Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.

Clinical finding of cutis laxa, characterized by wrinkled, redundant, sagging, nonelastic skin, is of growing significance due to its occurrence in several different inborn errors of metabolism (IEM). Metabolic cutis laxa results from Menkes syndrome, caused by a defect in the ATPase copper transporting alpha (ATP7A) gene; congenital disorders of glycosylation due to mutations in subunit 7 of the component of oligomeric Golgi (COG7)-congenital disorders of glycosylation (CDG) complex; combined disorder of N- and O-linked glycosylation, due to mutations in ATPase H+ transporting V0 subunit a2 (ATP6VOA2) gene; pyrroline-5-carboxylate reductase 1 deficiency; pyrroline-5-carboxylate synthase deficiency; macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, due to Ras and Rab interactor 2 (RIN2) mutations; transaldolase deficiency caused by mutations in the transaldolase 1 (TALDO1) gene; Gerodermia osteodysplastica due to mutations in the golgin, RAB6-interacting (GORAB or SCYL1BP1) gene; and mitogen-activated pathway (MAP) kinase defects, caused by mutations in several genes [protein tyrosine phosphatase, non-receptor-type 11 (PTPN11), RAF, NF, HRas proto-oncogene, GTPase (HRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), MEK1/2, KRAS proto-oncogene, GTPase (KRAS), SOS Ras/Rho guanine nucleotide exchange factor 2 (SOS2), leucine rich repeat scaffold protein (SHOC2), NRAS proto-oncogene, GTPase (NRAS), and Raf-1 proto-oncogene, serine/threonine kinase (RAF1)], which regulate the Ras-MAPK cascade. Here, we further expand the list of inborn errors of metabolism associated with cutis laxa by describing the clinical presentation of a 17-month-old girl with Leigh-like syndrome due to enoyl coenzyme A hydratase, short chain, 1, mitochondria (ECHS1) deficiency, a mitochondrial matrix enzyme that catalyzes the second step of the beta-oxidation spiral of fatty acids and plays an important role in amino acid catabolism, particularly valine.

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT-PET after first cycle and MRI in response assessment.

PURPOSE: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18F-FLT-PET for response assessment. METHODS: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. RESULTS: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVmax was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. CONCLUSIONS: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18F-FLT-PET imaging.

Geometric data perturbation-based personal health record transactions in cloud computing.

Cloud computing is a new delivery model for information technology services and it typically involves the provision of dynamically scalable and often virtualized resources over the Internet. However, cloud computing raises concerns on how cloud service providers, user organizations, and governments should handle such information and interactions. Personal health records represent an emerging patient-centric model for health information exchange, and they are outsourced for storage by third parties, such as cloud providers. With these records, it is necessary for each patient to encrypt their own personal health data before uploading them to cloud servers. Current techniques for encryption primarily rely on conventional cryptographic approaches. However, key management issues remain largely unsolved with these cryptographic-based encryption techniques. We propose that personal health record transactions be managed using geometric data perturbation in cloud computing. In our proposed scheme, the personal health record database is perturbed using geometric data perturbation and outsourced to the Amazon EC2 cloud.

Intraparenchymal pericatheter cyst following disconnection of ventriculoperitoneal shunt system.

Ventriculoperitoneal (VP) shunt is one of the most commonly performed procedures in neurosurgery, but it is also the procedure, which is most prone to complications. Spread of cerebrospinal fluid (CSF) into the brain parenchyma is a rare complication of VP shunt and can take the form of CSF edema or a porencephalic cyst. We describe a case of a 1½-year-old child who presented to us with seizures. Computed tomography scan revealed pericatheter porencephalic cyst. Surgical exploration revealed a disconnected VP shunt system. Patient was neurologically observed after shunt extraction. He was seizure free and radiological follow-up showed resolution of cyst. Ours is the first case to document the presence of pericatheter cyst following complete disconnection of shunt system. Though shunt revision is the accepted treatment modality, careful neurological observation can be done after shunt removal especially in asymptomatic cases with compensated hydrocephalus.

Optimal Ensemble learning model for COVID-19 detection using chest X-ray images.

COVID-19 pandemic is the main outbreak in the world, which has shown a bad impact on people's lives in more than 150 countries. The major steps in fighting COVID-19 are identifying the affected patients as early as possible and locating them with special care. Images from radiology and radiography are among the most effective tools for determining a patient's ailment. Recent studies have shown detailed abnormalities of affected patients with COVID-19 in the chest radiograms. The purpose of this work is to present a COVID-19 detection system with three key steps: "(i) preprocessing, (ii) Feature extraction, (iii) Classification." Originally, the input image is given to the preprocessing step as its input, extracting the deep features and texture features from the preprocessed image. Particularly, it extracts the deep features by inceptionv3. Then, the features like proposed Local Vector Patterns (LVP) and Local Binary Pattern (LBP) are extracted from the preprocessed image. Moreover, the extracted features are subjected to the proposed ensemble model based classification phase, including Support Vector Machine (SVM), Convolutional Neural Network (CNN), Optimized Neural Network (NN), and Random Forest (RF). A novel Self Adaptive Kill Herd Optimization (SAKHO) approach is used to properly tune the weight of NN to improve classification accuracy and precision. The performance of the proposed method is then compared to the performance of the conventional approaches using a variety of metrics, including recall, FNR, MCC, FDR, Thread score, FPR, precision, FOR, accuracy, specificity, NPV, FMS, and sensitivity, accordingly.

