Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174

Τρίτη 22 Ιανουαρίου 2019

Daily briefing: How to deal with not getting tenure

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Altered Functional Connectivity of Cerebello-Cortical Circuit in Multiple System Atrophy (Cerebellar-Type).

Altered Functional Connectivity of Cerebello-Cortical Circuit in Multiple System Atrophy (Cerebellar-Type).

Front Neurosci. 2018;12:996

Authors: Ren S, Zhang H, Zheng W, Liu M, Gao F, Wang Z, Chen Z

Abstract
Multiple system atrophy (MSA) is regarded as a progressive neurodegenerative disease mainly divided into MSA-p type with Parkinsonism and MSA-c type with cerebellar ataxia as the main symptom. However, its neural mechanism is still unclear. In this study, we only focus on the MSA-c type. The purpose of this study is to explore the functional connectivity changes of the cerebello-cortical circuit in MSA-c type by using resting state functional magnetic resonance imaging (rs-fMRI). Thirty-six subjects (18 MSA and 18 normal controls) participated in this study and the rs-fMRI data were collected by applying resting state amplitude of low-frequency fluctuations (ALFF), we found the significant decreased ALFF in the MSA patients relative to controls, which included left cerebellum 8 area, 9 area, 7b area and Cru1 as well as vermis 7. Then we select the brain region of cerebellum 8 area as seed to investigate whole brain functional connectivity alteration in the MSA patients. When comparing to controls, several regions showed decreased connectivity in the MSA patients including bilateral cerebellum anterior lobe, left cerebellum posterior lobe, left dentate, bilateral pons, inferior parietal lobule (IPL), lingual gyrus (LG), parahippocampus (PHG), and middle temporal gyrus (MTG). In addition, there were closely correlation between functional connectivities and clinical performances in the MSA patients. The current study confirmed that the disrupted functional connectivity of specific cerebello-cortical circuit in the MSA patients, which is responsible for the clinical performances.

PMID: 30662394 [PubMed]

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Electrophysiology Meets Printed Electronics: The Beginning of a Beautiful Friendship.

Electrophysiology Meets Printed Electronics: The Beginning of a Beautiful Friendship.

Front Neurosci. 2018;12:992

Authors: Inzelberg L, Hanein Y

Abstract
Electroencephalography (EEG) and surface electromyography (sEMG) are notoriously cumbersome technologies. A typical setup may involve bulky electrodes, dangling wires, and a large amplifier unit. Adapting these technologies to numerous applications has been accordingly fairly limited. Thanks to the availability of printed electronics, it is now possible to effectively simplify these techniques. Elegant electrode arrays with unprecedented performances can be readily produced, eliminating the need to handle multiple electrodes and wires. Specifically, in this Perspective paper, we focus on the advantages of electrodes printed on soft films as manifested in signal transmission at the electrode-skin interface, electrode-skin stability, and user convenience during electrode placement while achieving prolonged use. Customizing electrode array designs and implementing blind source separation methods can also improve recording resolution, reduce variability between individuals and minimize signal cross-talk between nearby electrodes. Finally, we outline several important applications in the field of neuroscience and how each can benefit from the convergence of electrophysiology and printed electronics.

PMID: 30662393 [PubMed]

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Wavelet Fuzzy Brain Emotional Learning Control System Design for MIMO Uncertain Nonlinear Systems.

Wavelet Fuzzy Brain Emotional Learning Control System Design for MIMO Uncertain Nonlinear Systems.

Front Neurosci. 2018;12:918

Authors: Zhao J, Lin CM, Chao F

Abstract
This paper aims to present a novel efficient scheme in order to more effectively control the multiple input and multiple output (MIMO) uncertain nonlinear systems. A wavelet fuzzy brain emotional learning controller (WFBELC) model is proposed, which is comprises the benefit of wavelet function, fuzzy theory and brain emotional neural network. When it is used as the main tracking controller for a MIMO uncertain nonlinear systems, the performances of the system, such as the approximation ability, the learning performance and the convergence rate, will be effectively improved. Meanwhile, the gradient descent method is used to adjust the parameters online of WFBELC and the Lyapunov function is employed to guarantee the rapid convergence of the control systems. For the sake of the further illustrating the superiority of this model, two examples of uncertain nonlinear systems, a Duffing-Holmes chaotic system and a Chua's chaotic circuit, are studied. After compared with other models, the test results show that the proposed model can be applied to obtain more satisfactory control performance and be more suitable to deal with the influence of the uncertainty of the MIMO nonlinear systems.

