and analyzed to assess the differential expression of Egr-1 and TF. The proinflammatory and prothrombogenic activities of Egr-1 in vasculature were evaluated in vitro and in vivo by overexpressing it using adenovirus. The expression of both Egr-1 and TF was significantly increased in the thrombus-covered wall compared with the thrombus-free wall, in which their up-regulation in the thrombus-covered wall was strongly correlated with each other (p < 0.005, r = 0.717). Adenoviral overexpression of Egr-1 in human vascular smooth muscle and endothelial cells was found to up-regulate the expression of TF and inflammation-related genes. Moreover, Egr-1 overexpression in endothelial cells increased their adhesiveness to monocytes and also substantially promoted the intravascular thrombus formation in vivo, as shown in the inferior vena cava ligation experiment of the rat. |
Does the presence of a below-ground neighbour alter within-plant seed size distribution in Phaseolus vulgaris? | Considerable variation in seed size commonly exists within plants, and is believed to be favoured under natural selection. This study aims to examine the extent to which seed size distribution depends on the presence of competing neighbour plants. Phaseolus vulgaris plants rooting with or without a conspecific neighbour were grown in soil with high or low nutrient availability. Seeds were harvested at the end of the growth cycle, the total nitrogen and phosphorus invested in seed production were measured and within-plant seed size distribution was quantified using a set of statistical descriptors. Exposure to neighbours' roots induced significant changes in seed size distribution. Plants produced proportionally more large seeds and fewer small ones, as reflected by significant increases in minimal seed size, mean seed size, skewness and Lorenz asymmetry coefficient. These effects were different from, and in several cases opposite to, the responses when the soil nutrient level was reduced, and were significant after correction for the amount of resources invested in seed production. | Polymorphisms in factor H (fH), an inhibitor of the alternative pathway (AP) of complement activation, are associated with increased risk for age-related macular degeneration (AMD). The authors investigated the therapeutic use of a novel recombinant form of fH, CR2-fH, which is targeted to sites of complement activation, in mouse choroidal neovascularization (CNV). CR2-fH consists of the N terminus of mouse fH, which contains the AP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. Laser-induced CNV was analyzed in factor-B-deficient mice or in mice treated with CR2-fH, soluble CR2 (targeting domain), or PBS. CNV progression was analyzed by molecular, histologic, and electrophysiological readouts. Intravenously administered CR2-fH reduced CNV size, preserved retina function, and abrogated the injury-associated expression of C3 and VEGF mRNA. CR2 and PBS treatment was without effect. In therapeutically relevant paradigms involving delayed treatment after injury, CR2-fH was effective in reducing CNV and provided approximately 60% of the amount of protection of that seen in factor B-deficient mice that lacked functional AP. After intravenous injection, CR2-fH localized to sites of C3 deposition in RPE-choroid. |
Does selenoprotein T exert an Essential Oxidoreductase Activity That Protects Dopaminergic Neurons in Mouse Models of Parkinson 's Disease? | Oxidative stress is central to the pathogenesis of Parkinson's disease (PD), but the mechanisms involved in the control of this stress in dopaminergic cells are not fully understood. There is increasing evidence that selenoproteins play a central role in the control of redox homeostasis and cell defense, but the precise contribution of members of this family of proteins during the course of neurodegenerative diseases is still elusive. We demonstrated first that selenoprotein T (SelT) whose gene disruption is lethal during embryogenesis, exerts a potent oxidoreductase activity. In the SH-SY5Y cell model of dopaminergic neurons, both silencing and overexpression of SelT affected oxidative stress and cell survival. Treatment with PD-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone triggered SelT expression in the nigrostriatal pathway of wild-type mice, but provoked rapid and severe parkinsonian-like motor defects in conditional brain SelT-deficient mice. This motor impairment was associated with marked oxidative stress and neurodegeneration and decreased tyrosine hydroxylase activity and dopamine levels in the nigrostriatal system. Finally, in PD patients, we report that SelT is tremendously increased in the caudate putamen tissue. These results reveal the activity of a novel selenoprotein enzyme that protects dopaminergic neurons against oxidative stress and prevents early and severe movement impairment in animal models of PD. | Immune monitoring (IM) has not been shown to be associated with cardiac allograft vasculopathy (CAV). Maximal intimal area, average percent stenosis, plaque volume, and maximal intimal thickness (MIT) were measured for matched baseline and one-yr IVUS segments in a blinded fashion. Patients were divided into quartiles by IM scores and outcomes compared. Optimal IM cutoff was determined. IM assays were measured at 63.7 ± 16.4 d after transplantation in fifty patients. Progression of maximal intimal area (p = 0.005), average percent stenosis (p < 0.001), plaque volume (p = 0.005), and MIT (p = 0.001) were increased across the quartiles. An optimal IM assay cutoff of 406.0 ng ATP/mL demonstrated a sensitivity of 66.7% and specificity of 94.3% for predicting rapid progression of MIT ≥ 0.5 mm. Mean IM scores for Group 1 vs. Group 2 were 176.4 ± 102.2 and 616.3 ± 239.5 ngATP/mL, respectively. Rapid progression of MIT ≥ 0.5 mm occurred in 5/38 patients (13.2%) in Group 1 vs. 10/12 patients (83.3%) in Group 2 (p < 0.001). The risk ratio for rapid progression with elevated IM was 11.7 (p < 0.001). |
Does kupffer cell depletion attenuate superoxide anion release into the hepatic sinusoids after lipopolysaccharide treatment? | The mechanisms involved in the beneficial effect of gadolinium chloride against endotoxin-induced liver damage were studied. Superoxide anions released into the hepatic sinusoids were examined in a liver perfusion model using the cytochrome C method. Gadolinium chloride treatment fully depleted ED2-positive cells from the liver and significantly attenuated superoxide anion release after a lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha) challenge. Moreover, gadolinium chloride treatment resulted in a significant decline in endothelial cell damage in the hepatic sinusoids as assessed by the purine nucleoside phosphorylase/glutamic-pyruvic transaminase ratio in the liver perfusate. Although gadolinium chloride treatment did not affect the level of serum TNF-alpha, it significantly reduced that of interleukin (IL)-8 and neutrophil migration in the hepatic sinusoids after the lipopolysaccharide challenge. | Depression is a common problem in patients with obstructive sleep apnea. The objective of this study was to examine whether depression is independently associated with lower self-reported sleep quality in patients with obstructive sleep apnea (OSA), after controlling for polysomnographic measures of sleep. The sample comprised 135 patients who had been referred to a university teaching hospital's multidisciplinary sleep medicine center for polysomnographic evaluation of OSA. The median age of the subjects was 45 (mean age, 46 years) 55% were female, 69% were white, 31% were black, and their mean body mass index was 37.9 +/- 11.2 kg/m2. Self-reported sleep quality during the past 2 weeks was assessed by the insomnia severity index. Polygraphic measures of sleep quality included the respiratory disturbance index, sleep onset latency, arousals for no apparent reason, sleep efficiency, and periodic leg movements associated with arousal. Depressive symptoms were assessed by the Beck Depression Inventory. None of the polygraphic measures of sleep quality was related to self-reported sleep quality or depression. Oxygen desaturation was correlated with self-reported sleep quality (r = 0.21, p =.02). Depression correlated with self-reported sleep quality (r = 0.55, p <.0001). In a multiple regression analysis, depression remained a significant predictor of self-reported sleep quality after controlling for all of the polysomnographic measures of sleep quality (F = 9.65, partial r2 = 0.28 p =.0001). |
Does axin2 expression identify progenitor cells in the murine prostate? | We previously reported that prostatic stem/progenitor cells are concentrated in the proximal region of prostatic ducts and express stem cell antigen 1 (Sca-1). As Wnt signaling is important for the maintenance of stem cells, we determined whether Sca-1 expressing cells also express Axin2, as Axin2 expression is highly suggestive of active Wnt signaling. Axin2 promoter reporter mice were used for whole mount and fluorescence activated cell sorting (FACS) analysis to determine its expression in the prostate. Axin2 expressing cells were also examined for the co-expression of Sca-1. We also used a chemical activator of Wnt signaling, BIO, to determine the effects of Wnt signaling on the growth of primary prostate cells in vitro. We show that Axin2 expression is present in all lobes and is regulated by androgens with the highest Axin2 expression in the lateral and dorsal prostate. Furthermore, a fraction of Axin2 expressing cells co-express Sca-1, suggesting that some progenitor cells have active Wnt signaling. Lastly, we demonstrate that activation of the Wnt pathway may result in increased growth, consistent with a role for Wnt signaling in maintenance and/or expansion of the progenitor cell population. | We evaluated the adequacy of nutrient intake in comparison with the Indonesian Estimated Average Requirement (EARs) among pregnant Indonesian women and explain the short-term effect of economic crisis on nutrient intake and iron status. Cross-sectional study. Purworejo District, Central Java, located 60 km west of Yogyakarta Province, Indonesia. During the period from 1996 to 1998, up to six 24 h recalls were performed during the second trimester of pregnancy among 450 women. Nutrient intake and iron status was evaluated in relation to date of data collection relative to the economic crisis that emerged in August 1997. A computer program (Inafood) was developed to calculate nutrient intake. : Forty percent of the pregnant women were at risk of inadequate intake of energy and protein, and 70% were at risk of inadequate intake of vitamin A, calcium and iron even before the crisis. Our results also demonstrate an effect of short-term economic crisis on nutrient intake and iron status. When the crisis emerged, urban poor experienced a decrease in intake of most nutrients. During the crisis, rich women experienced a significant decrease in fat (P<0.05). Negative changes in fat density during crisis were experienced by the rich and the rural, poor, and access to rice field subgroups (P<0.01). A significant increase in carbohydrate densities was seen for the rich and rural, poor, and access to rice fields groups (P<0.05). Urban poor experienced decreased serum ferritin concentration (P<0.05), whereas rich women experienced a significant increase (P<0.05). |
Does obstructive sleep apnea syndrome increase pedestrian injury risk in children? | To evaluate pedestrian behavior, including reaction time, impulsivity, risk-taking, attention, and decision-making, in children with obstructive sleep apnea syndrome (OSAS) compared with healthy controls. Using a case control design, 8- to 16-year-olds (n = 60) with newly diagnosed and untreated OSAS engaged in a virtual reality pedestrian environment. Sixty-one healthy children matched using a yoke-control procedure by age, race, sex, and household income served as controls. Children with OSAS were riskier pedestrians than healthy children of the same age, race, and sex. Children with OSAS waited less time to cross (P < .01). The groups did not differ in looking at oncoming traffic or taking longer to decide to cross. | We investigated the role of neoadjuvant/adjuvant therapies on survival for resectable biliary tract cancer. We hypothesized that neoadjuvant and adjuvant therapy should improve the survival probability in these patients. This was a retrospective review of a prospective database of patients resected for gallbladder cancer (GBC) and cholangiocarcinoma (CC). One hundred fifty-seven patients underwent resection for primary GBC (n = 63) and CC (n = 94). Fisher's exact test, Student's t test, the log-rank test, and a Cox proportional hazard model determined significant differences. The 5-year overall survival rate after resection of GBC and CC was 50.6 % and 30.4 %, respectively. Of the patients, 17.8 % received neoadjuvant chemotherapy, 48.7 % received adjuvant chemotherapy, while 15.8 % received adjuvant chemoradiotherapy. Patients with negative margins of at least 1 cm had a 5-year survival rate of 52.4 % (p < 0.01). Adjuvant therapy did not significantly prolong survival. Neoadjuvant therapy delayed surgical resection on average for 6.8 months (p < 0.0001). Immediate resection increased median survival from 42.3 to 53.5 months (p = 0.01). |
Do [ Survivin mutants reverse the malignancy of HeLa cells ]? | Survivin was aberrantly expressed in most cancer tissues, suggesting that survivin plays an important role in carcinogenesis. This study was designed to investigate the function and mechanism of survivin mutants in tumor cells. The site-mutant and truncated survivin mutants were transfected into HeLa cells and selected using G418. Cell apoptosis was analyzed using flow cytometry. Protein level of cyclin D1 was detected by Western blot analysis. Survivin mutant plasmid expressed in the HeLa cells successfully. The expressed protein could be detected using related antibody. Colony formation ability significantly decreased in the HeLa cells with survivin mutants compared with that in the parental HeLa cells. The HeLa cells transfected instantly with survivin mutants could undergo apoptosis automatically. Meanwhile, survivin mutants could cause an increase of multinuclear HeLa cells. The effect of survivin-N showed more effective than that of survivin T34A. Survivin-N and survivin T34A could influence the expression of cyclin D1 and reduced its protein levels of 68% and 12%, respectively. | There is no evidence that a knee arthroscopy is more beneficial to middle-aged patients with meniscal symptoms compared to other treatments. This randomised controlled trial aimed to determine whether an arthroscopic intervention combined with a structured exercise programme would provide more benefit than a structured exercise programme alone for middle-aged patients with meniscal symptoms that have undergone physiotherapy. 150 out of 179 eligible patients, aged 45 to 64 (mean:54 ± 5), symptom duration more than 3 months and standing X-ray with Ahlbäck grade 0, were randomised to: (1) a physiotherapy appointment within 2 weeks of inclusion that included instructions for a 3-month exercise programme (non-surgery group); or (2) the same as (1) plus, within 4 weeks of inclusion, knee arthroscopy for resection of any significant meniscal injuries (surgery group). The primary outcome was change in pain at 12 months, assessed with the Knee Injury and Osteoarthritis Outcome Score (KOOSPAIN). In the Intention-To-Treat analysis, pain at 12 months was significantly lower in the surgery than in the non-surgery group. The change in KOOSPAIN was significantly larger in the surgery than in the non-surgery group (between-group difference was 10.6 points of change; 95% CI: 3.4 to 17.7, P = 0.004). The As-Treated analysis results were consistent with the Intention-To-Treat analysis results. |
Do specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature? | To compare the genetic relationship between cyclin D1-positive and cyclin D1-negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs. Seventy-one cyclin D1-positive and six cyclin D1-negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH). Cyclin D1-negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1-positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity. | To evaluate the safety and efficacy of a once-daily gastroretentive formulation of gabapentin (G-GR; 1800 mg). This was an 11-week, double-blind, randomized, placebo-controlled Phase 3 clinical trial in patients with postherpetic neuralgia. Patients underwent a 2-week dose titration, 8 weeks of stable dosing, and 1 week of dose tapering. The primary endpoint was the change in average daily pain intensity score from Baseline to Week 10 using Baseline Observation Carried Forward (BOCF) imputation. Four-hundred and fifty-two patients (mean age 65.6 y, BMI 29 Kg/m) were randomized. Baseline average daily pain intensity score during the week prior to randomization was 6.6 and 6.5 for the G-GR and placebo treatment groups, respectively. Three hundred and seventy-seven patients completed the study (84% G-GR, 83% placebo). G-GR significantly reduced BOCF change in average daily pain intensity compared with placebo (-2.1 vs. -1.6; G-GR vs. placebo, P=0.013). Compared with placebo, more G-GR-treated patients reported "much" or "very much" improvement (patient global impression of change, 43% vs. 34%; P<0.0434), and G-GR reduced sleep interference (-2.3 vs. -1.59; P<0.0001), although neither endpoint was considered statistically significant based on a stringent hierarchical statistical paradigm. Other secondary endpoints showed similar trends. The most common adverse events were dizziness (G-GR, 11.3% vs. placebo, 1.7 %) and somnolence (G-GR, 5.4% vs. placebo, 3.0%). |
Does low-dose aspirin affect the clinicopathological features of gastric cancer? | There have been investigations on the chemopreventive effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in gastric cancer and also on the association between cyclo-oxygenase 2 expression and the clinicopathological features of gastric cancer. However, it is not yet clear whether the cardioprotective properties of low-dose aspirin could affect the biological behavior of gastric cancer. This study was aimed at investigating the association between the use of low-dose aspirin and clinicopathological features of gastric cancer in human. A case-control study was performed retrospectively by comparing the clinicopathological parameters between two groups of gastric cancers, 47 (30.5%) low-dose aspirin users and 107 (69.5%) non-aspirin users who were diagnosed and underwent operation for gastric cancers. The gastric cancers of aspirin user group showed favorable clinicopathological features, such as earlier tumor stage (overall stage, T and N stage: p < 0.001, <0.001, and 0.002, respectively), smaller size (p = 0.03), and intestinal type rather than diffuse type (p = 0.004). But these differences were significant only in non-cardiac cancer while cardiac cancer patients showed no significant association with low-dose aspirin usage (overall stage, T stage, N stage, tumor size, and histological type: p <0.001, <0.001, 0.003, 0.035, and 0.004, respectively, by Cochran-Mantel-Haenszel statistics). | To determine the impact of the time interval from the end of sperm preparation (TSP) to intrauterine insemination (IUI) on the outcome. Prospective multicentre cohort study. Seven French centers (assisted reproduction group in northeastern France, four academic centers, and three clinics). Eight hundred sixty-two IUI cycles (709 patients) managed by gonadotropins were studied. Cycles were stimulated by either FSH or hMG, and hCG was administrated when the leading follicle diameter measured >15 mm. IUIs were performed ∼ 36 hours after ovulation triggering. Generalized linear mixed models for binary outcomes were used to model clinical pregnancy (CP) to assess the effect of TSP adjusted for other predictors (such as maternal age, semen quality, and indication of IUI treatment). The TSP effect was significant, featuring an inverse U-shaped curve admitting an optimum interval of ∼ 40-80 minutes improving CP compared with other values. Other significant predictors were total motile spermatozoa inseminated, maternal age, and unexplained infertility. |
Does subchronic exposure to static magnetic field differently affect zinc and copper content in murine organs? | Static magnetic fields (SMF) have been widely used in research, medicine and industry. Since zinc and copper play an important role in biological systems, we studied the effects of the subchronic continuous SMF exposure on their distribution in murine tissues. For 30 days, mice were exposed to inhomogeneous, vertical, downward or upward oriented SMF of 1 mT averaged intensity with spatial gradient in vertical direction. SMF decreased the amount of copper and zinc in liver. In brain, zinc levels were increased and copper levels were decreased. In spleen, zinc content was reduced, while copper amount remained unchanged. | Risk scoring systems are used increasingly to assess patients with upper gastrointestinal hemorrhage (UGIH). There have been comparative studies to identify the best system, but most have been retrospective and included small sample sizes, few patients with severe bleeding and with low mortality. We aimed to identify the optimal scoring system. We performed a prospective study to compare the accuracy of the Glasgow Blatchford score (GBS), an age-extended GBS (EGBS), the Rockall score, the Baylor bleeding score, and the Cedars-Sinai Medical Center predictive index in predicting patients' (1) need for hospital-based intervention or 30-day mortality, (2) suitability for early discharge, (3) likelihood of rebleeding, and (4) mortality. We analyzed the area under receiver operating characteristic (AUROC) curve, sensitivity, specificity, and positive and negative predictive values for each system. The study included 831 consecutive patients admitted with UGIH during a 2-year period. The GBS and EGBS better predicted patients' need for hospital-based intervention or 30-day mortality than the other systems (AUROC, 0.93; P < .001) and were also better in identifying low-risk patients (sensitivity values, 0.27-0.38; specificity values, 0.099-1). The EGBS identified a significantly higher proportion of low-risk patients than the GBS (P = .006). None of the systems accurately predicted which patients would have rebleeding or patients' 30-day mortality, on the basis of low AUROC and specificity values. |
Is protoporphyrin IX fluorescence photobleaching a useful tool to predict the response of rat ovarian cancer following hexaminolevulinate photodynamic therapy? | Accurate dosimetry was shown to be critical to achieve effective photodynamic therapy (PDT). This study aimed to assess the reliability of in vivo protoporphyrin IX (PpIX) fluorescence photobleaching as a predictive tool of the hexaminolevulinate PDT (HAL-PDT) response in a rat model of advanced ovarian cancer. Intraperitoneal 10(6) NuTu 19 cells were injected in 26 female rats Fisher 344. Peritoneal carcinomatosis was obtained 26 days post-tumor induction. Four hours post-intraperitoneal HAL (Photocure ASA, Oslo, Norway) injection, a laparoscopic procedure (D-light AutoFluorescence system, Karl Storz endoscope, Tuttlingen, Germany) and a fluorescence examination were made for 22 rats. The first group (LASER group, n=26) was illuminated with laser light using a 532 nm KTP laser (Laser Quantum, Stockport, UK) on 1 cm(2) surface at 45 J/cm(2). The second group (NO LASER group, n=26) served as controls. Biopsies were taken 24 hours after PDT. Semi-quantitative histology was performed and necrosis value was determined: 0--no necrosis to 4--full necrosis. Fluorescence was monitored before and after illumination on complete responders (NV=3-4; n=20) and non-responders (NV=0-2; n=6). High PpIX photobleaching corresponded with complete responders whereas low photobleaching corresponded with non-responders (P<0.05). A direct linear correlation was shown between photobleaching and necrosis (R(2)=0.89). | To examine the association between breastfeeding pattern and growth in the first year of life. A cross-sectional survey was carried out on 349 mothers with infants <12 months in a rural and a semi-urban community in Mangochi district, Malawi. Data on socio-demographic characteristics, infant weight, length and feeding patterns since birth were collected. Multivariate linear regression was performed to test the association between feeding pattern and infant anthropometric status. Exclusive breastfeeding (EBF) until 6 months was practised by 13.1% semi-urban and 1.3% rural mothers. No infant was exclusively breastfed beyond 6 months. Breastfeeding was continued among all infants who had stopped EBF. Among infants 6-12 months of age, duration of EBF during the first 6 months was positively associated with length-for-age Z-score (LAZ) (regression coefficient=0.19, 95% confidence interval: 0.06, 0.31) in a model adjusted for socio-demographic factors. Urban residence and female gender yielded positive associations in the same model. The model explained 27% of the variation in LAZ. Among infants <6 months, duration of EBF was not significantly associated with LAZ, but being female and urban residence yielded positive associations. Breastfeeding patterns were not associated with weight-for-age Z-score (WAZ) or weight-for-height Z-score (WLZ) either in the 0-6-month or in the 6-12-month group. Birth outside a health facility was negatively associated with WAZ and WLZ in the older group. |
Does transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuate K/BxN mouse serum-induced arthritis in vivo? | 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. | During pulmonary vein isolation for treatment of atrial fibrillation (AF), a significant delay in atrio-pulmonary vein (PV) conduction is often observed. We sought to investigate this conduction delay in various PV in individual patients. We studied 385 AF patients (mean age: 54 +/- 11 years, 74 women) who underwent segmental PV isolation (PVI). A circular decapolar catheter was used to record electrograms at the PV ostia. The time delay from local atrial potential to PV potential was measured in each vein. Conduction delay (CD) was defined as the longest time interval >20 ms observed during PVI. For patients treated for the first time, CD was more frequently observed in the left common and the right and left superior PVs (84.2%, 67.9%, and 66.2%, respectively) and less frequently in the left and right inferior and right middle PVs (54.3%, 40.0%, and 30.8%, respectively). Veins with CD required more ablation applications (12.4 vs 9.9) and a higher ablated segmental fraction (72.3% vs 63.7%). CD was observed in 75.2% (109/145) of the PVs in which focal activity was detected. Older patients had a higher incidence of PVs with CD than younger patients. There were no gender differences. |
Do increased interleukin-23/17 axis and C-reactive protein are associated with severity of acute pancreatitis in patients? | The interleukin (IL)-23/IL-17 axis plays an important role in various inflammatory conditions but its function in acute pancreatitis (AP) is not well understood. The present study investigated the relationship between serum levels of IL-23, IL-17, and C-reactive protein (CRP) in patients and the severity of AP. Eighty-five patients with AP were categorized into mild group, moderately severe group, and severe group according to the revised Atlanta classification, 2012. Serum levels of IL-23 and IL-17 were measured by enzyme-linked immunosorbent assay in patients 48 hours after admission. The CRP levels of patients were also measured on admission and 48 hours after admission. The serum levels of CRP of patients on admission and 48 hours after admission and levels of IL-23 and IL-17 of patients 48 hours after admission increased alone with the severity of AP, respectively (P < 0.01). The serum levels of IL-23 and IL-17 in the patients were correlated with CRP levels (r = 0.234, r = 0.552, P < 0.001, respectively). | Conventional volumetric studies have shown that brain structures functionally and anatomically related to the hippocampus are smaller in patients with drug-refractory medial temporal lobe epilepsy (MTLE). To determine the extent of gray matter atrophy in the brains of patients with MTLE and to examine the pattern of atrophy. We performed a voxel-based morphometric study of 43 consecutive patients with unilateral drug-refractory MTLE (21 patients with right-sided MTLE and 22 patients with left-sided MTLE) whose magnetic resonance images showed signs of unilateral hippocampal atrophy. The data from the patients with MTLE were compared with the data from 49 healthy control subjects to identify differences between groups in gray matter concentration (GMC). Academic hospital's epilepsy clinic. We observed that patients with left- and right-sided MTLE exhibited GMC reduction in the hippocampus ipsilateral to the seizure origin. In addition, we found GMC reduction in the ipsilateral parahippocampal and isocortical temporal regions. Patients with MTLE also showed GMC reduction in subcortical nuclei such as the thalamus and caudate, in the cerebellum, in the midbrain, and in parieto-occipital regions. |