Feature Selection and Dwarf Mongoose Optimization Enabled Deep Learning for Heart Disease Detection.

Heart disease causes major death across the entire globe. Hence, heart disease prediction is a vital part of medical data analysis. Recently, various data mining and machine learning practices have been utilized to detect heart disease. However, these techniques are inadequate for effectual heart disease prediction due to the deficient test data. In order to progress the efficacy of detection performance, this research introduces the hybrid feature selection method for selecting the best features. Moreover, the missed value from the input data is filled with the quantile normalization and missing data imputation method. In addition, the best features relevant to disease detection are selected through the proposed hybrid Congruence coefficient Kumar-Hassebrook similarity. In addition, heart disease is predicted using SqueezeNet, which is tuned by the dwarf mongoose optimization algorithm (DMOA) that adapts the feeding aspects of dwarf mongoose. Moreover, the experimental result reveals that the DMOA-SqueezeNet method attained a maximum accuracy of 0.925, sensitivity of 0.926, and specificity of 0.918.

Using deep learning to detect digitally encoded DNA trigger for Trojan malware in Bio-Cyber attacks.

This article uses Deep Learning technologies to safeguard DNA sequencing against Bio-Cyber attacks. We consider a hybrid attack scenario where the payload is encoded into a DNA sequence to activate a Trojan malware implanted in a software tool used in the sequencing pipeline in order to allow the perpetrators to gain control over the resources used in that pipeline during sequence analysis. The scenario considered in the paper is based on perpetrators submitting synthetically engineered DNA samples that contain digitally encoded IP address and port number of the perpetrator's machine in the DNA. Genetic analysis of the sample's DNA will decode the address that is used by the software Trojan malware to activate and trigger a remote connection. This approach can open up to multiple perpetrators to create connections to hijack the DNA sequencing pipeline. As a way of hiding the data, the perpetrators can avoid detection by encoding the address to maximise similarity with genuine DNAs, which we showed previously. However, in this paper we show how Deep Learning can be used to successfully detect and identify the trigger encoded data, in order to protect a DNA sequencing pipeline from Trojan attacks. The result shows nearly up to 100% accuracy in detection in such a novel Trojan attack scenario even after applying fragmentation encryption and steganography on the encoded trigger data. In addition, feasibility of designing and synthesizing encoded DNA for such Trojan payloads is validated by a wet lab experiment.

Tay-Sach disease with "cherry-red spot"--first reported case in Malaysia.

We present a rare case of Tay-Sachs disease with retinal 'cherry-red spots' in a 19-month-old Malay child. Molecular genetic studies confirmed the diagnosis. The case highlights that 'cherry-red spot' is a useful clinical clue in Tay-Sachs disease and several other lysosomal storage disorders. It serves as an ideal illustration of the eye as a window to inborn error of metabolism.

Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency.

OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis.

Massive benign osteoblastoma of the suboccipital bone and foramen magnum region.

Benign osteoblastoma is an uncommon primary bone tumor frequently found in the vertebral column and long tubular bones, and rarely occurring in the calvarium. A case of a massive benign osteoblastoma of the suboccipital bone and foramen magnum region in a 9-year-old boy is reported. He presented with progressively worsening nuchal pain and headaches secondary to a bony lesion in the suboccipital and foramen magnum region. Computed tomography (CT) of the brain showed a large midline occipital/suboccipital bony lesion extending to either side (R > L) and extending from the torcula till the foramen magnum region, causing moderate obstructive hydrocephalus. The atlas was uninvolved by the tumor. In addition, the cerebellum was pushed anteriorly squashing the fourth ventricle. The tumor was completely resected with wide margins via a suboccipital route. At follow-up after 7 years, the patient was asymptomatic, and CT imaging demonstrated no recurrence. The occurrence of benign osteoblastoma in the suboccipital bone and foramen magnum region has not been reported earlier in the pediatric population. Surgical extirpation of the lesion with wide margins is advocated and can produce an excellent long-term outcome. Serial vigilant follow-up along with sequential imaging is advocated even in cases with complete resection to detect early recurrence and possible malignant transformation.

Collagenofibrotic glomerulopathy: A case of glomerular deposition disease in the Indian subcontinent and review of the literature.

