Interleukin-1ß has trophic effects in microglia and its release is mediated by P2X7R pore.

BACKGROUND: Enhanced expression of the purinergic P2X7 receptor (P2X7R) occurs in several neuroinflammatory conditions where increased microglial activation is a co-existing feature. P2X7 receptors can function either as a cation channel or, upon continued stimulation, a large pore. P2X7R-over-expression alone is sufficient to drive microglial activation and proliferation in a process that is P2X7R pore dependent, although the biological signaling pathway through which this occurs remains unclear. Once activated, microglia are known to release a number of bioactive substances that include the proinflammatory cytokine interleukin-1ß (IL-1ß). Previous studies have linked P2X7R stimulation to the processing and release of IL-1ß, but whether the channel or pore state of P2X7R is predominant in driving IL-1ß release is unknown and is a major aim of this study. In addition, we will determine whether IL-1ß has trophic effects on surrounding microglia. METHODS: Electron microscopy and immunohistochemistry were used to delineate the sub-cellular localization of P2X7R and IL-1ß in primary hippocampal rat cultures. FM1-43 fluorescent dye and confocal microscopy were used to quantify vesicular exocytosis from microglia expressing the pore-forming P2X7R versus a non-pore-forming point mutant, P2X7RG345Y. IL-1ß in culture was quantified with an enzyme-linked immunosorbent assay (ELISA). IL-1ß intracellular processing was blocked with inhibition of caspase 1 (with a synthetic peptide antagonist), and its extracellular form was neutralized with an IL-1ß neutralizing antibody. Microglial activation and proliferation was quantified immunohistochemically with confocal microscopy. RESULTS: P2X7R and IL-1ß were co-localized in lysosomes. Vesicular exocytosis was higher in microglia expressing the pore-forming P2X7R compared to those expressing the non-pore-forming mutant. There was increased IL-1ß in cultures expressing the pore-forming P2X7R, and this proinflammatory cytokine was found to mediate the trophic effects of P2X7R pore in microglia. Inhibition of IL-1ß production and function resulted in a significant decrease in P2X7R-mediated microglial activation and proliferation. CONCLUSIONS: IL-1ß is a mediator of microglial activation and proliferation, and its release/production is P2X7R pore dependent. Blockade of P2X7R pore could serve as a therapeutic target in alleviating the degree of inflammation seen in neurodegenerative and neoplastic conditions.

Antiepileptic drug combinations not involving valproate and the risk of fetal malformations.

OBJECTIVE: To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined. METHODS: An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014). RESULTS: Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025). SIGNIFICANCE: The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

Graph Signal Processing, Graph Neural Network and Graph Learning on Biological Data: A Systematic Review.

Graph networks can model data observed across different levels of biological systems that span from population graphs (with patients as network nodes) to molecular graphs that involve omics data. Graph-based approaches have shed light on decoding biological processes modulated by complex interactions. This paper systematically reviews graph-based analysis methods of Graph Signal Processing (GSP), Graph Neural Networks (GNNs) and graph topology inference, and their applications to biological data. This work focuses on the algorithms of graph-based approaches and the constructions of graph-based frameworks that are adapted to a broad range of biological data. We cover the Graph Fourier Transform and the graph filter developed in GSP, which provides tools to investigate biological signals in the graph domain that can potentially benefit from the underlying graph structures. We also review the node, graph, and interaction oriented applications of GNNs with inductive and transductive learning manners for various biological targets. As a key component of graph analysis, we provide a review of graph topology inference methods that incorporate assumptions for specific biological objectives. Finally, we discuss the biological application of graph analysis methods within this exhaustive literature collection, potentially providing insights for future research in biological sciences.

Reduced total number of enlarged perivascular spaces in post-traumatic epilepsy patients with unilateral lesions - a feasibility study.

BACKGROUND: We investigated the value of automated enlarged perivascular spaces (ePVS) quantification to distinguish chronic traumatic brain injury (TBI) patients with post-traumatic epilepsy (PTE+) from chronic TBI patients without PTE (PTE-) in a feasibility study. METHODS: Patients with and without PTE were recruited and underwent an MRI post-TBI. Multimodal auto identification of ePVS algorithm was applied to T1-weighted MRIs to segment ePVS. The total number of ePVS was calculated and corrected for white matter volume, and an asymmetry index (AI) derived. RESULTS: PTE was diagnosed in 7 out of the 99 participants (male=69) after a median time of less than one year since injury (range 10-22). Brain lesions were observed in all 7 PTE+ cases (unilateral=4, 57%; bilateral=3, 43%) as compared to 40 PTE- cases (total 44%; unilateral=17, 42%; bilateral=23, 58%). There was a significant difference between PTE+ (M=1.21e-4, IQR [8.89e-5]) and PTE- cases (M=2.79e-4, IQR [6.25e-5]) in total corrected numbers of ePVS in patients with unilateral lesions (p=0.024). No differences in AI, trauma severity and lesion volume were seen between groups. CONCLUSION: This study has shown that automated quantification of ePVS is feasible and provided initial evidence that individuals with PTE with unilateral lesions may have fewer ePVS compared to TBI patients without epilepsy. Further studies with larger sample sizes should be conducted to determine the value of ePVS quantification as a PTE-biomarker.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Development of representative magnetic resonance imaging-based atlases of the canine brain and evaluation of three methods for atlas-based segmentation.

OBJECTIVE: To develop representative MRI atlases of the canine brain and to evaluate 3 methods of atlas-based segmentation (ABS). ANIMALS: 62 dogs without clinical signs of epilepsy and without MRI evidence of structural brain disease. PROCEDURES: The MRI scans from 44 dogs were used to develop 4 templates on the basis of brain shape (brachycephalic, mesaticephalic, dolichocephalic, and combined mesaticephalic and dolichocephalic). Atlas labels were generated by segmenting the brain, ventricular system, hippocampal formation, and caudate nuclei. The MRI scans from the remaining 18 dogs were used to evaluate 3 methods of ABS (manual brain extraction and application of a brain shape-specific template [A], automatic brain extraction and application of a brain shape-specific template [B], and manual brain extraction and application of a combined template [C]). The performance of each ABS method was compared by calculation of the Dice and Jaccard coefficients, with manual segmentation used as the gold standard. RESULTS: Method A had the highest mean Jaccard coefficient and was the most accurate ABS method assessed. Measures of overlap for ABS methods that used manual brain extraction (A and C) ranged from 0.75 to 0.95 and compared favorably with repeated measures of overlap for manual extraction, which ranged from 0.88 to 0.97. CONCLUSIONS AND CLINICAL RELEVANCE: Atlas-based segmentation was an accurate and repeatable method for segmentation of canine brain structures. It could be performed more rapidly than manual segmentation, which should allow the application of computer-assisted volumetry to large data sets and clinical cases and facilitate neuroimaging research and disease diagnosis.

Description of technique and lower reference limit for magnetic resonance imaging of hippocampal volumetry in dogs.

OBJECTIVE: To evaluate the use of high-resolution MRI for hippocampal volumetry in dogs and to define a lower reference limit for hippocampal formation (HF) volume. ANIMALS: 20 dogs (with no history of seizures and no underlying structural brain disease) that underwent MRI of the brain. PROCEDURES: The MRI protocol included a high-resolution T1-weighted 3-D ultrafast gradient-echo sequence aligned in a dorsal plane perpendicular to the long axis of the HF. Images obtained with MRI were retrospectively analyzed by 2 observers (A and B). Intraobserver and interobserver agreement were calculated with the Lin concordance correlation coefficient. Volume measurements of the HF were adjusted for intracranial volume, and a lower 95% reference limit for adjusted HF volume was calculated. RESULTS: There was substantial intraobserver agreement (Lin concordance correlation coefficient, 0.97 [95% confidence interval {CI}, 0.94 to 0.99]) but poor interobserver agreement (Lin concordance correlation coefficient, 0.63 [95% CI, 0.37 to 0.79]). The lower 95% reference limit for adjusted HF volume was 0.56 cm(3) (90% CI, 0.52 to 0.60 cm(3)) for the right HF and 0.55 cm(3) (90% CI, 0.52 to 0.58 cm(3)) for the left HF. CONCLUSIONS AND CLINICAL RELEVANCE: HF volumes should be adjusted for intracranial volume to account for the large variation in canine skull size. The amount of time required to perform HF volumetry and low interobserver agreement may restrict this technique to research applications, such as the investigation of epileptic patients for hippocampal sclerosis or other cognitive disorders.

Depression in temporal lobe epilepsy surgery patients: an FDG-PET study.

PURPOSE: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery. METHODS: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n=9) versus those who did not (n=14) and between those in whom postoperative depression developed (n=13) versus those in whom it did not (n=10). A significant region of hypometabolism was set at p<0.001 for a cluster of >or=20 contiguous voxels. RESULTS: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t=4.64; p<0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t=5.10; p<0.001). CONCLUSIONS: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.