PMID: 30662392 [PubMed]

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Pathway Instability Is an Effective New Mutation-Based Type of Cancer Biomarkers.

Pathway Instability Is an Effective New Mutation-Based Type of Cancer Biomarkers.

Front Oncol. 2018;8:658

Authors: Zolotovskaia MA, Sorokin MI, Roumiantsev SA, Borisov NM, Buzdin AA

Abstract
DNA mutations play a crucial role in cancer development and progression. Mutation profiles vary dramatically in different cancer types and between individual tumors. Mutations of several individual genes are known as reliable cancer biomarkers, although the number of such genes is tiny and does not enable differential diagnostics for most of the cancers. We report here a technique enabling dramatically increased efficiency of cancer biomarkers development using DNA mutations data. It includes a quantitative metric termed Pathway instability (PI) based on mutations enrichment of intracellular molecular pathways. This method was tested on 5,956 tumor mutation profiles of 15 cancer types from The Cancer Genome Atlas (TCGA) project. Totally, we screened 2,316,670 mutations in 19,872 genes and 1,748 molecular pathways. Our results demonstrated considerable advantage of pathway-based mutation biomarkers over individual gene mutation profiles, as reflected by more than two orders of magnitude greater numbers by high-quality [ROC area-under-curve (AUC)>0.75] biomarkers. For example, the number of such high-quality mutational biomarkers distinguishing between different cancer types was only six for the individual gene mutations, and already 660 for the pathway-based biomarkers. These results evidence that PI value can be used as a new generation of complex cancer biomarkers significantly outperforming the existing gene mutation biomarkers.

PMID: 30662873 [PubMed]

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DGKZ Acts as a Potential Oncogene in Osteosarcoma Proliferation Through Its Possible Interaction With ERK1/2 and MYC Pathway.

DGKZ Acts as a Potential Oncogene in Osteosarcoma Proliferation Through Its Possible Interaction With ERK1/2 and MYC Pathway.

Front Oncol. 2018;8:655

Authors: Yu W, Tang L, Lin F, Yao Y, Shen Z

Abstract
Osteosarcoma (OS) is one of the most common primary bone tumors in children and young adults. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Thus, it is important to explore novel effective therapeutic targets in the treatment of osteosarcoma. Diacylglycerol kinase zeta (DGKZ) is a recently identified gene potentially associated with certain human carcinogenesis. However, the role of DGKZ in proliferation of osteosarcoma is still unclear. In this study, DGKZ's expression was firstly investigated in OS tumor samples and correlated with poor outcome in OS patients. Silence of DGKZ by shRNA hampered osteosarcoma cell growth and promoted cell apoptosis in vitro. In vivo, DGKZ's knockout also suppressed xenograft tumor proliferation as determined by bioluminescence imaging and weight/volume measurements. Meanwhile, Affymetrix GeneChip and Ingenuity Pathway Analysis (IPA) revealed that DGKZ knockdown resulted in a decreased activity of MYC pathway, and several target genes expression in MYC pathway were altered, including CCND1, CDKN2B, CDK6, PCNA, and EGR1. Furthermore, immunoprecipitation coupled with mass spectrometry (IP-MS) analysis was used to identify proteins that interacted with DGKZ in OS cells and revealed ERK1/2, a key MYC-interactor, to associate with DGKZ. Together, our study demonstrated that DGKZ might act as an oncogene in osteosarcoma via its possible interaction with ERK1/2 and MYC pathway.

PMID: 30662872 [PubMed]

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The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.

The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.

Front Oncol. 2018;8:584

Authors: Zhao X, Little P, Hoyle AP, Pegna GJ, Hayward MC, Ivanova A, Parker JS, Marron DL, Soloway MG, Jo H, Salazar AH, Papakonstantinou MP, Bouchard DM, Jefferys SR, Hoadley KA, Ollila DW, Frank JS, Thomas NE, Googe PB, Ezzell AJ, Collichio FA, Lee CB, Earp HS, Sharpless NE, Hugo W, Wilmott JS, Quek C, Waddell N, Johansson PA, Thompson JF, Hayward NK, Mann GJ, Lo RS, Johnson DB, Scolyer RA, Hayes DN, Moschos SJ

Abstract
Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.

