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Systemic inflammation plays a central role in the pathophysiology of psoriasis. This study examined accessible systemic inflammatory markers in patients with psoriasis vulgaris and psoriatic arthritis. We aimed to evaluate their association with psoriasis severity, the presence of arthritis, and drug continuation rates. The findings revealed that neutrophil, monocyte, and platelet count, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, systemic inflammation response index, systemic immune/inflammation index (SII), and CRP were positively correlated with Psoriasis Area and Severity Index scores. Patients presenting with higher platelet/lymphocyte ratio (PLR) or CRP values were more likely to be diagnosed with psoriatic arthritis than with psoriasis vulgaris in the multivariate regression analysis. Importantly, patients with higher pretreatment neutrophil or platelet count, PLR, and SII were associated with lower treatment continuation rates of conventional systemic agents. Higher pretreatment scores of systemic inflammatory markers did not affect treatment retention rates of biologics. These findings suggest that several accessible systemic inflammatory markers may effectively assess underlying systemic inflammation and may provide an indication for a therapeutic approach in patients with psoriasis vulgaris and psoriatic arthritis. [ABSTRACT FROM AUTHOR]

Objectives. Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains a challenge in management. Transarterial chemoembolization (TACE) has been used for patients with PVTT but efficiency was limited with a median overall survival of 4 to 6.1 months. The aim of this study is to evaluate the efficiency of TACE combined with sorafenib in HBV background HCC with PVTT. Methods. A total of 498 patients were enrolled in the study including 69 patients who received TACE combined with sorafenib and 429 patients treated with TACE alone between January 1st, 2008, and April 30st, 2014. Using the 1:2 propensity score matching, 138 well-balanced patients were enrolled. Overall survival (OS) was compared between the two groups. The Kaplan-Meier method was used to evaluate the OS, and the differences between groups were analyzed with a log-rank test. Results. TACE combined with sorafenib improved the OS of the patients compared with TACE alone (13.0 vs 6.0 months, p<0.001). After propensity score matching, the median OS of combination therapy and TACE were 13.0 and 7.0 months, respectively (p=0.001). Subgroup analysis revealed that the patients younger than 60 years old, male patients, AFP more than 400ng/ml, tumor size more than 5cm, or type III/IV PVTT had OS benefits from TACE combined with sorafenib. Conclusions. Compared with TACE therapy alone, TACE combined with sorafenib could improve OS in HBV background HCC patients with PVTT. The patients who are younger, male, or with more tumor burden may benefit more from combination therapy. [ABSTRACT FROM AUTHOR]

Background: Klebsiella pneumoniae is an opportunistic pathogen and many strains are multidrug resistant. KPC is one of the most problematic resistance mechanisms, as it confers resistance to most β-lactams, including carbapenems. A promising platform technology for treating infections caused by MDR pathogens is the nucleic acid-like synthetic oligomers that silence bacterial gene expression by an antisense mechanism. Objectives: To test a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) in a mouse model of K. pneumoniae infection. Methods: PPMOs were designed to target various essential genes of K. pneumoniae and screened in vitro against a panel of diverse strains. The most potent PPMOs were further tested for their bactericidal effects in broth cultures and in established biofilms. Finally, a PPMO was used to treat mice infected with a KPC-expressing strain. Results: The most potent PPMOs targeted acpP, rpmB and ftsZ and had MIC75s of 0.5, 4 and 4 μM, respectively. AcpP PPMOs were bactericidal at 1-2 x MIC and reduced viable cells and biofilm mass in established biofilms. In a mouse pneumonia model, therapeutic intranasal treatment with -30 mg/kg AcpP PPMO improved survival by 89% and reduced bacterial burden in the lung by -3 logs. Survival was proportional to the dose of AcpP PPMO. Delaying treatment by 2, 8 or 24 h post-infection improved survival compared with control groups treated with PBS or scrambled sequence (Scr) PPMOs. Conclusions: PPMOs have the potential to be effective therapeutic agents against KPC-expressing, MDR K. pneumoniae. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene.Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo .Results: In vitro , the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.Conclusions: These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem-resistant infections in multiple genera of Gram-negative pathogens. [ABSTRACT FROM AUTHOR]

The exact effect of glycine pre-treatment on brain ischemic tolerance (IT) remains quite controversial. The objective of this study was to investigate the potential effects of glycine on IT. We used rat models of both in vitro ischemia (oxygen and glucose deprivation) and in vivo ischemia (transient middle cerebral artery occlusion). Low doses of glycine (L-Gly) significantly decreased hippocampal ischemic LTP (i-LTP), infarct volume, and neurological deficit scores which were administered before ischemia was induced in rats, whereas high doses of glycine exerted deteriorative effects under the same condition. These findings suggested that exogenous glycine may induce IT in a dose-dependent manner. Furthermore, L-Gly-dependent neuronal protection was inversed by L689, a selective NMDAR glycine site antagonist both in vitro (abolished i-LTP depression) and in vivo (increased infarct size reduction), but not glycine receptor (GlyR) inhibitor strychnine. Importantly, L-Gly-induced IT was achieved by NR2A-dependent cAMP-response element binding protein phosphorylation. These data imply that glycine pre-treatment may represent a novel strategy for inducing IT based on synaptic NMDAR-dependent neuronal transmission. [ABSTRACT FROM AUTHOR]

