Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype

BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase. RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236) between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT). CONCLUSION: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Security-centric ranking algorithm and two privacy scores to mitigate intrusive apps

Smartphone users are constantly facing the risks of losing their private information to third-party mobile applications. Studies have revealed that the vast majority of users either do not pay attention to privacy or unable to comprehend privacy messages. Developers though have exploited this fact by asking users to grant their apps an enormous number of permissions. In this article, we propose and evaluate a new security-centric ranking algorithm built on top of the Elasticsearch engine to help users evade such apps. The algorithm calculates an intrusiveness score for an app based on its requested permissions, received system actions, and users' privacy preferences. As such, we further propose a new approach to capture these preferences. We evaluate the ranking algorithm using a million Android applications, contextual data and APK files, that we collect from the Google Play store. The results show that the scoring and reranking steps add minor overhead. Moreover, participants of the user studies gave positive feedback for the ranking algorithm and the privacy preferences solicitation approach. These results suggest that our proposed system would definitely protect the privacy of mobile users and pushes developers into requesting least amount of privileges. Still, there are many risks that endanger the users' privacy

Surfactant-Assisted Emulsification and Surfactant-Based Dispersive Liquid-Liquid Microextraction Method for Determination of Cu(II) in Food and Water Samples by Flame Atomic Absorption Spectrometry

Background: Copper (Cu) is an essential metal for humans at certain concentrations. However, it can be toxic at higher concentrations. Therefore, determination of Cu content of foodstuff is important. Objective: The aim of the study was to develop a simple, economical, and environmentally friendly surfactant-mediated extraction method for the determination of Cu using surfactants and flame atomic absorption spectrometry (FAAS). Methods: A nonionic surfactant-assisted emulsification and surfactant-based dispersive liquid-liquid microextraction method was developed for the separation, preconcentration, and determination of Cu by FAAS. Triton X-15 nonionic surfactant, which is insoluble in water, was used as an extractive agent. Triton X-114 (TX-114) nonionic water-soluble surfactant was used as a disperser solvent. Dithizone was used as a complexing agent for complexation of Cu(II) at pH 4. Results: The detection and quantitation limits of the method were determined as 1.61 and 3.82 mu g/L, respectively. The preconcentration factor was obtained as 50. Relative SD based on 10 replicates was obtained as 3.7%. Accuracy of the developed method was proved using certified standard reference materials. Cu(II) content of edible mushroom samples was determined between 12 and 19 mu g/g. Recoveries were obtained between 96 and 101%. Conclusions: The developed surfactant-assisted emulsification and surfactant-based dispersive liquid-liquid microextraction method has represented the wide linear ranges, low detection limit, and high preconcentration factor for Cu ions. Highlights: TX-114 surfactant was used as both sticking agent and disperser solvent. The method does not require expert personnel and high operational costs. The method is environmentally friendly because mainly surfactants and low-toxicity organic solvents are used in the recommended procedure

Ion-pair solvent-based liquid-liquid microextraction and spectrophotometric determination of E102, E110, E124, E129 and E133 in confectioneries and beverages

In the present study, a new ion-pair solvent including tetra-n-butyl-ammonium iodide and 1-pentanol was prepared for the first time and it was used for microextraction and UV-Vis spectrophotometric determination of tartrazine (E102), sunset yellow (E110), ponceau 4r (E124), allura red (E129) and brilliant blue (E133). Analytical parameters of the procedure such as pH, concentration of ion-pair solvent and its volume, times of vortex and centrifugation were optimized. Interference effect of matrix ions and dyes were investigated after optimization of the parameters. Limits of detection between 24 and 82 mu g L-1 and limits of quantification in the range of 80-275 mu g L-1 were determined for the examined dyes. Preconcentration factor was obtained as 15 for each of the dyes. Relative standard deviations were found between 3.2 and 6.1%. Linear dynamic ranges were obtained between 0.28 and 20 mu g mL(-1) for the determined dyes. Procedure was applied to various food samples including energy drinks, powdered juice samples, syrups and candies. Analyte addition-recovery studies were also performed both for validation of procedure and determination of dye concentrations in the real samples. Food dye contents of real samples were determined between 5.9 and 52.4 mu g mL(-1) for liquid samples and 6.2 and 135.2 mu g g(-1) for solid samples with satisfactory recovery results ranging from 93 to 103%. Finally, the greenness of the developed procedure was assessed using two tools, the Green Analytical Procedure Index and Analytical Eco-Scale.Scientific Project Unit of Nigde OEmer Halisdemir University [FMT 2023/2-BAGEP]This study was supported financially by Scientific Project Unit of Nigde OEmer Halisdemir University with project number of FMT 2023/2-BAGEP

Single and Simultaneous Solid-Phase Extraction and UV-Vis Determination for Monitoring E129, E133 and E110 in Foodstuffs