PMID: 30662871 [PubMed]

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Spectral Photon-Counting Molecular Imaging for Quantification of Monoclonal Antibody-Conjugated Gold Nanoparticles Targeted to Lymphoma and Breast Cancer: An In Vitro Study.

Spectral Photon-Counting Molecular Imaging for Quantification of Monoclonal Antibody-Conjugated Gold Nanoparticles Targeted to Lymphoma and Breast Cancer: An In Vitro Study.

Contrast Media Mol Imaging. 2018;2018:2136840

Authors: Moghiseh M, Lowe C, Lewis JG, Kumar D, Butler A, Anderson N, Raja A

Abstract
The purpose of the present study was to demonstrate an in vitro proof of principle that spectral photon-counting CT can measure gold-labelled specific antibodies targeted to specific cancer cells. A crossover study was performed with Raji lymphoma cancer cells and HER2-positive SKBR3 breast cancer cells using a MARS spectral CT scanner. Raji cells were incubated with monoclonal antibody-labelled gold, rituximab (specific antibody to Raji cells), and trastuzumab (as a control); HER2-positive SKBR3 breast cancer cells were incubated with monoclonal antibody-labelled gold, trastuzumab (specific antibody to HER2-positive cancer cells), and rituximab (as a control). The calibration vials with multiple concentrations of nonfunctionalised gold nanoparticles were used to calibrate spectral CT. Spectral imaging results showed that the Raji cells-rituximab-gold and HER2-positive cells-trastuzumab-gold had a quantifiable amount of gold, 5.97 mg and 0.78 mg, respectively. In contrast, both cell lines incubated with control antibody-labelled gold nanoparticles had less gold attached (1.22 mg and 0.15 mg, respectively). These results demonstrate the proof of principle that spectral molecular CT imaging can identify and quantify specific monoclonal antibody-labelled gold nanoparticles taken up by Raji cells and HER2-positive SKBR3 breast cancer cells. The present study reports the future potential of spectral molecular imaging in detecting tumour heterogeneity so that treatment can be tuned accordingly, leading to more effective personalised medicine.

PMID: 30662379 [PubMed - in process]

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Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: A literature review.

Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: A literature review.

Crit Rev Oncol Hematol. 2019 Jan;133:163-170

Authors: Belgioia L, Desideri I, Errico A, Franzese C, Daidone A, Marino L, Fiore M, Borghetti P, Greto D, Fiorentino A, AIRO Giovani Italian Association of Radiation Oncology-Young Members Working Group

Abstract
PURPOSE: Aim of the present review is to assess present data about the use of the association of Radiotherapy (RT) and targeted therapy/immunotherapy (TT/IT) in elderly people.
DESIGN: PubMed database was searched for English literature published up to December 2017 using the keywords "radiotherapy" combined with "bevacizumab", "cetuximab", "trastuzumab", "erlotinib", "gefitinib", "sorafenib", "sunitinib", "vismodegib", "sonidegib", "ipilimumab", "pembrolizumab", "nivolumab". Studies performing RT and TT/IT in people aged >65-years were evaluated focusing on safety, toxicity and efficacy. Studies eligible for inclusion were: case reports, retrospective/prospective studies in which RT and new drugs were used concomitantly or sequentially, focusing on elderly sub-group.
RESULTS: The systematic search identified 626 records. After exclusion of duplicates, full-text review, cross-referencing and paper that did not respect the inclusion criteria, 81 studies were included in this review. In elderly patients the combination of RT with cetuximab or bevacizumab seems feasible but with higher reported side effects. Patients' age should not limit the association of trastuzumab and RT in HER2 positive breast cancer. The concurrent administration of TKIs and RT appears to be feasible and effective. Regarding the Immune Check Point inhibitors and RT, tolerance seems similar among older and younger people but definitive data are lacking. Instead, the association of RT and vismodegib/sonidegib remains investigational.
CONCLUSION: TT/IT in association of RT seems to be safe, but in elderly patients data concerning safety and toxicity are limited. Specific clinical trials on this population are encouraged.

PMID: 30661652 [PubMed - in process]

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Engineering of CRISPR-Cas12b for human genome editing

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Treatment of Hypertensive Cardiogenic Edema with Intravenous High-Dose Nitroglycerin in a Patient Presenting with Signs of Respiratory Failure: A Case Report and Review of the Literature.

Treatment of Hypertensive Cardiogenic Edema with Intravenous High-Dose Nitroglycerin in a Patient Presenting with Signs of Respiratory Failure: A Case Report and Review of the Literature.

