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Objective: To compare the treatment efficacy and safety of tofacitinib (TOF) versus methotrexate (MTX) in Takayasu arteritis (TAK).Methods: Fifty-three patients with active disease from an ongoing prospective TAK cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and TOF, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analysed during 12 months.Results: The CR rate was higher in the TOF group than in the MTX group (6 months: 85.19% vs 61.54%, p=0.07; 12 months: 88.46% vs 56.52%, p=0.02). During 12 months' treatment, patients in the TOF group achieved a relatively lower relapse rate (11.54% vs 34.78%, p=0.052) and a longer median relapse-free duration (11.65±0.98 vs 10.48±2.31 months, p=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the TOF group than that in the MTX group (p<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (p>0.05). Prevalence of side effects was low in both groups (3.70% vs 15.38%, p=0.19).Conclusion: TOF was superior to MTX for CR induction, a tendency to prevent relapse and tapering of the GCs dose in TAK treatment. A good safety profile for TOF was also documented in patients with TAK. [ABSTRACT FROM AUTHOR]

Background: Predicting recovery of consciousness is one of the most essential functions of anesthesia depth monitors in anesthesia practice. Perfusion index and bispectral index are 2 indicators of the anesthesia depth monitoring with different working principles. The progression of the anesthesia emergence stages reflected by those monitors has not been well understood, especially in pediatric patients. The goals of this study were to compare the prediction probabilities of perfusion index and bispectral index in predicting awakening and in differentiating the different levels of arousal during emergence after sevoflurane anesthesia in children undergoing open inguinal hernia repairs. Methods: Forty-five patients, aged 1 to 5 years, ASA Status I or II and scheduled for elective open inguinal hernia repairs under general anesthesia were enrolled. The perfusion index and bispectral index were monitored simultaneously during anesthesia recovery. The University of Michigan Sedation Scale was applied to evaluate the clinical arousal levels during emergence. The prediction probability was used to assess the performance of perfusion index and bispectral index in predicting awakening and distinguishing different levels of arousal corresponding to the University of Michigan Sedation Scale during recovery. Results: The prediction probability of perfusion index (PkPI-Awakening = .81, 95% CI 0.73-0.89) in differentiating full consciousness from unconsciousness during recovery was comparable to that of bispectral index (PkBIS- Awakening = .86, 95% CI 0.79- 0.92) (P = .47). The prediction probability for perfusion index (PkPI-UMSS = .61, 95% CI 0.55-0.73) and bispectral index (PkBIS-UMSS = .64, 95% CI 0.53-0.69) had similar performance in distinguishing different University of Michigan Sedation Scale levels. Conclusion: Both the perfusion index and bispectral index performed comparably well in predicting awakening and different arousal levels when emerging from sevoflurane anesthesia in children. [ABSTRACT FROM AUTHOR]

Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein (2) to enhance the aqueous solubility of the obtained derivative (3). DPPH (1,1-diphenyl-2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate (3) could be a better agent for ischemic cerebrovascular disease treatment. [ABSTRACT FROM AUTHOR]

Aims Neuroimaging studies have demonstrated both structural and functional abnormalities in widespread brain regions in patients with subcortical vascular mild cognitive impairment (sv MCI). However, whether and how these changes alter functional brain network organization remains largely unknown. Methods We recruited 21 patients with sv MCI and 26 healthy control ( HC) subjects who underwent resting-state functional magnetic resonance imaging scans. Graph theory-based network analyses were used to investigate alterations in the topological organization of functional brain networks. Results Compared with the HC individuals, the patients with sv MCI showed disrupted global network topology with significantly increased path length and modularity. Modular structure was also impaired in the sv MCI patients with a notable rearrangement of the executive control module, where the parietal regions were split out and grouped as a separate module. The sv MCI patients also revealed deficits in the intra- and/or intermodule connectivity of several brain regions. Specifically, the within-module degree was decreased in the middle cingulate gyrus while it was increased in the left anterior insula, medial prefrontal cortex and cuneus. Additionally, increased intermodule connectivity was observed in the inferior and superior parietal gyrus, which was associated with worse cognitive performance in the sv MCI patients. Conclusion Together, our results indicate that sv MCI patients exhibit dysregulation of the topological organization of functional brain networks, which has important implications for understanding the pathophysiological mechanism of sv MCI. [ABSTRACT FROM AUTHOR]

