Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.     

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies

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Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin β receptor (LTβR) in human cells stimulated by the shared ligand LIGHT

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-α receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTβR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTβR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTβR. Higher expression of HVEM was associated with cell survival, while unopposed LTβR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTβR modulates canonical NF-κB and pro-apoptotic signals stimulated by LIGHT.     

Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation

Quantitative prediction of unbound drug fraction (f_u) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of f_u values under pathological conditions. The primary objective of this study was to predict f_u values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling f_u in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting f_u in hepatic insufficiency, particularly for albumin-bound drugs.     

The genetic variability of glycoproteins among respiratory syncytial virus subtype A in China between 2009 and 2013

Human respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and children under 5 years of age. The novel genotype ON1 has a 72-nucleotide duplication, which is the largest duplicated genome portion of RSV. Whether the ON1 genotype will follow the pattern of the BA genotype, which has a 60-nucleotide duplication, and become the predominant RSV-A strain is a global concern. To obtain information regarding the prevalence of the ON1 genotype in Chongqing in Southwestern China, we examined the circulation pattern of RSV-A identified over four consecutive years (June 2009 to August 2013). In this study, 312 (12%) RSV-A strains were isolated from 2601 nasopharyngeal aspirates, and partial G gene was sequenced successfully in 250 isolates. Of the sequenced Chongqing RSV-A isolates, 237 (94.8%) strains were the NA1 genotype, 4 (1.6%) strains were the NA3 genotype, 4 (1.6%) strains were the NA4 genotype, 1 (0.4%) strain was the GA1 genotype, and 4 (1.6%) strains were identified as the ON1 genotype. Analysis of the distribution, phylogeny, and evolution of the ON1 strains that were collected globally until December 2013 revealed that the ON1 genotype has rapidly disseminated across the world under positive selection pressures. Future studies will determine whether this new genotype will continue to spread and become the dominant strain of RSV-A worldwide. These findings may contribute to the understanding of RSV evolution and to the potential development of a vaccine against RSV.     

Rapid Spread and Diversification of Respiratory Syncytial Virus Genotype ON1, Kenya

Respiratory syncytial virus genotype ON1, which is characterized by a 72-nt duplication in the attachment protein gene, has been detected in >10 countries since first identified in Ontario, Canada, in 2010. We describe 2 waves of genotype ON1 infections among children admitted to a rural hospital in Kenya during 2012. Phylogenetic analysis of attachment protein gene sequences showed multiple introductions of genotype ON1; variants distinct from the original Canadian viruses predominated in both infection waves. The genotype ON1 dominated over the other group A genotypes during the second wave, and some first wave ON1 variants reappeared in the second wave. An analysis of global genotype ON1 sequences determined that this genotype has become considerably diversified and has acquired signature coding mutations within immunogenic regions, and its most recent common ancestor dates to ≈2008–2009. Surveillance of genotype ON1 contributes to an understanding of the mechanisms of rapid emergence of respiratory viruses.     

Ultrasonic atomization and subsequent desolvation for monoclonal antibody (mAb) to the glycoprotein (GP) IIIa receptor into drug eluting stent

An eluting-stent system with mAb dispersed in the PLLA (poly (L-lactic acid)) was validated in vitro. Specifically designed spray equipment based on the principle of ultrasonic atomization was used to produce a thin continuous PLLA (poly (L-lactic acid)) polymer coating incorporating monoclonal antibody (mAb). This PLLA coating was observed in light microscopy (LM) and scanning electron microscopy (SEM). The concentration of the monoclonal antibody (mAb) to the platelet glycoprotein (GP) IIIa receptor and the eluting rate were then measured by a radioisotope technique with ¹²⁵I-labelled GP IIIa mAb. An in vitro perfusion circuit was designed to evaluate the release rates at different velocities (10 or 20 ml min^?1). The PLLA coating was thin and transparent, uniformly distributed on the surface of the stent. Three factors influenced its thickness: PLLA concentration, duration and gas pressure. The concentration of mAb was influenced by the duration of absorption and the concentration of the mAb solution; the maximum was 1662.23 ± 38.83 ng. The eluting rate was fast for the first 2 h, then decreased slowly and attained 80% after 2 weeks. This ultrasonic atomization spray equipment and technological process to prepare protein eluting-stents were proved to be effective and reliable.     

IgM monoclonal gammopathy–associated neuropathies with different IgM specificity

Background and purpose: Antibodies directed against myelin‐associated glycoprotein (MAG) are believed to be the most frequent biologic marker of the neuropathies associated with IgM monoclonal gammopathy of undetermined significance (MGUS). The objective of this study was to examine the prevalence of antiganglioside and/or sulfatide‐positive patients and their clinical findings, including therapeutic response, compared to anti‐MAG‐positive or seronegative patients. Methods: We prospectively followed 46 patients with MGUS who were diagnosed in our tertiary referral centers for polyneuropathy since 1997. All patients underwent nerve conduction studies and were tested for anti‐MAG, gangliosides, and sulfatide antibodies. All the anagraphic and clinical data (including symptoms, disability scale, therapy, secondary malignancy development) were recorded in a database and compared between three patients’ groups (anti‐MAG‐positive; antiganglioside/sulfatide‐positive; no reactivity). Results: Anti‐MAG reactivity was present in 17 (37%) patients; other 17 patients (37%) had antiganglioside/sulfatide reactivity and 12 (26%) had no reactivity. Patients with antiganglioside/sulfatide positivity, although heterogeneous by a clinical and neurophysiological point of view, had the most severe neuropathic manifestations and a higher disability score at nadir (P < 0.001). These patients had a better response to both intravenous immunoglobulin therapy and rituximab. Conclusions: Our results suggest that antiganglioside/sulfatide‐positive patients form a relevant portion of patients with MGUS‐associated polyneuropathy seen in tertiary care centers and should be considered in future studies on treatment response.