Am J Case Rep. 2019 Jan 21;20:83-90

Authors: López-Rivera F, Cintrón Martínez HR, Castillo LaTorre C, Rivera González A, Rodríguez Vélez JG, Fonseca Ferrer V, Méndez Meléndez OF, Vázquez Vargas EJ, González Monroig HA

Abstract
BACKGROUND Pulmonary edema is the accumulation of fluid in the lung secondary to increased hydrostatic pressure. Hypertensive cardiogenic pulmonary edema presents with a sudden onset of severe dyspnea, tachycardia, and tachypnea, and can occur when the systolic blood pressure exceeds 160 mmHg in association with acute decompensated congestive cardiac failure (CCF). A case is presented of hypertensive cardiogenic pulmonary edema treated with high-dose nitroglycerin and includes a review of the literature. CASE REPORT A 63-year-old Hispanic male with a medical history of hypertension, coronary artery disease, heart failure with a reduced ejection fraction of 35%, chronic kidney disease (CKD) and diabetes mellitus, presented as an emergency with acute, severe dyspnea. The patient was initially managed with 100% oxygen supplementation and intravenous (IV) high-dose nitroglycerin (30 mcg/min), which was titrated every 3 minutes, increasing by 15 mcg/min until a dose of 120 mcg/min was reached. After 18 minutes of aggressive therapy, the patient's condition improved and he no longer required mechanical ventilation. CONCLUSIONS Hypertensive cardiogenic pulmonary edema is a challenging clinical condition that should be diagnosed and managed as early as possible, and distinguished from respiratory failure due to other causes. Although hypertensive cardiogenic pulmonary edema is usually managed acutely with high-dose diuretics, this case has highlighted the benefit of high-dose IV nitroglycerin, and review of the literature supports this treatment approach.

PMID: 30662059 [PubMed - in process]

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Teratogenicity of antiepileptic drugs.

Teratogenicity of antiepileptic drugs.

Curr Opin Neurol. 2019 Jan 16;:

Authors: Tomson T, Battino D, Perucca E

Abstract
PURPOSE OF REVIEW: We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure.
RECENT FINDINGS: Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation.
SUMMARY: The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

PMID: 30664067 [PubMed - as supplied by publisher]

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Why are patients with epilepsy not getting treatment?

Why are patients with epilepsy not getting treatment?

Lancet Neurol. 2019 Feb;18(2):127

Authors: The Lancet Neurology

PMID: 30663599 [PubMed - in process]

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Identification of a novel biomarker for pyridoxine-dependent epilepsy: Implications for newborn screening.

Identification of a novel biomarker for pyridoxine-dependent epilepsy: Implications for newborn screening.

J Inherit Metab Dis. 2019 Jan 21;:

Authors: Wempe MF, Kumar A, Kumar V, Choi YJ, Swanson MA, Friederich MW, Hyland K, Yue WW, Van Hove JLK, Coughlin CR

Abstract
Pyridoxine-dependent epilepsy (PDE) is often characterized as an early onset epileptic encephalopathy with dramatic clinical improvement following pyridoxine supplementation. Unfortunately, not all patients present with classic neonatal seizures or respond to an initial pyridoxine trial, which can result in the under diagnosis of this treatable disorder. Restriction of lysine intake and transport is associated with improved neurologic outcomes, although treatment should be started in the first year of life to be effective. Because of the documented diagnostic delay and benefit of early treatment, we aimed to develop a newborn screening method for PDE. Previous studies have demonstrated the accumulation of Δ1 -piperideine-6-carboxylate and α-aminoadipic semialdehyde in individuals with PDE, although these metabolites are unstable at room temperature limiting their utility for newborn screening. As a result, we sought to identify a biomarker that could be applied to current newborn screening paradigms. We identified a novel metabolite, 6-oxo-pipecolate, which accumulates in substantial amounts in blood, plasma, urine and cerebral spinal fluid of individuals with PDE. Using a stable isotope labeled internal standard, we developed a non-derivatized liquid chromatography tandem mass spectrometry-based method to quantify 6-oxo-pipecolate. This method replicates the analytical techniques used in many laboratories and could be used with few modifications in newborn screening programs. Furthermore, 6-oxo-pipecolate was measurable in urine for four months even when stored at room temperature. Herein, we report a novel biomarker for PDE that is stable at room temperature and can be quantified using current newborn screening techniques. This article is protected by copyright. All rights reserved.

