Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations

Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua, which often necessitate admission to the intensive care unit (ICU) and pose an important mortality risk. We describe two previously healthy unrelated teenage girls, who both were admitted with generalized tonic-clonic seizures and visual symptoms leading to a DNA-supported diagnosis of juvenile-onset Alpers' syndrome. Despite combined treatment with anti-epileptic drugs, both patients developed status epilepticus requiring admission to the ICU. Intravenous magnesium as anti-convulsant therapy was initiated, resulting in clinical and neurophysiological improvement and rapid extubation of both patients. Treating status epilepticus in juvenile-onset Alpers' syndrome with magnesium has not been described previously. Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered

Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis

CONTEXT: Prebiopsy multiparametric magnetic resonance imaging (mpMRI) is increasingly used in prostate cancer diagnosis. The reported negative predictive value (NPV) of mpMRI is used by some clinicians to aid in decision making about whether or not to proceed to biopsy. OBJECTIVE: We aim to perform a contemporary systematic review that reflects the latest literature on optimal mpMRI techniques and scoring systems to update the NPV of mpMRI for clinically significant prostate cancer (csPCa). EVIDENCE ACQUISITION: We conducted a systematic literature search and included studies from 2016 to September 4, 2019, which assessed the NPV of mpMRI for csPCa, using biopsy or clinical follow-up as the reference standard. To ensure that studies included in this analysis reflect contemporary practice, we only included studies in which mpMRI findings were interpreted according to the Prostate Imaging Reporting and Data System (PIRADS) or similar Likert grading system. We define negative mpMRI as either (1) PIRADS/Likert 1-2 or (2) PIRADS/Likert 1-3; csPCa was defined as either (1) Gleason grade group ≥2 or (2) Gleason grade group ≥3. We calculated NPV separately for each combination of negative mpMRI and csPCa. EVIDENCE SYNTHESIS: A total of 42 studies with 7321 patients met our inclusion criteria and were included for analysis. Using definition (1) for negative mpMRI and csPCa, the pooled NPV for biopsy-naïve men was 90.8% (95% confidence interval [CI] 88.1-93.1%). When defining csPCa using definition (2), the NPV for csPCa was 97.1% (95% CI 94.9-98.7%). Calculation of the pooled NPV using definition (2) for negative mpMRI and definition (1) for csPCa yielded the following: 86.8% (95% CI 80.1-92.4%). Using definition (2) for both negative mpMRI and csPCa, the pooled NPV from two studies was 96.1% (95% CI 93.4-98.2%). CONCLUSIONS: Multiparametric MRI of the prostate is generally an accurate test for ruling out csPCa. However, we observed heterogeneity in the NPV estimates, and local institutional data should form the basis of decision making if available. PATIENT SUMMARY: The negative predictive values should assist in decision making for clinicians considering not proceeding to biopsy in men with elevated age-specific prostate-specific antigen and multiparametric magnetic resonance imaging reported as negative (or equivocal) on Prostate Imaging Reporting and Data System/Likert scoring. Some 7-10% of men, depending on the setting, will miss a diagnosis of clinically significant cancer if they do not proceed to biopsy. Given the institutional variation in results, it is of upmost importance to base decision making on local data if available

A Greedy Iterative Layered Framework for Training Feed Forward Neural Networks

info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FCCI-INF%2F29168%2F2017/PT" Custode, L. L., Tecce, C. L., Bakurov, I., Castelli, M., Cioppa, A. D., & Vanneschi, L. (2020). A Greedy Iterative Layered Framework for Training Feed Forward Neural Networks. In P. A. Castillo, J. L. Jiménez Laredo, & F. Fernández de Vega (Eds.), Applications of Evolutionary Computation - 23rd European Conference, EvoApplications 2020, Held as Part of EvoStar 2020, Proceedings (pp. 513-529). (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); Vol. 12104 LNCS). Springer. https://doi.org/10.1007/978-3-030-43722-0_33In recent years neuroevolution has become a dynamic and rapidly growing research field. Interest in this discipline is motivated by the need to create ad-hoc networks, the topology and parameters of which are optimized, according to the particular problem at hand. Although neuroevolution-based techniques can contribute fundamentally to improving the performance of artificial neural networks (ANNs), they present a drawback, related to the massive amount of computational resources needed. This paper proposes a novel population-based framework, aimed at finding the optimal set of synaptic weights for ANNs. The proposed method partitions the weights of a given network and, using an optimization heuristic, trains one layer at each step while “freezing” the remaining weights. In the experimental study, particle swarm optimization (PSO) was used as the underlying optimizer within the framework and its performance was compared against the standard training (i.e., training that considers the whole set of weights) of the network with PSO and the backward propagation of the errors (backpropagation). Results show that the subsequent training of sub-spaces reduces training time, achieves better generalizability, and leads to the exhibition of smaller variance in the architectural aspects of the network.authorsversionpublishe

The relationship between basal and acute HPA axis activity and aggressive behavior in adults

The hypothalamic–pituitary–adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones

Amyloid Formation by the Pro-Inflammatory S100A8/A9 Proteins in the Ageing Prostate

BACKGROUND: The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon--prostate tissue remodelling in middle-aged and elderly men. METHODOLOGY/PRINCIPAL FINDINGS: By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. CONCLUSIONS/SIGNIFICANCE: These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.Original Publication:Kiran Yanamandra, Oleg Alexeyev, Vladimir Zamotin, Vaibhav Srivastava, Andrei Shchukarev, Ann-Christin Brorsson, Gian Gaetano Tartaglia, Thomas Vogl, Rakez Kayed, Gunnar Wingsle, Jan Olsson, Christopher M Dobson, Anders Bergh, Fredrik Elgh and Ludmilla A Morozova-Roche, Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate., 2009, PloS one, (4), 5, e5562.http://dx.doi.org/10.1371/journal.pone.000556

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

The evolutionary significance of polyploidy

Polyploidy, or the duplication of entire genomes, has been observed in prokaryotic and eukaryotic organisms, and in somatic and germ cells. The consequences of polyploidization are complex and variable, and they differ greatly between systems (clonal or non-clonal) and species, but the process has often been considered to be an evolutionary 'dead end'. Here, we review the accumulating evidence that correlates polyploidization with environmental change or stress, and that has led to an increased recognition of its short-term adaptive potential. In addition, we discuss how, once polyploidy has been established, the unique retention profile of duplicated genes following whole-genome duplication might explain key longer-term evolutionary transitions and a general increase in biological complexity

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bia