Objective: A mixed treatment comparison (MTC) was performed to investigate the relative efficacy and safety of licensed pharmaceuticals for moderate-to-severe restless legs syndrome (RLS). Methods: RLS trials published over the past 10 years were identified via systematic literature searches of MEDLINE, Embase, Cochrane CENTRAL, and manufacturers’ websites. MTC was performed with WinBUGS software using a Bayesian approach. Identified primary outcomes: change in International RLS Study Group Rating Scale (IRLS) at week 12 and end of maintenance (EoM). Secondary outcomes: IRLS and Clinical Global Impression – Improvement Scale (CGI-I) responders, RLS-6 items and adverse events (AEs). Results: Twenty-eight clinical trials were identified. Fifteen were included in the primary analysis. Indirect comparisons were established among gabapentin enacarbil, pramipexole, ropinirole, rotigotine and placebo. Overall, the four active treatments showed similar efficacies as assessed by changes in IRLS scores, IRLS responders, CGI-I responders, and RLS-6 scores. The sole exception was change in IRLS at week 12, for which rotigotine was likely more efficacious than ropinirole (mean difference: −2.52 [95% CrI: −4.74, −0.40]). Indirect comparisons on safety endpoints indicated ropinirole was associated with a higher risk of nausea than the other agents, and was more likely to result in discontinuations due to lack of efficacy than pramipexole. Nausea was likely more frequent with pramipexole than gabapentin enacarbil, and rotigotine was more likely to result in discontinuation due to AEs than ropinirole and pramipexole. Conclusions: This MTC confirmed the superiority of gabapentin enacarbil, pramipexole, ropinirole, and rotigotine above placebo in alleviating RLS symptoms. Compared to ropinirole, rotigotine showed some additional benefit in terms of change in IRLS at Week 12. Choice of RLS drugs requires careful evaluation of effectiveness and safety profiles in clinical practice. Due to lack of head-to-head trials, inconsistency could not be assessed in our analysis. Head-to-head trials on a more homogeneous population are needed to validate the MTC results. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPARγ agonists involving the endogenous PPARγ ligands and selective PPARγ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPARγ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPARγ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPARγ agonists were fully addressed. [ABSTRACT FROM AUTHOR]

The induction of a strong mucosal immune response is essential to building successful HIV vaccines. Highly attenuated recombinant HIV vaccinia virus can be administered mucosally, but even high doses of immunization have been found unable to induce strong mucosal antibody responses. In order to solve this problem, we studied the interactions of recombinant HIV vaccinia virus Tiantan strain (rVTT-gagpol) in mucosal epithelial cells (specifically Caco-2 cell layers) and in BALB/c mice. We evaluated the impact of this virus on HIV antigen delivery and specific immune responses. The results demonstrated that rVTT-gagpol was able to infect Caco-2 cell layers and both the nasal and lung epithelia in BALB/c mice. The progeny viruses and expressed p24 were released mainly from apical surfaces. In BALB/c mice, the infection was limited to the respiratory system and was not observed in the blood. This showed that polarized distribution limited antigen delivery into the whole body and thus limited immune response. To see if this could be improved upon, we stimulated unpolarized budding of the virus and HIV antigens by treating both Caco-2 cells and BALB/c mice with colchicine. We found that, in BALB/c mice, the degree of infection and antigen expression in the epithelia went up. As a result, specific immune responses increased correspondingly. Together, these data suggest that polarized budding limits antigen delivery and immune responses, but unpolarized distribution can increase antigen expression and delivery and thus enhance specific immune responses. This conclusion can be used to optimize mucosal HIV vaccine strategies. [ABSTRACT FROM AUTHOR]