PMID: 30663059 [PubMed - as supplied by publisher]

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Drug repurposing for Dravet syndrome in scn1Lab-/- mutant zebrafish.

Drug repurposing for Dravet syndrome in scn1Lab-/- mutant zebrafish.

Epilepsia. 2019 Jan 20;:

Authors: Sourbron J, Partoens M, Scheldeman C, Zhang Y, Lagae L, de Witte P

Abstract
Dravet syndrome (DS) is a severe genetic epileptic encephalopathy with onset during the first year of life. Zebrafish models recapitulating human diseases are often used as drug discovery platforms, but also for drug repurposing testing. It was recently shown that pharmacological modulation of three serotonergic (5-HT) receptors (5-HT1D , 5-HT2C , 5-HT2A ) exerts antiseizure effects in a zebrafish scn1Lab-/- mutant model of DS. Using the zebrafish DS model, our aim was to examine the possibility of repurposing efavirenz (EFA), lisuride (LIS), and rizatriptan (RIZA), marketed medicines with a 5-HT on- or off-target profile, as antiepileptic drugs for DS. To examine whether these compounds have a broader antiseizure profile, they were tested in pentylenetetrazol and ethyl ketopentenoate (EKP) zebrafish models. Pharmacological effects were assessed by locomotor behavior, local field potential brain recordings, and bioluminescence. EFA was active in all models, whereas LIS was selectively active in the zebrafish DS model. Mainly, a poor response was observed to RIZA. Taken together, our preclinical results show that LIS could be a potential candidate for DS treatment. EFA was also active in the EKP model, characterized by a high level of treatment resistance, and hence these data are potentially important for future treatment of drug-resistant epilepsy.

PMID: 30663052 [PubMed - as supplied by publisher]

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Human Pluripotent Stem Cell-Derived Striatal Interneurons: Differentiation and Maturation In Vitro and in the Rat Brain.

Human Pluripotent Stem Cell-Derived Striatal Interneurons: Differentiation and Maturation In Vitro and in the Rat Brain.

Stem Cell Reports. 2019 Jan 02;:

Authors: Noakes Z, Keefe F, Tamburini C, Kelly CM, Cruz Santos M, Dunnett SB, Errington AC, Li M

Abstract
Striatal interneurons are born in the medial and caudal ganglionic eminences (MGE and CGE) and play an important role in human striatal function and dysfunction in Huntington's disease and dystonia. MGE/CGE-like neural progenitors have been generated from human pluripotent stem cells (hPSCs) for studying cortical interneuron development and cell therapy for epilepsy and other neurodevelopmental disorders. Here, we report the capacity of hPSC-derived MGE/CGE-like progenitors to differentiate into functional striatal interneurons. In vitro, these hPSC neuronal derivatives expressed cortical and striatal interneuron markers at the mRNA and protein level and displayed maturing electrophysiological properties. Following transplantation into neonatal rat striatum, progenitors differentiated into striatal interneuron subtypes and were consistently found in the nearby septum and hippocampus. These findings highlight the potential for hPSC-derived striatal interneurons as an invaluable tool in modeling striatal development and function in vitro or as a source of cells for regenerative medicine.

PMID: 30661995 [PubMed - as supplied by publisher]

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Effect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs - A randomized controlled trial.

Effect of high dose vitamin d supplementation on vitamin d nutrition status of pre-pubertal children on anti-epileptic drugs - A randomized controlled trial.