Objective: To explore the correlation of blood-cerebrospinal fluid (CSF) barrier (BCB) dysfunction with the therapeutic effect of antitubercular agents and their resistance, hoping to provide theoretical evidence for improvement of the therapeutic effect. Methods: Albumin in CSF and serum was assayed by IMMAGE. The CSF/serum albumin ratio (QALB) was used to evaluate the permeability of the BCB. Real-time fluorescence quantitative PCR was used to detect the amount of Mycobacterium tuberculosis DNA, and an MTBDRplus reagent kit was used to determine the type of drug resistance of the M. tuberculosis.Results: The correlation analysis showed that significant correlation existed between the grade of severity of tuberculous meningitis and the QALB, and the grade of severity and the total leukocyte count in the CSF, for which the correlation coefficients were 0.366 (p < 0.05) and 0.365 (p < 0.05), respectively. The QALB in the group of patients who recovered was significantly higher than that in those patients who experienced disease progression (p = 0.019). Conclusions: Our study showed that the permeability of the BCB correlated with the cure rate in tuberculous meningitis. Specifically, in the treatment of tuberculous meningitis, it is of key importance to utilize the benefit of the permeability of the BCB to achieve a better outcome. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Shegan Mahuang Decoction (SMD) is a classic traditional Chinese medicine (TCM) formula for asthma treatment, but the anti-asthma mechanism of SMD is still not fully studied. In this study, we established an ovalbumin (OVA)-induced asthma rat model and treated it with SMD to observe its anti-asthma effect and explore the related mechanism. We evaluated the anti-inflammatory effect of SMD via testing the levels of immunoglobulin E (IgE), C-reactive protein (CRP), interleukin-4 (IL-4), interleukin-6 (IL-6) in serum and performing the hematoxylin-eosin (H&E) staining of lung tissue slices. We analyzed the variations of metabolites and proteins in the lung tissue of different groups using liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics and TMT-based proteomics approaches. The metabolic biomarkers and differentially expressed proteins (DEPs) were picked, and the related signal transduction pathways were also investigated. In addition, the key proteins on the signaling pathway were validated through western blotting (WB) experiment to reveal the anti-asthma mechanism of SMD. The results showed that the SMD could significantly reduce the serum levels of IgE, CRP, IL-4, and IL-6 and attenuate the OVA-induced pathological changes in lung tissue. A total of 34 metabolic biomarkers and 84 DEPs were screened from rat lung tissue, which were mainly associated with lipid metabolism, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, the excessive production of reactive oxygen species (ROS), and lysosome pathway. Besides, SMD could inhibit the myeloid differentiation factor 88 (MyD88)/inhibitor of kappa B kinase (IKK)/nuclear factor-kappa B (NF-κB) signaling pathway to exhibit anti-inflammatory activities. SMD exhibited a therapeutic effect on asthma, which possibly be exerted by inhibiting the MyD88/IKK/NF-κB signaling pathway. [Display omitted] • The therapeutic effect of SMD against OVA-induced asthma was studied by using the LC-MS-based multi-omics strategy. • The biomarkers and DEPs were mainly associated with lipid metabolism, NADPH oxidase activation, ROS production, etc. • SMD exerted the ani-asthma effect possibly by inhibiting the MyD88/IKK/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Interferon alpha (IFNα) plays an important role in the pathogenesis of different autoimmune diseases. IFNα is widely used for the treatment of chronic viral infections, particularly chronic hepatitis C virus infection; however, several case reports have emerged describing autoimmune conditions, such as Graves’ disease (GD), that have developed in the patients receiving IFNα. The mechanism by which IFNα is involved in GD remains poorly understood. We investigated the expression of IFNα and IFNα-inducible genes (IFIGs) in GD and found that IFIGs were overexpressed in 60% of 54 clinical diagnostic GD patients. These elevated IFIGs correlated with serological levels of autoantibody to thyroid stimulating hormone receptor (TSHR). Recombinant human IFNα stimulated primary cultured thyrocytes resulted in not only high level expression of IFIGs, but also, more importantly, expression of MHC-II antigens (HLA-DR3 and HLA-DR5) and TSHR in GD subjects. Furthermore, thyroid gland tissues from GD patients over express HLA-DR, TSHR and IFNα receptors at both messenger RNA and protein levels. Taken together, these data indicated that in GD patients, IFNα can function on thyroid tissue to induce a number of genes, particularly MHC class II molecules which may enhance autoantigen presentation of TSHR on thyrocytes. [Copyright &y& Elsevier]