Do increased insomnia symptoms predict the onset of back pain among employed adults? | Back pain is among the most prevalent pain disorders causing chronic disability among adults, and insomnia is a common co-morbidity. However, whether insomnia precedes back pain or vice versa remains unclear. The current study tested the temporal association between insomnia and back pain. A longitudinal design was used to investigate whether changes in insomnia over time predict the onset of back pain and vice versa. The study was conducted on a cohort of active healthy working adults (N = 2,131, 34% women) at three time points (T1, T2, and T3) over a period of 3.7 years (range = 2.2-5.12) years. Logistic regression analysis was used to test whether increased insomnia symptoms from T1 to T2 predicted the onset of new back pain. Ordinary least squares regression was used to test whether the existence of back pain at T2 predicted an increase in insomnia from T2 to T3. The results indicated that after controlling for socioeconomic variables, self-reported health, lifestyle behaviors, and anthropometrics, a T1-T2 increase in insomnia symptoms was associated with a 1.40-fold increased risk of back pain at T3 (OR = 1.40; 95% CI = 1.10-1.71). No support was found for reverse causation; i.e., that back pain predicts subsequent increase in insomnia. | Lung injury after cardiopulmonary bypass is a serious complication for infants with congenital heart disease and pulmonary hypertension. Excessive neutrophil sequestration in the lung occurring after reestablishment of pulmonary circulation implies that interaction between neutrophils and pulmonary endothelium is the major cause of lung injury. Thirty infants with either ventricular septal defect or atrioventricular septal defect and with pulmonary hypertension were enrolled in this study. We performed continuous pulmonary perfusion during total cardiopulmonary bypass on 16 patients (perfused group) and conventional cardiopulmonary bypass on 14 patients (control group). PaO2/FiO2 and neutrophil counts were assessed from immediately before surgery to 24 hours after termination of cardiopulmonary bypass. PaO2/FiO2 was higher in the perfused group than in the control group, and the difference was significant throughout the study period. Neutrophil counts decreased below prebypass values in both groups at 30 minutes after aortic unclamping, and the difference was significant in the control group but was not in the perfused group. Duration of postoperative ventilatory support was significantly less in the perfused group. |
Is shc a substrate of the rat intestinal epidermal growth factor receptor tyrosine kinase? | Epidermal growth factor (EGF) has been shown to induce intestinal proliferation and maturation; however, little information is available regarding substrates of the intestinal EGF receptor tyrosine kinase. The purpose of this study was to determine if src homologous collagen-like protein (Shc) was an in vivo substrate of the intestinal EGF receptor. Ten-day-old rats were treated with EGF or were breast-fed. In some experiments, IEC-6 cells were treated with EGF. Intestinal tissue and cell fractions were studied by immunodetection to compare the tyrosine phosphorylation state and the subcellular localization of intestinal proteins. The total tyrosine phosphorylation state of intestinal proteins was increased threefold by EGF. Tyrosine phosphorylation of the EGF receptor and Shc were rapidly increased by EGF. The association of Grb2 with Shc increased fourfold and fivefold. Plasma membrane translocation of Shc and associated phosphotyrosyl proteins was increased within 30 seconds of EGF treatment. | Evaluation of sinus and atrioventricular nodes function as a potential factor responsible for prolonged bradycardia, asystole, or both in patients with cardioinhibitory and non-cardioinhibitory vasovagal syncope (VVS). The study included 258 patients (mean age = 47.7 +/- 17.2 years; range 18-62; 147 females) with a history of VVS. They were divided among four groups, according to results of head-up tilt test (HUTT). All patients underwent standard HUTT, carotid sinus massage (CSM), and rapid transesophageal atrial pacing for evaluation of total sinus node recovery time (SNRT), and corrected sinus node recovery time (CNRT), resting and intrinsic heart rate (IHR), and Wenckebach point (WP). Values of SNRT > 1,500 ms, CNRT > 525 ms, WP < 130 bpm, and CSM-induced pause >3 seconds were considered abnormal. SNRT, CNRT, and WP before and after pharmacological blockade, resting heart rate, and IHR did not differ significantly among the study groups. The prevalence of mild sinus node dysfunction (SND), decreased value of WP, and cardioinhibitory carotid sinus hypersensitivity was similar among all study groups. |
Does endothelial caveolin-1 regulate pathologic angiogenesis in a mouse model of colitis? | Increased vascular density has been associated with progression of human inflammatory bowel diseases (IBDs) and animal models of colitis. Pathologic angiogenesis in chronically inflamed tissues is mediated by several factors that are regulated at specialized lipid rafts known as caveolae. Caveolin-1 (Cav-1), the major structural protein of caveolae in endothelial cells, is involved in the regulation of angiogenesis, so we investigated its role in experimental colitis. Colitis was induced by administration of dextran sodium sulfate to wild-type and Cav-1(-/-) mice, as well as Cav-1(-/-) mice that overexpress Cav-1 only in the endothelium. Colon tissues were analyzed by histologic analyses. Leukocyte recruitment was analyzed by intravital microscopy; angiogenesis was evaluated by immunohistochemistry and in vivo disk assays. Cav-1 protein levels increased after the induction of colitis in wild-type mice. In Cav-1(-/-) mice or mice given a Cav-1 inhibitory peptide, the colitis histopathology scores, vascular densities, and levels of inflammatory infiltrates decreased significantly compared with controls. Lower levels of leukocyte and platelet rolling and adhesion colitis also were observed in Cav-1(-/-) mice and mice given a Cav-1 inhibitory peptide, compared with controls. Cav-1(-/-) mice that received transplants of wild-type bone marrow had a lower colitis score than wild-type mice. Data from mice that overexpress Cav-1 only in the endothelium indicated that endothelial Cav-1 is the critical regulator of colitis. Genetic deletion or pharmacologic inhibition of endothelial Cav-1 also significantly decreased vascular densities and angiogenesis scores, compared with controls. | To determine whether sulfasalazine can prevent apoptosis in spermatogenic cells by preventing the activation of NF-kappaB in spermatogenic epithelium in experimental testicular torsion. Thirty-two adult male Sprague-Dawley rats were subjected to unilateral 720 degree testicular torsion for durations of 0 h and 2 h, then the torsion was relieved. The ischemic/reperfused testes were collected for the detection of NF-kappaB expression with Western blotting and immunohistochemistry techniques, and detection of apoptosis with TUNEL techniques. The NF-kappaB coefficient of spermatogenic epithelium and the apoptosis index of spermatogenic cells were significantly different in the operation and the sham-operation groups after experimental testicular torsion (P<0.01). |
Is the endogenous pathway a major route for deep sternal wound infection? | Deep wound infections pose an increasing problem in cardiac surgery patients. Prospective infection monitoring is thus a means of identifying possible risk factors. Within a period of 5 months, a total of 376 adult patients, 260 men and 116 women, with a mean age of 62.6 years (range 18-88), underwent coronary bypass grafting (n=281) or other cardiac surgery procedures (n=95). Nasal cultures were taken preoperatively from every patient, as well as cultures of the wound during surgery and when dressings were changed thereafter. In addition, nasal cultures were taken from all the medical and nursing staff. To differentiate endogenous and exogenous infection pathways, DNA fingerprint analysis was performed. A total of 38 patients (10.1%) developed a wound infection, in 14 patients this happened to be a deep wound infection, in 24 patients a superficial one. Five sternal wound infections were associated with mediastinitis (1.3%). The occurrence of a wound infection overall resulted in prolonged hospitalization (29.4+/-24 vs. 11.9+/-6.9 days, P=0.001), but not in increased hospital mortality (4.4% vs. 3.9%). Obesity, diabetes mellitus and nasal carriage of Staphylococcus aureus proved to be independent risk factors with an odds ratio of 2.07, 2.26 and 2.28, respectively. In all but one of the sternal colonizations with S. aureus, DNA fingerprint analysis demonstrated an identical pattern of S. aureus from the patient's nose and sternum, indicating an endogenous infection pathway. | Progesterone (P) and its 5alpha-reduced metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP), facilitate sexual behavior of rodents via agonist-like actions at intracellular progestin receptors (PRs) and membrane GABA(A)/benzodiazepine receptor complexes (GBRs), respectively. Given that ovarian secretion of progestins declines with aging, whether or not senescent mice are responsive to progestins was of interest. Homozygous PR knockout (PRKO) or wild-type mice that were between 10-12 (mid-aged) or 20-24 (aged) months of age were administered P or 3alpha,5alpha-THP, and the effect on lordosis were examined. Effects of a progestin-priming regimen that enhances PR-mediated (experiment 1) or more rapid, PR-independent effects of progestins (experiments 2 and 3) on sexual behavior were examined. Levels of P, 3alpha,5alpha-THP, and muscimol binding were examined in tissues from aged mice (experiment 4). Wild-type, but not PRKO, mice were responsive when primed with 17beta-estradiol (E(2); 0.5 microg) and administered P (500 microg, subcutaneously). Mid-aged wild-type mice demonstrated greater increases in lordosis 6 h later compared to their pre-P, baseline test than did aged wild-type mice (experiment 1). Lordosis of younger and older wild-type, but not PRKO, mice was significantly increased within 5 min of intravenous (IV) administration of P (100 ng), compared with E(2)-priming alone (experiment 2). However, wild-type and PRKO mice demonstrated significant increases in lordosis 5 min after IV administration of 3alpha,5alpha-THP, an effect which was more pronounced in mid-aged than in aged animals (100 ng-experiment 3). In tissues from aged wild-type and PRKO mice, levels of P, 3alpha,5alpha-THP, and muscimol binding were increased by P administration (experiment 4). PR binding was lower in the cortex of PRKO than that of wild-type mice. |
Does cervical spinal cord stimulation increase cerebral cortical blood flow in an experimental cerebral vasospasm model? | Cerebral microcirculatory changes during cerebral vasospasm after aneurysmal subarachnoid haemorrhage (SAH) are still controversial and uncertain. The aim of our study is to demonstrate that spinal cord stimulation (SCS) augments cerebral cortical microcirculatory blood flow in an experimental cerebral vasospasm model by using Laser Doppler Flowmetry (LDF). The experiments were carried out on 24 New Zealand rabbits. Three experimental groups were designed. In group 1, Cerebral cortical blood flow (CCoBF) was evaluated by LDF in 8 rabbits. In group 2, Intracisternal saline injection and cervical epidural electrode placement without SCS were performed in 8 animals before LDF. In group 3, LDF was performed before and after SCS on the 4th day of SAH in 8 rabbits. CCoBF parameters obtained from LDF data were compared. The occurrence of vasospasm after SAH was demonstrated with significant changes in LDF values. In all SAH animals, SCS resulted in significant increase (approximately 30%) in CCoBF. This increase was observed to continue even after the cessation of the stimulation. | To test whether the chronic users of celecoxib, a selective cyclo-oxygenase-2 inhibitor, had less Helicobacter pylori-related intestinal metaplasia or if such users' intestinal metaplasia could be prone to disappear after H. pylori eradication. The study enrolled 150 chronic celecoxib users and 216 non-users who underwent pan-endoscopy to detect H. pylori infection and its related intestinal metaplasia. One hundred and three H. pylori-infected patients with intestinal metaplasia (43 chronic celecoxib users and 60 non-users) received anti-H. pylori therapy and completed the 12-month follow-up to survey the regression of intestinal metaplasia by mean intestinal metaplasia score. There were no differences in the prevalence of H. pylori-related intestinal metaplasia between the chronic celecoxib users and controls (P > 0.05). On the 12th month of follow-up, chronic celecoxib users had a lower mean intestinal metaplasia score (1.2 vs. 1.8, P < 0.005) and a higher regression rate of intestinal metaplasia (42% vs. 20%, P = 0.027) than non-users. |
Is the ADAMTS13-von Willebrand factor axis involved in the pathophysiology of kidney ischemia-reperfusion injury? | The ADAMTS13-von Willebrand factor (vWF) axis has been suggested to play a critical role in the pathophysiology of ischemia-reperfusion injury (IRI) in the heart or brain. Therefore, we aimed to investigate whether this axis was involved in the pathophysiology of IRI-induced acute kidney injury. We performed renal IRI in ADAMTS13 knockout (KO) or wild type (WT) mice. Functional and histological kidney damage, and inflammation were compared and the effect of anti-vWF antibodies in ADAMTS13 KO mice was assessed. Following IRI, the blood and kidney ADAMTS13 levels were significantly decreased. vWF expression was significantly upregulated in both the medulla and cortex of injured kidneys as shown by immunohistochemistry and western blot analyses. There was also an increased level of vWF dimers after IRI. In ADAMTS13 KO mice, kidney vWF levels were further increased and this was associated with greater endothelial and epithelial injury compared to WT mice, suggesting an important role of vWF in renal IRI. In addition, the number of Gr-1 | The majority of new mothers in Sweden initiate breastfeeding and many experience initial difficulties. This experience is an important cause of early breastfeeding cessation. To increase understanding, there is a need to explore the lived experiences of the decision to continue or cease breastfeeding. The aim of this study is therefore to explain and understand how this decision is influenced by the meaning of severe initial difficulties. A lifeworld hermeneutical approach was used for the study. The study was conducted in Sweden with eight mothers who experienced severe difficulties with initial breastfeeding. All except one were interviewed on two different occasions resulting in fifteen interviews. The interviews were conducted between 2010 and 2013. Mothers who experience severe difficulties with initial breastfeeding feel both overtaken and violated not only by their own infants and their own bodies but also by their anger, expectations, loneliness and care from health professionals. These feelings of being overtaken and invaded provoke an existential crisis and place mothers at a turning point in which these feelings are compared and put in relation to one another in the negotiation of the decision to continue or cease breastfeeding. This decision thus depends on the possibility of feeling secure with the breastfeeding relationship. If insecurity dominates, this can, in severe cases, create a feeling of fear of breastfeeding that is so great that there is no alternative but to stop breastfeeding. |
Do histone deacetylase inhibitors differentially mediate apoptosis in prostate cancer cells? | Histone deacetylase (HDAC) inhibitors have shown significant anti-proliferative and apoptotic properties on various cancer cells, including prostate cancer, and are therefore being evaluated as treatment modalities. However, the specific effect of HDAC inhibitors on androgen-sensitive and androgen-independent cell lines have not been thoroughly studied which we hypothesized could be different. We therefore assessed whether three structurally unrelated HDAC inhibitors, trichostatin A (TSA), depsipeptide (FR901228), and sodium butyrate, affect cell death in the prostate cancer cell lines LNCaP, DU-145, and PC-3. To investigate the extent and the nature of cell death, we used Trypan blue exclusion assay, phase-contrast light microscopy, fluorescence microscopy, and Western blot analyses. At concentrations where they potentiate transcriptional activation, all three HDAC inhibitors induced cell death in LNCaP and DU-145 cells, but not in PC-3 cells, within the timeline of the experiments. HDAC inhibitor-induced cell death in LNCaP and DU-145 cells showed several characteristic apoptotic features, such as cell shrinkage, nuclear condensation, and poly(ADP) ribose polymerase cleavage. However, there were differences in the way LNCaP and DU-145 cells responded to treatment with various HDAC inhibitors. For example, whereas TSA and FR901228 were more effective in inducing apoptosis in LNCaP cells compared with DU-145 cells, the reverse was true for sodium butyrate. Moreover, within the same cell line, TSA, FR901228, and sodium butyrate exhibited different potencies for induction of apoptosis. | Acute intestinal infection leads to persistent intestinal smooth muscle hypercontractility and pain hypersensitivity after resolution of the infection in animal models. We investigated whether postinfectious irritable bowel syndrome (PI-IBS) is associated with abnormalities in phasic contractions of the colon, smooth muscle tone, and pain sensitivity compared to non-PI-IBS (NI-IBS) or healthy controls (HC). Two hundred and eighteen Rome III-positive IBS patients and 43 HC participated. IBS patients were designated PI-IBS, if their IBS symptoms began following an episode of gastroenteritis characterized by two or more of: fever, vomiting, or diarrhea. Pain threshold to phasic distentions of the descending colon was assessed using a barostat. Colonic motility was assessed with the barostat bag minimally inflated to the individual operating pressure (IOP), at 20 mmHg above the IOP, and following a test meal. IBS symptom severity and psychological symptoms were assessed by the IBS Severity Scale (IBS-SS) and the Brief Symptom Inventory-18 (BSI-18). Twenty two (10.1%) met criteria for PI-IBS. Both IBS and HC groups showed a significant increase in motility index during intraluminal distention and following meals. The magnitude of the response to distention above (orad to) the balloon was significantly greater in PI-IBS compared with NI-IBS (p < 0.05) or HC (p < 0.01). Differences between PI-IBS and NI-IBS were not significant for IBS symptom severity, pain threshold, barostat bag volumes, or any psychological score on the BSI-18. |
Are perception and reflex responses to intestinal distention in humans modified by simultaneous or previous stimulation? | Intestinal reflexes induced by distention in dogs are facilitated by either simultaneous or previous distentions. The aim of this study was to determine whether these phenomena also modulate the responses to intestinal distention, particularly perception, in humans. Perception and intestinal relaxation were measured in 11 healthy subjects in response to increasing jejunal balloon distentions tested (by stimulus-response trials) alone, as control, and with conditioning distentions applied either simultaneously, immediately (10 seconds) before at the same site, or immediately before and 5 cm distant. In 8 additional subjects, the effect of prolonged (90-minute) conditioning distention was tested. Conditioning had more pronounced effects on perception than on intestinal reflexes. Perception of intestinal distention increased (by 84 +/- 47%; P < 0.05) when a simultaneous distention was applied nearby. By contrast, perception decreased (by 38 +/- 12%; P < 0.05) when a previous distention was applied at the same but not at an adjacent site. Prolonged intestinal distention elicited remarkably stable perception during a 90-minute period. The effects of conditioning were unrelated to intestinal compliance because it remained unchanged. | Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS) as important human pathogens are causes of nosocomial infections worldwide. Burn patients are at a higher risk of local and systemic infections with these microorganisms. A screening method for MRSA by using a multiplex polymerase chain reaction (PCR) targeting the 16S ribosomal RNA (rRNA), mecA, and nuc genes was developed. The aim of the present study was to investigate the potential of this PCR assay for the detection of MRSA strains in samples from burn patients. During an 11-month period, 230 isolates (53.11%) of Staphylococcus spp. were collected from burn patients. The isolates were identified as S. aureus by using standard culture and biochemical tests. DNA was extracted from bacterial colonies and multiplex PCR was used to detect MRSA and MRCoNS strains. Of the staphylococci isolates, 149 (64.9%) were identified as S. aureus and 81 (35.21%) were described as CoNS. Among the latter, 51 (62.97%) were reported to be MRCoNS. From the total S. aureus isolates, 132 (88.6%) were detected as MRSA and 17 (11.4%) were methicillin-susceptible S. aureus (MSSA). The presence of the mecA gene in all isolates was confirmed by using multiplex PCR as a gold standard method. |
Does miR-433 inhibit oral squamous cell carcinoma ( OSCC ) cell growth and metastasis by targeting HDAC6? | The aim of this study was to determine expression levels of miR-433 in oral squamous cell carcinomas (OSCCs) and adjacent normal tissues, and explore its biological functions in OSCCs. miR-433 level in oral squamous cell carcinomas (OSCCs) and adjacent normal tissues was tested by real-time qPCR. The effect of miR-433 on cell growth was detected by MTT and colony formation assays. The tumorigenicity of miR-433 transfected OSCCs was evaluated in nude mice model. Transwell and wound healing assays were performed to detect the effect of miR-433 on OSCCs cell invasion and migration. Luciferase reporter gene assays were performed to identify the interaction between miR-433 and 3'UTR of HDAC6 mRNA. The protein level of HDAC6, BCL2, CCNE1, MMP1 and MMP9 was determined by Western blotting. Immunohistochemistry analysis was performed to detect the expression of HDAC6 in oral squamous cell carcinomas (OSCCs) and adjacent normal tissues. We found that miR-433 was frequently down-regulated in OSCCs compared with adjacent normal tissues. Restoring miR-433 expression in OSCC cells dramatically suppressed cells growth, invasion and migration. Importantly, our data showed that miR-433 downregulated the expression of HDAC6 through directly targeting its 3'UTR. | Asymmetric dimethylarginine (ADMA) has raised considerable interest, as it is an endogenous inhibitor of nitric oxide synthesis. While increased plasma levels of ADMA have been reported in different cardiovascular disease states, its association with symmetric dimethylarginine (SDMA) has not been evaluated in a prospective population-based study. We performed a mass spectrometry-based analysis of ADMA and SDMA in the plasma of 572 participants of the Bruneck study. Levels of ADMA and SDMA were significantly correlated with each other (r=0.189, p<0.001). Age and parameters of renal function, however, showed a stronger influence on SDMA than on ADMA. Both ADMA and SDMA were predictive of cardiovascular disease in multivariate analysis and the associated hazard ratios over the 5-year observation period were of similar strength: 3.86 (1.36-10.9) and 7.91 (1.94-32.3) for ADMA and SDMA, respectively (p=0.011 and 0.004). Separate analyses focused on quintile groups of SDMA revealed that the increase in cardiovascular risk was mainly confined to the top category (>0.80 micromol/L). |
Is recurrence of febrile seizures in the respiratory season associated with influenza A? | To investigate the association of viral infections and febrile seizures (FS). From April 1998 to April 2002, a prospective, population-based study was carried out among general practitioners to assess the incidence of FS in their practices. Data thus obtained were compared with the incidence of common viral infections recorded in a national registry. Poisson regression analysis was performed to investigate whether the season or the type of infection was associated with the variation observed in FS incidence. Throughout the 4-year period, 267 of 303 (88%) of general practitioners in the Dutch province of Friesland participated in the study. The estimated observation period was approximately 160,000 patient-years. We registered 654 cases of FS in 429 children. The estimated incidence of FS was 2.4 in 1000 patient-years. Poisson regression analysis revealed a positive correlation between recurrent FS and influenza A ( P = .01). | Activation of Akt and increased expression of integrin β(3) are the two most important changes that have been linked to the attainment of metastatic potential by prostate cancer cells. However, a direct link between Akt activity and inside-out activation of integrin β(3) in mediating prostate cancer cell metastatic properties is not established. Using functional and biochemical approaches, we examined the role of Akt1 in the affinity modulation of integrin β(3) in prostate cancer cells. Although expression of murine TRAMP and human PC3 cells with constitutively active Akt1 (CA-Akt1) enhanced their affinity for integrin α(v)β(3) specific ligands and motility on various extracellular matrix proteins, the reverse was observed with the expression of dominant-negative Akt1 (DN-Akt1). Although enhanced motility and transendothelial migration of CA-Akt1-expressing cells were blunted by co-expression with DN-integrin β(3) or upon pre-treatment with integrin β(3)-blocking antibodies (LM 609), impaired motility and transendothelial migration of DN-Akt1-expressing cells were rescued by pre-treatment of prostate cancer cells with integrin β(3)-activating antibodies, AP7.4. |
Does hydrolysis of casein accelerate gastrointestinal transit via reduction of opioid receptor agonists released from casein in rats? | Protein hydrolysate accelerates gastrointestinal transit (GIT) and feeding advancement in preterm infants compared to native protein. In rat pups, opioid receptor agonists released from casein during digestion such as beta-casomorphins slow down GIT. We hypothesized that hydrolysis of casein reduces the opioid activity released during digestion thereby accelerating GIT compared to native casein. The aim of the present study was to investigate whether casein hydrolysate accelerates GIT compared to native casein and whether pretreatment with naloxone, an opioid receptor blocker, abolishes this difference in rat pups. In a randomized controlled trial following a 2 x 2 factorial design, 216 female Wistar rat pups were fed with pellets based on hydrolyzed or native casein. After pretreatment with naloxone or normal saline, carmine red was administered by oro-gastric gavage as a tracer for GIT velocity measurement. Four hours later the animals were sacrificed, their intestine was removed and the length of the colon from the cecocolonic junction to the anus was measured. GIT was recorded as percentage of the total colonic length (percentage of colonic transit) passed by carmine red. Data were given as mean +/- SD. GIT was significantly higher with hydrolyzed casein compared to native casein formula (77.4 +/- 17 and 51.2 +/- 20%), but there was no difference after naloxone pretreatment (77.1 +/- 16 and 76.5 +/- 17%). | To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p<0.001) 8 hours post intervention. During the follow-up period, 70 (53%) patients developed restenosis. Increasing levels of C5a (quartiles) at baseline were significantly associated with an increased risk for restenosis (p=0.0092). Adjusted hazard ratios (95% confidence intervals) for restenosis with increasing quartiles of baseline serum C5a levels were 1.24 (0.60 to 2.58), 1.93 (0.95 to 3.93), and 2.08 (1.02 to 4.21), respectively, compared to the lowest quartile. This effect was independent of nonspecific inflammation as reflected by plasma levels of C-reactive protein. |
Is abnormal gastroesophageal flap valve highly associated with gastroesophageal reflux disease among subjects undergoing routine endoscopy in Taiwan? | Gastroesophageal flap valve (GEFV) grade predicts severe gastroesophageal reflux disease in Caucasians, but its role in other populations is unclear. This study evaluated the significance of endoscopic grading of the GEFV in Taiwanese subjects. Five hundred and six consecutive patients undergoing routine check-ups at the National Taiwan University Hospital were enrolled. Symptoms of upper gastrointestinal disease and endoscopic severity of esophageal mucosal injury were correlated to GEFV grades according to the Hill classification. The frequency of abnormal valves (Hill grades III or IV) was 27.3%. Of these, 42.7% had erosive esophagitis (EE). The majority of patients with EE were classified as Los Angeles grades A and B (79.7 and 16.9%, respectively). The prevalence of EE, hiatal hernia and, to a lesser degree, non-erosive reflux disease, increased with altered GEFV. Patients with abnormal valves were younger and more likely to be male, overweight, and to have atypical and extraesophageal symptoms. | Arginine deiminase (ADI) and L-arginine (L-Arg) can act as anti-tumor agents in-vitro and in-vivo. However, the mechanism of ADI and L-Arg as anti-tumor agents has not been clearly shown. With the goal of understanding the role of ADI and L-Arg in inhibition of cell growth, we used the Ramos human lymphoma cell line, which is known to be ADI-sensitive, and observed the p53 and NF-κBp65 protein expression after ADI and arginine treatment. After determining an optimal experimental ADI concentration (0.01 U/ml), we studied the effects of ADI treatment, when combined with different concentrations of L-arginine (control, ADI only, ADI with 10 mM/ml Arg, ADI with 30 mM/ml Arg, and ADI with 50 mM/ml Arg). An MTT assay was used to assess cell survival after treatment, Western blot analysis to determine the levels of the NF-κBp65, p53 and NO mediators and nitric oxide assays were used to determine nitrite levels. |