Clin Nutr ESPEN. 2019 Feb;29:36-40

Authors: Viraraghavan VR, Seth A, Aneja S, Singh R, Dhanwal D

Abstract
BACKGROUND AND AIMS: Patients on long term anti-epileptic drug therapy are prone for Vitamin D deficiency for a myriad of reasons. The aim of this research was to study the effect of high dose vitamin D supplementation on vitamin D nutrition status of children newly started on anti-epileptic drug therapy.
MATERIALS: This randomized controlled trial was conducted in a tertiary care Children's Hospital at New Delhi from November 2011 to March 2013. Eighty three children in the age group 5-10 years newly started on anti-epileptic drugs (AED) were randomized into two groups; group A - the intervention group, to whom 60,000 IU vitamin D3 was given orally/month under direct supervision along with AED for a period of 6 months, and group B- the control group, to whom AED without vitamin D3 was given. Serum 25(OH)D, ionized calcium (iCa), total calcium (tCa), inorganic phosphate (iP), alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels were assayed at baseline and at the end of 6 months and were compared within and between the two groups.
RESULTS: The mean 25(OH)D in Group A was maintained at 6 months follow up [ 26 ng/ml, 95% CI 20-34 ng/ml] compared to baseline [25 ng/ml, 95% CI -19 to 33 ng/ml] [ p = 0.83]. In group B, there was a significant decrease in 25(OH)D levels at 6 months [13 ng/ml (95% CI 9 ng/ml-17 ng/ml)] compared to baseline [18 ng/ml (95% CI 13-24 ng/ml)] [p = 0.01]. At 6 months, mean serum 25(OH)D was significantly higher in group A as compared to group B (p = 0.005).
CONCLUSION: To conclude, oral administration of 60,000 IU vitamin D3/month is sufficient to maintain serum 25(OH)D level and prevent development of vitamin D deficiency in children newly started on AED over a period of 6 months. Non supplementation leads to the lowering of serum 25(OH)D in these children.
TRIAL REGISTRATION NUMBER: CTRI/2017/08/009234.

PMID: 30661698 [PubMed - in process]

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From next generation sequencing to targeted treatment of non-acquired epilepsies.

From next generation sequencing to targeted treatment of non-acquired epilepsies.

Expert Rev Mol Diagn. 2019 Jan 19;:

Authors: Møller RS, Hammer TB, Rubboli G, Lemke JR, Johannesen KM

Abstract
INTRODUCTION: Within the last decade, next generation sequencing (NGS) has resulted in remarkable advances in the field of epilepsy genetics. NGS has become a routine part of the diagnostic workup in many countries. A workup that has led to higher diagnostic yields and insights into the underlying disease mechanisms. Areas covered: In this review, we report on the recent contributions of NGS testing to the diagnosis and the understanding of pathophysiological mechanisms, phenotypic variability, and genetic heterogeneity of different epilepsies including developmental and/or epileptic encephalopathies, focal and generalized epilepsies. Furthermore, we discuss how the increased knowledge of the genetic architecture of the epilepsies can be translated into more personalized treatment. Expert Opinion/Commentary: Targeted gene panels or whole exome sequencing can provide a genetic diagnosis for up to 30% of patients with early-onset epilepsy. Despite current technical limitations, NGS-based technologies can become the new first-tier diagnostic tests in the epilepsies. As the pool of genetically diagnosed patients has increased, so has the demand for more accurate treatment. Approximately 25% of epilepsy patients with de novo mutations have genetic diagnoses with potential targets for precision medicine approaches, thus illustrating the enormous utility of genetic testing for therapeutic decision-making.

PMID: 30661434 [PubMed - as supplied by publisher]

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Regional cortical thickness changes accompanying generalized tonic-clonic seizures.

Regional cortical thickness changes accompanying generalized tonic-clonic seizures.

Neuroimage Clin. 2018;20:205-215

Authors: Ogren JA, Tripathi R, Macey PM, Kumar R, Stern JM, Eliashiv DS, Allen LA, Diehl B, Engel J, Rani MRS, Lhatoo SD, Harper RM

Abstract
Objective: Generalized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.
Methods: High-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P < 0.05 corrected).
Results: Increased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right-sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration.
Significance: Cortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk.

PMID: 30094170 [PubMed - indexed for MEDLINE]

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Construction of a novel far-red fluorescence light-up probe for visualizing intracellular peroxynitrite

Publication date: 15 May 2019

Source: Talanta, Volume 197

Author(s): Wangbo Qu, Changhe Niu, Xiaoyu Zhang, Wei Chen, Fabiao Yu, Heng Liu, Xiuhua Zhang, Shengfu Wang

Abstract

Peroxynitrite (ONOO^-) is an important reactive oxygen species (ROS), which can react with a variety of biologically active species and cause many diseases, such as cancer, neurodegenerative disorders. Herein, we develop a novel far-red fluorescent probe DCM-KA, which is equipping with α-ketoamide moiety caged DCM-NH₂. The probe exhibits fluorescence off-on response to ONOO^- over other biological interfering analytes by ONOO^--induced α-ketoamide deprotection reaction. More importantly, the probe is biocompatible and has been successfully utilized to visualize endogenous ONOO^- production in macrophage cell line J774A.1.

Graphical abstract

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