Background: Experiments have reported that granulocyte colony stimulating factor (G-CSF) can mobilize stem cells. However, few studies have examined the effect of G-CSF on bone marrow mononuclear cell (BMMC) mobilization, in particular regarding their capability to home to acutely injured liver.Aims: The aim of this study was to evaluate the effort of G-CSF on BMMC homing to the liver following chemically-induced hepatic failure.Methods: BMMC were isolated from mice, pre-labeled with PKH26 and infused into the mice in which hepatic injury had been induced followed by administration of G-CSF or vehicle. Livers were studied by fluorescent microscopy after transplantation of pre-labeled BMMC.Results: PKH26 labeled cells were found in liver tissue at 102 ± 10 cells/high power field in the BMMC+G-CSF group and 30 ± 5 cells/high power field in the BMMC group, but none in the G-CSF group and the control group (P < 0.05). In the former two groups the majority of PKH26 labeled cells colocalized with proliferative cell nuclear antigen (PCNA). The number of PCNA positive cells in the BMMC+G-CSF group was 20 ± 4 cells/high power field, while in the BMMC group it was 14 ± 2 cells/high power field, in the G-CSF group 12 ± 2 cells/high power field, and 8 ± 1 cells/high power field in the control group. Moreover, albumin expression was increased in the BMMC+G-CSF treated group (149 ± 7/high power field) relative to the BMMC group (48 ± 6/high power field), the G-CSF group (44 ± 5/high power field) and the vehicle group (30 ± 6/high power field), with the former three groups showing elevated levels as compared to vehicle control (30 ± 6) (P < 0.05).Conclusion: Transplanted BMMC may home to injured liver, which appears to be enhanced by G-CSF administration. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (8): 706–712 Background Four cardiac hormones, i.e. atrial natriuretic peptide (ANP), vessel dilator, long-acting natriuretic peptide (LANP) and kaliuretic peptide (KP), have anticancer effects both in vitro and in vivo. The sustained decrease in number of human pancreatic adenocarcinoma cells for 3 days secondary to the four hormones noted previously suggests a decrease in proliferation of pancreatic cancer cells not eliminated after initial treatment. Materials and methods Four cardiac hormones were evaluated for their ability to directly decrease proliferation of human pancreatic cancer cells with comparison of their effects on proliferation on normal human lung, kidney, prostate and endothelial cells. Results ANP, LANP, vessel dilator and KP decreased the proliferation of viable human pancreatic adenocarcinoma cells by 39%, 73%, 26% and 32% respectively at their 0·01 μM concentrations compared with the proliferation of untreated pancreatic cancer cells. Maximal inhibition of proliferation (81%) occurred with LANP at its 0·1 μM concentration in dose-response studies. At these same concentrations, there was no decrease in proliferation of human kidney, lung, prostate or endothelial cells compared with untreated kidney, lung, prostate or endothelial cells. Conclusion Four cardiac hormones have strong anti-proliferative effects on human pancreatic adenocarcinoma cells while sparing human kidney, lung, prostate and endothelial cells from a similar strong anti-proliferative effect. This anti-proliferative effect on pancreatic cancer cells helps to explain why human pancreatic cancers in vivo treated with the cardiac hormones decrease to less than 10% of the volume of untreated pancreatic cancers as they proliferate less. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (5): 408–413 Background Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, have anticancer effects in vitro and in vivo. Epidermal growth factor’s mechanism of cancer formation involves the activation of Ras. Materials and methods These four cardiac hormones were evaluated for their ability to inhibit mitogen (epidermal growth factor) activation of Ras. Results Epidermal growth factor increased the activation of Ras by 68%, 85% and 90% at its 1, 2 and 5 ng mL−1 concentrations. Vessel dilator, long-acting natriuretic peptide, atrial natriuretic peptide and kaliuretic peptide inhibited 5 ng mL−1 epidermal growth factor’s stimulation of Ras by 73%, 79%, 33% and 45%, respectively, at their 1 μM concentrations. Their effects on epidermal growth factor’s activation of Ras were specific with addition of the cardiac hormones’ respective antibodies (5 μM) blocking 95%, 93%, 100% and 100% ( P < 0·001 for each) of their ability to inhibit epidermal growth factor’s stimulation of Ras. Conclusions Four cardiac hormones specifically inhibit epidermal growth factor’s activation of Ras. This investigation would suggest that these cardiac hormones’ anticancer effects involve the inhibition of mitogens such as epidermal growth factor’s ability to activate Ras as well as inhibiting unstimulated basal activity of Ras. [ABSTRACT FROM AUTHOR]

Insulin’s ability to contribute to cancer formation and proliferation is mediated in part by converting inactive GDPRas to the active form of Ras, i.e., GTP-Ras. Four endogenous cardiac hormones, i.e., vessel dilator, atrial natriuretic peptide (ANP), long-acting natriuretic peptide (LANP) and kaliuretic peptide, which eliminate up to 80% of human pancreatic adenocarcinomas, 2/3rds of human breast cancers and up to 86% of human small-cell lung cancers in athymic mice were evaluated for the ability to decrease insulin’s conversion of GDP-Ras to GTPRas. Vessel dilator, ANP, kaliuretic peptide and LANP decreased the activation of unstimulated Ras 95%, 90%, 90% and 83%, respectively. Dose-response experiments revealed that 1 µM of regular human insulin caused a 100% conversion of GDP-Ras to GTP-Ras. Vessel dilator, LANP, ANP and kaliuretic peptide, each at 1 µM, inhibited 88%, 94%, 56%, and 47%, respectively, of insulin’s (1 µM) activation of Ras. The addition of antibodies (5 µM) to vessel dilator, LANP, ANP and kaliuretic peptide allowed 75%, 50%, 70%, and 96% of insulin’s activation of Ras with the respective cardiac hormones present, suggesting that their effects were specific. This study indicates that four cardiac hormones inhibit insulin’s activation of Ras as another mechanism of their anticancer effects, i.e., blocking mitogenic stimulation of Ras. [ABSTRACT FROM AUTHOR]