Collagenofibrotic glomerulopathy (CG) is a rare renal disease with unknown etiology, defined by deposition of Type III collagen fibers in the subendothelial space and mesangium seen on supported by electron microscopy. There are merely 19 cases reported in the literature from the Indian subcontinent. Herein, we present a case report of CG from the Indian subcontinent and review its literature mainly focusing on histopathological findings.

Tuberculous temporal brain abscess mimicking otogenic pyogenic abscess.

Tuberculous brain abscess is a rare manifestation of central nervous system tuberculosis. We report the case of a tuberculous temporal lobe abscess in a 14-year-old female child that mimicked an otogenic pyogenic brain abscess. The patient had no prior history of tuberculosis. She had chronic otitis media and presented with signs of raised intracranial tension. Radiological imaging was suggestive of an acute pyogenic left temporal lobe abscess. A left temporal craniotomy was performed and the abscess was completely excised. Histological examination was consistent with a chronic abscess, and bacterial cultures were negative. A left radical mastoidectomy was also carried out. However, she presented with repeated abscess formation at the same site over the next 8 weeks, which was refractory to surgical therapy and broad-spectrum antibiotic administration. Furthermore, the purulent exudate showed strong positivity in the PCR test for tubercular bacilli. After administration of antituberculous treatment, she showed gradual clinical and radiological improvement. At follow-up after 2 years, she is asymptomatic. CT imaging at 2 years showed total resolution of abscess. Tuberculous abscess in the temporal lobe following otogenic infection has not been reported in the pediatric population. Although rare, the possibility of tuberculous etiology should be borne in mind as a differential diagnosis of acute abscess of otogenic origin, especially in endemic areas where the incidence of chronic otitis media as well as tuberculosis is high. The pathogenesis and treatment of tuberculous brain abscess in children is reviewed in light of the current literature on the subject.

Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet.

Fumarate hydratase deficiency (FHD) caused by biallelic alterations of the FH (fumarate hydratase) gene is a rare disorder of the tricarboxylic acid cycle, classically characterized by encephalopathy, profound psychomotor retardation, seizures, a spectrum of brain abnormalities and early death in childhood. Less common milder phenotypes with moderate cognitive impairment and long-term survival have been reported. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). There is currently no recommended disease modifying treatment for FHD and only isolated reports of unsuccessful dietary modifications. Herein, we describe the safe and possibly disease modifying effect of a high fat, low carbohydrate diet in a 14-year-old female with severe FHD.

Coordinate diurnal regulation of hepatic acyl-coenzyme A: cholesterol acyltransferase and cellular levels of esterified cholesterol.

Hepatic ACAT, HMG-CoA reductase and both cellular free and esterified cholesterol were measured at 3 h intervals over a 24 h period in the rat. ACAT exhibited a characteristic low amplitude diurnal rhythm with maximum activity at the mid-light phase that was significantly higher than the minimum activity observed at the mid-dark phase. The cellular esterified cholesterol concentration showed a diurnal rhythm that closely paralleled the rhythm of ACAT activity. The cellular free cholesterol concentration was not significantly altered during the 24 h cycle. In rats fed cholesterol, the diurnal rhythm of ACAT was still maintained despite the increase in ACAT activity during the entire 24 h cycle suggesting that the ACAT rhythm is the result of changes in the level of ACAT protein expression. The results also indicate that the diurnal rhythms of ACAT and HMG-CoA reductase are generated by a process independent of the LDL receptor rhythm. All three rhythms are also independent of changes in the level of free cholesterol in the cell.

The substrate for cholesterol 7alpha-hydroxylase.

The rates of incorporation of (14C) cholesterol into cholesteryl esters and 5-cholestene-3beta,7alpha-diol (7alpha-hydroxycholesterol) by rat liver microsomes, measured under conditions in which esterification and 7alpha-hydroxylation are varied independently, indicated that cholesterol is the substrate for cholesterol 7alpha-hydroxylase. The specific activities of cholesteryl esters and 7alpha-hydroxycholeste ol in incubations of microsomes labelled with (14C)cholesterol in vitro or in vivo suggest that 7alpha-hydroxycholesterol and esterified cholesterol are not derived from the same pool of free cholesterol.

On the mechanism of regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and of acyl coenzyme A:cholesterol acyltransferase by dietary fat.