Is symptom change with exercise a temporary phenomenon for people with multiple sclerosis? | To determine the impact of a single exercise session on function, fatigue, and sensory symptoms for people with multiple sclerosis (MS). This pilot study was designed as a before-after trial. Demographic and response-to-exercise measures were taken before exercise, repeated immediately after exercise, and followed up again 24 hours later. Three metropolitan centers of an MS society. A prospective sample of 34 subjects with MS who were referred for physiotherapy for an exercise program and who could attend an MS society center. Subjects performed an individually prescribed exercise session, which was at a commencement level and included strengthening, stretches, and fitness exercises. Subjects exercised for between 5 to 45 minutes (mean, 17.4 min) at an intensity of 7 to 17 (median, 12) on the Borg rating of perceived exertion (RPE) scale. All outcome measures were self-rated by subjects and included the Borg RPE scale, a questionnaire for sensory symptom description, and visual analog scales for rating of fatigue, function, and intensity of sensory symptoms. Subjective levels of fatigue and function immediately postexercise and 24 hours postexercise did not differ significantly from pre-exercise levels. However, over 40% of subjects experienced a temporary increase in number of sensory symptoms, 44% experienced an increase in the intensity of sensory symptoms, and 29% experienced an increase in both number and intensity immediately postexercise. | The aim of this study was to evaluate the expression of DACT1 in human placenta tissue and the relationship between DACT1 and target genes of the Wnt signaling pathway. Real-time PCR and western blotting were used to detect the expression of DACT1 and the target genes of Wnt signaling pathway in human placenta tissue. And the relationship between them was analyzed using SPSS 19. Real-time PCR results showed that DACT1 expression was significantly higher in 49- to 71-day placenta tissues (mean value = 0.020) than that in 39- to 48-day (the mean value = 0.009). The mRNA expressions of the Wnt signaling pathway target genes, CCND1, CCND2, FOSL1, DAB2 and JUN, were also increased expressed in human placenta tissues. Significant positive associations between DACT1 and CCND1, CCND2, FOSL1, DAB2 and JUN were observed. Western blotting analysis showed that the protein expression of DACT1, CCND1, CCND2, FOSL1, DAB2 and JUN displayed the increasing trend in 43-, 49- and 71-day placenta samples. |
Does elevated protein kinase C-δ contribute to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling? | Apoptosis of smooth muscle cells (SMCs) is a prominent pathological characteristic of abdominal aortic aneurysm (AAA). We have previously shown that SMC apoptosis stimulates proinflammatory signaling in a mouse model of AAA. Here, we test whether protein kinase C-δ (PKCδ), an apoptotic mediator, participates in the pathogenesis of AAA by regulating apoptosis and proinflammatory signals. Mouse experimental AAA is induced by perivascular administration of CaCl(2). Mice deficient in PKCδ exhibit a profound reduction in aneurysmal expansion, SMC apoptosis, and transmural inflammation as compared with wild-type littermates. Delivery of PKCδ to the aortic wall of PKCδ(-/-) mice restores aneurysm, whereas overexpression of a dominant negative PKCδ mutant in the aorta of wild-type mice attenuates aneurysm. In vitro, PKCδ(-/-) aortic SMCs exhibit significantly impaired monocyte chemoattractant protein-1 production. Ectopic administration of recombinant monocyte chemoattractant protein-1 to the arterial wall of PKCδ(-/-) mice restores inflammatory response and aneurysm development. | Liver injury leads to generation of reactive oxygen and nitrogen species, which can react to produce peroxynitrite (ONOO-). We investigated whether ONOO- and its metabolites modulate extracellular matrix remodeling. Stellate cells (HSC) were incubated with pure ONOO- or SIN-1 (a ONOO- donor). Western blot, nuclear in vitro transcription, Northern blot, qPCR, and promoter transactivation analysis for COL1A1 and COL1A2 were carried out. Rats were fed alcohol or injected with CCl4 to cause alcohol-induced liver injury and an early fibrogenic response. HSC incubated with ONOO- or SIN-1 showed similar viability, proliferation, COL1A1 and COL1A2 transcription rates, and mRNA levels as controls. There was a time- and dose-dependent down-regulation of collagen I and alpha-Sma proteins and up-regulation of MMP1 and TNFalpha, indicating decreased HSC activation. These effects were blocked by ONOO- scavengers. SIN-1 or ONOO- increased nitrosylation of MMP1/MMP13 and transactivation of the MMP1, MMP13, and TNFalpha promoters. A TNFalpha neutralizing antibody or GSH-ethyl ester blocked MMP1 promoter transactivation; whereas TNFalpha or l-buthionine sulfoximine, which depletes GSH, further enhanced it. Pretreatment with SIN-1 or ONOO- reduced the TGFbeta pro-fibrogenic response in HSC. In vivo experiments validated the protective role of ONOO- on the early fibrogenic response. However, highly activated HSC, such as myofibroblasts and HSC from chronic alcohol-fed rats, were resistant to the anti-fibrogenic actions of ONOO- due to higher levels of GSH, a ONOO- scavenger, overproduction of pro-fibrogenic TGFbeta, and reactive oxygen species. |
Are the D9N , N291S , and T495G Polymorphisms of the Lipoprotein Lipase Gene Associated with Cerebral Infarction? | Lipoprotein lipase (LPL) plays an important role in plasma lipoprotein metabolism and its polymorphisms are possibly implicated in the etiology of ischemic cerebrovascular disease (CVD). The aim of this work was to determine the association of the of D9N, N291S, and T495G polymorphisms of the LPL gene as a risk factor for the development of CVD. A case-control study was conducted that included 100 patients with CVD and 120 healthy controls. All the subjects were genotyped for the D9N, N291S, and T495G polymorphisms of the LPL gene through polymerase chain reaction-restriction fragment length polymorphism, and the results were analyzed for their association with CVD. The D9N genotype was not significantly correlated with CVD; the odds ratio (OR) between the control subjects and CVD patients was .29 (95% confidence interval [CI], .03-2.66; P = .27). The N291S polymorphism was not significantly correlated with CVD either; the OR between the control subjects and CVD patients was 1.2 (95% CI, .07-19.46; P = .89). And the T495G mutation was not significantly correlated with CVD; the OR between the control subjects and the CVD patients was 1.21 (95% CI, .7-2.08; P = .48). | Dimethyl sulfoxide (DMSO), an agent that provides symptomatic relief in patients with interstitial cystitis (IC) works via an unknown mechanism. We investigated whether DMSO acts as a chemical stimulant of mast cell degranulation. A radioimmunoassay (RIA) specific for histamine was used to test this hypothesis. Twelve women with strictly diagnosed IC were treated with intravesical instillations of DMSO. Treatments were repeated at varying intervals, and each patient received three to six treatments. Urine histamine levels were measured before and after each intravesical instillation of DMSO. Dilutional effects of DMSO were corrected for by conversion of urine histamine concentration to urine histamine:creatinine ratio. The RIA was unaffected by the addition of DMSO to urine. No consistent change in the urine histamine:creatinine ratio following DMSO instillation was found. Trend analysis revealed no trend in the histamine:creatinine ratio with time. |
Do nitric oxide and cGMP induce COX-2 expression and PGE2 production in human granulosa cells through CREB signaling pathway? | 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. | A growing number of studies have highlighted impairments in the ability of individuals with autism spectrum disorders to recall specific, personally experienced material. These difficulties have been related to underlying problems with autonoetic consciousness, namely the subjective awareness of one's own existence in subjective time. The current paper describes the manifestation of these difficulties in three individuals diagnosed with Asperger syndrome. For the people described, lifelong collecting and hoarding behaviours appeared to serve the function of constituting and maintaining aspects of their sense of self, particularly the sense of continuity and agency over time. On the basis of this clinical information and previous research into self-related processes in people with autism spectrum disorders, an initial model of collecting and hoarding behaviours amongst individuals with Asperger syndrome was formulated. The implications of this formulation for both clinical practice and future research are discussed. |
Does methotrexate inhibit NF-κB activity via long intergenic ( noncoding ) RNA-p21 induction? | To determine interrelationships between the expression of long intergenic (noncoding) RNA-p21 (lincRNA-p21), NF-κB activity, and responses to methotrexate (MTX) in rheumatoid arthritis (RA) by analyzing patient blood samples and cell culture models. Expression levels of long noncoding RNA and messenger RNA (mRNA) were determined by quantitative reverse transcription-polymerase chain reaction. Western blotting and flow cytometry were used to quantify levels of intracellular proteins. Intracellular NF-κB activity was determined using an NF-κB luciferase reporter plasmid. Patients with RA expressed reduced basal levels of lincRNA-p21 and increased basal levels of phosphorylated p65 (RelA), a marker of NF-κB activation. Patients with RA who were not treated with MTX expressed lower levels of lincRNA-p21 and higher levels of phosphorylated p65 compared with RA patients treated with low-dose MTX. In cell culture using primary cells and transformed cell lines, MTX induced lincRNA-p21 through a DNA-dependent protein kinase catalytic subunit (DNA PKcs)-dependent mechanism. Deficiencies in the levels of PRKDC mRNA in patients with RA were also corrected by MTX in vivo. Furthermore, MTX reduced NF-κB activity in tumor necrosis factor α-treated cells through a DNA PKcs-dependent mechanism via induction of lincRNA-p21. Finally, we observed that depressed levels of TP53 and lincRNA-p21 increased NF-κB activity in cell lines. Decreased levels of lincRNA-p21 did not alter NFKB1 or RELA transcripts; rather, lincRNA-p21 physically bound to RELA mRNA. | Dumping syndrome is a well-described consequence of Roux-en-Y gastric bypass. Although the condition can benefit some patients with morbid obesity, a subset will develop intractable dumping syndrome characterized by symptomatic episodes with most meals. We describe the first series of patients successfully treated endoscopically for intractable dumping syndrome. Endoscopic gastrojejunal anastomotic reduction was performed in patients with intractable dumping syndrome after Roux-en-Y gastric bypass using a combination of argon plasma coagulation, endoscopic suturing, and fibrin glue. The technical feasibility of endoscopic anastomotic reduction and the clinical improvement in dumping symptoms were assessed by clinical follow-up. Endoscopic anastomotic reduction was technically successful in 6 consecutive patients with a dilated gastrojejunal anastomosis and intractable dumping syndrome. One patient reported hematemesis 2 days after the procedure that was treated endoscopically. No other significant complications occurred. Complete and persistent resolution of the dumping symptoms was achieved in all patients, with a median follow-up of 636 days. |
Are serum visfatin concentrations positively correlated with serum triacylglycerols and down-regulated by overfeeding in healthy young men? | Visfatin is an insulin-mimicking adipokine. Visfatin is elevated in obesity and type 2 diabetes. However, its role in glucose and lipid metabolism in healthy humans is unclear. The objective was to investigate the correlations of visfatin with phenotypes of glucose, lipids, and body composition and the responses of visfatin to short-term overfeeding in healthy young men. Sixty-one healthy young men were recruited from the Newfoundland population. Serum visfatin, interleukin 6, glucose, insulin, total cholesterol, HDL cholesterol, LDL cholesterol, and triacylglycerol concentrations were measured with an autoanalyzer, and percentage body fat (%BF) and percentage trunk fat (%TF) were measured with dual-energy X-ray absorptiometry. Insulin resistance and beta cell function were assessed with the homeostasis model. All measurements were completed at baseline and after a 7-d overfeeding protocol exceeding the baseline requirement by 70%. Subjects were classified on the basis of %BF as lean (<21%), overweight (21-25.9%), or obese (>or=26%). Multiple regression analysis showed that triacylglycerols correlated with fasting serum visfatin (P < 0.001). Moreover, serum visfatin decreased 19% overall-23% in lean, 9% in overweight, and 18% in obese subjects (P < 0.0001)-after the overfeeding protocol. None of the variables measured, including interleukin 6, were associated with the reduction in visfatin. In contrast with the findings in mice, visfatin concentrations before and after overfeeding did not correlate with glucose, insulin, insulin resistance, beta cell function, %BF, or %TF. | 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. |
Do polymorphisms in glutathione S-transferase genes increase risk of prostate cancer biochemical recurrence differentially by ethnicity and disease severity? | Genetic polymorphisms that modify the detoxifying activity of glutathione S-transferases (GSTs) can affect the level of carcinogenic metabolites created by endogenous steroid hormones and exogenous chemical substances. Although the GSTM1 null genotype has been shown to increase prostate cancer mortality in Caucasians, potential associations between GST polymorphisms and prostate cancer biochemical recurrence (BCR) have not been well studied, particularly in African-Americans. We examined potential associations between the GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphisms and BCR, after prostatectomy, in 168 African-American and 226 Caucasian patients treated at Henry Ford Hospital in Detroit, Michigan using Cox proportional hazards modeling. We found that African-Americans with the GSTT1 null genotype had increased BCR risk compared to those having GSTT1 present (hazard ratio (HR) = 2.30; 95% CI = 1.01–5.18; p = 0.04); and African-Americans with the GSTT1 null genotype and high grade tumors had an even greater risk (HR = 7.82; 95% CI = 2.49–24.50; p < 0.001). In Caucasians, an increased risk was observed in those patients with high grade tumors and the GSTM1 null genotype (HR = 2.88; 95% CI = 1.16–7.14; p = 0.02). Similar associations were observed for advanced stage and more aggressive (high grade or advanced stage) disease. | Medical emergencies in dental practice are generally perceived as being rare. Nonetheless, recent studies have shown that incidents occur on a regular basis. Therefore, patients have the right to expect necessary skills to manage life-threatening situations from every dentist. To observe students' attitude and self-assessment towards emergency medical care (EMC) and its practical appliance. Students of dentistry took part in small group sessions for adult and paediatric basic life support. Participants filled out pre-post questionnaires regarding knowledge and attitude towards EMC (6, respectively, 10-point Likert scale). Additionally, feedback was asked for the quality of course and tutors. Forty dental students in their last 2 years of study registered for the EMC courses. The majority had never attended any first-aid course; the mean age was 25% and 75% were women. A comparison between pre- and post-evaluation showed that the participation in practical training easily enhances the students' awareness of EMC importance as well as self-confidence in managing emergencies. After the course, 71% shared the opinion that retraining should be obligatory for all medical personnel. At the same time, students' self-assessment of confidence for specific tasks got significant upgrades in every aspect. |
Is unreamed Intramedullary Nailing a better alternative than External Fixator for Gustilo grade IIIB Tibial Fractures based on a meta-analysis? | There remains a controversy between unreamed intramedullary nailing and external fixation to treat Gustilo grade IIIB tibial fractures. To evaluate the comparative effectiveness and safeness of both methods for this type of fracture, we performed this meta-analysis. Relevant original studies were searched in MEDLINE, EMBASE, China National Knowledge Infrastructure, and Cochrane Central Database (all through February 2014). Studies included in this meta-analysis had to compare the effectiveness or complications and provided sufficient data of interest. The patients treated by both methods were similar statistically in demography and injury mechanism. The Stata 11.0 was used to analyze all data. Six studies involving 163 participants were included. Unreamed intramedullary nailing was associated with reduced time to union (standardized mean difference, -1.14; 95% confidence interval, -2.04 to -0.24) and lower rates of superficial infection (odds ratio: 0.39; 95% confidence interval: 0.17-0.87) and malunion (odds ratio: 0.27; 95% confidence interval: 0.09-0.78). However, there were no significant differences in other adverse events including delayed union, non-union, deep infection, and fixation failure. | We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1α was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1α was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1α knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. |
Does the advanced glycation end product pentosidine correlate to IL-6 and other relevant inflammatory markers in rheumatoid arthritis? | Oxidative stress and inflammatory processes accelerate the formation of advanced glycation end products (AGE), e.g. of pentosidine. The aim of this study was to investigate the relationships between levels of pentosidine in serum and synovial fluid, proinflammatory cytokines, other markers of inflammatory activity, and the state of radiologically visible bone destruction in patients with rheumatoid arthritis (RA). One hundred thirty-three nondiabetic RA patients and 56 age-matched, healthy subjects were included. Serum and synovial fluid pentosidine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and rheumatoid factor levels were determined. In 30 patients, the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and TNF-alpha and the soluble receptors sIL-2R, sIL-6R, sTNF-alpha, and RI/RII were also measured. Serum levels of pentosidine were on average significantly higher in RA patients than in healthy subjects and correlated significantly to ESR, CRP, and serum levels of IL-6. Serum and synovial fluid pentosidine did not show any differences. Rheumatoid factor-positive RA patients had higher pentosidine levels in the synovial fluid than rheumatoid factor-negative patients. Correlations could not be found between pentosidine and the other cytokines or cytokine receptors measured. | To empirically derive the optimal measure of pharmacologic cardiovascular support in infants undergoing cardiac surgery with bypass and to assess the association between this score and clinical outcomes in a multi-institutional cohort. Prospective, multi-institutional cohort study. Cardiac ICUs at four academic children's hospitals participating in the Pediatric Cardiac Critical Care Consortium during the study period. Children younger than 1 year at the time of surgery treated postoperatively in the cardiac ICU. None. Three hundred ninety-one infants undergoing surgery with bypass were enrolled consecutively from November 2011 to April 2012. Hourly doses of all vasoactive agents were recorded for the first 48 hours after cardiac ICU admission. Multiple derivations of an inotropic score were tested, and maximum vasoactive-inotropic score in the first 24 hours was further analyzed for association with clinical outcomes. The primary composite "poor outcome" variable included at least one of mortality, mechanical circulatory support, cardiac arrest, renal replacement therapy, or neurologic injury. High vasoactive-inotropic score was empirically defined as more than or equal to 20. Multivariable logistic regression was performed controlling for center and patient characteristics. Patients with high vasoactive-inotropic score had significantly greater odds of a poor outcome (odds ratio, 6.5; 95% CI, 2.9-14.6), mortality (odds ratio, 13.2; 95% CI, 3.7-47.6), and prolonged time to first extubation and cardiac ICU length of stay compared with patients with low vasoactive-inotropic score. Stratified analyses by age (neonate vs infant) and surgical complexity (low vs high) showed similar associations with increased morbidity and mortality for patients with high vasoactive-inotropic score. |
Is pTEN loss associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma? | Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy. PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G | Studies that investigate the subjective benefit from a bone conduction implant (BCI) sound processor in patients with single-sided sensorineural deafness (SSD) have been limited to examining short- and mid-term benefit. In the current study, we performed a survey among 44 SSD BCI users with a median follow-up time of 50 months. Forty-four experienced SSD BCI users participated in the survey, which consisted of the Abbreviated Profile of Hearing Aid Benefit, the Single-Sided Deafness Questionnaire, the Short Hearing Handicap Inventory for Adults, and a self-made user questionnaire. For patients with tinnitus, the Tinnitus Questionnaire was also completed. The results of the survey were correlated with contralateral hearing loss, age at implantation, duration of the hearing loss at the time of implantation, duration of BCI use, and the presence and burden of tinnitus. In total, 86% of the patients still used their sound processor. The Abbreviated Profile of Hearing Aid Benefit and the Short Hearing Handicap Inventory for Adults show a statistically significant overall improvement with the BCI. The Single-Sided Deafness Questionnaire and the user questionnaire showed that almost 40% of the patients reported daily use of the sound processor. However, the survey of daily use reveals benefit only in certain circumstances. Speech understanding in noisy situations is rated rather low, and 58% of all patients reported that their BCI benefit was less than expected. |
Does tapered-cuff Endotracheal Tube Prevent Early Postoperative Pneumonia Compared with Spherical-cuff Endotracheal Tube after Major Vascular Surgery : A Randomized Controlled Trial? | Patients undergoing major vascular surgery often develop postoperative pneumonia that impacts their outcomes. Conflicting data exist concerning the potential benefit of tapered-shaped cuffs on tracheal sealing. The primary objective of this study was to assess the efficiency of a polyvinyl chloride tapered-cuff endotracheal tube at reducing the postoperative pneumonia rate after major vascular surgery. Secondary objectives were to determine its impact on microaspiration, ventilator-associated pneumonia rate, and inner cuff pressure. This prospective randomized controlled study included 109 patients who were randomly assigned to receive either spherical- (standard cuff) or taper-shaped (tapered cuff) endotracheal tubes inserted after anesthesia induction and then admitted to the intensive care unit after major vascular surgery. Cuff pressure was continuously recorded over 5 h. Pepsin and α-amylase concentrations in tracheal aspirates were quantified on postoperative days 1 and 2. The primary outcome was the early postoperative pneumonia frequency. Comparing the tapered-cuff with standard-cuff group, respectively, postoperative pneumonia rates were comparable (42 vs. 44%, P = 0.87) and the percentage (interquartile range) of cuff-pressure time with overinflation was significantly higher (16.1% [1.5 to 50] vs. 0.6% [0 to 8.3], P = 0.01), with a 2.5-fold higher coefficient of variation (20.2 [10.6 to 29.4] vs. 7.6 [6.2 to 10.2], P < 0.001). Although microaspiration frequencies were high, they did not differ between groups. | This study is in an attempt to evaluate the diagnostic significance to predict the spermatogenesis of azoospermic men in examination of serum follicle-stimulating hormone (FSH) combination with serum inhibin B (INHB). Quantitative examination of serum FSH and INHB was performed in 95 case of azoospermic men. According to their classifications of testicular biopsy with histopathological examination, there were 20 patients of Sertoli cell only, 25 of hypospermatogenesis, 18 of spermatogenic maturation arrest (complete or incomplete), and 32 of normal spermatogenesis. The association of serum FSH and INHB levels with histopathological classifications were analyzed by using statistical software. Serum FSH, INHB and INHB/FSH levels of Sertoli cell only differed with statistical significance from hypospermatogenesis, spermatogenic maturation arrest and normal spermatogenesis (P<0.05). FSH, in which there were no statistical significance among the latter three classifications (P>0.05). Serum FSH, INHB and INHB/FSH levels were no relationship with maturation arrest (P>0.05), but were negatively related to the other classifications (P<0.05). INHB level less than 28.55 pg/ml predicted Sertoli cell only in a sensitivity of 97% and a specificity of 85%. |
Is mean platelet volume a predictor of ST resolution following thrombolysis in acute ST elevation myocardial infarction? | Larger mean platelets volumes (MPV) are thrombogenic and frequently seen after ST-segment elevation myocardial infarction (STEMI). This study aimed to examine the association of MPV and resolution of ST-segment after thrombolysis in STEMI patients as and its impact on clinical outcome. Patients presenting to the emergency department with the diagnosis of first STEMI and were referred to thrombolysis were screened. Patients with ≥50% ST-segment resolution (STR) 90minutes after thrombolysis were assigned as "Responder" and those with <50% STR were assigned as "Non-Responders". Demographic, clinical comorbidities and risk factor were recorded along with and angiographic data. In-hospital occurrence of major adverse cardiac events (MACE), including acute heart failure (AHF), reinfarction and death were investigated. Additionally, the patients were followed for 6 additional months after their discharge from the hospital. STR≥50% was seen in 60.2% of patients after thrombolysis. Responders had significantly lower MPV (P=0.001) and the critical MPV values were 8.0 femtoliter (fL) and 8.2fL in predicting STR and MACE. Patients with MPV ≥8.2fL had lower probability of STR and higher rates of AHF (P<0.001), and MACE (P=0.001) compared to the patients with lower platelet volume. In multivariate regression, MPV was an independent predictor of STR (P<0.001) as well as MACE (HR=4.8, 95% CI of 1.8-12.4; P=0.001). Triple vessel disease was another independent factor that predicted MACE. | Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of 5' adenosine monophosphate-activated protein kinase (AMPK) activator resveratrol and AICAR to inhibit microglial activation and to limit the decrease in antinociceptive effects of morphine. The microglial cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using the hot plate and tail-flick tests. (1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase phosphorylation, nuclear factor-κB translocation and mRNA expression of pro-inflammatory cytokines [including interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α], inducible nitric oxide synthase and Toll-like receptor-4, and these changes are inhibited by resveratrol. (2) Resveratrol activates AMPK to suppress morphine-induced BV-2 cell activation. AICAR, another AMPK activator, can mimic the effects of resveratrol, whereas compound C, an AMPK inhibitor, reverses the inhibitory effects of resveratrol treatment. (3) Systemic or spinal administration of resveratrol with morphine significantly blocks microglial activation in the spinal cord and then attenuates the development of acute and chronic morphine tolerance in both male and female mice. |
Is meiotic spindle configuration differentially influenced by FSH and epidermal growth factor during in vitro maturation of mouse oocytes? | To ascertain whether different hormonal treatment protocols could affect metaphase II (MII) spindle morphology, meiotic spindle organization was detected in prepubertal mouse oocytes matured under conditions allowing spontaneous, FSH- or epidermal growth factor (EGF)-dependent meiotic maturation. Oocyte-cumulus complexes (OCCs) were matured either spontaneously (control; n=270) or in the presence of hypoxanthine (Hx) plus FSH (n=400) or EGF (n=370). Spindles were detected by immunofluorescence analysis. In vivo ovulated (IVO) oocytes were processed similarly. IVO oocytes displayed spindles underlying the oolemma and with focused poles marked by spots of gamma-tubulin, whereas the majority (89%) of control oocytes had barrel-shaped spindles, positioned away from the oolemma, and with gamma-tubulin distributed along microtubules. Similar configuration/localization was found in 85% of the oocytes matured in vitro in the presence of Hx and FSH. In the presence of Hx-EGF, 35% of the oocytes showed spindles with an IVO-like configuration, although gamma-tubulin was homogeneously distributed throughout microtubules. Independently of spindle shape, 52% of EGF-stimulated oocytes had spindles positioned near the oolemma, in comparison to just 24% of FSH-treated and 13% of control oocytes. | HIV-infected individuals bear increased cardiovascular risk even in the absence of traditional cardiovascular risk factors. In the general population, coronary artery calcium (CAC) scanning is of value for cardiovascular risk stratification, but whether a CAC score of zero implies a low noncalcified coronary plaque burden in HIV-infected persons is unknown. We assessed the prevalence of noncalcified coronary plaque and compared noncalcified coronary plaque burden between HIV-infected and HIV-uninfected participants who had CAC scores of zero in the Multicenter AIDS Cohort Study (MACS) using coronary computed tomography (CT) angiography. HIV infection was associated with the presence of noncalcified coronary plaque among these men with CAC scores of zero. In a model adjusted only for age, race, centre, and pre- or post-2001 cohort, the prevalence ratio for the presence of noncalcified plaque was 1.27 (95% confidence interval 1.04-1.56; P = 0.02). After additionally adjusting for cardiovascular risk factors, HIV infection remained associated with the presence of noncalcified coronary plaque (prevalence ratio 1.31; 95% confidence interval 1.07-1.6; P = 0.01). |