Our method concentrates on and constructs the distinguished single gene network. An integrated method was proposed based on linear programming and a decomposition procedure with integrated analysis of the significant function cluster using Kappa statistics and fuzzy heuristic clustering. We tested this method to identify ATF2 regulatory network module using data of 45 samples from the same GEO dataset. The results demonstrate the effectiveness of such integrated way in terms of developing novel prognostic markers and therapeutic targets. [ABSTRACT FROM AUTHOR]

AbstractAim:Insulin-like growth factor-1 (IGF-1) is an important hypertrophic and cell cycle progression factor for a number of cell types. It has been proven that IGF-1 is involved in the regulation of thyroid proliferation and cell cycle progression; however, the exact mechanism of this regulation has not been fully elucidated. In the present study, we investigated the effect of IGF-1 on the expression of cyclin D1, an important cell cycle regulatory protein, and a signaling pathway involved in IGF-1's effect on cyclinD1 expression in FRTL thyroid cells.Methods:FRTL thyroid cells were treated with IGF-1 or vector control for 24 h. As appropriate to individual experiments, a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and/or a nuclear factor-κB (NF-κB) inhibitor, BAY11-7082, were added 1 h prior to IGF-1 treatment. Western blotting was used to detect cyclin D1 protein expression. Immunofluorescence was performed to analyze the expression of IκBα, an NF-κB inhibitory protein. Cell cycle analysis was performed by fluorescence activated cell sorting (FACS).Results:IGF-1 increased the cyclin D1 expression in thyroid cells. This increase was blocked by pretreatment with LY294002 or BAY11-7082. Further studies showed that IGF-1 specifically induced NF-κB activity. Treatment with IGF-1 could accelerate cell cycle progression from G0/G1 to S phase, whereas this progression was inhibited by the presence of LY294002 or BAY11-7082.Conclusion:In summary, the results of the present study show that in FRTL cells, IGF-1 promotes cell cycle progression via an upregulation of cyclin D1 expression, at least partially through the PI3K/NF-κB signaling pathway.Acta Pharmacologica Sinica (2009) 30: 113–119; doi: 10.1038/aps.2008.8; published online 8th December 2008 [ABSTRACT FROM AUTHOR]

Abstract: Primary writing tremor (PWT) is considered to be a type of task-specific tremor in which tremor predominantly occurs and interferes with handwriting. The pathophysiology of PWT is not clear. Primary writing tremor may be a variant of essential tremor, a type of focal dystonia such as writer’s cramp, or a separate nosological entity. Botulinum toxin injections and deep brain stimulation may be treatment choices for primary writing tremor. [ABSTRACT FROM AUTHOR]

Eosinophil-derived TGF-beta has been implicated in remodeling events in asthma. We hypothesized that reduction of bronchial mucosal eosinophils with anti-IL-5 would reduce markers of airway remodeling. Bronchial biopsies were obtained before and after three infusions of a humanized, anti-IL-5 monoclonal antibody (mepolizumab) in 24 atopic asthmatics in a randomized, double-blind, placebo-controlled study. The thickness and density of tenascin, lumican, and procollagen III in the reticular basement membrane (RBM) were quantified immunohistochemically by confocal microscopy. Expression of TGF-beta1 mRNA by airway eosinophils was assessed by in situ hybridization, and TGF-beta1 protein was measured in bronchoalveolar lavage (BAL) fluid by ELISA. At baseline, airway eosinophil infiltration and ECM protein deposition was increased in the RBM of asthmatics compared with nonasthmatic controls. Treating asthmatics with anti-IL-5 antibody, which specifically decreased airway eosinophil numbers, significantly reduced the expression of tenascin, lumican, and procollagen III in the bronchial mucosal RBM when compared with placebo. In addition, anti-IL-5 treatment was associated with a significant reduction in the numbers and percentage of airway eosinophils expressing mRNA for TGF-beta1 and the concentration of TGF-beta1 in BAL fluid. Therefore eosinophils may contribute to tissue remodeling processes in asthma by regulating the deposition of ECM proteins. [ABSTRACT FROM AUTHOR]