Therapeutic plasma exchange in pediatric patients with acute demyelinating syndromes of the central nervous system: A single-center experience

BackgroundTherapeutic plasma exchange (TPE) is an extracorporeal treatment that can be used in adult and pediatric patients with acute demyelinating syndromes of the central nervous system. In this study, the efficacy and safety of TPE was evaluated in 10 pediatric patients who underwent TPE that were unresponsive to corticosteroid treatment.MethodsRecords of 10 pediatric patients who underwent TPE in our pediatric intensive care unit (PICU) between May 2017 and June 2020 were used. Expanded Disability Status Scale (EDSS), Gait Scale (GS), and Visual Outcome Scale (VOS) were applied to the patients before and after TPE.ResultsOf the 10 patients who underwent TPE, five were diagnosed with multiple sclerosis (MS), three with transverse myelitis (TM), and two with acute disseminated encephalomyelitis (ADEM). The median age of the patients was 13.3 years (IQR 8-15), and the median day from symptom onset to onset of TPE was 12.5 days (IQR 7-28). A total of 104 TPE sessions were performed successfully. While no complications were encountered in three patients during the sessions, the most common complication was hypofibrinogenemia. The decrease in EDSS and GS scores was found to be consistent with the clinical response of the patients. There was no statistically significant decrease in the VOS.ConclusionsWith this study, we can say that TPE is a feasible, effective, and safe treatment modality in children with acute demyelinating syndromes of the central nervous system.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Positive Culture During Reimplantation Increases the Risk of Reinfection in Two-Stage Exchange Arthroplasty Despite Administrating Prolonged Antibiotics: A Retrospective Cohort Study and Meta-Analysis

Background

The significance of a positive culture at reimplantation remains an important topic of consideration given the lack of clear metrics for when reimplantation can be performed. The purpose of this study is thus to investigate the (1) association between a positive culture during reimplantation and failure following 2-stage exchange arthroplasty and the (2) influence of prolonged antibiotics on these patients.

Care,agency and criminality: Making sense of authorised extended distribution in the accounts of key stakeholders

IntroductionOne of the current harm reduction debates in Australia concerns the legalisation of the extended distribution of sterile needles and syringes, a practice that is currently unlawful in most Australian settings.MethodsWe used data from a unique pilot program of authorised extended distribution to document the opinions held by 22 key stakeholders -service staff, drug users and police - about the risks and benefits of authorisation, and to analyse the ways in which drug users were understood within these.ResultsOpinions were strongly in favour of authorising extended distribution, based on the belief that this would reduce the transmission of hepatitis C. However, stakeholders also identified that distributors risked attention from police and some noted that the consequences of this would be borne by distributors themselves and not the services that support them. These opinions rested on specific assumptions about people who inject, some of which reflect negative constructions of drug users as a source of danger to the public or as helpless ‘addicts’ with little control over their risk reduction. But there were other representations that positioned drug users more positively as responsible agents with a strong duty of care to themselves and others whose choices are often limited by inadequate service structures. Staff participants drew on these understandings in careful and strategic ways, arguing for the rationality and expertise of drug users, while also problematizing the individualised approach that any form of authorised extended distribution might take.ConclusionWe argue that localised and incremental changes such as those that took place to support this pilot project, and the extensive support for extended distribution among stakeholders in this study including police, creates meaningful opportunities to think about extended distribution differently, which can in turn support conditions for future discussions about legislative change.     

Identification of IgG1 Aggregation Initiation Region by Hydrogen Deuterium Mass Spectrometry

Antibody aggregates are a potential risk for immunogenicity; therefore, rational approaches to improve associated aggregation properties need to be developed. Here, we report the amino acid region responsible for aggregation initiation. Two types of therapeutic IgG1 antibody monomer samples were prepared: IgG1 mAb40-3M stored at 40°C for 3 months, which existed in monodisperse state, and the monomer mAb65-5m, which was dissociated from small soluble aggregates by heating at 65°C for 5 min. Hydrogen deuterium exchange mass spectrometry of mAb40-3M identified 2 sites in the Fc region (site 1, F239-M256; site 2, S428-G450) with increased exchange rates. Site 1 includes a region reported as being susceptible to structural change induced by stress. Exposure of site 1 was undetected after 2 months of storage at 40°C but was subsequently detectable after 3 months. As site 2 is spatially close to site 1, the structural change of site 1 could propagate site 2. Besides these 2 regions, hydrogen deuterium exchange mass spectrometry of mAb65-5m identified an exposure of I257-W281 in Fc (site 3), within which a peptide sequence with high aggregation tendency was discovered. We thus concluded that exposure of site 3 is a trigger for the association of a partially denatured antibody.     

Therapeutic plasma exchange for exogenous insulin antibody syndrome in combined variable immunodeficiency: a case report

A 32-year-old male with type I diabetes presented with profound hypoglycemia due to exogenous insulin antibody syndrome in the setting of newly-diagnosed common variable immunodeficiency. Immunomodulatory therapy was not initially effective, but after the initiation of plasma exchange hypoglycemia resolved, and glucose lability improved.