Fc-Fc interactions of human IgG4 require dissociation of heavy chains and are formed predominantly by the intra-chain hinge isomer

Human IgG4 antibodies are remarkable not only because they can dynamically exchange half-molecules (Fab-arm exchange) but also for their ability to interact with the Fc part of IgG4 and other IgG subclasses. This rheumatoid factor-like binding of IgG4 does not appear to take place spontaneously, because it is only observed to solid-phase or antigen-bound IgG. We hypothesized that Fc-Fc interactions might involve (partial) dissociation of heavy chains. We investigated the molecular basis of these Fc-Fc interactions, and found that the structural features important for the exchange reaction also control the Fc binding activity. In particular, if arginine-409 in the CH(3)-CH(3) interface in IgG4 is mutated to lysine (the equivalent in IgG1), Fc-Fc interactions are formed 3 orders of magnitude less efficiently compared to the wild-type. This mutation was previously found to increase the CH(3)-CH(3) interaction strength in IgG4. Furthermore, of the two hinge isomers of IgG4, the intra-chain (non-covalently linked) form was found to form Fc-Fc interactions, but not the inter-chain form. Together, these results demonstrate that Fc-Fc interactions of IgG4 involve (partial or complete) dissociation of heavy chains. The promiscuity to other IgG subclasses suggests that IgG4 might act as scavenger to IgG molecules with impaired structural integrity.     

Mental rotation strategies reflected in event‐related (de)synchronization of alpha and mu power

During a mental rotation task of hands, participants mentally rotate their hand into the orientation of the shown hand. These mental movements are subject to the body's biomechanical constraints. In this study, we investigated whether the involvement of motor processes during the mental rotation process, as reflected in mu‐power desynchronization, is also influenced by one's movement capabilities. We performed an EEG study and used a delayed response mental rotation task of hands to examine the event‐related desynchronization differences between movements that are biomechanically easy and difficult to perform. Our results show an increase in event‐related desynchronization of the mu power for biomechanically easy compared to difficult‐to‐adopt postures. These findings provide further evidence for the notion that motor simulations can only be performed for movements that can already be performed overtly.     

Development and Evaluation of an Affordable Real-Time Qualitative Assay for Determining HIV-1 Virological Failure in Plasma and Dried Blood Spots

Virological failure (VF) has been identified as the earliest, most predictive determinant of HIV-1 antiretroviral treatment (ART) failure. Due to the high cost and complexity of virological monitoring, VF assays are rarely performed in resource-limited settings (RLS). Rather, ART failure is determined by clinical monitoring and to a large extent immunological monitoring. This paper describes the development and evaluation of a low-cost, dried blood spot (DBS)-compatible qualitative assay to determine VF, in accordance with current WHO guideline recommendations for therapy switching in RLS. The assay described here is an internally controlled qualitative real-time PCR targeting the conserved long terminal repeat domain of HIV-1. This assay was applied to HIV-1 subtypes A to H and further evaluated on HIV-1 clinical plasma samples from South Africa (n = 191) and Tanzania (n = 42). Field evaluation was performed in Uganda using local clinical plasma samples (n = 176). Furthermore, assay performance was evaluated for DBS. This assay is able to identify VF for all major HIV-1 group M subtypes with equal specificity and has a lower detection limit of 1.00E+03 copies/ml for plasma samples and 5.00E+03 copies/ml for DBS. Comparative testing yielded accurate VF determination for therapy switching in 89% to 96% of samples compared to gold standards. The assay is robust and flexible, allowing for “open platform” applications and producing results comparable to those of commercial assays. Assay design enables application in laboratories that can accommodate real-time PCR equipment, allowing decentralization of testing to some extent. Compatibility with DBS extends access of sampling and thus access to this test to remote settings.     

The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis

Journal of Neurology - Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional...     

Psychotropic medications,including short acting benzodiazepines,strongly increase the frequency of falls in elderly

ObjectivesFalls in the elderly are common and often serious. The aim of this study was to examine the association between the use of different classes of psychotropic medications, especially short acting benzodiazepines, and the frequency of falling in elderly.Study design This retrospective cohort study was performed with patients who visited the day clinic of the department of geriatric medicine of the University Medical Center Utrecht in the Netherlands between 1 January 2011 and 1 April 2012.Measurements Frequencies of falling in the past year and medication use were recorded. Logistic regression analysis was performed to assess the relationship between the frequency of falling in the past year and the use of psychotropic medications.ResultsDuring this period 404 patients were included and 238 (58.9%) of them had experienced one or more falls in the past year. After multivariate adjustment, frequent falls remained significantly associated with exposure to psychotropic medications (odds ratio [OR] 1.96; 95% confidence interval [CI] 1.17–3.28), antipsychotics (OR 3.62; 95% CI 1.27–10.33), hypnotics and anxiolytics (OR 1.81; 95% CI 1.05–3.11), short-acting benzodiazepines or Z-drugs (OR 1.94; 95% CI 1.10–3.42) and antidepressants (OR 2.35; 95% CI 1.33–4.16).ConclusionsThis study confirms that taking psychotropic medication, including short-acting benzodiazepines, strongly increases the frequency of falls in elderly. This relation should be explicitly recognized by doctors prescribing for older people, and by older people themselves. If possible such medication should be avoided for elderly patients especially with other risk factors for falling.     

Patterns of suicide mortality in England and Wales before and after the suicide of the actor Robin Williams

Purpose

There is international evidence supporting an association between sensational reporting of suicide and a subsequent increase in local suicide rates, particularly where reporting the death of a celebrity. We aimed to explore whether the observed increase in suicides in the United States, Canada and Australia in the 5 months following the 2014 suicide of the popular actor Robin Williams was also observed in England and Wales.

Method

We used interrupted time-series analysis and a seasonal autoregressive integrated moving averages (SARIMA) model to estimate the expected number of suicides during the 5 months following Williams’ death using monthly suicide count data for England and Wales from the UK Office for National Statistics (ONS) 2013–2014.

Results

Compared with the observed 2051 suicide deaths in all age groups from August to December 2014, we estimated that we would have expected 1949 suicides over the same period, representing no statistically significant excess.

Conclusions

This finding is an outlier among previous studies and contrasts with the approximately 10% increase in suicides found in similar analyses conducted in other high-income English-speaking countries with established media reporting guidelines.

     

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19⁺ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19⁺ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.     

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, The Gene Involved in Classic Late‐Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl‐peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl‐peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1‐variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype–phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.