The activity and the kinetic properties of hydroxymethylglutaryl-CoA reductase and of acyl-CoA:cholesterol acyltransferase in the liver microsomal fraction have been compared between rats fed on either unsaturated or on saturated fat. When rats wre fed for 12h on a compounded diet containing either safflower seed oil or tristearin the composition of the fatty acyl chains of the microsomal phospholipids was shown to be relatively more unsaturated in the rats that received the unsaturated fat. The activity of hydroxymethylglutaryl-CoA reductase in the microsomal fraction was considerably reduced in rats fed on compounded diet containing unsaturated fat whereas this dietary condition resulted in a considerable increase in the activity of acyl-CoA:cholesterol acyltransferase. Similar effects were observed after feeding rats for 12 h on a commercial diet supplemented with either safflower seed oil or with tristearin. The addition of 2% cholesterol to the fat-supplemented diets resulted in both cases in a decrease in hydroxymethylglutaryl-CoA reductase and an increse in acyl-CoA:cholesterol acyltransferase activity as compared with the corresponding values from the rats fed on the fat-supplemented diets with no cholesterol. The Arrhenius plots of hydroxymethylgutaryl-CoA reductase in the microsomal fraction from rats fed on fat-supplemented commercial diet for 12 h showed breaks in the activation energy at 29.6 degrees C for the preparations from rats fed on tristearin and 28 degrees C for those from rats fed on safflower seed oil. The activation energy of the enzyme was lower above and higher below the break for the preparations from rat fed on the unsaturated fat-supplemented diet. Similar differences were obtained from the comparison of the Arrhenius plots in the preparations from rats fed on saturated fat and those in the preparations from rats fed on unsaturated fat when the diet was compounded and given to the animals for 36 h. The addition of 2% cholesterol to the commercial diet supplemented with either saturated or unsaturated fat resulted in Arrhenius plots with a constant activation energy between 37 and 22 degrees C for the enzyme in microsomal preparations from both groups of rats. The apparent Km value for hydroxymethylglutaryl-CoA was lower for the reductase in microsomal preparations from rats fed on the unsaturated fat as compared with that for the enzyme in microsomal preparations from rats fed on saturated fat. There was also a decrease in the apparent Km value for oleic acid for the acyltransferase from rats fed on unsaturated fat as compared with that for the enzyme in the microsomal preparation from the rats fed on saturated fat. The results of the present study are consistent with higher concentration of free cholesterol in endoplasmic reticular membrane in the environment of the reductase and that of acyltransferase following the administration of dietary unsaturated fat as compared with that following the administation of saturated fat.

Quantification of LDL cholesteryl ester contribution to biliary steroids in the rat.

The proportion of LDL cholesteryl ester converted to biliary steroids was quantified in the rat. The pre-existing pool of bile was allowed to drain for 10-12 h through a bile duct cannula. A single intravenous pulse injection of LDL labelled with [3H]cholesterol linoleyl ester was made, followed by a constant infusion of the same material in order to maintain constant specific radioactivity in plasma. A new steady state was achieved within 6 h and bile samples were then collected hourly until 12 h. Although substantial amounts (53-61 micrograms/h) of cholesteryl ester were released into the liver during LDL catabolism, only a very small fraction (0.8-1.90 micrograms/h) was found in biliary steroids. The proportion of LDL cholesteryl esters contributing to biliary steroids was only 1-2%. These results perhaps explain why perturbations to accelerate bile acid excretion have no effect on plasma LDL cholesterol concentration in the rat.

On the mechanism for the regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, of cholesterol 7alpha-hydroxylase and of acyl-coenzyme A:cholesterol acyltransferase by free cholesterol.

The administration of mevalonic acid to rats by intravenous injection resulted in a dose- and time-dependent increase in the activity of cholesterol 7alpha-hydroxylase in the liver microsomal fraction, a decrease in the microsomal activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and no significant change in the activity of acyl-coenzyme A:cholesterol acyltransferase or in the concentration of free and of esterified cholesterol in the liver microsomal fraction. However, the increased hepatic cholesterogenesis that follows the injection of mevalonic acid resulted in an increase of the size of the intracellular pool of cholesterol that is in the environment of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acts as substrate for cholesterol 7alpha-hydroxylase. The administration of mevalonic acid to rats by stomach tube resulted in an increase in the activity of cholesterol 7alpha-hydroxylase and of acyl-coenzyme A:cholesterol acyltransferase and in the concentration of cholesterol esters in the liver microsomal fraction, while there was a considerable decrease in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

The effect of portacaval anastomosis on plasma lipoprotein metabolism in rats.

1. The effect of portacaval anastomosis on the metabolism of plasma lipoproteins was investigated in rats. 2. When compared with sham-operated pair-fed controls, plasma high density lipoprotein cholesterol concentration was decreased, plasma low density lipoprotein cholesterol concentration was increased and plasma total cholesterol concentration was unchanged in the portacaval anastomosis rats. Maximal incorporation of [14C]leucine into the total circulating mass of protein was decreased in the very low density lipoprotein and high density lipoprotein fractions and, possibly, in the low density lipoprotein fraction, but there was no change in maximal incorporation into albumin. It is concluded that portacaval anastomosis diminishes the rate of synthesis of high density lipoprotein and very low density lipoprotein proteins and, possibly, of low density lipoprotein proteins.