Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Both advanced solid tumors and HCV have previously been associated with memory B-cell dysfunction. In this study, we sought to dissect the effect of viral infection, cirrhosis, and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Peripheral blood from healthy donors, HCV-infected patients with F1-F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related HCC, and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B cells were stimulated with anti-cluster of differentiation (CD)40 antibodies and Toll-like receptor (TLR)9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin (Ig) production, and CD4(+) T-cell allostimulatory capacity. CD27(+) memory B cells and, more specifically, CD27(+) IgM(+) B cells were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B cells in cirrhotics were hyporesponsive to CD40/TLR9 activation, as characterized by CD70 up-regulation, tumor necrosis factor beta secretion, IgG production, and T-cell allostimulation. Last, blockade of TLR4 and TLR9 signaling abrogated the activation of healthy donor B cells by cirrhotic plasma, suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis. CONCLUSION: Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of HCV infection. These B-cell defects may explain, in part, the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.     

A Comparative Evaluation of the Linear Dimensional Accuracy of Four Impression Techniques using Polyether Impression Material

There is much discussion in the dental literature regarding the superiority of one impression technique over the other using addition silicone impression material. However, there is inadequate information available on the accuracy of different impression techniques using polyether. The purpose of this study was to assess the linear dimensional accuracy of four impression techniques using polyether on a laboratory model that simulates clinical practice. The impression material used was Impregum Soft?, 3 M ESPE and the four impression techniques used were (1) Monophase impression technique using medium body impression material. (2) One step double mix impression technique using heavy body and light body impression materials simultaneously. (3) Two step double mix impression technique using a cellophane spacer (heavy body material used as a preliminary impression to create a wash space with a cellophane spacer, followed by the use of light body material). (4) Matrix impression using a matrix of polyether occlusal registration material. The matrix is loaded with heavy body material followed by a pick-up impression in medium body material. For each technique, thirty impressions were made of a stainless steel master model that contained three complete crown abutment preparations, which were used as the positive control. Accuracy was assessed by measuring eight dimensions (mesiodistal, faciolingual and inter-abutment) on stone dies poured from impressions of the master model. A two-tailed t test was carried out to test the significance in difference of the distances between the master model and the stone models. One way analysis of variance (ANOVA) was used for multiple group comparison followed by the Bonferroni’s test for pair wise comparison. The accuracy was tested at α = 0.05. In general, polyether impression material produced stone dies that were smaller except for the dies produced from the one step double mix impression technique. The ANOVA revealed a highly significant difference for each dimension measured (except for the inter-abutment distance between the first and the second die) between any two groups of stone models obtained from the four impression techniques. Pair wise comparison for each measurement did not reveal any significant difference (except for the faciolingual distance of the third die) between the casts produced using the two step double mix impression technique and the matrix impression system. The two step double mix impression technique produced stone dies that showed the least dimensional variation. During fabrication of a cast restoration, laboratory procedures should not only compensate for the cement thickness, but also for the increase or decrease in die dimensions.     

The association of pre‐operative STOP‐BANG scores with postoperative critical care admission

The STOP‐BANG questionnaire screens for obstructive sleep apnoea. We retrospectively analysed the independent association of pre‐operative variables with postoperative critical care admission using multivariable logistic regression for patients undergoing elective surgery from January to December 2011. Of 5432 patients, 338 (6.2%) were admitted postoperatively to the critical care unit. In multivariate analysis, the odds ratios (95% CI) for critical care admission were: 2.2 (1.1–4.6), p = 0.037; 3.2 (1.2–8.1), p = 0.017; and 5.1 (1.8–14.9), p = 0.002, for STOP‐BANG scores of 4, 5 and ≥ 6, respectively. The odds ratio was also independently increased for: each year of age, 1.015 (1.004–1.026), p = 0.019; asthma, 1.6 (1.1–2.4), p = 0.016; obstructive sleep apnoea, 3.2 (1.9–5.6), p < 0.001; and for ASA physical status 2, 3 and ≥ 4, 2.1 (1.4–3.3), 6.5 (3.9–11.0), 6.3 (2.9–13.8), respectively, p < 0.001 for all.     

Patterns and prognostic indicators of response to CML treatment in a multi-country medical record review study

We conducted a review of patient medical records to assess treatment response patterns and prognostic indicators of response among chronic myeloid leukemia (CML) patients in the United States, the United Kingdom, Germany, and Japan. All 1,063 patients selected met the following inclusion criteria: aged 18 or older and in chronic phase at the time of diagnosis, Philadelphia chromosome and/or BCR-ABL positive, received first-line treatment with imatinib, and not enrolled in a randomized clinical trial during the period of retrospective review. Multivariable logistic regression models were used to evaluate prognostic indicators of complete hematological response (CHR), complete cytogenetic response (CCyR), and complete or major molecular response (C/MMR). Among patients treated with first-line imatinib, CHR at three months, CCyR at 12 months, and C/MMR at 18 months were observed in 53, 53.1, and 57.8 % of patients, respectively. Among patients treated with second-line dasatinib or nilotinib, CHR was achieved at three months in 49 and 42 %, CCyR at 12 months in 32 and 23 %, and MMR at 18 months in 30.5 and 26.1 % of patients, respectively. Prognostic indicators of first-line response included age, race, and Sokal score. For second-line treatment, duration of first-line hematological response and choice of drug used were also significant.     

