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KCNT1-related epilepsy: An international multicenter cohort of 27 pediatric cases.
Borlot, F, Abushama, A, Morrison-Levy, N, Jain, P, Puthenveettil Vinayan, K, Abukhalid, M, Aldhalaan, HM, Almuzaini, HS, Gulati, S, Hershkovitz, T, et al
Epilepsia. 2020;(4):679-692
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Abstract
OBJECTIVE Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants. METHODS A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics. RESULTS Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy. SIGNIFICANCE Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.
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The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury: A prospective study.
Lyu, M, Zhou, J, Chen, H, Bai, H, Song, J, Liu, T, Cheng, Y, Ying, B
Medicine. 2019;(44):e17821
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Abstract
Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (PBonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686-6.139, PBonferroni correction = .003) or dominant model (PBonferroni correction = .003), as well as rs117806152 (Additive model: PBonferroni correction = .05; dominant model: PBonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (PBonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (PBonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487-6.896, PBonferroni correction = .02) and dominant model (PBonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI.
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The relation of serum nesfatin-1 level with anthropometric and metabolic parameters in children and adolescents: A prospective observational study.
Kim, SH, Ahn, MB, Cho, WK, Cho, KS, Jung, MH, Suh, BK
Medicine. 2019;(19):e15460
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Nesfatin-1, a recently discovered anorexigenic neuropeptide, seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. The aim of this study was to evaluate the relation of serum nesfatin-1 level with metabolic and anthropometric parameters in children and adolescents.This study prospectively included 78 Korean children and adolescents (42 obese/overweight group and 36 healthy control group). Fasting serum nesfatin-1 was quantitatively assayed by ELISA. Lipid profile, fasting blood glucose, fasting insulin, and the homeostasis model assessment of insulin resistance (HOMA-IR) were measured as metabolic parameters.Serum nesfatin-1 levels were significantly lower in obese/overweight group than in control group (median 1.4 vs 2.0 ng/mL; P = .003). Pubertal subjects have the lower serum nesfatin-1 level than pre-pubertal subjects (median 1.5 vs 2.6 ng/mL; P = .02). Nesfatin-1 levels negatively correlated with chronological age (r = -0.37; P = .001), BMI (r = -0.33; P = .003), and BMI SDS (r = -0.26; P = .02).In conclusion, our results suggest that serum nesfatin-1 negatively correlated with BMI in children and adolescents. It suggests that nesfatin-1 might have an important role in regulation of food intake in obese children and adolescents.
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Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.
Kannoth, S, Nambiar, V, Gopinath, S, Anandakuttan, A, Mathai, A, Rajan, PK
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(3):455-460
Abstract
Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage-gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment.
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DHCR24 predicts poor clinicopathological features of patients with bladder cancer: A STROBE-compliant study.
Liu, XP, Yin, XH, Meng, XY, Yan, XH, Cao, Y, Zeng, XT, Wang, XH
Medicine. 2018;(39):e11830
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To investigate the prognostic value of DHCR24 for patients with bladder cancer (BC). We used public bladder cancer microarray studies to evaluate the expression of DHCR24 between normal bladder tissues and BC cells, to investigate the relationship between the expression of DHCR24 and the clinical features of BC patients. Survival analysis was performed to investigate the correlation between DHCR24 expression and the survivals of BC patients. Gene set enrichment analysis was conducted to identify relevant mechanisms. The results showed that DHCR24 was up-regulated in BC cells compared with that in normal bladder tissues (P = .0389). Results of chi-square test suggested that BC patients in DHCR24 low expression group were proved to have better clinical characteristics (including tumor grade, disease progression, T staging, and N staging) as compared with those in DHCR24 low expression group (P < .0001, P = .002, P = .005, and P = .002, respectively). BC patients in DHCR24 low expression group were associated with better cancer-specific survival and overall survival (P < .0001 and P = .0008, respectively). DHCR24 might promote the proliferation of BC cells through several oncogenesis-associated biological processes (estrogen response, heme metabolism, P53 pathway, cholesterol homeostasis, mTORC1 signaling, peroxisome, xenobiotic metabolism, glycolysis, and protein secretion). Thus, DHCR24 might be a therapeutic target for patients with BC.
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Increased membrane localization of pannexin1 in human corneal synaptosomes causes enhanced stimulated ATP release in chronic diabetes mellitus.
Cui, H, Liu, Y, Qin, L, Wang, L, Huang, Y
Medicine. 2016;(49):e5084
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In the present study, we investigated the potential changes in the corneal nerve terminals in non-insulin-dependent diabetes mellitus of moderate duration. The dissected corneas were subjected to a protocol of ultracentrifugation to obtain synaptosomes of sensory nerve terminals. Within these nerve varicosities, 2 major mechanisms were examined, viz., alterations of the mechanosensitive channel pannexin1 and ATP release on stimulation of these terminals. We hypothesized that altered cellular location and function of the pannexin channel may contribute to altered mechanosensitivity of the cornea, which in turn may affect wound healing and primary visual function of the cornea. The chief rationale for focusing on examining the pannexin channel is due to its role in mechanosensitivity, as well as its glycosylation property. Pannexin1 remains unchanged between diabetic subjects in comparison to nondiabetic controls. However, lectin immunoassay showed that pannexin1 is significantly more glycosylated in diabetic corneal synaptosomes. Membrane biotinylation assay showed that membrane localization of pannexin1 is significantly enhanced in diabetic samples. Furthermore, S-nitrosylation of the glyco-pannexin1 is significantly decreased in comparison to pannexin1 obtained from corneal varicosities of normoglycemic subjects. The diabetic corneal synaptosomes show enhanced ATP release after potassium chloride stimulation, when compared to controls. Furthermore, we have shown that S-nitrosylation of pannexin1 actually diminishes the ability of pannexin1 to release ATP. Thus, much like the peripheral nerves, the corneal nerves also show increased hypersensitivity in diabetes of chronic duration. All of these pathological changes may cumulatively alter corneal function in diabetes.