Do insulin resistant rats display enhanced rewarding effects of nicotine? | Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non-insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward. | Ureaplasma spp are the most commonly isolated microorganisms in association with preterm birth. Maternal erythromycin administration is a standard treatment for preterm prelabor rupture of membranes. There is little evidence of its effectiveness in eradicating Ureaplasma spp from the intrauterine cavity and fetus. We used a sheep model of intrauterine Ureaplasma spp infection to investigate the efficacy of repeated maternal intramuscular and intraamniotic erythromycin treatment to eradicate such an infection. Thirty ewes with singleton pregnancies received an intraamniotic injection of 10(7) color change units of erythromycin-sensitive Ureaplasma parvum serovar 3 at 55 days' gestation. At 116 days' gestation, 28 ewes with viable fetuses were randomized to receive (1) intraamniotic and maternal intramuscular saline solution treatment (n = 8), (2) single intraamniotic and repeated maternal intramuscular erythromycin treatment (n = 10), or (3) single maternal intramuscular and repeated intraamniotic erythromycin treatment (n = 10). Fetuses were surgically delivered at 125 days' gestation. Treatment efficacy was assessed by culture, quantitative polymerase chain reaction, and histopathologic evaluation. Animals treated with intraamniotic erythromycin had significantly less viable U parvum serovar 3 in the amniotic fluid at delivery. However, neither combination of maternal intramuscular and intraamniotic erythromycin treatment successfully cleared U parvum serovar 3 from the amniotic fluid or fetal tissues. Three de novo erythromycin-resistant U parvum isolates were identified in erythromycin-treated animals. |
Is ibutilide , a methanesulfonanilide antiarrhythmic , a potent blocker of the rapidly activating delayed rectifier K+ current ( IKr ) in AT-1 cells . Concentration- , time- , voltage- , and use-dependent effects? | Ibutilide is an action potential-prolonging antiarrhythmic currently in clinical trials. The drug shares structural similarities with E-4031 and dofetilide, specific blockers of the rapidly activating delayed rectifier K+ current (IKr). However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block IKr but rather increases a slow inward sodium current. In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial tumor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical IKr is the major delayed rectifier and can be readily recorded in isolation from other currents. In AT-1 cells, ibutilide and dofetilide were both potent IKr blockers, with EC50 values of 20 (n = 12) and 12 (n = 8) nmol/L, respectively, at +20 mV. The time and voltage dependence of IKr inhibition by the two compounds were virtually identical. The following characteristics were most consistent with open channel block: (1) block increased with depolarizing pulses; (2) block increased with longer pulses; (3) currents deactivated more slowly in the presence of drug, resulting in a "crossover" typical of open channel block; and (4) with repetitive pulsing after drug wash-in, use-dependent block was observed. | There is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population. RKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNFalpha were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of >or=2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses. During 15 years of followup, the prevalence of RKOA (K/L grade >or=2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 x 10(-5)), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94-3.87). |
Is insulin resistance the major determinant for microalbuminuria in severe hypertriglyceridemia : implication for high-risk stratification? | The significance of high triglyceride levels as a risk factor for coronary heart disease is uncertain. We hypothesized that oral glucose tolerance test (OGTT) and certain novel markers may help to identify high-risk patients. We recruited 80 subjects with severe hypertriglyceridemia (age 27-73 years) without clinical proteinuria and diabetes mellitus (DM) which were diagnosed by fasting glucose <126 mg/dL from Hyperlipidemia Clinic of National Taiwan University Hospital for this study. We applied OGTT to evaluate occult DM and homeostasis model assessment (HOMA)-insulin resistance (IR) score to evaluate insulin resistance, and the measurements of microalbuminuria as a marker of vascular damage. In addition, serum or plasma markers of inflammation and fibrinolysis, fasting glucose and insulin as well as traditional cardiovascular risk factors were also evaluated. The serum level of triglyceride was higher in patients with microalbuminuria than in those without (14.1+/-5.7 vs. 9.6+/-3.9 mmol/L, p=0.025). Patients with microalbuminuria had higher fasting blood glucose and insulin, higher post-OGTT glucose and insulin, higher prevalence of newly developed diabetes mellitus (DM) (39% vs. 11%, p=0.007) and higher HOMA-IR (6.2+/-4.4 vs. 3.3+/-2.0, p<0.001). Among all the inflammatory and fibrinolytic markers, only soluble intercellular adhesion molecule showed significant different between these two groups. Multiple logistic regression analysis showed that among the serum markers, only HOMA-IR level was significantly related to microalbuminuria. | to investigate the origin characters of snore in simple snorers and provide the basis for its treatment. Thirty-two simple snorers diagnosed by polysomnography were induced to sleep by propofol and dexmedetomidine, then we observed the vibration sites, pattern and concomitant collapse of soft tissue in pharyngeal cavity by nasendoscopy. Thirteen cases showed palatal fluttering only, and 1 case showed vibration of epiglottis only. Six cases showed palatal fluttering with vibration of epiglottis, and 2 cases showed palatal fluttering with vibration of epiglottis and tongue base. Five cases showed palatal fluttering with vibration of pharyngeal lateral wall, and 5 cases showed palatal fluttering with vibration of lateral wall, epiglottis and tongue base together. Palate and pharyngeal lateral wall vibrated strongly and always collapsed with vibrating, but epiglottis and tongue base usually vibrated slightly and seldom collapsed. |
Does the NAD ( + ) precursor nicotinamide riboside decrease exercise performance in rats? | Nicotinamide adenine dinucleotide (NAD(+)) and its phosphorylated form (NADP(+)) are key molecules in ubiquitous bioenergetic and cellular signaling pathways, regulating cellular metabolism and homeostasis. Thus, supplementation with NAD(+) and NADP(+) precursors emerged as a promising strategy to gain many and multifaceted health benefits. In this proof-of-concept study, we sought to investigate whether chronic nicotinamide riboside administration (an NAD(+) precursor) affects exercise performance. Eighteen Wistar rats were equally divided in two groups that received either saline vehicle or nicotinamide riboside at a dose of 300 mg/kg body weight/day for 21 days via gavage. At the end of the 21-day administration protocol, both groups performed an incremental swimming performance test. The nicotinamide riboside group showed a tendency towards worse physical performance by 35 % compared to the control group at the final 10 % load (94 ± 53 s for the nicotinamide riboside group and 145 ± 59 s for the control group; P = 0.071). | Low rates of influenza immunization among health care workers (HCWs) pose a potential health risk to patients in primary care practices. Despite previous educational efforts and programs to reduce financial barriers, HCW influenza immunization rates remain low. Variation in practice-level organizational culture may affect immunization rates. To explore this relationship, we examined organizational cultures and HCWs' influenza immunization behaviors in three family medicine practices. We used a multi-method comparative case study. A field researcher used participant observation, in-depth interviews, and key informant interviews to collect data in each practice in November-December 2003. A diverse team used grounded theory to analyze text data. Organizational culture varied among practices and differing HCW immunization rates were observed. The most structured and business-like practice achieved immunization of all HCWs, while the other two practices exhibited greater variation in HCW immunization rates. Physicians in the practices characterized as chaotic/disorganized or divided were immunized at higher rates than other members of the practices. |
Do neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis? | Autophagy is a fundamental cell biological process whereby eukaryotic cells form membranes in the cytoplasm to sequester diverse intracellular targets. Although significant progress has been made in understanding the origins of autophagosomal organelles, the source of lipids that support autophagic membrane formation remain an important open question. Here we show that lipid droplets as cellular stores of neutral lipids including triglycerides contribute to autophagic initiation. Lipid droplets, as previously shown, were consumed upon induction of autophagy by starvation. However, inhibition of autophagic maturation by blocking acidification or using dominant negative Atg4(C74A) that prohibits autophagosomal closure did not prevent disappearance of lipid droplets. Thus, lipid droplets continued to be utilized upon induction of autophagy, but not as autophagic substrates in a process referred to as lipophagy. We considered an alternative model whereby lipid droplets were consumed not as a part of lipophagy, but as a potential contributing source to the biogenesis of lipid precursors for nascent autophagosomes. We carried out a screen for a potential link between triglyceride mobilization and autophagy and identified a neutral lipase, PNPLA5, as being required for efficient autophagy. PNPLA5, which localized to lipid droplets, was needed for optimal initiation of autophagy. PNPLA5 was required for autophagy of diverse substrates, including degradation of autophagic adaptors, bulk proteolysis, mitochondrial quantity control, and microbial clearance. | There is growing awareness of the need to explore patient reported outcomes in clinical trials. In the Scandinavian Surgical Outcomes Research Group we are conducting several clinical trials in cooperation between Danish and Swedish surgical researchers, and we use questionnaires aimed at patients from both countries. In relation to this and similar international cooperation, the validity and reliability of translated questionnaires are central aspects. The purpose of this study was to explore which methodological measures were used in studies reporting translation of questionnaires. Furthermore, we wanted to make some methodological suggestions for clinical researchers who are faced with having to translate a questionnaire. We designed a research study based on a survey of the literature and extracted data from published studies reporting the methodological process when translating questionnaires on health related quality of life for different diseases. We retrieved 187 studies and out of theses we included 52 studies. The psychometric properties of the translated versions were validated using different tests. The focus was on internal validity (96%), reliability (67%) criterion validity (81%), and construct validity (62%). For internal validity Cronbach's alpha was used in 94% of the studies. |
Does improvement of Bovine Nucleus Pulposus Cells Isolation lead to Identification of Three Phenotypically Distinct Cell Subpopulations? | Strategies to promote intervertebral disc (IVD) regeneration have been hindered by the lack of knowledge of IVD fundamental cellular/molecular components. One of the key points to be addressed is the characterization of nucleus pulposus (NP) cell population(s). This study establishes an improved method for bovine NP (bNP) cell isolation, whose procedure is still not consensual among the literature, allowing a thorough characterization of cell (sub)populations that exist in the young NP. bNP was digested with distinct enzymes (collagenase-type-I, collagenase-type-II, and collagenase-type-XI) at different concentrations (0.5, 1.0, and 2.0 mg/mL), for 4 and 19 h. Cell yield, viability/apoptosis, and morphology were analyzed by flow cytometry and imaging flow cytometry. Identification of cell subpopulations within NP and its phenotype was investigated by assessing expression of CD29, CD44, CD45, CD34, CD146, and Brachyury. It was found that bNP cells present a similar morphology independently of the digestive enzyme used. However, cell yield was greatly improved by Coll-XI (2 mg/mL) treatment for a short digestion period. Interestingly, three subpopulations, with different sizes and auto-fluorescence, were consistently identified by flow cytometry. And crucially, differential expression of cell markers was found among these subpopulations. | This study was designed to: [1] measure, for the first time, metastin (kisspeptin) levels in women with polycystic ovary syndrome (PCOS), a condition associated with hypersecretion of LH and hyperandrogenemia; and [2] investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances. Clinical study. University hospital. Twenty-eight obese and overweight (body mass index [BMI] >25 kg/m2) women with PCOS, 28 normal weight (BMI <25 kg/m2) women with the syndrome, and 13 obese and overweight controls (ovulatory women without clinical or biochemical hyperandrogenemia) were selected. Blood samples were collected between day 3 and day 6 of a spontaneous bleeding episode in the PCOS groups and a menstrual cycle of the controls, at 9:00 AM, after an overnight fast. Circulating levels of LH, FSH, PRL, T, Delta4-androstenedione (A), DHEAS, 17alpha-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were measured. Both normal weight women with PCOS and obese controls were less insulin resistant and had significantly higher metastin levels, compared to obese and overweight women with the syndrome. Plasma kisspeptin levels were negatively correlated with BMI, free androgen index, and indices of insulin resistance. |
Do large-volume low apparent diffusion coefficient lesions predict poor survival in bevacizumab-treated glioblastoma patients? | Glioblastomas treated with bevacizumab may develop low-signal apparent diffusion coefficient (low-ADC) lesions, which may reflect increased tumor cellularity or atypical necrosis. The purpose of this study was to examine the relationship between low-ADC lesions and overall survival (OS). We hypothesized that growing low-ADC lesions would be associated with shorter OS. We retrospectively identified 52 patients treated with bevacizumab for the first (n = 42, 81%) or later recurrence of primary glioblastoma, who had low-ADC lesions and 2 post-bevacizumab scans ≤90 days apart. Low-ADC lesion volumes were measured, and normalized 5th percentile histogram low-ADC values were recorded. Using OS as the primary endpoint, semiparametric Cox models were fitted to ascertain univariate and multivariate hazard ratios (HRs) with significance at P = .05. Median OS was 9.1 months (95% CI = 7.2-14.3). At the second post-bevacizumab scan, the volume of the low-ADC lesion (median: 12.94 cm(3)) was inversely associated with OS, with larger volumes predicting shorter OS (HR = 1.014 [95% CI = 1.003-1.025], P = .009). The percent change in low-ADC volume (median: 6.8%) trended toward increased risk of death with growing volumes (P = .08). Normalized 5th percentile low-ADC value and its percent change were not associated with OS (P > .51). Also correlated with shorter OS were the pre-bevacizumab nonenhancing volume (P = .025), the first post-bevacizumab enhancing volume (P = .040), and the second post-bevacizumab enhancing volume (P = .004). | Microbial leakage and colonization between implants and their abutments may cause inflammatory reactions in the peri-implant tissues. This study evaluated microbial leakage at the implant-abutment interface with a new in vitro model. Bacterial leakage was tested during dynamic loading in a 2-axis chewing simulator. The authors theorized that dynamic loading would decrease the stability of the implant-abutment connections and thereby lead to bacterial penetration along the gap. Five different implant systems with 8 standard implant-abutment combinations for single molar crowns were tested. The internal aspects of the implants were inoculated with a bacterial suspension and connected to the superstructure with the recommended torque. The specimens were immersed in a nutrient solution and loaded with 1,200,000 cycles of 120 N in the chewing simulator. Statistically significant differences (P < or = .05) between implant systems with respect to number of chewing cycles until bacterial penetration were found. |
Are chronic respiratory disease and high altitude associated with depressive symptoms in four diverse settings? | Depression is a prevalent comorbidity of chronic respiratory disease (CRD), and may indicate worse clinical outcomes. The relationship between depression and living with chronic hypoxia due to CRD or residence at altitude has received little attention in resource-poor settings. To investigate the association between CRD conditions and depressive symptoms in four settings in Peru. We collected data on CRD and depressive symptoms in adults aged ⩾35 years. Depressive symptoms were measured according to the Center for Epidemiologic Studies Depression scale. Multivariable ordinal logistic regression was used to assess the adjusted odds of being in a higher category of depressive symptoms as a function of CRD. We analyzed data from 2953 participants (mean age 55.3 years, 49% male). The prevalence of major depressive symptoms was 19%, with significant variation according to setting. Participants with at least one CRD (OR 1.34, 95%CI 1.06-1.69) and those living at altitude (OR 1.64, 95%CI 1.10-2.43) had an increased adjusted odds of being in a higher category of depressive symptoms. | Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification. We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26-84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4. |
Is the surgical error examination a novel method for objective technical knowledge assessment? | Objective analysis of surgical skill is necessary. A novel method of assessment using simple error analysis in synthetic models is examined for construct validity. Two examination protocols were devised using synthetic models. These contained either a purpose made error or were representative of good surgical practice. Protocol one contained models of skin closure and minor operations. Protocol two in addition more complex procedures. Face validity was established by the approval of senior surgeons. Junior surgeons were recruited to undertake the assessment. A p value of less than 0.05 was deemed to be significant. Eighty-nine surgeons were recruited. Both protocol one and two were able to discriminate between groups at statistically significant levels. | ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells. Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette (ABC) transporters. We determined the effects of cabazitaxel, a novel tubulin-binding taxane, and paclitaxel on paclitaxel-resistant, ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant, ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter. Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2, LLC-MDR1-WT, and HEK293/ABCC10 cells. Moreover, cabazitaxel had low efficacy, whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1, indicating a direct interaction of both drugs with the transporter. |
Is [ Agrobacterium tumefaciens-mediated transformation of uracil auxotroph Aspergillus fumigatus an efficient method for target gene knockout ]? | To investigate the efficiency of Agrobacterium tumefaciens mediated transformation of Aspergillus fumigatus by using pyrG as a recessive selectable marker. FAP1 and SHO1 genes target sequences, composed of a selectable marker pyrG and the flanking sequences of the FAP1 and the SHO1 genes, were cloned into a binary plasmid pDHt/sk, respectively. The produced plasmids were transformed into A. tumefaciens. The A. tumefaciens and uracil auxotroph A. fumigatus were cocultured in induction medium without uricil and uridine at 24 degrees C for 48 h. To inhibit growth of A. tumefaciens and to select transformants, the cultures were transferred to 37 degrees C and incubated for another 48 h. In this study, A. tumefaciens-mediated transformation of A. fumigatus produced high homologous recombination rates, which was 44% (7 of 16) for FAP1 and 35% (7 of 20) for SHO1. | Population-based studies of associations between subclinical hypercortisolism and risk for disease states, such as type 2 diabetes mellitus, have been difficult to assess because of imprecise measures of glucocorticoid exposure. Alternative measures (salivary cortisol and adrenal gland volume) have not been systematically compared with 24-h urine free cortisol (UFC) in a healthy population. Our objectives were: 1) to determine whether 24-h UFC and total daily salivary cortisol correlated with each other, adrenal gland volume, and salivary cortisol after dexamethasone suppression and 2) to evaluate the association of adrenal gland volume with salivary cortisol after dexamethasone suppression. This was a cross-sectional study of 20 healthy, premenopausal African-American women aged 18-45 yr. Salivary cortisol was assessed at six time points throughout the day simultaneous with 24-h UFC collection. Adrenal gland volume was measured by computed tomography scan. Dexamethasone-suppressed salivary cortisol was measured at 0800 h after administration of 0.5 mg dexamethasone at 2300 h the prior evening. Dexamethasone-suppressed salivary cortisol levels correlated strongly with individual, timed salivary cortisol measurements, total daily salivary cortisol (rs=0.75; P=0.0001; n=20), and adrenal gland volume (rs=0.66; P=0.004; n=17). Total daily salivary cortisol and adrenal gland volume also correlated (rs=0.46; P=0.04; n=19). In contrast, 24-h UFC levels did not correlate with any of the other hypothalamic-pituitary-adrenal axis measures. |
Is amyloid-beta found in drusen from some age-related macular degeneration retinas , but not in drusen from normal retinas? | Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the elderly. Increased understanding of the pathogenesis is necessary. Amyloid-beta (Abeta), a major extracellular deposit in Alzheimer's disease plaques, has recently been found in drusen, the hallmark extracellular deposit in AMD. The goal of this study was to characterize the distribution and frequency of Abeta deposits in drusen from AMD and normal post mortem human retinas to gain additional insight about the potential role of Abeta in AMD patho genesis. Immunocytochemistry was performed with three Abeta antibodies on sections from 9 normal and 9 AMD (3 early, 3 geographic atrophy, 3 exudative AMD) retinas. Five sections from each eye were evaluated. Abeta positive deposits in drusen were identified using epifluorescence and confocal microscopy. Antibodies were pre-adsorbed with Abeta peptide to verify specificity. Some sections were stained with PAS-hematoxylin to aid in evaluation of morphology. To test and optimize immunocytochemistry, Abeta was detected in amyloid plaques from Alzheimer's brains. Abeta label was blocked by pre-adsorption of antibody with Abeta peptide, verifying specificity. Four of the 9 AMD retinas and none of the 9 normal retinas had Abeta positive drusen. Two of the early AMD eyes had a few A[beta] positive drusen, each with a few Abeta-containing vesicles, and 2 of the geographic atrophy (GA) eyes had many Abeta positive drusen with many Abeta containing vesicles. | Narcotic agents are frequently administered to manage increased intestinal motility in patients with short bowel syndrome, but long-term use is associated with gastrointestinal (GI) complaints. This analysis evaluated the incidence of narcotic use and abdominal adverse events among patients with short bowel syndrome receiving teduglutide. Pooled data from patients who received ≥1 dose of teduglutide 0.05 mg/kg/d (n = 77) or placebo (n = 59) in either of 2 randomized, double-blind, phase III studies were analyzed. Of 136 patients, 52 (38%) received narcotics. GI adverse events occurred more often among patients who received narcotics than among those who did not (abdominal pain, 51% vs 21%; nausea, 42% vs 11%; abdominal distension, 17% vs 8%; vomiting, 19% vs 6%). Logistic regression analysis indicated that the probability of GI adverse events was significantly increased in patients with narcotic use (P = .0009). In contrast, teduglutide treatment, as well as the interaction between teduglutide and narcotic use, did not affect the probability of GI adverse events. |
Is the recent decline in mammography rates limited to low- to average-risk women? | There has recently been a decline in mammography rates noted in the general population. We sought to determine whether similar trends hold in high-risk populations. Mammography rates from the National Health Interview Survey for 2000 and 2005 were analyzed for differences among risk-stratified populations of women over the age of 40. Although high-risk women (those with a personal of family history of breast cancer) were more likely to report having had a mammogram than lower risk women, they, too, showed a small decline in mammography rates. This, however, did not reach statistical significance. The decline in mammography rates in lower risk women, however, was significant and correlated with that of the general population. | To investigate the in vivo effect of atrial natriuretic peptide (ANP) and its signaling pathway during orthotopic rat liver transplantation. Rats were infused with NaCl, ANP (5 microg/kg), wortmannin (WM, 16 microg/kg), or a combination of both for 20 min. Livers were stored in UW solution (4 degrees C) for 24 h, transplanted and reperfused. Apoptosis was examined by caspase-3 activity and TUNEL staining. Phosphorylation of Akt and Bad was visualized by Western blotting and phospho-Akt-localization by confocal microscopy. ANP-pretreatment decreased caspase-3 activity and TUNEL-positive cells after cold ischemia, indicating antiapoptotic effects of ANP in vivo. The antiapoptotic signaling of ANP was most likely caused by phosphorylation of Akt and Bad, since pretreatment with PI 3-kinase inhibitor WM abrogated the ANP-induced reduction of caspase-3 activity. Interestingly, analysis of liver tissue by confocal microscopy showed translocation of phosphorylated Akt to the plasma membrane of hepatocytes evoked by ANP. |
Is intensity-Modulated Radiation Therapy Associated with Perioperative or Survival Benefit over 3D-Conformal Radiotherapy for Rectal Cancer? | The use of intensity-modulated radiation therapy (IMRT) in rectal cancer has steadily increased over traditional 3D conformal radiotherapy (3D-CRT) due to perceived benefit of delivering higher treatment doses while minimizing exposure to surrounding tissues. However, IMRT is technically challenging and costly, and its effects on rectal cancer outcomes remain unclear. Adults with clinical stage II and III rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy with 45-54 Gy of radiation and surgery were included from the 2006-2013 National Cancer Data Base. Patients were grouped based the modality of radiation received: IMRT or 3D-CRT. Multivariable regression modeling adjusting for demographic, clinical, and treatment characteristics was used to examine the impact of IMRT vs. 3D-CRT on pathologic downstaging, resection margin positivity, sphincter loss surgery, 30-day unplanned readmission and mortality after surgery, and overall survival. Among 7386 patients included, 3330 (45 %) received IMRT and 4056 (55 %) received 3D-CRT. While the mean radiation dose delivered was higher with IMRT (4735 vs. 4608 cGy, p < 0.001), it was associated with higher risks of positive margins (adjusted odds ratio (OR) 1.57; p < 0.001) and sphincter loss surgery (OR 1.32; p < 0.001). There were no differences between IMRT and 3D-CRT in the likelihood of pathologic downstaging (OR 0.89, p = 0.051), unplanned readmission (OR 0.79; p = 0.07), or 30-day mortality (OR 0.61; p = 0.31) after surgery. Additionally, there were no differences in overall survival at 8 years (IMRT vs. 3D-CRT: 64 vs. 64 %; adjusted hazard ratio 1.06, p = 0.47). | Sphingosine 1-phosphate is a naturally occurring biologically active lysophospholipid. Recent studies suggested that sphingosine 1-phosphate is released into the blood flow from activated platelets upon stimulation to exert multiple biological phenomenon. The purpose of this study was to assess the effects of sphingosine 1-phosphate on sinus automaticity, ventricular contraction and coronary blood flow. The canine isolated, blood-perfused sinoatrial node and papillary muscle preparations were used. Sphingosine 1-phosphate increased the sinoatrial rate, while it decreased the coronary blood flow, which was followed by a weak negative inotropic effect. These positive chronotropic and coronary vasoconstrictor effects were not attenuated by the beta- and alpha-adrenoceptor antagonists atenolol and prazosin, respectively. Furthermore, sphingosine 1-phosphate did not affect the adenylate cyclase activity of the membrane preparations made from the canine right atrium and right ventricle, indicating the involvement of a novel signaling pathway in sphingosine 1-phosphate-induced cardiac effects. |
