Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine

In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years.     

Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization

The aim of this study was to synthetize cocrystals of nateglinide, an antidiabetic agent of biopharmaceutics classification system Class IIa, as a strategy to improve both the solubility and the dissolution rate of the drug. Benzamide was selected by a screening procedure as a suitable coformer, and binary mixtures with different compositions were prepared and analyzed by differential scanning calorimetry (DSC). An in-depth analysis of DSC data allowed obtaining both the eutectic mixture and cocrystal compositions. The rationale of such an analysis was highlighted and explained. Cocrystals were prepared by kneading and solvent evaporation. Their formation was proved by DSC and confirmed by X-ray powder diffraction, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. The functional groups involved in the interaction leading to cocrystals formation were investigated by spectroscopic techniques. The in vitro dissolution profiles show that cocrystals have definite better pharmaceutical performances than the pure drug.     

A Study of Crystalline Mechanism of Penetration Sealer Materials

It is quite common to dispense a topping material like crystalline penetration sealer materials (CPSM) onto the surface of a plastic substance such as concrete to extend its service life span by surface protections from outside breakthrough. The CPSM can penetrate into the existing pores or possible cracks in such a way that it may form crystals to block the potential paths which provide breakthrough for any unknown materials. This study investigated the crystalline mechanism formed in the part of concrete penetrated by the CPSM. We analyzed the chemical composites, in order to identify the mechanism of CPSM and to evaluate the penetrated depth. As shown in the results, SEM observes the acicular-structured crystals filling capillary pores for mortar substrate of the internal microstructure beneath the concrete surface; meanwhile, XRD and FT-IR showed the main hydration products of CPSM to be C-S-H gel and CaCO₃. Besides, MIP also shows CPSM with the ability to clog capillary pores of mortar substrate; thus, it reduces porosity, and appears to benefit in sealing pores or cracks. The depth of CPSM penetration capability indicated by TGA shows 0–10 mm of sealer layer beneath the concrete surface.     

Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C

Interferon can induce autoantibodies and autoimmune reactions. This study reviewed the clinical, serological, and HLA phenotypical features of patients who developed autoimmune hepatitis during interferon therapy for chronic hepatitis C, analyzing their response to immunosuppressive treatment. The diagnosis of chronic hepatitis C was based on positivity for viral RNA and a liver biopsy specimen obtained before interferon treatment. Sera were tested for autoantibodies by indirect immunofluorescence assay. HLA typing was performed by applying a standard microlymphocytotoxicity method. Of 144 patients with chronic hepatitis C treated with interferon, 7 women deteriorated during treatment; serum transaminase, γ-globulin, and immunoglobulin G levels increased; and serum autoantibodies became positive. Interferon was interrupted, a diagnosis of autoimmune hepatitis was established, and immunosuppressive therapy was initiated. All patients responded to this treatment. The 7 patients had similar HLA typing to those with autoimmune hepatitis, with DR4 in 2 patients (67%) with type 2 autoimmune hepatitis, and with DR3 and DR52 in 2 (50%) and 4 (100%) patients, respectively, with type 1 autoimmune hepatitis; additionally, 5 patients (71%) had DQ2, and 4 (57%) had both DR52 and DQ2. In female patients with chronic hepatitis C, a genetic susceptibility to autoimmune hepatitis may exist, possibly triggered by immunostimulating effects during interferon therapy. Immunosuppressive treatment has been well tolerated and seems to be effective.     

Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly

The cyclopic and laterality phenotypes in model organisms linked to disturbances in the generation or propagation of Nodal-like signals are potential examples of similar impairments resulting in birth defects in humans. However, the types of gene mutation(s) and their pathogenetic combinations in humans are poorly understood. Here we describe a mutational analysis of the human NODAL gene in a large panel of patients with phenotypes compatible with diminished NODAL ligand function. Significant reductions in the biological activity of NODAL alleles are detected among patients with congenital heart defects (CHD), laterality anomalies (e.g. left–right mis-specification phenotypes), and only rarely holoprosencephaly (HPE). While many of these NODAL variants are typical for family-specific mutations, we also report the presence of alleles with significantly reduced activity among common population variants. We propose that some of these common variants act as modifiers and contribute to the ultimate phenotypic outcome in these patients; furthermore, we draw parallels with strain-specific modifiers in model organisms to bolster this interpretation.     

运用ROC曲线方法评价TRAb、TPO-Ab和TGA在Graves'病和HT鉴别诊断中的意义

目的:应用临床诊断性能(ROC)曲线方法评价TSH受体抗体(TRAb)、甲状腺过氧化物酶抗体(TPO-Ab)和甲状腺球蛋白抗体(TGA)在Graves'病(格雷夫斯病)和桥本甲状腺炎鉴别诊断中的意义.方法:以甲状腺细针穿刺细胞学检查结果作为诊断金标准,以采用化学发光法测定63例自身免疫性甲状腺病患者血清的TRAb、TP...     

Monitoring bypassing agent therapy – a prospective crossover study comparing thromboelastometry and thrombin generation assay

The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg^?1 activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post‐infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 μg kg^?1 and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2–3 folds from baseline 15–30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two‐fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive.