Automated Subfield Volumetric Analysis of Amygdala, Hippocampus, and Thalamic Nuclei in Mesial Temporal Lobe Epilepsy

Purpose: Identifying relationships between clinical features and quantitative characteristics of the amygdala-hippocampal and thalamic subregions in mesial temporal lobe epilepsy (mTLE) may offer insights into pathophysiology and the basis for imaging prognostic markers of treatment outcome. Our aim was to ascertain different patterns of atrophy or hypertrophy in mesial temporal sclerosis (MTS) patients and their associations with postsurgical seizure outcomes. To assess this aim, this study is designed in 2 folds: (1) hemispheric changes within MTS group and (2) association with postsurgical seizure outcomes. Methods and materials: 27 mTLE subjects with mesial temporal sclerosis (MTS) were scanned for conventional 3D T1w MPRAGE images and T2w scans. With respect to 12 months post-surgical seizure outcomes, 15 subjects reported being seizure free (SF) and 12 reported continued seizures. Quantitative automated segmentation and cortical parcellation were performed using Freesurfer. Automatic labeling and volume estimation of hippocampal subfields, amygdala, and thalamic subnuclei were also performed. The volume ratio (VR) for each label was computed and compared between (1) between contralateral and ipsilateral MTS using Wilcoxon rank-sum test and (2) SF and not seizure free (NSF) groups using linear regression analysis. False Discovery rate (FDR) with significant level of 0.05 were used in both analyses to correct for multiple comparisons. Results: Amygdala: The medial nucleus of the amygdala was the most significantly reduced in patients with continued seizures when compared to patients who remained seizure free. Hippocampus: Comparison of ipsilateral and contralateral volumes with seizure outcomes showed volume loss was most evident in the mesial hippocampal regions such as CA4 and hippocampal fissure. Volume loss was also most explicit in the presubiculum body in patients with continued seizures at the time of their follow-up. Ipsilateral MTS compared to contralateral MTS analysis showed the heads of the ipsilateral subiculum, presubiculum, parasubiculum, dentate gyrus, CA4, and CA3 were more significantly affected than their respective bodies. Volume loss was most noted in mesial hippocampal regions. Thalamus: VPL and PuL were the most significantly reduced thalamic nuclei in NSF patients. In all statistically significant areas, volume reduction was observed in the NSF group. No significant volume reductions were noted in the thalamus and amygdala when comparing ipsilateral to contralateral sides in mTLE subjects. Conclusions: Varying degrees of volume loss were demonstrated in the hippocampus, thalamus, and amygdala subregions of MTS, especially between patients who remained seizure-free and those who did not. The results obtained can be used to further understand mTLE pathophysiology

A framework for the detection of de novo mutations in family-based sequencing data

Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants and short insertions and deletions (indels) from sequence data collected in parent-offspring trios. We compute the joint probability of the data given the genotype likelihoods in the individual family members, the known familial relationships and a prior probability for the mutation rate. Candidate de novo mutations (DNMs) are reported along with their posterior probability, providing a systematic way to prioritize them for validation. Our tool is integrated in the Genome Analysis Toolkit and can be used together with the ReadBackedPhasing module to infer the parental origin of DNMs based on phase-informative reads. Using simulated data, we show that PBT outperforms existing tools, especially in low coverage data and on the X chromosome. We further show that PBT displays high validation rates on empirical parent-offspring sequencing data for whole-exome data from 104 trios and X-chromosome data from 249 parent-offspring families. Finally, we demonstrate an association between father's age at conception and the number of DNMs in female offspring's X chromosome, consistent with previous literature reports

Amelioration of Rheumatoid Arthritis by <i>Fragaria nubicola</i> (Wild Strawberry) via Attenuation of Inflammatory Mediators in Sprague Dawley Rats

Background and Objectives: Fragaria nubicola has never been evaluated scientifically for its anti-arthritic potential despite its use in folkloric systems of medicine. The research was conducted to assess the potential of F. nubicola against rheumatoid arthritis. Materials and Methods: The current study provided scientific evidence by evaluating the effects of plants using an in vivo CFA-induced model of arthritic rats and subsequent microscopic histopathological evaluation of ankle joints along with the determination of paw edema using a digital water displacement plethysmometer. The study also gave insight by determining levels of pro-inflammatory cytokines, matrix metalloproteinase enzymes (MMPs), prostaglandin E2 (PGE2), nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), and biochemical and hematological parameters. GCMS analysis was also conducted for the identification of possible anti-inflammatory plant constituents. Results: The data showed that F. nubicola-treated groups attenuated the progression of arthritis and paw edema. Microscopic histopathological evaluation validated the anti-arthritic potential by showing amelioration of bone erosion, infiltration of inflammatory cells, and pannus formation. RT-PCR analysis displayed that treatment with F. nubicola down-regulated IL1β, IL6, TNFα, NF-κB, VEGF, MMP2, MMP3, and MMP9 levels. Moreover, ELISA exhibited a reduction in levels of PGE2 levels in treatment groups. The levels of RBCs, platelets, WBCs, and Hb content were found to be nearly similar to negative control in the treated group. Statistically, a non-significant difference was found when all groups were compared for urea, creatinine, ALT, and AST analysis, indicating the safety of plant extract and fractions at test doses. GCMS analysis of extract and fractions showed the existence of many anti-inflammatory and antioxidant phytochemicals. Conclusion: In conclusion, F. nubicola possessed anti-arthritic properties that might be attributed to the amelioration of MMPs and pro-inflammatory cytokines