Do hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis? | Overexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice. Here, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl(4)) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen. | Administration of tissue plasminogen activator (tPA) for acute ischemic stroke remains controversial in community practice. Well-organized hierarchic systems of acute stroke care have been proposed to link community hospitals to comprehensive stroke centers. We report safety and functional outcomes in patients treated with tPA in our regional emergency stroke network and compare them with results reported from the trial conducted by the National Institute of Neurological Disorders and Stroke (NINDS). Through a statewide communications and transport network, our brain attack center gives emergency medicine staff in the state and surrounding area immediate access to stroke specialists. The team provides consultation about the administration of tPA for ischemic stroke, using the NINDS protocol. Consultations, treatment, and outcomes are documented in our database. From 1996 to 2005, the brain attack center completed 2,670 consultations and diagnosed 1,788 patients with ischemic stroke. Two hundred forty patients (9% of all consultations; 13.4% of those with acute ischemic stroke) received tPA. Percentages of patients with symptomatic intracranial hemorrhage and 3-month modified Rankin scale scores less than or equal to 1, compared with those in the NINDS trial, were as follows: 3.3% versus 6.4% and 53% versus 43% (P=.04). Mortality rates were 13% (network) versus 17% (NINDS). |
Do meniscus Injuries Alter the Kinematics of Knees With Anterior Cruciate Ligament Deficiency? | Most knee joint biomechanics studies have involved knees with an isolated anterior cruciate ligament (ACL) injury. However, a large portion of patients with injured ACLs have accompanied meniscus tearing. In this study, the in vivo alteration of knee biomechanics after tearing the ACL with or without combined medial or lateral meniscus tear was investigated during stair-ascending activity. The kinematic behavior of ACL-deficient knees changes with a combined medial or lateral meniscus tear. Controlled laboratory study. Twenty-one patients with injured ACLs (contralateral side intact) were recruited before undergoing ACL reconstruction. Among these patients, 5 had isolated ACL injuries (group I), 8 had combined ACL and medial meniscus injuries (group II), and 8 had combined ACL and lateral meniscus injuries (group III). Bilateral magnetic resonance scans were obtained on each patient to construct 3-dimensional anatomic knee models. Both knees were then scanned during stair-climbing activity using a dual fluoroscopic imaging system. The knee kinematics during stair climbing were reproduced using a bone model image matching method. Anteroposterior and mediolateral translations and axial tibial rotation of the knee during stair ascent were then compared between the injured and intact contralateral knees of the patients. On average, injured knees in groups I and III showed more than 2 mm increased anterior tibial translation close to full knee extension. In group II, no statistically significant difference was observed between the injured and contralateral side in anteroposterior translation. Near full extension, in groups I and III, injured knees had less than 1 mm of increased medial tibial translation compared with the contralateral side, whereas in group II, a 1.0-mm increase in lateral tibial shift was observed in the injured knees. With regard to axial tibial rotation, group I showed an increased external tibial rotation (approximately 5°), group II had little variation, whereas group III had increased internal tibial rotation (approximately 3°). | To explore the antiviral efficacy of small interfering RNAs (siRNAs)/shRNA targeting preC/C of HBV in human hepatoma cells Huh-7 and HepG2.2.15 cells. Three 21 nucleotide(nt) siRNAs for treating HBV preC/C gene were designed and synthesized according to the HBV genome in GenBank accession numbers (U95551); simultaneously, one 21-nt-long non-homologous siRNA was also designed randomly for negative control. They were cloned into vector pU6 for constructing shRNA-expressing plasmids pU6-C1, pU6-C2, pU6-C3 and control pU6-C4. To assess the function of siRNAs, a reporter gene system was constructed. The HBV preC/C gene was synthesized by PCR with pT-HBV1.3 as the template. The preC/C gene was then inserted into the enhanced green fluorescent protein expression vector (EGFP-N1) in order to construct the recombinant plasmid pEGFP-preC/C (E-C), which carries the EGFP reporter gene. The three shRNA-expressing plasmids-pU6-C1, pU6-C2, or pU6-C3-was each then cotransfected into Huh-7 cells along with either reporter gene expression vector E-C or the controls; or these three plasmids-pU6-C1, pU6-C2, or pU6-C3-was each cotransfected into HepG2.2.15 cells along with the controls. First, upon determination of the number of cells exhibiting EGFP expression in Huh-7cells as detected by an BH-2 fluorescence microscope and FACS-440 flow cytometry at different times after cotransfection, the investigators evaluated the inhibitory efficiency of the three shRNA-expressing plasmids by an EGFP reporter system in cultured cells. Subsequently, the expression amount of HBsAg and HBeAg in HepG2.2.15 cell supernatant at 24, 48, 72 and 96 h post-cotransfection was detected by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence was used to detect the expression of HBsAg and HBcAg at 72 h post-cotransfection in HepG2.2.15 cells. The copy level of HBV mRNA transcripts cDNA in HepG2.2.15 cells was further investigated through quantitative real-time polymerase chain reaction (real-time PCR). In comparison with single plasmid transfection pEGFP-N1 or E-C, fluorescence microscope examination and flow cytometry detection at 48 hours after cotransfection indicated that the expression of the reporter gene EGFP in cotransfected group Huh-7 cell involving pU6-C1, pU6-C2 or pU6-C3 resulted in an 80% reduction in EGFP signal relative to the controls (P < 0.01). It was also found through immunofluorescence that the expression of HBsAg and HBcAg in HepG2.2.15 cells was reduced markedly (P < 0.01), that the copy level of HBV mRNA transcripts cDNA as detected at 48 hours after cotransfection by quantitative real-time PCR was reduced respectively by 73.9% ± 1.2% (P = 0.029), 48.2% ± 1.8% and 35.8% ± 1.4% (P = 0.037, 0.040) relative to the control, that it conformed with that detected by fluorescence microscope/flow cytometry, ELISA, and immunofluorescence (P < 0.01). Thereby further corroborating the antiviral efficacy of RNAi. The efficacy was obvious at 48 h, reaching a peak at 72 h. |
Does application site affect the pharmacokinetics of topical testosterone applied to the axilla compared with the inner arm? | This study compared the pharmacokinetics of a single dose of 1% testosterone solution after application to the inner arm or the axilla as application sites for transdermal testosterone therapy. Healthy, not pregnant, premenopausal women, 18 to 45 years of age with a body mass index of 20 to 28 kg/m(2) were enrolled into a single-center, open-label, randomized, 2-way crossover study. Serum total testosterone (TT), free testosterone (fT), and sex hormone binding globulin concentrations were measured. Pharmacokinetic parameters determined from serum TT and fT included area under the serum concentration versus time curve from time zero (pre-dose) until 72 hours post-dose (AUC0-72), Cmax, and Tmax. Descriptive statistics were performed on serum concentrations of TT and fT for each site. ANOVA was performed on AUC0-72 and Cmax. A single-dose application of 1% testosterone solution to the inner arm and the axilla produced clear increases in TT and fT. Slower and lower increases in TT and fT were observed after treatment to the inner arm. Based on baseline-corrected AUC versus time curves, the bioavailability of 1% testosterone solution was increased 2-fold for the axilla compared with the inner arm. | This study examined the predictive factors of preference for residential care in cognitively intact and impaired elders and their family caregivers. It was hypothesized that disagreement in preference for residential care between the elders and their caregivers was greater in the cognitively impaired. A cross-sectional survey was conducted during June 2007 to March 2008 in Hong Kong, and 707 community-dwelling elders aged 65 and above and 705 family caregivers were interviewed. Cognitively impaired elders were over-sampled to give reliable estimates for that sub-group. A structural questionnaire was used to collect data on preference for residential care and potential factors. Logistic regression was used to identify the predictors. More cognitively impaired elder-caregiver dyads (37.4%) had disagreement in preference for residential care than cognitively intact elder-caregiver dyads (20.5%) (p < .001). From the elders' perspective, less preference for residential care was associated with cognitive impairment, whereas greater preference was associated with depression (for cognitively intact elders), more usage of community service and functional impairment. From the caregivers' perspective, greater preference for residential care was associated with greater caregiver burden, or care-recipients having cognitive or functional impairment, or more usage of community services. |
Does polysialic acid/neural cell adhesion molecule modulate the formation of ductular reactions in liver injury? | In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/-4+/-, and St8sia2-/-4-/-). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/-4+/- and St8sia2-/-4-/- mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma. | Previous studies focusing on the changes of heart rate, systolic blood pressure and dyspnea caused by the six-minute (6MWT) and shuttle walking distance tests (ISWT) have produced conflicting data. The present study aims at comparing the cardiovascular and dyspnea responses to 6MWT and ISWT in patients with chronic obstructive pulmonary disease (COPD). Twenty patients with clinically stable COPD (age, 56 +/- 9 yrs; BMI, 27.8 +/- 7.7 kg.m(-2); FEV1%pred, 42 +/- 19%; mean +/- Sx) performed three 6MWTs and two ISWTs using standardised protocols. The distances walked in the third 6MWT and second ISWT were 458 +/- 105 and 365 +/- 116 m, respectively. There was a significant correlation between the distances covered in the two tests (r = 0.87; p < 0.001). The 6MWT and ISWT showed similar correlation coefficients with the Baseline Dyspnea Index (r = 0.86; p < 0.001 and r = 0.76; p < 0.001), the Clinical Symptom Scale (r= -0.72; p < 0.001 and r= -0.55; p = 0.011), FEV1 L (r = 0.36; NS and r = 0.30; NS), PImax (r = 0.59; p < 0.008 and r = 0.60; p = 0.001) and the mean pulmonary artery pressure, Doppler echocardiography (r= -0.51; p < 0.029 and r = -0.51; p = 0.032). Although the response to ISWT tended to be greater, we found no statistically significant differences between the two tests in the changes of heart rate (HR), systolic blood pressure (SBP) and dyspnea (Borg) (deltaHR, 17.9 +/- 13.4 vs 23.8 +/- 15.4; deltaSBP, 7.7 +/- 14.6 vs 13.0 +/- 17.0 and deltaBorg, 1.7 +/- 1.1 vs 2.2 +/- 0.9; NS). |
Do outcomes of trauma patients after transfer to a level I trauma center? | : Trauma center physicians need to know the patient's prognosis to make appropriate clinical decisions when they take over the care of a transferred patient. We sought to compare the survival of injured patients after transfer to a trauma center with survival from a comparable time after injury among patients who had been admitted to the trauma center directly from the scene of injury. : Study included 2,867 patients 18 years to 84 years of age with at least one Abbreviated Injury Scale score >/=3 injury transferred to a trauma center and 7,570 patients admitted directly to a trauma center. The outcome was death within one year after injury. Cox proportional hazards model for death was used accounting for time since injury, adjusted for age group, gender, injury severity, injury mechanism, and comorbidities. : Overall, there was almost no increase in the adjusted risk of death for transfer patients in the year after injury [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.78, 1.27]. The adjusted risk of death was higher in transfer patients than nontransfer patients between 50 days and 365 days after injury (HR 1.28, 95% CI 0.79, 2.07), but not within the first 50 days (HR 0.95, 95% CI 0.76, 1.18). However these modest differences in survival within each period were not statistically significant. | To examine the expression and cellular distribution pattern of endothelial nitric oxide synthase (eNOS) in the developing human retina and to compare its expression with that in rats. Expression of eNOS was examined by immunohistochemistry in retinas of humans ranging from 8.5 to 28 weeks of gestation (WG) and of rats. In the developing human retina, eNOS expression was first detected in the proximal margin of the neuroblastic layer in the incipient fovea-surrounding area at 12 WG. At 17 to 28 WG, eNOS-immunoreactive cells were located in the innermost part of the inner nuclear layer and in the ganglion cell layer, expanding to both temporal and nasal retinas and the processes projecting into the inner plexiform layer. These eNOS-positive cells coexpressed syntaxin and glutamate decarboxylase, and are probably GABAergic amacrine cells. The onset of eNOS expression in developing amacrine cells, however, preceded the invasion of retinal vasculature, long before vascular function involving these cells can be expected, suggesting that eNOS has a role not only in vasoregulation but also in retinal development. From 20 WG on, eNOS was also detected in the photoreceptors adjacent to the fovea. eNOS expression in amacrine cells and photoreceptors was observed in the central-to-peripheral and temporal-to-nasal gradients. However, in the developing rat retina, eNOS was expressed exclusively in the vascular endothelial cells. |
Does diltiazem enhance the effects of triazolam by inhibiting its metabolism? | Triazolam is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme and interacts with midazolam, another substrate of this enzyme. Therefore the possible interaction between triazolam and diltiazem is worth investigation. A balanced, randomized, double-blind crossover study design was used, with an interval of 2 weeks between phases. Ten healthy volunteers were given 60 mg diltiazem orally or placebo three times a day for 2 days. On the second day they received a single 0.25 mg oral dose of triazolam, after which plasma samples were collected and effects of triazolam measured for up to 17 hours. Diltiazem increased the mean area under the triazolam concentration-time curve threefold (p < 0.001) and the elimination half-life (p < 0.001) and the peak plasma concentration of triazolam twofold (p < 0.005). The increased concentrations of triazolam during the diltiazem phase were associated with increased and prolonged pharmacodynamic effects. | The differentiation of mesenchymal stem cells (MSCs) into chondrocytes provides an attractive basis for the repair and regeneration of articular cartilage. Under clinical conditions, chondrogenesis will often need to occur in the presence of mediators of inflammation produced in response to injury or disease. The purpose of this study was to examine the effects of 2 important inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha), on the chondrogenic behavior of human MSCs. Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative reverse transcription-polymerase chain reaction analysis and examination of aggregates by histologic and immunohistochemical analyses. The possible involvement of NF-kappaB in mediating the effects of IL-1beta was examined by delivering a luciferase reporter construct and a dominant-negative inhibitor of NF-kappaB (suppressor-repressor form of IkappaB [srIkappaB]) with adenovirus vectors. Both IL-1beta and TNFalpha inhibited chondrogenesis in a dose-dependent manner. This was associated with a marked activation of NF-kappaB. Delivery of srIkappaB abrogated the activation of NF-kappaB and rescued the chondrogenic response. Although expression of type X collagen followed this pattern, other markers of hypertrophic differentiation responded differently. Matrix metalloproteinase 13 was induced by IL-1beta in a NF-kappaB-dependent manner. Alkaline phosphatase activity, in contrast, was inhibited by IL-1beta regardless of srIkappaB delivery. |
Do subanesthetic concentrations of isoflurane suppress learning as defined by the category-example task? | Previously, we found unconscious (implicit) learning in subjects given subanesthetic, but not anesthetic, concentrations of isoflurane. Other investigators, using different learning tasks, have reported implicit learning at anesthetic concentrations. We investigated whether one of these tasks might provide a more sensitive test of implicit learning. In addition, to determine whether suppression of explicit or implicit learning is dose-dependent, we studied one of the tasks at three subanesthetic concentrations. We applied a category-example task at 0.15, 0.28, and 0.4 minimum alveolar concentration (MAC) of isoflurane, and a behavior task only at 0.4 MAC. After anesthesia, we determined whether volunteers more frequently listed an example of a category (e.g., flute as an example of musical instrument) presented during anesthesia and/or demonstrated a behavior (touching ear, chin, or knee) suggested to them at 0.4 MAC. Results from the category task indicated implicit learning only at 0.15 MAC, a concentration that also permitted significant explicit learning. Explicit learning was demonstrated at 0.28 but not at 0.4 MAC (ED50 of 0.20 MAC and ED95 of 0.4 MAC). Results from the behavior task revealed neither implicit nor explicit learning. | Galectin-9 (Gal-9) is a β-galactoside-binding lectin that interacts with sugar moieties on glycoproteins and glycolipids of cells and pathogens. Gal-9 is known as an immune modulator that induces cell death via interaction with T cell immunoglobulin and mucin domain-3 (Tim3), a co-inhibitory receptor, and it inhibits production of several pro-inflammatory cytokines (TNF, IL-6 and IL-1α) and enhances production of IL-10. To understand the immune pathology of malaria, the Gal-9 in plasma was measured. Plasma samples and clinical parameters were obtained from 50 acute malaria cases (nine severe and 41 uncomplicated cases) from Thailand at three time points: day 0, day 7 and day 28. Gal-9 levels were determined by ELISA. A total of 38 species of cytokines and chemokines were measured using a BioPlex assay. Gal-9 levels were higher at day 0 compared to day 7 and day 28 (P < 0.0001). Gal-9 levels were also higher in severe malaria (SM) cases compared to uncomplicated (UM) cases at day 0 and day 7 (923 vs 617 pg/mL; P = 0.03, and 659 vs 348 pg/mL; P = 0.02 respectively). Median Gal-9 levels were higher in patients with blood urea nitrogen to creatinine ratio (BUN/creatinine) ≥20 (mg/dL) than in patients with BUN/creatinine <20 (mg/dL) at day 0 (817.3 vs 576.2 pg/mL, P = 0.007). Gal-9 was inversely significantly correlated with chloride levels in both SM and UM cases (r s = -0.73 and r s = -0.46, respectively). In both UM and SM cases, Gal-9 was significantly associated with pro- and anti-inflammatory cytokines and chemokines such as TNF, IL-6, IFN-α2, IFN-γ, IL-1Ra and IL-10. These correlations were observed at day 0 but disappeared at day 28. |
Does circulating Hepcidin-25 be Reduced by Endogenous Estrogen in Humans? | Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. We used a sensitive and specific dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. | The geriatric population is rapidly increasing in number with increased demand on health care resources including those spent on the treatment of maxillofacial trauma. The purpose of this analysis was to investigate the independent and cumulative associations between potential risk factors (age, gender, mechanism of injury, drug use, and alcohol use) for and the severity of geriatric facial trauma. This was a cross-sectional analysis of secondary data of geriatric (individuals aged ≥65 years) facial trauma using the Allegheny General Hospital Trauma Registry database. Data were collected for diagnosis codes that reflected facial trauma (International Classification of Diseases, Ninth Revision codes 802.0 to 802.9, 800.1 to 801.9, and 803.0 to 804.9) and specific mechanisms of injury (E810 to E819, motor vehicle traffic accidents; E880 to E888, accidental falls; and E960 to E969, injury purposely inflicted by other persons). The Facial Injury Severity Scale (FISS) is a validated measurement that was used to determine the severity of the facial trauma and calculated through analysis of the abstracted data obtained from the trauma registry and patient records. Pearson correlations, 2-way independent t test, 1-way analysis of variance, and multiple linear regression were used to test hypotheses for independent and cumulative associations between the risk factors for and the severity of geriatric facial trauma. Statistical significance was set at the P < .05 level. The sample was composed of 229 patients with a mean age of 72.3 ± 4.5 years. A statistically significant association between mechanism of injury and the severity of geriatric facial trauma (P = .019) was found. Specifically, interpersonal violence (assault) was associated with the greatest facial trauma severity (FISS score, 4.2) when compared with motor vehicle collisions (FISS score, 2.2; P = .011) and falls (FISS score, 2.4; P = .016). |
Does zwolle risk score predict contrast-induced acute kidney injury in STEMI patients undergoing PCI? | Contrast-induced acute kidney injury (CI-AKI) is a common complication in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The Mehran risk score was defined originally in elective PCI and may be predictive of CI-AKI. The aim of the present study was to investigate whether the Zwolle score predicts CI-AKI in patients with acute STEMI undergoing primary PCI. We analyzed the data of 314 consecutive patients (mean age 56.3 ± 11.4 years) with acute STEMI undergoing primary PCI. The study population was divided into two groups according to CI-AKI development. The Mehran score, Zwolle score, baseline characteristics, and in-hospital outcomes were recorded. Patients with CI-AKI had higher Mehran and Zwolle scores. In a receiver operating characteristic (ROC) curve analysis, high area under the curve (AUC) values were determined for Zwolle and Mehran scores (0.85 and 0.79, respectively) for CI-AKI development. A Zwolle score greater than 2 predicted CI-AKI with a sensitivity of 76.3 % and a specificity of 75.4 %. A Mehran score greater than 5 predicted CI-AKI with a sensitivity of 71.1 % and a specificity of 73.6 %. | Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. |
Is mycoplasma penetrans infection a potential cause of immunoglobulin A nephropathy : a new animal model? | A new animal model of immunoglobulin A nephropathy (IgAN) was made by infecting mice with Mycoplasma penetrans (Mpe). To examine the pathogenesis of IgAN induced by Mpe infection, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and nuclear factor-kB (NF-kB) protein levels were compared among study groups. To make an experimental IgAN animal model, mice were infected with Mpe, SP-4 medium or phosphate-buffered saline (PBS) via the urinary tract. To compare changes in the classical IgAN model, TNF-alpha and IL-6 RNA expression levels were measured using RT-PCR, and NF-kB protein was measured using EMSA. By producing a urinary tract infection with Mpe, we developed a new animal model of IgAN with a 100% success rate. There was no difference with the classical animal model. We also observed IgG deposition in 66.67% of the Mpe-infection group. Glomerular cell and mesangial matrix proliferation was greater in the Mpe-infection group than in the control groups (p<0.05). In the Mpe-infection and classical groups, TNF-alpha and IL-6 expression levels were much higher than in the control groups (p<0.01). NF-kB expression was much higher in the Mpe-infection group (p<0.05). | Apolipoprotein E4 (APOE4) allele is an important risk factor for breast cancer and affects clearance of chylomicron remnants. Tamoxifen therapy increases serum triglyceride levels and sometimes inducing severe hypertriglyceridemia in breast cancer patients. Thirty-three women with breast cancer were recruited to examine the APOE polymorphism and fasting plasma lipid profiles before and after tamoxifen treatment for 6 months. We found that plasma lipid profiles changed in accordance with the APOE4 allele after tamoxifen treatment for 6 months. Especially plasma triglyceride levels significantly decreased in the APOE4-positive patients (p=0.025), while there was no change in APOE4-negative patients (p=0.189). The total plasma cholesterol levels were reduced in APOE-4 positive patients after 6-month tamoxifen treatment (p=0.014). The levels of plasma low density lipoprotein cholesterol and high density lipoprotein cholesterol significantly decreased in both APOE4-negative and APOE4-positive patients. |
Does a Rb1 promoter variant with reduced activity contribute to osteosarcoma susceptibility in irradiated mice? | Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility. Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb1 was tested for its influence on mRNA expression using reporter assay. A common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation. | Asthma morbidity and mortality is highest among inner-city populations. Suboptimal beliefs about the chronicity of asthma may perpetuate poor asthma control among inner-city asthmatics. This study sought to characterize beliefs about the chronicity of disease and its correlates in a cohort of inner-city adults with persistent asthma. Prospective, longitudinal, observational cohort study. One hundred ninety-eight adults hospitalized with asthma over a 12-month period at an inner-city teaching hospital. Sociodemographics, clinical history, disease beliefs, and self-management behaviors were collected by interview. Information on self-reported use of inhaled corticosteroids (ICS), peak flowmeters, and regular asthma visits was collected during hospitalization, and 1 month and 6 months after discharge. This cohort was predominantly low income and nonwhite, with high rates of prior intubation, oral steroid use, and emergency department visits and hospitalizations. Overall, 53% of patients believed they only had asthma when they were having symptoms, what we call the no symptoms, no asthma belief. Men patients, those > or = 65 years old, and those with no usual place of care had greater odds of having the no symptoms, no asthma belief, and those receiving oral steroids all or most of the time or with symptoms most days had half the odds of having this belief (p < 0.05 for all). The no symptoms, no asthma belief was negatively associated with beliefs about always having asthma, having lung inflammation, or the importance of using ICS, and was positively associated with expecting to be cured. The acute disease belief was associated with one-third lower odds of adherence to ICS when asymptomatic at all three time periods (p < 0.02 for all). |
Does hemoglobin level influence tumor response and survival after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma? | Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy confers a survival benefit on patients with esophageal cancer. However, nCRT might be less meaningful for poor responders. Thus, being able to predict responses would help ensure the selection of optimal therapy. We reviewed data from 123 patients with esophageal squamous cell carcinoma (ESCC) who underwent nCRT that comprised concurrent radiation (40 Gy) and chemotherapy followed by esophagectomy. We assessed associations between clinical and blood data obtained before starting nCRT and the pathologic response. We compared good (Japan Esophageal Society response evaluation criteria grades 3/2; n = 89, 72.4%) and poor (grades 1/0; n = 34, 27.6%) responders. Performance status (p = 0.02), hemoglobin level (p = 0.005), and platelet counts (p = 0.03) were statistically significant pretherapeutic factors for a response to nCRT. Multivariable analysis subsequently selected the hemoglobin level (odds ratio 1.52; 95% confidence interval 1.08-2.15; p = 0.02) as the sole independent predictor. Receiver operating characteristic curves showed that the optimal cutoff for pretherapeutic hemoglobin was 13 g/dl for predicting a response. We found that 48.8 and 17.1% of patients with hemoglobin level ≤13 and >13 g/dl, respectively, were poor responders (p = 0.0002), with 5-year overall survival rates of 40.9 and 58.9%, respectively (p = 0.048). | Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions. Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks. The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels. |
