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Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described.
However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients.
Eleven myasthenia gravis patients (age: 70.64 +/- 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 +/- 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors.
Structural brain changes were determined by applying voxel-based morphometry using high-resolution T-1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels.
Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200).
Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions.
Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.
Klaus et al. compared myasthenia gravis patients to matched healthy control subjects and identified functional alterations in memory functions as well as structural alterations in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus.
Background:
From birth to young adulthood, health and development of young people are strongly linked to their living situation, including their family's socioeconomic position (SEP) and living environment. The impact of regional characteristics on development in early childhood beyond family SEP has been rarely investigated. This study aimed to identify regional predictors of global developmental delay at school entry taking family SEP into consideration.
Method:
We used representative, population-based data from mandatory school entry examinations of the German federal state of Brandenburg in 2018/2019 with n=22,801 preschool children. By applying binary multilevel models, we hierarchically analyzed the effect of regional deprivation defined by the German Index of Socioeconomic Deprivation (GISD) and rurality operationalized as inverted population density of the children's school district on global developmental delay (GDD) while adjusting for family SEP (low, medium and high)
Results:
Family SEP was significantly and strongly linked to GDD. Children with the highest family SEP showed a lower odds for GDD compared to a medium SEP (female: OR=4.26, male: OR=3.46) and low SEP (female: OR=16.58, male: OR=12.79). Furthermore, we discovered a smaller, but additional and independent effect of regional socioeconomic deprivation on GDD, with a higher odds for children from a more deprived school district (female: OR=1.35, male: OR=1.20). However, rurality did not show a significant link to GDD in preschool children beyond family SEP and regional deprivation.
Conclusion:
Family SEP and regional deprivation are risk factors for child development and of particular interest to promote health of children in early childhood and over the life course.
The investigation of protein structures, functions and interactions often requires modifications to adapt protein properties to the specific application. Among many possible methods to equip proteins with new chemical groups, the utilization of orthogonal aminoacyl-tRNA synthetase/tRNA pairs enables the site-specific incorporation of non-canonical amino acids at defined positions in the protein. The open nature of cell-free protein synthesis reactions provides an optimal environment, as the orthogonal components do not need to be transported across the cell membrane and the impact on cell viability is negligible. In the present work, it was shown that the expression of orthogonal aminoacyl-tRNA synthetases in CHO cells prior to cell disruption enhanced the modification of the pharmaceutically relevant adenosine A2a receptor. For this purpose, in complement to transient transfection of CHO cells, an approach based on CRISPR/Cas9 technology was selected to generate a translationally active cell lysate harboring endogenous orthogonal aminoacyl-tRNA synthetase.
Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three-months-old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D-reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory- and maladaptive processes including cognitive impairment following stroke needs to be further investigated.
Stunting
(2021)
Introduction Airway infection with pathogens and its associated pulmonary exacerbations (PEX) are the major causes of morbidity and premature death in cystic fibrosis (CF). Preventing or postponing chronic infections requires early diagnosis. However, limitations of conventional microbiology-based methods can hamper identification of exacerbations and specific pathogen detection. Analyzing volatile organic compounds (VOCs) in breath samples may be an interesting tool in this regard, as VOC-biomarkers can characterize specific airway infections in CF. Areas covered We address the current achievements in VOC-analysis and discuss studies assessing VOC-biomarkers and fingerprints, i.e. a combination of multiple VOCs, in breath samples aiming at pathogen and PEX detection in people with CF (pwCF). We aim to provide bases for further research in this interesting field. Expert opinion Overall, VOC-based analysis is a promising tool for diagnosis of infection and inflammation with potential to monitor disease progression in pwCF. Advantages over conventional diagnostic methods, including easy and non-invasive sampling procedures, may help to drive prompt, suitable therapeutic approaches in the future. Our review shall encourage further research, including validation of VOC-based methods. Specifically, longitudinal validation under standardized conditions is of interest in order to ensure repeatability and enable inclusion in CF diagnostic routine.
Objective
For an effective control of the SARS-CoV-2 pandemic with vaccines, most people in a population need to be vaccinated. It is thus important to know how to inform the public with reference to individual preferences–while also acknowledging the societal preference to encourage vaccinations. According to the health care standard of informed decision-making, a comparison of the benefits and harms of (not) having the vaccination would be required to inform undecided and skeptical people. To test evidence-based fact boxes, an established risk communication format, and to inform their development, we investigated their contribution to knowledge and evaluations of COVID-19 vaccines.
Methods
We conducted four studies (1, 2, and 4 were population-wide surveys with N = 1,942 to N = 6,056): Study 1 assessed the relationship between vaccination knowledge and intentions in Germany over three months. Study 2 assessed respective information gaps and needs of the population in Germany. In parallel, an experiment (Study 3) with a mixed design (presentation formats; pre-post-comparison) assessed the effect of fact boxes on risk perceptions and fear, using a convenience sample (N = 719). Study 4 examined how effective two fact box formats are for informing vaccination intentions, with a mixed experimental design: between-subjects (presentation formats) and within-subjects (pre-post-comparison).
Results
Study 1 showed that vaccination knowledge and vaccination intentions increased between November 2020 and February 2021. Study 2 revealed objective information requirements and subjective information needs. Study 3 showed that the fact box format is effective in adjusting risk perceptions concerning COVID-19. Based on those results, fact boxes were revised and implemented with the help of a national health authority in Germany. Study 4 showed that simple fact boxes increase vaccination knowledge and positive evaluations in skeptics and undecideds.
Conclusion
Fact boxes can inform COVID-19 vaccination intentions of undecided and skeptical people without threatening societal vaccination goals of the population
Nonparametric goodness-of-fit testing for parametric covariate models in pharmacometric analyses
(2021)
The characterization of covariate effects on model parameters is a crucial step during pharmacokinetic/pharmacodynamic analyses. Although covariate selection criteria have been studied extensively, the choice of the functional relationship between covariates and parameters, however, has received much less attention. Often, a simple particular class of covariate-to-parameter relationships (linear, exponential, etc.) is chosen ad hoc or based on domain knowledge, and a statistical evaluation is limited to the comparison of a small number of such classes. Goodness-of-fit testing against a nonparametric alternative provides a more rigorous approach to covariate model evaluation, but no such test has been proposed so far. In this manuscript, we derive and evaluate nonparametric goodness-of-fit tests for parametric covariate models, the null hypothesis, against a kernelized Tikhonov regularized alternative, transferring concepts from statistical learning to the pharmacological setting. The approach is evaluated in a simulation study on the estimation of the age-dependent maturation effect on the clearance of a monoclonal antibody. Scenarios of varying data sparsity and residual error are considered. The goodness-of-fit test correctly identified misspecified parametric models with high power for relevant scenarios. The case study provides proof-of-concept of the feasibility of the proposed approach, which is envisioned to be beneficial for applications that lack well-founded covariate models.
This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.
Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E-2 (PGE(2)) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE(2) to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE(2) synthesis. PGE(2) in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE(2) in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.