Anti-Arthritic and Immunomodulatory Potential of Methanolic, n-Hexane, and Ethyl Acetate Fractions of Bark of <i>Acacia modesta</i> on Complete Freund’s Adjuvant-Induced Arthritis in Rats

Rheumatoid arthritis is an autoimmune disorder and topic of interest for researchers due to its increasing frequency and limited treatment. Acacia modesta Wall is known to treat rheumatic disorders in the traditional system of medicinal plants. Traditional medicines are still required for the treatment of this disease due to the large number of side-effects caused by commercial medicines. In the current study, the antiarthritic potential of methanolic extract (AM-metha), n-hexane (AM-hexa) fraction, and ethyl acetate (AM-etha) fraction of the bark of A. modesta against a complete Freund’s adjuvant rat model was evaluated. Evaluation using a digital plethysmometer, macroscopic evaluation, and histopathological evaluation were conducted to determine the paw volume and arthritic scoring. ELISA was performed to assess the PGE2 levels. RT-PCR was used to evaluate the expression levels of MMP2, MMP3, MMP9, NF-κB, IL6, IL1β, TNFα, and VEGF. Biochemical and hematological analyses were also conducted. GC/MS was also carried out to analyze the presence of medicinal compounds. The data revealed a marked reduction in the paw volume, arthritic scoring, and histopathological parameters, indicating the anti-arthritic potential of the plant. Treatment with plant extracts and fractions markedly down-regulated MMP2, MMP3, MMP9, NF-κB, IL6, IL1β, TNFα, and VEGF levels. Similarly, PGE2 levels were also found to be ameliorated in the treatment groups, indicating the immunomodulatory property of plant bark. Plant treatment nearly normalized hematological parameters such as counts of WBCs, RBCs, and platelets, along with Hb content, thereby validating the anti-arthritic activity. GC/MS analysis disclosed the presence of strong anti-inflammatory compounds such as lupeol, oleic acid, and squalene. The study showed that A. modesta possesses anti-arthritic and immunomodulatory potential linked to significant down-regulation of pro-inflammatory and inflammatory biomarkers

Automated subfield volumetric analysis of amygdala, hippocampus, and thalamic nuclei in mesial temporal lobe epilepsy

Purpose: Identifying relationships between clinical features and quantitative characteristics of the amygdala-hippocampal and thalamic subregions in mesial temporal lobe epilepsy (mTLE) may offer insights into pathophysiology and the basis for imaging prognostic markers of treatment outcome. Our aim was to ascertain different patterns of atrophy or hypertrophy in mesial temporal sclerosis (MTS) patients and their associations with post-surgical seizure outcomes. To assess this aim, this study is designed in 2 folds: (1) hemispheric changes within MTS group and (2) association with postsurgical seizure outcomes. Methods and materials: 27 mTLE subjects with mesial temporal sclerosis (MTS) were scanned for conventional 3D T1w MPRAGE images and T2w scans. With respect to 12 months post-surgical seizure outcomes, 15 subjects reported being seizure free (SF) and 12 reported continued seizures. Quantitative automated segmentation and cortical parcellation were performed using Freesurfer. Automatic labeling and volume estimation of hippocampal subfields, amygdala, and thalamic subnuclei were also performed. The volume ratio (VR) for each label was computed and compared between (1) between contralateral and ipsilateral MTS using Wilcoxon rank-sum test and (2) SF and not seizure free (NSF) groups using linear regression analysis. False Discovery rate (FDR) with significant level of 0.05 were used in both analyses to correct for multiple comparisons. Results: Amygdala: The medial nucleus of the amygdala was the most significantly reduced in patients with continued seizures when compared to patients who remained seizure free. Hippocampus: Comparison of ipsilateral and contralateral volumes with seizure outcomes showed volume loss was most evident in the mesial hippocampal regions such as CA4 and hippocampal fissure. Volume loss was also most explicit in the presubiculum body in patients with continued seizures at the time of their follow-up. Ipsilateral MTS compared to contralateral MTS analysis showed the heads of the ipsilateral subiculum, presubiculum, parasubiculum, dentate gyrus, CA4, and CA3 were more significantly affected than their respective bodies. Volume loss was most noted in mesial hippocampal regions. Thalamus: VPL and PuL were the most significantly reduced thalamic nuclei in NSF patients. In all statistically significant areas, volume reduction was observed in the NSF group. No significant volume reductions were noted in the thalamus and amygdala when comparing ipsilateral to contralateral sides in mTLE subjects. Conclusions: Varying degrees of volume loss were demonstrated in the hippocampus, thalamus, and amygdala subregions of MTS, especially between patients who remained seizure-free and those who did not. The results obtained can be used to further understand mTLE pathophysiology. Clinical relevance/application: In the future, we hope these results can be used to deepen the understanding of mTLE pathophysiology, leading to improved patient outcomes and treatments