Does stochastic modeling suggest that noise reduces differentiation efficiency by inducing a heterogeneous drug response in glioma differentiation therapy? | Glioma differentiation therapy is a novel strategy that has been used to induce glioma cells to differentiate into glia-like cells. Although some advances in experimental methods for exploring the molecular mechanisms involved in differentiation therapy have been made, a model-based comprehensive analysis is still needed to understand these differentiation mechanisms and improve the effects of anti-cancer therapeutics. This type of analysis becomes necessary in stochastic cases for two main reasons: stochastic noise inherently exists in signal transduction and phenotypic regulation during targeted therapy and chemotherapy, and the relationship between this noise and drug efficacy in differentiation therapy is largely unknown. In this study, we developed both an additive noise model and a Chemical-Langenvin-Equation model for the signaling pathways involved in glioma differentiation therapy to investigate the functional role of noise in the drug response. Our model analysis revealed an ultrasensitive mechanism of cyclin D1 degradation that controls the glioma differentiation induced by the cAMP inducer cholera toxin (CT). The role of cyclin D1 degradation in human glioblastoma cell differentiation was then experimentally verified. Our stochastic simulation demonstrated that noise not only renders some glioma cells insensitive to cyclin D1 degradation during drug treatment but also induce heterogeneous differentiation responses among individual glioma cells by modulating the ultrasensitive response of cyclin D1. As such, the noise can reduce the differentiation efficiency in drug-treated glioma cells, which was verified by the decreased evolution of differentiation potential, which quantified the impact of noise on the dynamics of the drug-treated glioma cell population. | Older patients with chronic cardiac conditions are more vulnerable to falls and injuries. Cardiovascular conditions, prevalent in older people, are also the frequent cause of potentially harmful fall injuries among this group. The need to identify the fall risk-related factors that cluster with arrhythmia and syncope is relevant as it will potentially reduce patients' risk for falls and fall injuries. The paper describes the process taken to design, develop and implement a practice-change initiative that specifically focuses on cardiac-related falls and injuries. A review of best practice guidelines, related studies and patients' profiles from chart audits were utilized to obtain evidence-based information to develop this assessment and intervention falls guide. Prior to the development of this guide, the charts of six patients were reviewed to assess specific data including age, history of falls, type of injury, cognitive function and underlying medical conditions. The developed Assessment and intervention falls guide was utilized with seven patients in the Cardiology Unit who were admitted with diagnosis of syncope and atrial fibrillation to assess their risk for falls. |
Does selective pharmacological blockade of the TRPV1 receptor suppress sensory reflexes of the rodent bladder? | We investigated the pharmacological effect of TRPV1 antagonists in anesthetized rodent models of bladder function. The TRPV1 antagonists JNJ17203212 and JYL1421 were evaluated in the anesthetized rat volume induced micturition reflex model. JNJ17203212 was further evaluated in this model in capsaicin (Sigma) desensitized rats, and in rat capsaicin and mouse citric acid models of irritant induced detrusor overactivity. Systemic JNJ17203212 and JYL1421 administration in the anesthetized rat volume induced micturition reflex model resulted in an increased micturition threshold volume. JNJ17203212 also decreased bladder contraction amplitude but JYL1421 had no effect. Capsaicin desensitization significantly increased baseline micturition threshold volume and decreased bladder contraction amplitude in the volume induced micturition reflex model compared to those in sham treated controls and JNJ17203212 produced no further effect after capsaicin desensitization. JNJ17203212 was also effective in 2 models of irritant induced detrusor overactivity, preventing the decrease in micturition threshold volume and the increase in bladder contraction amplitude observed with intravesical instillation of 10 microM capsaicin, and the decreased voiding interval induced by intravesical citric acid. | Is a perioperative metastatic screening programme indicated in patients presenting with primary operable breast cancer and no signs of distant metastases? The impact of staging results (chest X-ray, bone scanning, liver ultrasound) for prognosis, treatment, quality of life and costs was retrospectively analysed in 1 076 patients with an operable breast cancer and no clinical signs of metastases. Staging examinations revealed 30 (2.8 %) distant metastases, 130 (12.1 %) suspect findings and excluded metastases in 916 (85.1 %) patients. Further diagnostic procedures confirmed distant metastases in 7 (5.4 %) and excluded them in 123 (94.6 %) out of 130 patients with suspect findings. Distant metastases were detected more frequently with increasing tumor size (pT < or = 2.0 cm: 1.6 %, pT 2.1-5.0 cm: 3.0 %, respectively pT > 5.0 cm: 15.1 %; p < 0.001) and increasing number of involved axillary lymph nodes (pN0: 1.4 %, pN1-3 +: 1.8 %, pN4-9 +: 4.0 %, pN > 10 +: 12.5 %; p < 0.001). Due to false positive findings 123 (11.4 %) patients had to live for a significant period of time with the psychological distress of suspected metastatic disease. The abandonment of a perioperative screening in 1 076 patients saves costs of at least euro 259,366.68. |
Is sUMOylation of the α-kleisin subunit of cohesin required for DNA damage-induced cohesion? | Cohesion between sister chromatids is fundamental to ensure faithful chromosome segregation during mitosis and accurate repair of DNA damage postreplication. At the molecular level, cohesion establishment involves two defined events, a chromatin binding step and a chromatid entrapment event driven by posttranslational modifications on cohesin subunits. Here, we show that modification by the small ubiquitin-like protein (SUMO) is required for sister chromatid tethering after DNA damage. We find that all subunits of cohesin become SUMOylated upon exposure to DNA damaging agents or presence of a DNA double-strand break. We have mapped all lysine residues on cohesin's α-kleisin subunit Mcd1 (Scc1) where SUMO can conjugate. We demonstrate that Mcd1 SUMOylation-deficient alleles are still recruited to DSB-proximal regions but are defective in tethering sister chromatids and consequently fail to establish damage-induced cohesion both at DSBs and undamaged chromosomes. Moreover, we demonstrate that the bulk of Mcd1 SUMOylation in response to damage is carried out by the SUMO E3 ligase Nse2, a subunit of the related Smc5-Smc6 complex. SUMOylation occurs in cells with compromised Chk1 kinase activity, necessary for known posttranslational modifications on Mcd1, required for damage-induced cohesion. | Patients with obstructive sleep apnea (OSA) and coronary artery disease have a poor long-term prognosis. It is unknown whether the coronary blood flow (CBF) response to OSA is appropriate for myocardial metabolic requirements. Therefore, CBF was assessed during OSA, before and after the development of coronary artery endothelial dysfunction. University Hospital Animal Laboratory. Newborn lambs. Lambs were surgically instrumented for invasive hemodynamic monitoring and sleep-wake EEG recordings. A tracheostomy was inserted to control the upper airway and model OSA during sleep. Coronary artery endothelial dysfunction was created using infusions of lipopolysaccharide (LPS). The CBF response during OSA was assessed and compared to changes in myocardial work (rate-pressure product [RPP]), O2 saturation, and cortical arousal, before and after the LPS infusions. During OSA, CBF increased by 8.6% +/- 2.4% above baseline in the pre-LPS condition and 8.8% +/- 1.9% post-LPS, peaking following termination of the respiratory event. Pre-LPS, change in CBF post-apnea was independently correlated with change in RPP (R2 = 0.50), minimum SpO2 (R2 = 0.11) and the presence of cortical arousal (R2 = 0.04) (P < 0.01, forward stepwise regression analysis). Following LPS, the only predictor of CBF was degree of O2 desaturation (R2 = 0.14, P < 0.05). |
Does functional magnetic resonance imaging during urodynamic testing identify brain structures initiating micturition? | Normal voiding in neurologically intact patients is triggered by the release of tonic inhibition from suprapontine centers, allowing the pontine micturition center to trigger the voiding reflex. Supraspinal mechanisms of voluntary voiding in humans are just beginning to be described via functional neuroimaging. We further elucidated brain activity processes during voiding using functional magnetic resonance imaging in normal females to gain better understanding of normal voiding as well as changes that may occur in voiding dysfunction. We screened 13 healthy premenopausal female volunteers using baseline clinic urodynamics to document normal voiding parameters. We then recorded brain activity via functional magnetic resonance imaging and simultaneous urodynamics, including the pressure flow voiding phase. After motion correction of functional magnetic resonance images we performed activation and connectivity analyses in 10 subjects. Group analysis revealed consistent activation areas, including regions for motor control (cerebellum, thalamus, caudate, lentiform nucleus, red nucleus, supplementary motor area and post-central gyrus), emotion (anterior/posterior cingulate gyrus and insula), executive function (left superior frontal gyrus) and a focal region in the pons. Connectivity analysis demonstrated strong interconnectivity of the pontine micturition center with many short-range and long-range cortical clusters. | A melanoma vaccine incorporating six peptides designed to induce helper T-cell responses to melanoma antigens has induced Th1-dominant CD4(+) T-cell responses in most patients, and induced durable clinical responses or stable disease in 24% of evaluable patients. The present study tested whether this vaccine also induced antibody (Ab) responses to each peptide, and whether Ab responses were associated with T-cell responses and with clinical outcome. Serum samples were studied from 35 patients with stage III-IV melanomas vaccinated with 6 melanoma helper peptides (6MHP). IgG Ab responses were measured by ELISA. Associations with immune response and overall survival were assessed by log-rank test and χ(2) analysis of Kaplan-Meier data. Ab responses to 6MHP were detected by week 7 in 77% of patients, and increased to peak 6 weeks after the last vaccine and persisted to 6 months. Ab responses were induced most frequently to longer peptides. Of those with T-cell responses, 82% had early Ab responses. Survival was improved for patients with early Ab response (P = 0.0011) or with early T-cell response (P < 0.006), and was best for those with both Ab and T-cell responses (P = 0.0002). |
Do medullary pain facilitating neurons mediate allodynia in headache-related pain? | To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. | Proteinuria is associated with endothelial dysfunction (ED) and increased mortality. We investigated whether urinary protein excretion (UPE) is correlated with markers of ED and whether these markers affect the association of proteinuria with mortality in renal transplant recipients (RTR). Six hundred four RTR with a functioning graft for more than 1 year were included. RTR were divided according to UPE: less than 0.3, 0.3 to 1.0, and more than 1.0 g/24 hr. Soluble intercellular adhesion molecule type 1 (sICAM-1) and soluble vascular cellular adhesion molecule type 1 (sVCAM-1) were measured using ELISA. UPE (0.2 [0.0-0.5] g/24 hr), sICAM-1 (603 (514-721) ng/mL), and sVCAM-1 (952 [769-1196] ng/mL) were measured at 6.0 (2.6-11.4) years posttransplant. During follow-up for 5.3 (4.7-5.7) years, 94 (16%) RTR died. UPE was correlated with sVCAM-1 (standardized beta=0.13, P=0.001) but not with sICAM-1 (standardized beta=0.04, P=0.3). RTR with UPE more than 1.0 g/24 hr and high sICAM-1 (hazard ratio=4.7, 95% confidence interval 2.3-9.7, P<0.0001) or sVCAM-1 (hazard ratio=4.2, 95% confidence interval 2.0-8.6, P=0.0001) concentrations were at increased risk for death, whereas RTR with UPE more than 1.0 g/24 hr and low concentrations of sICAM-1 and sVCAM-1 were not. |
Does pharmacotherapy with 17β-estradiol and progesterone prevent development of mouse experimental autoimmune encephalomyelitis? | Pregnant women with multiple sclerosis (MS) show disease remission in the third trimester concomitant with high circulating levels of sex steroids. Rodent experimental autoimmune encephalomyelitis (EAE) is an accepted model for MS. Previous studies have shown that monotherapy with estrogens or progesterone exert beneficial effects on EAE. The aim of the present study was to determine if estrogen and progesterone cotherapy of C57BL/6 female mice provided substantial protection from EAE. A group of mice received single pellets of progesterone (100 mg) and 17 β-estradiol (2.5 mg) subcutaneously 1 week before EAE induction, whereas another group were untreated before EAE induction. On day 16 we compared the two EAE groups and control mice in terms of clinical scores, spinal cord demyelination, expression of myelin basic protein and proteolipid protein, macrophage cell infiltration, neuronal expression of brain-derived neurotrophic factor mRNA and protein, and the number of glial fribrillary acidic protein (GFAP)-immunopositive astrocytes. Clinical signs of EAE were substantially attenuated by estrogen and progesterone treatment. Steroid cotherapy prevented spinal cord demyelination, infiltration of inflammatory cells and GFAP+ astrogliocytes to a great extent. In motoneurons, expression of BDNF mRNA and protein was highly stimulated, indicating concomitant beneficial effects of the steroid on neuronal and glial cells. | Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor and might play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of gastric carcinoma was examined. HDGF expression in 317 patients with gastric carcinoma (233 males and 84 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry. Samples with >90% of tumor cells to express positive immunoreactivity similar to or stronger than that in endothelial cells both for nucleus and cytoplasm were regarded as HDGF index level 2, and others as HDGF index level 1. One hundred and eighty-two cases showed level 1 HDGF expression, whereas 135 cases showed level 2 HDGF expression. Patients with level 2 expression showed higher rates of proximal tumor location (P < 0.0001), large tumor size (P < 0.0001), infiltrative tumor growth (P < 0.0001), presence of vascular and lymphatic invasion (P < 0.0001 for both), presence of lymph node metastasis (P < 0.0001), deep tumor invasion (P < 0.0001), and poorer disease-free and overall survival (P < 0.0001 for both) compared to those with level 1 expression. Multivariate analysis revealed HDGF expression level as an independent prognosticator for disease-free and overall survival. |
Is human rights of persons with mental illness in Indonesia : more than legislation needed? | Although attention to human rights in Indonesia has been improving over the past decade, the human rights situation of persons with mental disorders is still far from satisfactory. The purpose of this paper is to examine the legal framework for protection of human rights of persons with mental disorder and the extent to which Indonesia's international obligations concerning the right to health are being met. We examined the Indonesian constitution, Indonesian laws relevant to the right to health, the structure and operation of the National Human Rights Commission, and what is known about violations of the human rights of persons with mental illness from research and the media. The focus of the Indonesian Constitution on rights pre-dated the Universal Declaration, Indonesia has ratified relevant international covenants and domestic law provides an adequate legal framework for human rights protections. However, human rights abuses persist, are widespread, and go essentially unremarked and unchallenged. The National Human Rights Commission has only recently become engaged in the issue of protection of the rights of persons with mental illness. | A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet. No difference in aortic root lesion size could be detected between CatS(+/+) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. |
Is endoglin a major susceptibility gene for intracranial aneurysm among Japanese? | A 6-base insertion (6bINS) polymorphism in intron 7 of the endoglin gene (ENG), which codes for a component of the transforming growth factor-beta receptor complex, was reported to be associated with intracranial aneurysm (IA) in a Japanese population. A recent report using a white population could not replicate the association. We tested for this association with high statistical power in our independent Japanese subjects and evaluated the linkage between markers on chromosome 9, which contains ENG, and IA. The sample for the linkage study comprised 179 individuals with IA in 85 nuclear families, with 104 possible affected sibpairs. For the association study of the 6bINS polymorphism and 4 single nucleotide polymorphisms (SNPs) in ENG, 172 Japanese patients with IA and 192 control subjects were examined. There was no evidence of linkage in the vicinity of ENG by analysis of affected sibpairs. The allele frequency of the 6bINS polymorphism was 104 of 344 (30.2%) in the total IA group and 122 of 382 (31.9%) in the control group. The statistical difference in allele frequency between the 2 groups was not significant (chi2=0.245, df=1, P=0.620). The power of the present association study was 98.3% at a significance level of 0.05 on the basis of the allele frequencies in the previous study. In addition, no associations between the 4 SNPs in ENG and IA were detected. | Maraviroc (MVC) is a potential candidate for 'on demand' preexposure prophylaxis. In the present study, we evaluated the efficacy of a single oral dose of MVC to prevent ex-vivo HIV-1 infection of rectal tissue in humans. Eight HIV-1-negative healthy volunteers received a single oral dose of MVC (300 or 600 mg), and two additional volunteers received tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, 300/200 mg) for 10 days. Rectal biopsies were performed prior to the ex-vivo challenge (day 0), at day 7 (4 h after MVC) or after 10 days with TDF/FTC. Rectal biopsies were infected ex-vivo, and viral inhibition and CCR5 occupancy was analyzed. MVC concentration in plasma and rectal tissue was measured just after biopsy and after viral incubation. Ex-vivo rectal tissue protection with MVC was incomplete in all but two participants, whereas TDF/FTC avoided ex-vivo infection in the two controls. Median dose-normalized concentration of MVC was significantly higher in rectal tissue than in plasma (561.1 and 155.1 ng/ml, respectively). A significant loss of MVC during the virus incubation (about 60%) and a low CCR5 occupancy (approximately 45%) were detected in rectal cells. |
Is [ Compared to whole body scanning thyroglobulin assay reliable in the follow-up of thyroidectomized patients with thyroid carcinoma ]? | To determine whether it is reliable to do thyroglobulin measurements during thyroid hormone substitution (Tg ON) alone or whether it is also necessary to do 131I total body scanning (TBS) and Tg measurements after withdrawal of thyroid hormone substitution (Tg OFF) in the follow-up of patients with differentiated thyroid carcinoma. Retrospective. University Hospital Nijmegen. 202 Patients (151 females and 51 males, mean age 50.6 years) with differentiated thyroid carcinoma were examined in the period 1970-90. All patients had undergone total thyroidectomy and if necessary 131I ablation. 27 Patients with Tg antibodies were excluded (13.4%). In 175 patients Tg OFF levels were compared with TBS and clinical and radiological data. In 81 of them Tg ON levels were also compared. Specificity of Tg OFF and Tg ON measurement was 83 and 88%. Sensitivity of Tg OFF and Tg ON measurement was 100 and 92%. In detecting local residual thyroid tissue Tg OFF was superior to Tg ON. In detecting metastases Tg OFF and Tg ON were both superior to TBS. | Dexmedetomidine (DEX) has been implicated in modulating the inflammatory response in central nervous system (CNS). However, the mechanism is still poorly understood. In this study, we evaluate the effects of DEX on lipopolysaccharide (LPS)-induced microglia activation and elucidate its possible signaling pathway involved in its anti-inflammatory effects. BV2 and primary microglia were pretreated with various concentrations of DEX (0·01, 0·1, 1, and 10 μM) and/or PD98059 for 1 hour, then microglia were incubated with LPS (1 μg/ml) for 24 hours. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were measured by Griess reagent and real-time polymerase chain reaction. Furthermore, two intracellular signaling cascades including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were investigated by western blot analysis. Dexmedetomidine significantly attenuated LPS-induced NO production and iNOS expression in both BV2 cells and primary microglial cells. Lipopolysaccharide activated both ERK1/2 and JNK signal pathways; however, DEX exerted a specific inhibitory effect on ERK1/2 rather than JNK. Intriguingly, treatment of primary microglia and BV2 cells with DEX in combination with ERK1/2 inhibitor (PD98059) enhanced attenuation of LPS-induced NO production and iNOS expression. |
Does analysis of RET protooncogene point mutations distinguish heritable from nonheritable medullary thyroid carcinomas? | The distinction of sporadic from inherited medullary thyroid carcinomas (MTCs) is of clinical importance because of the differences in prognosis, and the need for family screening for genetic counseling required in the latter. Germline mutations in the RET protooncogene are associated with multiple endocrine neoplasia (MEN) type 2A, familial medullary thyroid carcinoma (FMTC), and MEN type 2B. Somatic point mutations in the same gene have been identified in a subset of sporadically occurring medullary thyroid carcinomas. A nonisotopic polymerase chain reaction-(PCR) based single strand conformation polymorphism (SSCP) analysis and heteroduplex gel electrophoresis method was used to screen DNA extracted from 32 formaldehyde fixed and paraffin embedded MTC specimens and normal tissue or blood of the same patient for point mutations in RET exons 10, 11, and 16. Point mutations were identified by nonisotopic cycle sequencing of PCR-products using an automated DNA-sequencer. Results were compared with the disease phenotype, clinical findings, and follow-up. Six different missense germline mutations were identified at cysteine residues 618, 630, and 634 of the cysteine-rich extracellular RET domain encoded by exons 10 and 11 in all patients with FMTC and MEN 2A. The frequency of mutations at codon 634 was higher in patients with MEN 2A than with FMTC and a 634 Cys-->Arg mutation was associated with parathyroid disease in three patients. A germline Met-->Thr point mutation at codon 918 of the RET tyrosine kinase domain was identified in all three patients with MEN 2B. Two patients with clinically sporadic MTCs and negative family history exhibited a RET germline mutation at codon 634, indicating the presence of an nonpredicted inherited MTC. Furthermore, one patient had a 618 Cys-->Ser mutation in the tumor and nontumorous thyroid DNA but not in blood DNA, indicating a mosaic mutation affecting thyroid tissue but not blood cells. Tumor specific (somatic) Met-->Thr point mutations at codon 918 were identified in 5 of 13 sporadic MTCs. The remaining eight sporadic MTCs lacked mutations in all three RET exons tested. | Knowledge of sepsis-related end-organ inflammation in vivo is limited. We investigated the cytokine response in skin and in serum in sepsis and its relation to multiorgan failure (MOF) and survival. Cytokines were analysed in serum and in suction blister fluid of intact skin of 44 patients with severe sepsis and 15 healthy controls. Blister fluid and serum samples were collected within 48 h of the first sepsis-induced organ failure. This is a substudy of a larger follow-up study on wound healing in sepsis. Cytokine levels were higher in patients with sepsis vs. controls (interleukin [IL]-10, blisters: 65.9 vs. 4.3 pg/ml, P < 0.001, serum: 25.7 vs. 4.5 pg/ml, P = 0.004; IL-6, blisters: 41.9 vs. 0.03 pg/ml, P < 0.001, serum: 45.5 vs. 2.1 pg/ml, P < 0.001). Patients with MOF had higher levels of IL-10 (116.4 vs. 21.3 pg/ml, P = 0.015), IL-4 (0.7 vs. 0.07 pg/ml, P = 0.013) and basic fibroblast growth factor (bFGF) (25.9 vs. 9.5 pg/ml, P = 0.027) in blister fluid than patients without MOF. In blister fluid, survivors had lower levels of IL-10 (43.3 vs. 181.9 pg/ml, P = 0.024) and bFGF (15.8 vs. 31.9 pg/ml, P = 0.006) than non-survivors. In serum, survivors had higher levels of vascular endothelial growth factor (VEGF) (152.2 vs. 14.7 pg/ml, P = 0.012) and lower levels of IL-6 (38.5 vs. 91.1 pg/ml, P = 0.011) than non-survivors. The blister fluid levels of bFGF, TNF and VEGF did not correlate with the serum levels. |
Do novel cardiovascular risk factors completely explain the higher prevalence of peripheral arterial disease among African Americans . The San Diego Population Study? | This study was designed to determine whether novel cardiovascular disease (CVD) risk factors explain the high prevalence of peripheral arterial disease (PAD) among African Americans. Compared with Caucasians, African Americans have higher prevalence of PAD, an association that is not explained by traditional CVD risk factors. The degree to which novel CVD risk markers may explain the higher prevalence is uncertain. A nested case-control study within the San Diego Population Study was performed. The study evaluated 104 persons with PAD and 164 age- and gender-matched control subjects who were employees of a large public university and participated in a peripheral artery and venous disease study. Nine novel CVD risk factors (homocysteine, lipoprotein (a), C-reactive protein, fibrinogen, tumor necrosis factor-alpha, von Willebrand factor, prothrombin fragment 1-2, D-dimer, and plasmin antiplasmin) were measured. Multivariable logistic regression evaluated whether these novel factors attenuated the association of African-American race and PAD and whether there was differential ethnic susceptibility to the novel factors. African Americans had 3-fold higher odds of PAD in age- and gender-matched models (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.5 to 6.4; p < 0.01), an association that was modestly attenuated by adjustment for traditional (OR 2.4; 95% CI 0.9 to 6.1; p = 0.06) and novel CVD risk markers (OR 1.9; 95% CI 0.7 to 4.7; p = 0.18). Among the novel factors, the attenuation was primarily due to fibrinogen and lipoprotein (a). No interactions by novel CVD risk markers (both p values for interaction > or =0.24) were observed. | A focal cortical cryogenic brain injury has been reported to reduce the brain pentobarbital concentrations needed to prevent movement in response to pain in rats. This occurred despite any apparent behavioral changes in the awake animals. To determine whether this was true with other anesthetics, the authors determined the minimum alveolar concentration (MAC) for halothane in normothermic, normocarbic ventilated Sprague-Dawley rats previously subjected to a freezing injury of the parietal cortex. Injury was produced in halothane-anesthetized rats by applying a cold (-70 degrees C), 4-mm-diameter brass rod to the exposed dura for 5 or 15 s. Animals then were studied 3 days after injury, a time when cerebral metabolism in the ipsilateral hemisphere reaches a minimum. Minimum alveolar concentration was determined using a tail-clamp stimulus, combined with end-tidal anesthetic sampling. In addition, exploratory activity was measured by the open field test just before MAC determination, and spontaneous nocturnal motility was monitored by an electronic motion sensor during the night before testing. In normal animals subjected only to preparatory surgery, MAC was 1.10 +/- 0.07% (mean +/- SD). Almost identical values were found in rats subjected to 5- and 15-s cryogenic injuries (1.11 +/- 0.07% and 1.08 +/- 0.06%, respectively). There were no intergroup differences in open field test results or in spontaneous nocturnal activity. |