Understanding the interaction of Lipoarabinomannan with membrane mimetic architectures

Lipoarabinomannan (LAM) is a critical virulence factor in the pathogenesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. LAM is secreted in urine and serum from infected patients and is being studied as a potential diagnostic indicator for the disease. Herein, we present a novel ultra-sensitive and specific detection strategy for monomeric LAM based on its amphiphilic nature and consequent interaction with supported lipid bilayers. Our strategy involves the capture of LAM on waveguides functionalized with membrane mimetic architectures, followed by detection with a fluorescently labeled polyclonal antibody. This approach offers ultra-sensitive detection of lipoarabinomannan (10?fM, within 15?min) and may be extended to other amphiphilic markers. We also show that chemical deacylation of LAM completely abrogates its association with the supported lipid bilayers. The loss of signal using the waveguide assay for deacylated LAM, as well as atomic force microscopy (AFM) images that show no change in height upon addition of deacylated LAM support this hypothesis. Mass spectrometry of chemically deacylated LAM indicates the presence of LAM-specific carbohydrate chains, which maintain antigenicity in immunoassays. Further, we have developed the first three-dimensional structural model of mannose-capped LAM that provides insights into the orientation of LAM on supported lipid bilayers.     

Polymer-assisted synthesis and applications of hydroxyapatite (HAp) anchored nitrogen-doped 3D graphene foam-based nanostructured ceramic framework

In the present work, a hydroxyapatite anchored nitrogen-doped three-dimensional graphene (HAp-N3DG) skeletal network (foam) based nanostructured ceramic framework (CF) was developed through a polymer-assisted solvothermal route. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) studies reveal that the nano sized 0D HAp particles are anchored on the N3DG skeletal network with an average size of less than 50 nm. EDX and X-ray photoelectron spectroscopy (XPS) analysis confirmed the presence of Ca, P, O, N, and C. In addition, XPS analysis reveals the existence of N–C bonds in the prepared sample. The X-ray diffraction (XRD) patterns indicate the presence of hexagonal phase hydroxyapatite and the calculated average crystallite size was found to be 12 nm. The developed HAp-N3DG foam based nanostructured CF was found to have a mesoporous structure and the measured specific surface area (SSA) and the mean pore diameter were found to be 64.73 m² g⁻¹ and 23.6 nm, respectively. Electrochemical analysis shows that HAp anchored on nitrogen-doped 3D graphene foam based nanostructured CF has moderate electrochemical activity towards lithium ion charge/discharge. In addition, the prepared material showed adsorption activity values of 204.89 mg g⁻¹ and 243.89 mg g⁻¹ for the volatile organic compounds (VOCs) benzene and toluene, respectively. The present findings suggest that the newly developed HAp anchored nitrogen-doped 3DG (HAp-N3DG) skeletal network (foam) based nanostructured CF material can be used in energy devices and in the removal of volatile organic compounds. Moreover, the present study initiates a new kind of approach in energy device (lithium ion battery-LIB) research and in the removal of VOCs.

Hydroxyapatite anchored nitrogen-doped three-dimensional graphene (HAp-N3DG) skeletal network (foam) based nanostructured ceramic framework (CF) was developed through a polymer-assisted solvothermal route.     

Orthopaedic surgeon＇s nightmare： iatrogenic fractures of talus and medial malleolus following tibial nailing

Intramedullary interlocking nailing is the gold standard for treatment of tibial shaft fractures.The growing use of intramedullary nailing has resulted in an increased number of tibial nailing in daily...     

Interferon‐Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) as a Prognostic Marker for Local Control in T1‐2 N0 Breast Cancer Treated with Breast‐Conserving Surgery and Radiation Therapy (BCS + RT)

Interferon‐induced protein with tetratricopeptide repeats 1 (IFIT1) expression, involved in the regulation of translation, has been implicated to mediate resistance to chemotherapy and radiation in cancer cells in vitro. The purpose of this study was to evaluate the prognostic significance of IFIT1 protein expression in patients with breast cancer treated with Breast‐Conserving Surgery and Radiation Therapy (BCS + RT). A tissue microarray was constructed with specimens from 282 women with node‐negative, early‐stage (I/II) breast cancer who were treated with BCS + RT. Immunohistochemistry was used to stain for the IFIT1 protein. Cytoplasmic IFIT1 protein expression levels were correlated with clinicopathologic factors, local relapse‐free survival (LRFS), disease‐free survival (DFS), and overall survival (OS). IFIT1 positivity was found in 123 (49%) of cases. The median follow‐up time was 7.3 years. Eighty percent of the patients had T1 disease, 88% were human epidermal growth factor receptor 2 (HER2) negative, and 20% had triple‐negative breast cancer (TNBC). IFIT1 positivity was associated with estrogen receptor negative status (p = 0.002), progesterone receptor negative status (p = 0.02), TNBC (p = 0.01), and HER2‐positive status (p = 0.006). In univariate and multivariate analysis, IFIT1 positivity was associated with improved LRFS (p = 0.055 and p = 0.04, respectively). Using a log‐rank test, IFIT1 positivity was found to be associated with improved LRFS (94% versus 85%, p = 0.046) but not DFS or OS at 10 years. On subset analysis of the TNBC patients, IFIT1 positivity was found to correlate with improved LRFS (100% versus 53%, p = 0.004) and DFS in (87% versus 49%, p = 0.048) at 10 years. Elevated IFIT1 protein expression is associated with improved LRFS. In addition, our data suggest that IFIT1 expression may help risk stratify patients with TNBC who may benefit from more aggressive therapy. As there is limited data on IFIT1 in breast cancer, additional work is needed to ascertain its significance.