A column solid-phase extraction method based on adsorption of allura red (AR), brilliant blue (BB) and sunset yellow (SY) onto Dowex Optipore V493 adsorbent was developed for single and simultaneous preconcentration and spectrophotometric determination of AR, BB and SY. Effects of extraction parameters including pH, sample and eluent flow rates, amount of adsorbent, eluent type and volume, ionic strength and sample volume, etc., were investigated and optimized. At the optimum conditions, detection limits of the method were determined to be 0.55, 0.20 and 0.58 mu g L(-1)for AR, BB and SY, respectively. Dynamic ranges were linear between 0.055-6.0 mu g mL(-1)for AR, 0.020-4.2 mu g mL(-1)for BB and 0.058-10.0 mu g mL(-1)for SY. Preconcentration factor was determined to be 100. Relative standard deviations were below than 4%. In addition, adsorption isotherms with related to retentions of AR, BB and SY on the resin were investigated. Finally, recommended procedure was applied to foodstuff samples containing AR, BB and SY dyes. AR contents of real samples were determined between 20.40-27.21 mu g/mL and 6.85-21.25 mu g/g for liquid and solid samples, respectively. BB concentrations of real samples were determined between 5.06-43.30 mu g/mL and 3.15-10.05 mu g/g for liquid and solid samples, respectively. SY contents of liquid and solid samples were determined between 3.04-29.67 mu g/mL and 18.55-121.46 mu g/g, respectively. In order to prove applicability of the method, analyte addition technique was performed. Satisfactorily quantitative recovery results were obtained between 95 and 102%

Effective and selective Type V deep eutectic solvent based microextraction of E127 in foodstuffs and drugs

The effective and selective deep eutectic solvent (DES) based microextraction method was developed for the first time, using new generation Type V DES for the separation and determination of E127 (erythrosine) in foodstuffs and drugs. Dicyclohexylamine and diphenylamine were mixed at 1:5 mol ratio to create the DES. The essential parameters (pH, DES volume and vortex time) were optimized using Box-Behnken Design of Response Surface Methodology. The quadratic microextraction approach was favorable chemometric model design (R2=0.9945) for the method. The limits of detection and quantitation were determined to be 23 and 78 mu g/L, respectively. E127 was enriched to be thirty-fold at the optimum conditions. The concentrations of E127, ranging between 0.078 and 4.0 mu g/mL, were linearly determined using the equation A=62.114 C+3.8 (R2=0.9989). The interference effect of ions and dyes was investigated in detail. The relative standard deviation was lower than 6 % throughout the experiments. Analyte addition-recovery tests were applied to the real samples for determination of their E127 concentrations. The method was validated by calculating microextraction recoveries obtained from spiked tests. E127 contents of foodstuffs and drugs were determined between 8.8 and 42.4 mu g/g, with recovery values ranging from 94 % to 102 %. AGREEmethod and AGREEprep tools were used to define environmentally friendly index of the method

Vortex-assisted sequential liquid-phase micro-extraction of E127 and E129 in foodstuffs and pharmaceuticals

In the present study, sequential liquid-phase micro-extraction (LPME) method based on amphiphile (1-pentanol) and ion-pair agent as the green chemicals for micro-separation, preconcentration and UV-vis micro-spectrophotometric determination of Erythrosine (E127) and Allura red (E129) in foodstuffs and pharmaceuti-cals was developed for the first time. 1-pentanol was used as extraction solvent for micro-extraction of E127 and to prepare alkanol based ion-pair solvent with tetra-pentyl ammonium bromide for micro-extraction of E129. E127 and E129 were determined by spectrophotometer at 538 and 506 nm, respectively. Micro-separation and micro-extraction parameters of the methods including pH, type and volume of 1-pentanol and ion-pair solvent, time of vortex and centrifugation were examined in detail and optimized. At the optimum conditions, inter-ference effects of matrix components and effect of sample volume on the micro-extraction methods were investigated. Limit of detection and limit of quantification were found as 3.2 mu g/L, 8.4 mu g/L for E127 and 5.2 mu g/ L, 13.7 mu g/L for E129, respectively. 15 preconcentration factor was attained for each of the dyes. The possible extraction mechanisms of the alkanol based micro-extraction for E127 and ion-pair agent based micro-extraction for E129 were elucidated in detail and also showed with images. Finally, the proposed sequential micro -separation technique was validated by analyte addition and recovery studies and applied to determine E127 and E129 contents of commercially available foodstuffs and pharmaceuticals in Turkish markets and pharmacies

Simultaneous Spectrophotometric Determination of Brilliant Blue and Tartrazine in Diverse Sample Matrices after Solid Phase Extraction

Background: Brilliant blue (BB) and tartrazine (TZ) are manufactured from petroleum and its products. These are the most popular consumed food dyes and are widely used in foodstuffs. Therefore, overuse of these dyes in foodstuffs and consumption of excessive amounts of these dyes can lead to health problems in humans. Methods: A column solid-phase separation extraction method combined with UV-Vis spectrophotometry was preferred and developed for single and simultaneous determination of BB and TZ dyes. Methods: A column solid-phase separation extraction method combined with UV-Vis spectrophotometry was preferred and developed for single and simultaneous determination of BB and TZ dyes. Results: The preconcentration factor was obtained as 80. Relative standard deviations were below than 4%. Detection limits of the method were determined as 0.29 and 1.21 mu g/L for BB and TZ, respectively. Recovery values were obtained between 95-99% and 96-100% for BB and TZ, respectively. 10.9-235.7 mu g/g and 1.7-8.0 mu g/mL of BB contents of real samples were determined for solid and liquid samples, respectively. TZ concentrations of solid and liquid samples were ranged between 18.7-220.7 mu g/g and 5.9-7.5 mu g/mL, respectively. Conclusions: Quantitative extraction results and satisfactory recovery values showed that method was successful and applicable for determination of BB and TZ concentrations in real pharmaceutical, industrial, and foodstuff samples. Highlights: The method has exhibited a high preconcentration factor and effective separation against to matrix ions. The method did not need an experienced operator with high operation experience. Elution solvent can be chosen according to the availability of the chemicals in the laboratory and cheapness of the chemicals