Does traditional risk factor assessment capture the extent of cardiovascular risk in systemic lupus erythematosus? | Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis. However, the degree of endothelial dysfunction and its relationship to traditional and novel cardiovascular risk factors have not been examined in SLE. In a case-control design, 35 patients with clinically stable SLE and 35 control subjects matched for age, sex, body mass index and smoking status were studied. Arterial elasticity, lipid profile, homocysteine, measures of inflammation and oxidative stress were determined. Among traditional vascular risk factors, there was a nonsignificant trend towards lower blood pressure in the control subjects, whereas low-density lipoprotein (LDL) cholesterol levels were significantly lower in the SLE group (2.5 vs 3.3 mmol/L, P < 0.001). Patients with SLE had significantly lower small artery elasticity (SAE; 4.9 vs 7.0 ml/mmHg x 100, P < 0.001) and higher plasma homocysteine (11.4 vs 8.3 mmol/L, P = 0.002) than control subjects. Levels of serum sVCAM-1 (614 vs 494 ng/mL, P = 0.002), oxidized LDL (144 vs 97, P < 0.001) and CD40 ligand (4385 vs 1373 pg/ml, P = 0.001) were significantly higher in SLE. Oxidized LDL levels, older age at SLE diagnosis and higher disease damage scores correlated inversely with SAE but not traditional risk factors. | To investigate the role of nitric oxide (NO)-induced autophagy in human dental pulp cells (HDPCs) and the involvement of AMP-activated protein kinase (AMPK) pathway. The MTT assay was used to determine the cytotoxic effect of the NO donor sodium nitroprusside (SNP) in HDPCs. Apoptosis was detected by means of the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and apoptosis- or autophagy-related signal molecules were observed by Western blot analysis. Acidic autophagolysosomal vacuoles were stained with acridine orange to detect autophagy in the presence of 3-methyladenine (3MA) used to inhibit autophagy. To explore the mechanism underlying autophagy and its protective role against apoptosis, compound C, the chemical AMPK inhibitor, was used. Statistical analysis was performed using Student's t-test or analysis of variance (ANOVA) followed by the Student-Newman-Keuls test (p<0.05). SNP decreased viability of the HDPCs in a dose- and time-dependent manner. Exposing the HDPCs to SNP increased the levels of p62 and LC3-II, the typical markers of autophagy, and increased the number of acidic autophagolysosomal vacuoles, indicating the appearance of autophagy as detected by acridine orange staining (p<0.05). Pretreatment with 3MA decreased cell viability but increased cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, apoptosis indicators, in the SNP-treated HDPCs (p<0.05). SNP activated AMPK/ULK signaling, while the inhibition of AMPK by compound C enhanced apoptotic cell death induced by SNP in the HDPCs (p<0.05). |
Is brain maturation delayed in infants with complex congenital heart defects? | Small head circumferences and white matter injury in the form of periventricular leukomalacia have been observed in populations of infants with severe forms of congenital heart defects. This study tests the hypothesis that congenital heart defects delay in utero structural brain development. Full-term infants with hypoplastic left heart syndrome or transposition of the great arteries were prospectively evaluated with preoperative brain magnetic resonance imaging. Patients with independent risk factors for abnormal brain development (shock, end-organ injury, or intrauterine growth retardation) were excluded. Outcome measures included head circumferences and the total maturation score on magnetic resonance imaging. Total maturation score is a previously validated semiquantitative anatomic scoring system used to assess whole brain maturity. The total maturation score evaluates 4 parameters of maturity: (1) myelination, (2) cortical infolding, (3) involution of glial cell migration bands, and (4) presence of germinal matrix tissue. The study cohort included 29 neonates with hypoplastic left heart syndrome and 13 neonates with transposition of the great arteries at a mean gestational age of 38.9 +/- 1.1 weeks. Mean head circumference was 1 standard deviation below normal. The mean total maturation score for the cohort was 10.15 +/- 0.94, significantly lower than reported normative data in infants without congenital heart defects, corresponding to a delay of 1 month in structural brain development. | Extensive apoptosis of immune cells occurs in patients with cancer, and is possibly related to immune evasion by cancer cells. The present study was designed to investigate the correlation between apoptosis levels and Fas expression in CD8+ T lymphocytes in patients with gastric cancer. The expression of apoptosis markers (annexin V binding and caspase-3 activation) and the death receptor Fas in CD8+ T cells was evaluated by multicolor flow cytometry. Soluble Fas ligand (sFasL) in the sera was quantitated by enzyme-linked immunosorbent assay. In patients with gastric cancer, 18.7% +/- 10.5% (mean +/- SD) of CD8+ T cells bound annexin V compared with 11.7% +/- 7.9% in normal controls (P = 0.0282). Fas expression in CD8+ T cells was higher in patients with gastric cancer (69.2% +/- 15.3%) than normal controls (50.6% +/- 15.3%) (P = 0.0051). The proportion of apoptotic CD8+ T cells was significantly correlated with Fas expression in CD8+ T cells (r = 0.409, P = 0.0214). In patients, Fas+CD8+ T cells preferentially underwent apoptosis and showed high caspase-3 activation. Moreover, the proportion of apoptotic CD8+ T cells was inversely correlated with serum levels of soluble Fas ligand (r = -0.324, P = 0.0359). Fas expression in tumor infiltrating CD8+ T cells was significantly more frequent (80.3% +/- 13.4%) than in circulating CD8+ T cells (67.9% +/- 15.5%) (P = 0.0046). A decrease in the percentage of Fas+CD8+ T cells was observed after surgery (54.1% +/- 12.8%) compared with before surgery (65.9% +/- 17.0%) (P = 0.0284). |
Is n-chlorotaurine an effective antiviral agent against adenovirus in vitro and in the Ad5/NZW rabbit ocular model? | To determine whether N-chlorotaurine (NCT) demonstrates antiviral activity against adenovirus (Ad) in vitro and in the Ad5/NZW rabbit ocular model. The in vitro activity of NCT was evaluated by incubating different Ad serotypes with several concentrations of NCT for 1 hour and determining the reduction in Ad titers. In rabbit study 1, Ad5-infected eyes were treated with 2.5%, 2.0%, and 1.0% NCT; 0.5% cidofovir; or saline. NCT and saline groups were treated 10 times for 1 day and then 5 times daily for 6 days. In rabbit study 2, Ad5-infected eyes were treated with 1.0% NCT/0.1% ammonium chloride (NH4Cl), 0.1% NCT/1.0% NH4Cl, 0.1% NCT/0.1% NH4Cl, and 0.5% cidofovir or saline. The NCT and saline groups were treated five times daily for 10 days. Cidofovir-treated eyes received the authors' standard cidofovir dose regimen: twice daily for 7 days. In vitro, NCT demonstrated concentration-dependent direct inactivation of all ocular Ad serotypes tested. Rabbit study 1: 2.5%, 2.0%, 1.0% NCT, and cidofovir demonstrated significantly fewer positive cultures per total cultures during days 1 to 14, compared with saline. Rabbit study 2: 1.0% NCT/0.1% NH4Cl, 0.1% NCT/1.0% NH4Cl, 0.1% NCT/0.1% NH4Cl, and cidofovir demonstrated significantly fewer positive cultures per total cultures, during days 1 to 14; shorter durations of shedding; and lower mean combined titers, during days 7 to 14, compared with saline. Cidofovir was significantly more effective than NCT in several outcome measures in both rabbit studies. | Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). |
Does tonography demonstrate reduced facility of outflow of aqueous humor in myocilin mutation carriers? | To demonstrate the effect in vivo of the myocilin gene mutation Thr377Met on outflow facility of aqueous humor, as measured by tonography. Forty-two members of a pedigree known to carry the Thr377Met mutation were examined for glaucoma, evaluated with tonography, and screened for myocilin mutations. Tonography was used to calculate the coefficient of aqueous outflow facility (C), as well as the ratio of the resting intraocular pressure to C (P(0)/C). Subjects were reexamined for glaucoma 5 years after tonography. Seven subjects were excluded because of previous treatment known to alter facility of aqueous outflow. The mean outflow facility of the eyes of the 12 subjects carrying the Thr377Met mutation was significantly reduced compared with the 23 non-carriers' eyes using both C (P<0.001) and P(0)/C (P<0.001). Reduced outflow facility was also demonstrated in those mutation carriers who were not yet expressing clinical signs of glaucoma or ocular hypertension when measured using C (P = 0.015) and P(0)/C (P = 0.001). After 5 years, progression towards glaucoma had occurred in 5 of the myocilin mutation-carriers, 2 of whom showed bilateral progression; 3 carriers remained completely normal. Four subjects had bilateral glaucoma at the outset and remained unchanged. The carriers' eyes that progressed towards glaucoma had reduced outflow facility compared with those that remained normal, although the difference was not statistically significant. | The perioperative management of patients receiving oral anticoagulation therapy (OAC) who undergo pacemaker (PM) and defibrillator (ICD) surgery remains controversial. Low-molecular-weight heparin (LMWH) is often used; however, wound hematoma is a common complication. At a single academic Canadian center, between July 2003 and June 2005, details of perioperative OAC bridging and the rate of wound hematoma requiring reoperation or interruption of OAC were reviewed for all patients receiving LMWH bridging for PM or ICD surgery. A total of 148 PM/ICD patients underwent perioperative bridging with LMWH. A significant hematoma occurred in 23 patients, requiring reoperation in three patients. No patient died, developed infection, or stroke. The initial bridging regimen included LMWH (enoxaparin 1 mg/kg BID) given until evening prior to surgery, and reinitiated on postoperative day 3. In response to high rates of postoperative hematoma, subsequent protocols omitted the LMWH on the evening before surgery, all postoperative LMWH, or both. The use of LMWH the night before surgery had no effect on hematoma rates (12% vs 17%, P = 0.62); however, the use of any postoperative LMWH increased hematoma rates (23% vs 8%, P = 0.01). Hematoma rates were not increased in patients receiving acetylsalicylic acid (19% vs 16%, P = 0.62) or clopidogrel (25% vs 17%, P = 0.54). In a multivariate analysis, independent predictors of significant wound hematoma included postoperative LMWH (P = 0.001), a higher international normalized ratio on the day of surgery (P = 0.03), and male sex (P = 0.05). |
Does comparative genomic hybridization show complex genomic changes of plasmacytoid urothelial carcinoma? | To describe genomic imbalances in plasmacytoid urothelial carcinoma (PUC), which is a rare and aggressive variant of urothelial carcinoma (UC). In total, 25 formalin-fixed paraffin-embedded PUCs were analyzed by metaphase comparative genomic hybridization. Genomic imbalances were considered to be characteristic if they were detected in ≥ 20% of the cases. Chromosome regions deviating by ≥ 3 standard deviations from the average chromosome profile were scored as chromosomal gains or losses. Copy-number variations (CNVs) of CDH1 (16q 22.1), SNAI1 (20q 13.1), CCND1 (11q13.3), ERBB2 (17q12), and FOXO3 (6q21) were validated using quantitative polymerase chain reaction. Chromosomal aberrations were detected in every PUC analyzed, and the average number of aberrations was 10.24 (ranging from 1-15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). polymerase chain reaction-based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy-number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, whereas no copy-number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy-number alterations, with 9% of all cases showing an amplification. | To determine the effect of the Breathe Right (BR) external nasal dilator strip on treadmill exercise performed while wearing an upper maxillary mouthguard. Two-way repeated-measures design with subjects acting as their own controls. Subjects performed 2 randomly assigned bouts of incremental treadmill exercise (with and without the BR strip) while wearing upper maxillary mouthguards. Nineteen young, healthy, recreationally active men. we assessed subjective nasal patency levels at rest. We also recorded heart rate, dyspnea rating, and treadmill speed at 2 submaximal exercise levels and at volitional fatigue. Subjective nasal patency was significantly increased with the strip. Repeated-measures analyses of variance revealed a significant main effect of the BR strip on dyspnea ratings during exercise, but there was no effect of the strip on test duration, heart rate, or running speed during the tests. |
Does miRNA-150 downregulation promote pertuzumab resistance in ovarian cancer cells via AKT activation? | Pertuzumab is a humanized mAb that binds to the extracellular region of HER2/ErbB2 and is approved for treating breast cancer. Although ovarian cancer and breast cancer have comparable levels of HER2/ErbB2 expression, clinical studies of pertuzumab in epithelial ovarian cancer patients have not met the same level of success. To investigate the molecular mechanisms by which pertuzumab exerts its anti-tumor effects in ovarian cancer and the mechanisms by which cancer cells achieve pertuzumab resistance. We examined expression of miR-150 in ovarian cancer cells treated with pertuzumab or not. miR-150 knockdown impacts on pertuzumab treatment were analyzed by cell proliferation assay, apoptosis analysis and cell cycle analysis. Cell signal pathway was examined by western blot assay. Pertuzumab induced miRNA-150 expression in SKOV3 and SNU119 cells. Furthermore, suppression of miRNA-150 in both cell lines resulted in decreased drug sensitivity to pertuzumab and cell apoptosis. The blockage of G1/S checkpoint by pertuzumab was rescued as well. miRNA-150 knockdown activated PI3K-Akt pathway and LY294002 reversed the effect of miR-150 knockdown. | Investigation of the efficacy of implantation of monocyte-derived hepatocyte-like cells (NeoHeps) in acute liver failure. Extended liver resection or split liver transplantation is still associated with high morbidity and mortality because of postoperative liver insufficiency. In view of liver support systems, implantation of isolated hepatocytes or hepatocyte-like cells such as NeoHeps is increasingly under discussion. Twenty-four hours before subtotal hepatectomy, cells of different origin [A: human mononuclear cells (24 x 10(6)); B: NeoHeps (16 x 10(6)); C: NeoHeps (24 x 10(6)); D: rat hepatocytes (24 x 10(6))] were injected into the spleen of Wistar rats. After an observation period of 5 days, animal survival, postoperative weight, and signs of encephalopathy were recorded. At the end of the observation period, blood was collected for laboratory analysis. Transplantation of both rat hepatocytes and NeoHeps significantly improved animal survival when compared with control animals (group A: 21%), reaching 72% in group D (P = 0.001), 50% in group C (P = 0.04), and 36% in group B (P = 0.22). Moreover, animals in these groups postoperatively experienced less frequently signs of encephalopathy, as well as earlier weight increase when compared with group A. |
Does [ Studies on the chemical constituents of the stem of Alyxia sinensis ( I ) ]? | To demonstrate the chemical constituents of Alyxia sinensis. Phytochmical experiment was carried out, using column chromatograph technologies. Five compounds have been isolated from the petroleum ether soluble part of the stems of A. sinensis. Their structures have been elucidated respectively as heptatriacontane(1), octatriacontane(2), 20-noatriacontannone(3), 20-nonatriacontanone(4), 20-tetraacontanoe(5), physcion(6), emodin(7), chrysophanol(8), coumarin(9), stigmasterol acetate(10), beta-sitosterol acetate(11), lupeol(12), betulin(13), stigmasterol(14), beta-sitosterol(15), ursolic acid(16), oleanolic acid(17). | Few studies have investigated factors influencing participation rates for minority children with a chronic disease in clinical trials. The Silent Cerebral Infarct Multi-Center Clinical (SIT) Trial provides an opportunity to study the impact of demographic and socio-economic factors on randomization in a clinical trial among Black children. Our primary objective was to characterize the factors associated with successful randomization of children with sickle cell disease (SCD) and silent cerebral infarct (SCI) in the SIT Trial after initial consent. Differences in socio-economic and demographic variables, family history and disease-related variables were determined between eligible participants who were successfully randomized and those who were not randomized following initial consent. Head of household educational level and family income were examined separately for US versus non-US sites. Of 1,176 children enrolled in the SIT Trial, 1,016 (86%) completed screening. Of 208 (20%) children with qualifying SCI on pre-randomization MRI, 196 (94%) were successfully randomized. There were no differences in socio-economic, demographic, or disease-related variables between children who were or were not randomized. Participants from non-US sites were more likely to be randomized (22% vs. 12%, P = 0.011); although, randomization by country was associated with neither head of household education nor family income. |
Is carotid Intima-Media Thickness Associated with Markers of Atherosclerosis in Stroke Patients? | It has been argued that carotid intima-media thickness (IMT) could better reflect an adaptive response of the vessel wall rather than being a marker of atherosclerosis. We explore this hypothesis by analyzing the ARTICO data. The ARTICO study was designed to evaluate the prognostic value of the pathological ankle-brachial index (ABI) for the emergence of new vascular events in patients who have suffered a noncardioembolic stroke. Collected variables were as follows: vascular risk factors, mean waist perimeter, quantification of carotid IMT, characteristics of carotid plaques, ABI, and presence of microalbuminuria. A total of 591 patients with a complete carotid evaluation were available. There was no correlation between ABI and IMT (Spearman's, p NS). Logistic regression revealed that pathological ABI correlated significantly only with internal carotid artery stenosis greater than or equal to 50% (OR [odds ratio] 2.80, 1.66-4.71, P < .01) and peripheral artery disease (OR 3.33, 1.63-6.78, P < .01). However, multivariate regression analysis demonstrated that carotid IMT was independently associated with age (OR 1.05, 95% confidence interval [CI] 1.02-1.09, P < .01), hypertension (OR 1.83, 95% CI 1.02-3.26, P = .04), waist circumference (OR 1.03, 95% CI 1.01-1.05, P < .01), and microalbuminuria (OR 2.02, 95% CI 1.22-3.35, P < .01). | This study investigated the effects of monosialotetrahexosylganglioside (GM1) on the expression of N-methyl-D-aspartate receptor subunit 2B (NR2B) and phosphorylated (p)-cyclic AMP response element-binding protein (CREB) in the auditory cortex of rats with tinnitus. Tinnitus-like behavior in rats was tested with the gap prepulse inhibition of acoustic startle paradigm. We then investigated the NR2B mRNA and protein and p-CREB protein levels in the auditory cortex of tinnitus rats compared with normal rats. Rats treated for 4 days with salicylate exhibited tinnitus. NR2B mRNA and protein and p-CREB protein levels were upregulated in these animals, with expression returning to normal levels 14 days after cessation of treatment; baseline levels of NR2B and p-CREB were also restored by GM1 administration. |
Is complete soft tissue sarcoma resection a viable treatment option for select elderly patients? | Decreased performance status, comorbidities, and disease natural history may erode enthusiasm for soft tissue sarcoma (STS) resection in elderly patients. Consequently, we evaluated the outcome of elderly patients amenable to complete surgical resection treated at a single institution. Prospectively accrued data were used to identify patients with primary STS age >or=65 years (n = 325) who underwent complete macroscopic resection at our institution (1996-2007). Univariable and multivariable analyses were performed to identify prognostic factors. Median age at presentation was 72 years; 179 patients (55.1%) had associated comorbidities with an ASA score of >or=3. Extremity was the most common site (57.1%; n = 186), undifferentiated pleomorphic sarcoma the most common histology (60.4%; n = 197); 232 (71.2%) were high grade, 222 (68.3%) were >5 cm. Thirty-day postoperative mortality was 0.9% (n = 3); overall complication rate was 30.7% (n = 100), and mean postoperative hospital stay was 9 days (range, 1-84). Estimated median survival was 96 months, 5-year disease-specific survival (DSS) was 63%. Multivariable analysis identified age >or=75 year (HR = 2.03), tumor size: 5-15 vs <5 cm (HR = 3.54), or >15 vs <5 cm (HR = 10.33), and high-grade (HR = 5.53) as significant independent adverse prognostic factors. Compared with patients aged 65-74 years, older patients had more high grade tumors (P = .04), received chemotherapy less often (P < .0001), developed different patterns of recurrence (P < .05), and exhibited a shorter median survival (70 months; P = .05). | This study examined the relationship between plasma cholesterol and circulating triiodothyronine and oestradiol in 561 adolescent girls aged 11-17 with eating disorders. Plasma total cholesterol, high-density lipoprotein cholesterol, serum triodothyronine and oestradiol were measured at assessment, and historical weight data were obtained from growth charts provided by the school health services. Cholesterol levels were related to weight change, menstrual status and serum hormones. Plasma total cholesterol levels of >5.0 mmol/L were found in 38% of the 77 girls who were premenarcheal, 32% of the 199 with secondary amenorrhoea and 17% of those who were still menstruating. These cholesterol levels were inversely related to serum oestradiol and triiodothyronine concentrations, but not weight change, in amenorrhoic girls and were positively related to body mass index and inversely related to weight loss and serum triiodothyronine in girls who were still menstruating. |
Does the tumour suppressor Ras-association domain family protein 1A ( RASSF1A ) regulate TNF-α signalling in cardiomyocytes? | Tumour necrosis factor-α (TNF-α) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-α receptors (TNFRs), the mechanism of TNF-α signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-α signalling in cardiomyocytes. We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-α (10 µg/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-α receptor complex. In the absence of RASSF1A, signal transmission from the TNF-α receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors. | To evaluate the adequacy of retrobulbar block anesthesia only in vitreoretinal surgery. The study involved 90 patients, 25 who underwent 25-gauge transconjunctival sutureless vitrectomy and 65 who underwent 20-gauge standard pars plana vitrectomy. Twenty-five of the 90 patients also underwent combined phacoemulsification and posterior intraocular lens implantation. The efficacy of retrobulbar block anesthesia only was assessed by monitoring vital signs during surgery, reviewing patient responses to a questionnaire regarding their experience during surgery, and analyzing surgical outcomes. Four patients complained of moderate pain during surgery, but no patient complained of severe pain. Infiltrative anesthesia was additionally required in 14 patients. No patient experienced intraoperative complications due to head movement. Increased systolic blood pressure greater than 15 mm Hg occurred in 11 patients and increased respiratory rate by 3 breaths per minute or greater occurred in 7 patients. Anatomical and functional success rates were 95% and 80%, respectively. Complications included manageable retrobulbar bleeding (1 patient) and postoperative neovascular glaucoma (2 patients). |
Do a comparative study of gold UCLA-type and CAD/CAM titanium implant abutments? | The aim of this study was to evaluate the interface accuracy of computer-assisted designed and manufactured (CAD/CAM) titanium abutments and implant fixture compared to gold-cast UCLA abutments. An external connection implant system (Mark III, n=10) and an internal connection implant system (Replace Select, n=10) were used, 5 of each group were connected to milled titanium abutment and the rest were connected to the gold-cast UCLA abutments. The implant fixture and abutment were tightened to torque of 35 Ncm using a digital torque gauge, and initial detorque values were measured 10 minutes after tightening. To mimic the mastication, a cyclic loading was applied at 14 Hz for one million cycles, with the stress amplitude range being within 0 N to 100 N. After the cyclic loading, detorque values were measured again. The fixture-abutment gaps were measured under a microscope and recorded with an accuracy of ±0.1 µm at 50 points. Initial detorque values of milled abutment were significantly higher than those of cast abutment (P<.05). Detorque values after one million dynamic cyclic loadings were not significantly different (P>.05). After cyclic loading, detorque values of cast abutment increased, but those of milled abutment decreased (P<.05). There was no significant difference of gap dimension between the milled abutment group and the cast abutment group after cyclic loading. | The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C zeta (PKCzeta) and neutral sphingomyelinase (nSMase) in HPV. Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT-PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCzeta or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was approximately 10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response. |
Do cARD15/NOD2 single nucleotide polymorphisms confer susceptibility to type I psoriasis? | A psoriasis susceptibility locus on chromosome 16q was identified recently. This region coincides with a locus predisposing to Crohn's disease. Patients with Crohn's disease have a fivefold greater relative risk for development of psoriasis. In Crohn's disease mutation of the caspase recruitment domain family, member 15 (CARD15) gene (chromosome 16q12.1) confers susceptibility. In light of the overlap in linkage data, and the observation of comorbidity between Crohn's disease and psoriasis, it is plausible that both diseases share a common genetic factor. To assess the genetic contribution of CARD15 single nucleotide polymorphisms (SNPs) in the pathogenesis of type I psoriasis. Eight SNPs in CARD15 were genotyped in 148 patients with type I psoriasis and 192 unrelated controls, following a test for population stratification. Genotype and allele frequencies were compared along with estimated SNP haplotype frequencies. No differences were observed in genotype allele or haplotype frequencies between the case and control cohorts. | Although volume of intracerebral hemorrhage (ICH) is a predictor of mortality, it is unknown whether subsequent hematoma growth further increases the risk of death or poor functional outcome. To determine if hematoma growth independently predicts poor outcome, the authors performed an individual meta-analysis of patients with spontaneous ICH who had CT within 3 hours of onset and 24-hour follow-up. Placebo patients were pooled from three trials investigating dosing, safety, and efficacy of rFVIIa (n = 115), and 103 patients from the Cincinnati study (total 218). Other baseline factors included age, gender, blood glucose, blood pressure, Glasgow Coma Score (GCS), intraventricular hemorrhage (IVH), and location. Overall, 72.9% of patients exhibited some degree of hematoma growth. Percentage hematoma growth (hazard ratio [HR] 1.05 per 10% increase [95% CI: 1.03, 1.08; p < 0.0001]), initial ICH volume (HR 1.01 per mL [95% CI: 1.00, 1.02; p = 0.003]), GCS (HR 0.88 [95% CI: 0.81, 0.96; p = 0.003]), and IVH (HR 2.23 [95% CI: 1.25, 3.98; p = 0.007]) were all associated with increased mortality. Percentage growth (cumulative OR 0.84 [95% CI: 0.75, 0.92; p < 0.0001]), initial ICH volume (cumulative OR 0.94 [95% CI: 0.91, 0.97; p < 0.0001]), GCS (cumulative OR 1.46 [95% CI: 1.21, 1.82; p < 0.0001]), and age (cumulative OR 0.95 [95% CI: 0.92, 0.98; p = 0.0009]) predicted outcome modified Rankin Scale. Gender, location, blood glucose, and blood pressure did not predict outcomes. |
Is discontinuation of treatment of schizophrenic patients driven by poor symptom response : a pooled post-hoc analysis of four atypical antipsychotic drugs? | Stopping antipsychotic treatment can interrupt improvement and exacerbate the illness. The reasons for discontinuing treatment during controlled clinical trials were analyzed to explore this phenomenon. A post-hoc, pooled analysis was made of 4 randomized, double-blind clinical trials, 24-28 weeks in duration, involving 1627 patients with schizophrenia or a related disorder. Analyses combined all the atypical antipsychotic treatment groups in the studies. The majority of patients (53%) stopped their treatment at an early stage. Poor psychiatric response along with worsening symptoms was the most frequently given reason for discontinuing the course (36%), which was substantially more common than discontinuation due to poor tolerability of the medication (12%). This phenomenon was corroborated by less improvement in patients who discontinued treatment compared with those who completed, based on the PANSS total scores. Discontinuation due to poor response was, apparently, more predominantly linked to patient perception than to physicians' conclusions alone (80% vs. 20%). Discontinuation due to patient perception of poor response appeared to occur particularly early in the course of treatment. Patients who discontinued due to poor toleration of the medication responded in a more comparable manner with completers. | Recently we reported that fluid shear stress promotes endothelial cell differentiation from a mouse embryo mesenchymal progenitor cell line C3H10T1/2. However, it is not clear whether the transforming growth factor-beta 1 (TGF-beta1) system is associated with shear-induced endothelial differentiation. The purpose of this study was to determine the effect of shear stress on the expression of TGF-beta1 and its signaling molecules in C3H10T1/2 cells. Murine C3H10T1/2 cells were incubated on collagen Type 1-coated dishes, and subjected to a steady fluid shear stress of 15 dyn/cm(2) for 6, 12, and 24 h. The mRNA levels for TGF-beta1, TGF-beta receptors (TGF-beta R), and Smad molecules were determined with real-time PCR analysis and normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA levels. TGF-beta1 mRNA expression was down-regulated by 60% and 66% in shear stress-treated cells at 12 and 24 h, respectively, compared with static control group (P < 0.01). In addition, shear stress significantly decreased TGF-beta R1 mRNA levels by 30% and 50% in shear stress-treated cells at 12 and 24 h, respectively (P < 0.01). For TGF-beta R2, shear stress at 6, 12, and 24 h significantly reduced its expression by 93%, 95% and 97%, respectively, compared with static controls (P < 0.01). Furthermore, shear stress significant decreased mRNA levels of positive signaling molecules Smad2, Smad3, and Smad4 in a time-dependent manner (P < 0.01). However, shear stress significantly increased negative signaling molecule Smad7 mRNA levels by 100% at 24 h treatment compared with static control group (P < 0.01). |
