Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT)

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod-a novel neonatal Fc receptor inhibitor-was well tolerated and that acetylcholine receptor antibody-positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up-only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.Neurological Motor Disorder

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention

Transgenic tomatoes expressing human beta-amyloid for use as a vaccine against Alzheimer’s disease

Human β-amyloid (Aβ) is believed to be one of the main components of Alzheimer’s disease, so reduction of Aβ is considered a key therapeutic target. Using Agrobacterium-mediated nuclear transformation, we generated transgenic tomatoes for Aβ with tandem repeats. Integration of the human Aβ gene into the tomato genome and its transcription were detected by PCR and Northern blot, respectively. Expression of the Aβ protein was confirmed by western blot and ELISA, and then the transgenic tomato line expressing the highest protein level was selected for vaccination. Mice immunized orally with total soluble extracts from the transgenic tomato plants elicited an immune response after receiving a booster. The results indicate that tomato plants may provide a useful system for the production of human Aβ antigen

Study protocol: EXERcise and Cognition In Sedentary adults with Early-ONset dementia (EXERCISE-ON)

<p>Abstract</p> <p>Background</p> <p>Although the development of early-onset dementia is a radical and invalidating experience for both patient and family there are hardly any non-pharmacological studies that focus on this group of patients. One type of a non-pharmacological intervention that appears to have a beneficial effect on cognition in older persons without dementia and older persons at risk for dementia is exercise. In view of their younger age early-onset dementia patients may be well able to participate in an exercise program. The main aim of the EXERCISE-ON study is to assess whether exercise slows down the progressive course of the symptoms of dementia.</p> <p>Methods/Design</p> <p>One hundred and fifty patients with early-onset dementia are recruited. After completion of the baseline measurements, participants living within a 50 kilometre radius to one of the rehabilitation centres are randomly assigned to either an <it>aerobic exercise program in a rehabilitation centre</it> or a <it>flexibility and relaxation program in a rehabilitation centre</it>. Both programs are applied three times a week during 3 months. Participants living outside the 50 kilometre radius are included in a feasibility study where participants join in a <it>daily physical activity program set at home making use of pedometers</it>. Measurements take place at baseline (entry of the study), after three months (end of the exercise program) and after six months (follow-up). Primary outcomes are cognitive functioning; psychomotor speed and executive functioning; (instrumental) activities of daily living, and quality of life. Secondary outcomes include physical, neuropsychological, and rest-activity rhythm measures.</p> <p>Discussion</p> <p>The EXERCISE-ON study is the first study to offer exercise programs to patients with early-onset dementia. We expect this study to supply evidence regarding the effects of exercise on the symptoms of early-onset dementia, influencing quality of life.</p> <p>Trial registration</p> <p>The present study is registered within The Netherlands National Trial Register (ref: NTR2124)</p

Improved Mitochondrial Function with Diet-Induced Increase in Either Docosahexaenoic Acid or Arachidonic Acid in Membrane Phospholipids

Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca2+ load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca2+-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca2+ load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs

Validation of Reference Genes for the Relative Quantification of Gene Expression in Human Epicardial Adipose Tissue

BACKGROUND: Relative quantification is a commonly used method for assessing gene expression, however its accuracy and reliability is dependent upon the choice of an optimal endogenous control gene, and such choice cannot be made a priori. There is limited information available on suitable reference genes to be used for studies involving human epicardial adipose tissue. The objective of the current study was to evaluate and identify optimal reference genes for use in the relative quantification of gene expression in human epicardial fat depots of lean, overweight and obese subjects. METHODOLOGY/PRINCIPAL FINDINGS: Some of the commonly used reference genes including 18S, ACTB, RPL27, HPRT, CYCA, GAPDH, RPLPO, POLR2A and B2M were quantified using real-time PCR analysis. The expression stability of these genes was evaluated using Genorm, Normfinder and Bestkeeper algorithms. In addition, the effect of sample size on the validation process was studied by randomly categorizing subjects in two cohorts of n = 2 and n = 33. CONCLUSIONS/SIGNIFICANCE: CYCA, GAPDH and RPL27 were identified as the most stable genes common to all three algorithms and both sample sizes. Their use as reference gene pairs might contribute to the enhanced robustness of relative quantification in the studies involving the human epicardial adipose tissue

Cerebellar Asymmetry and Cortical Connectivity in Monozygotic Twins with Discordant Handedness

Handedness differentiates patterns of neural asymmetry and interhemispheric connectivity in cortical systems that underpin manual and language functions. Contemporary models of cerebellar function incorporate complex motor behaviour and higher-order cognition, expanding upon earlier, traditional associations between the cerebellum and motor control. Structural MRI defined cerebellar volume asymmetries and correlations with corpus callosum (CC) size were compared in 19 pairs of adult female monozygotic twins strongly discordant for handedness (MZHd). Volume and asymmetry of cerebellar lobules were obtained using automated parcellation.CC area and regional widths were obtained from midsagittal planimetric measurements. Within the cerebellum and CC, neurofunctional distinctions were drawn between motor and higher-order cognitive systems. Relationships amongst regional cerebellar asymmetry and cortical connectivity (as indicated by CC widths) were investigated. Interactions between hemisphere and handedness in the anterior cerebellum were due to a larger right-greater-than-left hemispheric asymmetry in right-handed (RH) compared to left-handed (LH) twins. In LH twins only, anterior cerebellar lobule volumes (IV, V) for motor control were associated with CC size, particularly in callosal regions associated with motor cortex connectivity. Superior posterior cerebellar lobule volumes (VI, Crus I, Crus II, VIIb) showed no correlation with CC size in either handedness group. These novel results reflected distinct patterns of cerebellar-cortical relationships delineated by specific CC regions and an anterior-posterior cerebellar topographical mapping. Hence, anterior cerebellar asymmetry may contribute to the greater degree of bilateral cortical organisation of frontal motor function in LH individuals

Adolescent self-harm in Ghana: a qualitative interview-based study of first-hand accounts

Background: Recent prevalence studies suggest that self-harm among adolescents in sub-Saharan Africa is as common as it is in high income countries. However, very few qualitative studies exploring first-person accounts of adolescent self-harm are available from sub-Saharan Africa. We sought to explore the experiences and first-person perspectives of Ghanaian adolescents reporting self-harm - for deeper reflections on the interpretive repertoires available in their cultural context for making sense of self-harm in adolescents. Methods: Guided by a semi-structured interview protocol, we interviewed one-to-one 36 adolescents (24 in-school adolescents and 12 street-connected adolescents) on their experiences of self-harm. We applied experiential thematic analysis to the data. Results: Adolescents’ description of the background to their self-harm identified powerlessness in the family context and unwanted adultification in the family as key factors leading up to self-harm among both in-school and street-connected adolescents. Adolescents’ explanatory accounts identified the contradictory role of adultification as a protective factor against self-harm among street-connected adolescents. Self-harm among in-school adolescents was identified as a means of “enactment of tabooed emotions and contestations”, as a “selfish act and social injury”, as “religious transgression”, while it was also seen as improving social relations. Conclusions: The first-person accounts of adolescents in this study implicate familial relational problems and interpersonal difficulties as proximally leading to self-harm in adolescents. Self-harm in adolescents is interpreted as an understandable response, and as a strong communicative signal in response to powerlessness and family relationship difficulties. These findings need to be taken into consideration in the planning of services in Ghana and are likely to be generalisable to many other countries in sub-Saharan Africa

Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

AbstractMany individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.</jats:p