Is [ Low expression of SLC22A1 associated with a poor prognosis of hepatocellular carcinoma : analysis of 303 patients ]? | To evaluate the association between SLC22A1 expression and the outcomes of hepatocellular carcinoma (HCC) patients. A tissue microarray of 303 HCC and matched adjacent noncancerous liver tissues (ANLTs) were constructed. The expression of SLC22A1 was tested by immunohistochemistry (IHC) and scored by two pathologists according to a 12-score scale (a score>6 was defined as high expression, and a score≤6 as low expression). The correlation of SLC22A1 expression with the clinicopathological features and the patients' outcome was analyzed. All the ANLTs had a IHC score of 12, as compared to only 29 (9.6%) of the HCC tissues. The patients were divided into 2 groups based on the IHC scores: 59% (180/303) in low expression group and 41% (123/303) in high expression group. The disease-free survival (DFS) rates and overall survival (OS) rates were significantly lower in low SLC22A1 expression group than in the high expression group. The 1-, 3-, and 5-year DFS rates were 43%, 31% and 27% in the low expression group, and were 58%, 47% and 43% in the high expression group, respectively. The 1-, 3-, and 5-year OS rates were 66%, 38% and 32% in low expression group, and were 80%, 57% and 50% in the high expression group, respectively. A low expression of SLC22A1 was positively correlated with the tumor diameter, BCLC stage, tumor differentiation, and AFP levels (P<0.05), and was an independent predictor of poor overall survival (HR=1.454; 95% CI, 1.050-2.013). | To assess the effects of eccentric work-induced hamstring fatigue on sagittal and transverse plane (axial) knee and ankle biodynamics and kinetics during a running crossover cut directional change (functional pivot shift). A pretest-posttest, single-group intervention experimental design was employed. All data were collected in a biodynamics laboratory. Twenty healthy athletic females were trained for 3 weeks in crossover cutting before testing. Data were sampled during 3 unfatigued and 3 fatigued (20% eccentric isokinetic knee-flexor torque reduction) crossover cut trials. Three-dimensional kinematic and ground reaction-force data were sampled at 200 Hz and 1000 Hz, respectively, and joint moment estimates were calculated. Data were standardized to initial force-plate heelstrike for comparisons of mean differences between conditions using paired t tests with Bonferroni adjustments. Pearson product-moment correlations compared kinematic and eccentric hamstring-torque relationships. During internal rotation phase 1, between heelstrike and impact absorption, mean internal rotation velocity increased by 21.2 degrees /s +/- 114 degrees /s. During internal rotation phase II, mean peak transverse plane knee rotation during propulsion decreased by 3.1 degrees +/- 9 degrees . During internal rotation phase II, mean peak ankle plantar flexor moment onsets occurred 12.7 +/- 53 milliseconds earlier, and this activation demonstrated a moderately positive relationship with the onset of mean peak knee internal rotation during propulsion and a weak negative relationship with mean peak hamstring torque/lean body weight. |
Are colorectal cancer stem cells enriched in xenogeneic tumors following chemotherapy? | Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC. Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent. | Compartment syndrome of the lower extremity can be a difficult diagnosis to make with serious consequences if diagnosis and intervention is delayed. Identifying patients who are more likely to develop this syndrome can help prevent the associated complications. The purpose of this study was to evaluate whether the anatomic location of the penetrating lower-extremity injuries can predict development of compartment syndrome. A retrospective chart review was performed of all patients admitted for a minimum of 23 hours to the University of South Alabama trauma center for penetrating lower-extremity trauma during the 8-year period from July 1998 through June 2006. Patients were entered in the study if wound trajectory was confined to the lower extremity between the inguinal ligament and the ankle. Injuries were categorized as above knee (AK) or below knee (BK), and whether the injury was in the proximal or distal half of the extremity segment. Clinical examination or compartmental pressures were used to diagnose BK compartment syndrome. A total of 321 patients sustained 393 lower-extremity injuries during the study period, of which 255 (65%) were AK and 138 (35%) were BK. Thirty-one (8%) lower extremities developed BK compartment syndrome with 29 (94%) secondary to penetrating injuries of the BK segment. All BK injuries that developed compartment syndrome were located in the proximal half of the BK segment. Eighteen (7%) AK injuries underwent BK 4-compartment fasciotomy, 16 (6%) of which were prophylactic after surgical intervention for AK vascular injury. Two patients (1%) developed postoperative BK compartment syndrome after superficial femoral vein ligation. All AK injuries that underwent fasciotomy sustained vascular injuries requiring surgical intervention. No BK compartment syndromes occurred in any patients with expectantly managed AK or distal BK injuries. |
Is plasma glucose and insulin regulation abnormal following gastric bypass surgery with or without neuroglycopenia? | Enhanced insulin sensitivity is commonly seen following Roux-en-Y gastric bypass surgery (RYGB) whereas symptomatic hypoglycemia post-RYGB seems to occur infrequently. It is unclear how different plasma glucose and insulin responses are in patients with symptomatic hypoglycemia (SX-RYGB) versus those who remain asymptomatic (ASX-RYGB), nor when compared with non-surgical controls with varying degrees of insulin sensitivity. Plasma glucose and insulin concentrations were determined following a 75-g oral glucose challenge in five groups: symptomatic and asymptomatic patients following RYGB (n = 9 each) and overweight/obese controls, divided into three subgroups (n = 30 each) on the basis of degree of insulin sensitivity measured by the insulin suppression test. SX-RYGB group had higher 30-min glucose after oral glucose compared with the ASX-RYGB group (p = 0.04). The two groups did not differ in peak glucose and insulin concentrations, nadir glucose concentration, or insulin-to-glucose ratio 30 min after oral glucose. These values were significantly different from the three control groups, and peak insulin concentrations post-RYGB were increased at every degree of insulin sensitivity as compared with the control groups. | Accumulation and infiltration of microglia/brain macrophages around and into glioma tissue promote tumor invasion and expansion. One tumor-promoting mechanism of microglia/brain macrophages is upregulation of membrane type 1 matrix metalloprotease (MT1-MMP), which promotes the degradation of extracellular matrix. MT1-MMP upregulation is induced by soluble factors released by glioma cells activating microglial Toll-like receptor 2 (TLR2). Versican identified by proteomics was silenced in glioma cells by short interference RNA and short hairpin RNA approaches and studied in vitro and after injection into mouse brains or organotypic brain slices. The splice variants V0/V1 of the endogenous TLR2 ligand versican are highly expressed in mouse and human glioma tissue. Versican-silenced gliomas induced less MT1-MMP expression in microglia both in vitro and in vivo, which resulted in smaller tumors and longer survival rates as compared with controls. Recombinant versican V1 induced significantly higher levels of MT1-MMP in wild-type microglia compared with untreated and treated TLR2 knockout microglial cells. Using glioma-injected organotypic brain slices, we found that the impact of versican signaling on glioma growth depended on the presence of microglia. Moreover, we found that TLR2 expression is upregulated in glioma-associated microglia but not in astrocytes. Additionally, an established TLR2 neutralizing antibody reduced glioma-induced microglial MT1-MMP expression as well as glioma growth ex vivo. |
Do family experiences and pediatric health services use associated with family-centered rounds? | Family-centered rounds (FCR) are defined as interdisciplinary bedside teaching rounds with active family participation. The objective of this study was to examine the association of FCR with family experiences and health services use. Prospective study comparing families with a child admitted to general pediatric inpatient services with and without FCR. The presence of FCR elements was assessed before study enrollment. Study data were obtained by an in-person interview, a follow-up phone interview <1 week after discharge, and medical record review. Family outcomes were informed by Consumer Assessment of Healthcare Providers and Systems measures. Health service use outcomes included hour of discharge, number of medications, and overall charges. Primary analyses included χ(2) and multivariate regression. Secondary analyses by using propensity score matching were performed to account for differences on observed variables. A total of 140 of 203 eligible families were enrolled; 97 completed follow-up surveys (49 on FCR team). Compared with non-FCR, FCR families were more likely to report consistent medical information (P < .001), the option of discussing care plan (P < .001), doctors listening carefully (P < .01), and doctors showing respect (P < .001). No differences were found in number of medications (mean 2.4 vs 2.9, P = .26) or discharge time (mean 3:06 pm versus 2:43 pm, P = .39). No difference was found for hospital charges after adjusting for length of stay outliers. | We investigated the pathway of autophagy signaling linked to sarcopenia of mice. Young adult (3-month) and aged (24- month) C57BL/6J mice were used. Using real-time PCR, Western blotting, and immunohistochemical microscopy, we evaluated the amounts of p62/SQSTM1, LC3, and Beclin-1 in the quadriceps muscle change with aging in mice. Marked fiber atrophy (30%) and many fibers with central nuclei were observed in the aged mice. Western blotting using homogenate of the cytosolic fraction clearly showed that the amounts of p62/SQSTM1 and Beclin-1 proteins were significantly increased in the aged skeletal muscle. The amounts of these proteins in both nuclear and membrane fractions did not change significantly with age. Immunofluorescence labeling indicated that aged mice more frequently possessed p62/SQSTM1-positive fibers in the cytosol in quadriceps muscle than young ones (aged: 14% vs. young: 1%). In aged muscle, p62/SQSTM1-positive fibers were significantly smaller than the surrounding p62/SQSTM1-negative fibers. Aging did not elicit significant changes in the mRNA levels of p62/SQSTM1 and Beclin-1, but decreased LC3 mRNA level. In aged muscle, the location of p62/SQSTM1 immunoreactivity was similar to that of Beclin-1 protein, but not LC3. |
Are irregular menstruation and hyperandrogenaemia in adolescence associated with polycystic ovary syndrome and infertility in later life : Northern Finland Birth Cohort 1986 study? | Do teenage girls with a history of menstrual irregularity and/or elevated androgen levels in adolescence exhibit an increased risk of polycystic ovary syndrome (PCOS) and/or infertility later on in adulthood? | The antibacterial activity of antimicrobial peptides is influenced by various factors such as salt content, pH and the presence of proteins. In this study, we explored the antibacterial action of the human cathelicidin LL-37 in physiologically relevant conditions, i.e. various human wound fluids, human plasma fractions and serum. Radial diffusion assays using Staphylococcus aureus and Escherichia coli were employed for the study of antibacterial effects of LL-37 in the presence of 12 different wound fluids, citrate-, heparin- or EDTA-plasma, or human serum. Glycosaminoglycan content of wound fluids was determined by an Alcian Blue-binding assay. Protein content of wound fluids was measured by the Bradford method. A slot-binding assay was used to study the effects of inhibitors on the interaction between LL-37 and glycosaminoglycans. Five of twelve wound fluids derived from acute wounds showed marked inhibitory effects on the antibacterial action of LL-37. The inhibition was significantly correlated with high glycosaminoglycan content in wound fluid. Analogous to these findings, heparin-plasma strongly inhibited the antibacterial effect of LL-37. The interaction between LL-37 and glycosaminoglycans was abrogated by the cationic polymers DEAE-dextran and chitosan, yielding increased activity of LL-37. |
Does percentage of smudge cells on routine blood smear predict survival in chronic lymphocytic leukemia? | Smudge cells are ruptured chronic lymphocytic leukemia (CLL) cells appearing on the blood smears of CLL patients. Our recent findings suggest that the number of smudge cells may have important biologic correlations rather than being only an artifact of slide preparation. In this study, we evaluated whether the smudge cell percentage on a blood smear predicted survival of CLL patients. We calculated smudge cell percentages (ratio of smudged to intact cells plus smudged lymphocytes) on archived blood smears from a cohort of previously untreated patients with predominantly early-stage CLL enrolled onto a prospective observational study. The relationship between percentage of smudge cells, patient survival, and other prognostic factors was explored. Between 1994 and 2002, 108 patients were enrolled onto the study and had archived blood smears available for review; 80% of patients had Rai stage 0 or I disease. The median smudge cell percentage was 28% (range, 1% to 75%). The percentage of smudge cells was lower in CD38(+) versus CD38(-) patients (P = .019) and in Zap70-positive versus Zap70-negative patients (P = .028). Smudge cell percentage as a continuous variable was associated with prolonged survival (P = .042). The 10-year survival rate was 50% for patients with 30% or less smudge cells compared with 80% for patients with more than 30% of smudge cells (P = .015). In multivariate analysis, the percentage of smudge cells was an independent predictor of overall survival. | Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin. We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated. In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA. |
Does magnetic bionanoparticle enhance homing of endothelial progenitor cells in mouse hindlimb ischemia? | Poor homing efficiency is one of the major limitations of current stem cell therapy. Magnetic bionanoparticles (MPs) obtained from Magnetospirillum sp. AMB-1 have a lipid bilayer membrane and ferromagnetic properties. We evaluated a novel priming strategy using MPs to enhance the homing of transplanted progenitor cells to target tissue. Effects of MP on proliferation, viability, and migration of late human endothelial progenitor cells (EPCs) were examined in vitro. Additionally, effects of MP on gene and protein expression related to survival and adhesion were evaluated. Homing and angiogenic efficiency of MP transferred late EPCs was evaluated in nude mouse hindlimb ischemia model. Below threshold concentration, MP transfer did not influence proliferation or survival of late EPCs, but enhanced migration and trans-endothelial migration of late EPCs toward magnet. Below threshold concentration, MP transfer did not influence gene and protein expression related to survival. In the mouse hindlimb ischemia model, late EPCs treated with high dose MP (5 ug/mL) showed enhanced homing of injected late EPCs in the ischemic limb by magnet, compared to low dose MP (1 ug/mL) treated late EPCs. In addition, high dose MP transferred EPC showed significantly better improvement of perfusion in ischemic limb compared to untreated EPC. | Mycobacterium tuberculosis is a pulmonary pathogen responsible for tuberculosis. Tuberculosis (TB) is characterized histologically by granulomas at the site of disease activity. Primary pathologic feature of TB is formation of a granuloma, and chemokines are known to play an important role in the formation of granulomas during infection. Therefore, the aim of this study was to evaluate the serum levels of CCL11, CCL24, and CCL26 in the TB patients in comparison to healthy controls. The population of this cross-sectional study included 300 patients suffering from TB and 100 healthy controls. Concentrations of CCL11, CCL24, and CCL26 were measured by enzyme linked immunosorbent assay (ELISA) technique. The results were analyzed using SPSS software package version 18. Differences were considered significant where p was less than 0.05. The results showed significant elevated serum levels of CCL11, CCL24, and CCL26 in TB patients compared to controls. |
Do anti-oxidant properties of N-acetyl-L-cysteine improve the immune resistance of mice fed dietary lipids to Listeria monocytogenes infection? | Current knowledge of the potential effects that several dietary lipids exert on immune functions indicates that these substances participate actively in the modulation of immune system by which they contribute to the improvement of the conditions of patients suffering from inflammatory disorders. However, long-chain n-3 polyunsaturated fatty acids induce an immunosuppressive status that leads to a reduction of the host natural resistance to infectious agents as well as to an enhancement of oxidative damage. Hence, the present study has been designed to evaluate the effects on the immune system of the antioxidant N-acetyl-L-cysteine (NAC) in mice fed dietary lipids and infected with Listeria monocytogenes. Balb/c mice were fed for 4 weeks with diets containing either olive oil (OO, 20% by weight), fish oil (FO, 20% by weight) or hydrogenated coconut oil (HCO, 20% by weight). After dietary lipid administration mice were experimentally infected with L. monocytogenes or treated with NAC (25mg/ml intraperitoneally). NAC at a concentration of 1mM promoted a loss of cell viability, although no differences were observed among the four groups. After injection of NAC in combination with L. monocytogenes, 25% of mice fed a low-fat (LF) diet survived. However, in the groups fed dietary lipids no effect on survival of mice was found. NAC participated in the reduction of superoxide anion generation measured with nitroblue tetrazolium (NBT) in the group fed a FO diet. Finally, NAC reduced the recovery of L. monocytogenes from spleen of mice fed diets containing LF or HCO. | Although previous studies have included early reexploration for bleeding as a risk factor in analyzing adverse outcomes after cardiac operations, reexploration for bleeding has not been systematically examined as a multivariate risk factor for increased morbidity and mortality after cardiac surgery. Furthermore, multivariate predictors of the need for reexploration have not been identified. Accordingly, we performed a retrospective analysis of 6100 patients requiring cardiopulmonary bypass from January 1, 1986, to December 31, 1993. Eighty-five patients who had ventricular assist devices were excluded from further analysis because of the prevalence of bleeding and the significant morbidity and mortality associated with placement of a ventricular assist device, unrelated to reexploration. In the remaining 6015 patients, potential adverse outcomes analyzed included operative mortality, mediastinitis, stroke, renal failure, adult respiratory distress syndrome, prolonged mechanical ventilation, sepsis, atrial arrhythmias, and ventricular arrhythmias. To control for the confounding effects of other risk factors, we performed a multivariate logistic regression analysis. Potential covariates considered in the logistic model included age, sex, race, history of reoperation, urgency of the operation, congestive heart failure, prior myocardial infarction, renal failure, diabetes, hypertension, chronic obstructive pulmonary disease or stroke, and the bypass and crossclamp time. The overall incidence of reexploration was 4.2% (253/6015). Four independent risk factors--increased patient age (p < 0.001), preoperative renal insufficiency (p = 0.02), operation other than coronary bypass (p < 0.001), and prolonged bypass time (p = 0.0.3)--were identified as predictors of the need for reexploration. The preoperative use of aspirin, heparin, or thrombolytic agents and the bleeding time were not identified as predictors. Reexploration for bleeding was identified as a strong independent risk factor for operative mortality (p = 0.005), renal failure (p < 0.0001), prolonged mechanical ventilation (p < 0.0001), adult respiratory distress syndrome (p = 0.03), sepsis (p < 0.0001), and atrial arrhythmias (p = 0.006). |
Is area level deprivation an independent determinant of prevalent type 2 diabetes and obesity at the national level in Germany . Results from the National Telephone Health Interview Surveys 'German Health Update ' GEDA 2009 and 2010? | There is increasing evidence that prevention programmes for type 2 diabetes mellitus (T2DM) and obesity need to consider individual and regional risk factors. Our objective is to assess the independent association of area level deprivation with T2DM and obesity controlling for individual risk factors in a large study covering the whole of Germany. We combined data from two consecutive waves of the national health interview survey 'GEDA' conducted by the Robert Koch Institute in 2009 and 2010. Data collection was based on computer-assisted telephone interviews. After exclusion of participants <30 years of age and those with missing responses, we included n=33,690 participants in our analyses. The outcome variables were the 12-month prevalence of known T2DM and the prevalence of obesity (BMI ≥ 30 kg/m(2)). We also controlled for age, sex, BMI, smoking, sport, living with a partner and education. Area level deprivation of the districts was defined by the German Index of Multiple Deprivation. Logistic multilevel regression models were performed using the software SAS 9.2. Of all men and women living in the most deprived areas, 8.6% had T2DM and 16.9% were obese (least deprived areas: 5.8% for T2DM and 13.7% for obesity). For women, higher area level deprivation and lower educational level were both independently associated with higher T2DM and obesity prevalence [highest area level deprivation: OR 1.28 (95% CI: 1.05-1.55) for T2DM and OR 1.28 (95% CI: 1.10-1.49) for obesity]. For men, a similar association was only found for obesity [OR 1.20 (95% CI: 1.02-1.41)], but not for T2DM. | Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. Erythroblastosis virus E26 oncogene homolog 1 (ETS1) is involved in the drug resistance of various cancer cells, and is overexpressed in drug-resistant human breast cancer cell lines. In this study, we investigated the effects of ETS1 on adriamycin resistance in MCF-7/ADR cells. siRNAs against ETS1 or negative control siRNAs was transfected to MCF-7/ADR breast cancer cells. Reverse transcription-PCR and Western blotting were used to determine the mRNA and protein expression of ETS1 and MDR1. The cytotoxicity of adriamycin was assessed using the MTT assay. Drug efflux was investigated by flow cytometry using the Rhodamine 123 intracellular accumulation assay. ETS1 mRNA and protein was significantly overexpressed in MCF-7/ADR cells, compared to MCF-7 cells. ETS1 siRNA successfully silenced ETS1 mRNA and protein expression. Silencing of ETS1 also significantly reduced the mRNA and protein expression levels of MDR1 (multidrug resistance 1; also known as ABCB1, P-glycoprotein/P-gp), which is a major ATP-binding cassette (ABC) transporter linked to multi-drug resistance in cancer cells. Silencing of ETS1 significantly increased the sensitivity of MCF-7/ADR cells to adriamycin, compared to cells transfected with negative control siRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in MCF-7/ADR cells transfected with ETS1 siRNA, indicating that silencing of ETS1 may reduce drug efflux. |
Is hemodynamic steroid responsiveness predictive of neurological outcome after traumatic brain injury? | To determine the impact of physiologic doses of hydrocortisone on neurologic outcome after traumatic brain injury (TBI). We conducted a retrospective study in a neurocritical care unit at a university teaching hospital. We included 29 patients with moderate and severe TBI requiring vasoactive drugs to maintain adequate arterial blood pressure who received corticosteroid. Infected patients were excluded. Blood cortisol levels were measured before and 30 and 60 minutes after the administration of a high-dose corticotropin stimulation test (HDST). Patients received hydrocortisone replacement therapy (200-300 mg/day) and vasoactive drugs requirements were noted. Intracranial pressure was managed according to a predefined protocol. A total of 14 out of 29 (48%) of patients were classified as responders to hydrocortisone (stopping vasoactive drugs within 3 days of starting hydrocortisone). The Glasgow Outcome Score (GOS) was used to assess neurologic outcome at 6 months. A favorable outcome (GOS 4 and 5) was observed in 11 out of 14 (79%) of responders and five out of 15 (33%) of nonresponders (p = 0.03). Of the responders, 12 out of 14 (85%) had a baseline cortisol below 414 nmol/L, and five out of 14 (36%) had primary adrenal insufficiency (AI) (primary AI: low baseline cortisol, and poor response to the HDST). Age, severity of injury, and response to hydrocortisone were predictive of outcome in multiple logistic regression analysis. | Defective apoptosis is a hallmark of cancer development and progression. Death receptors (DR4, FAS) and their ligands (TRAIL, FASL) are thought to mediate the major extrinsic apoptotic pathway in the cell. SNPs in these genes may lead to defective apoptosis. Hence, the present study aimed to investigate the association of functional SNPs of DR4 (rs20575, rs20576 and rs6557634), FAS (rs2234767) and FASL (rs763110) with gallbladder cancer (GBC) risk. This case-control study included 400 GBC and 246 healthy controls (HC). Genotyping was carried out by Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2.0, BIOSTAT, Englewood, NJ) to systematically summarize the possible association of SNP with cancer risk. Functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). False discovery rate (FDR test) was used in multiple comparisons. The DR4 C rs20575 A rs20576 A rs6557634, G rs20575 A rs20576 G rs6557634 and G rs20575 C rs20576 G rs6557634 haplotypes conferred two-fold increased risk for GBC. Among these, the DR4 C rs20575 A rs20576 A rs6557634 haplotype emerged as main factor influencing GBC susceptibility as the risk was not modulated by gender or gallstone stratification. Our meta-analysis results showed significant association of DR4 rs6557634 with overall cancer risk, GI cancers as well as in Caucasians. We didn't find any association of FAS and FASL SNPs with GBC susceptibility. |
Is hLA-Cw6 homozygosity in plaque psoriasis associated with streptococcal throat infections and pronounced improvement after tonsillectomy : A prospective case series? | Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. We sought to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602-negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively (P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively (P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively (P < .001). The homozygotes more often had psoriasis onset associated with a throat infection (P = .007) and an increased frequency of streptococcal throat infections per lifetime (P = .038). | Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. The encoding frequency (ke) maps the measured phase to tissue displacement while the strength of the encoding gradients affects image quality. 2D cine DENSE studies have used a ke of 0.10 cycles/mm, which is high enough to remove an artifact-generating echo from k-space, provide high sensitivity to tissue displacements, and dephase the blood pool. However, through-plane dephasing can remove the unwanted echo and dephase the blood pool without relying on high ke. Additionally, the high sensitivity comes with the costs of increased phase wrapping and intra-voxel dephasing. We hypothesized that ke below 0.10 cycles/mm can be used to improve image characteristics and provide accurate measures of cardiac mechanics. Spiral cine DENSE images were obtained for 10 healthy subjects and 10 patients with a history of heart disease on a 3 T Siemens Trio. A mid-ventricular short-axis image was acquired with different ke: 0.02, 0.04, 0.06, 0.08, and 0.10 cycles/mm. Peak twist, circumferential strain, and radial strain were compared between acquisitions employing different ke using Bland-Altman analyses and coefficients of variation. The percentage of wrapped pixels in the phase images at end-systole was calculated for each ke. The dephasing of the blood signal and signal to noise ratio (SNR) were also calculated and compared. Negligible differences were seen in strains and twist for all ke between 0.04 and 0.10 cycles/mm. These differences were of the same magnitude as inter-test differences. Specifically, the acquisitions with 0.04 cycles/mm accurately quantified cardiac mechanics and had zero phase wrapping. Compared to 0.10 cycles/mm, the acquisitions with 0.04 cycles/mm had 9 % greater SNR and negligible differences in blood pool dephasing. |
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