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1. Ictal EEG Source Imaging for Presurgical Evaluation of Refractory Focal Epilepsy

   Habib MA, Ibrahim F, Mohktar MS, Kamaruzzaman SB, Rahmat K, Lim KS

   World Neurosurg, 2016 Apr;88:576-585.

   PMID: 26548833 DOI: 10.1016/j.wneu.2015.10.096

   Abstract

   BACKGROUND: Electroencephalography source imaging (ESI) is a promising tool for localizing the cortical sources of both ictal and interictal epileptic activities. Many studies have shown the clinical usefulness of interictal ESI, but very few have investigated the utility of ictal ESI. The aim of this article is to examine the clinical usefulness of ictal ESI for epileptic focus localization in patients with refractory focal epilepsy, especially extratemporal lobe epilepsy.

   METHODS: Both ictal and interictal ESI were performed by the use of patient-specific realistic forward models and 3 different linear distributed inverse models. Lateralization as well as concordance between ESI-estimated focuses and single-photon emission computed tomography (SPECT) focuses were assessed.

   RESULTS: All the ESI focuses (both ictal and interictal) were found lateralized to the same hemisphere as ictal SPECT focuses. Lateralization results also were in agreement with the lesion sides as visualized on magnetic resonance imaging. Ictal ESI results, obtained from the best-performing inverse model, were fully concordant with the same cortical lobe as SPECT focuses, whereas the corresponding concordance rate is 87.50% in case of interictal ESI.

   CONCLUSIONS: Our findings show that ictal ESI gives fully lateralized and highly concordant results with ictal SPECT and may provide a cost-effective substitute for ictal SPECT.

   MeSH terms: Drug Resistant Epilepsy/diagnosis*; Drug Resistant Epilepsy/surgery*; Adolescent; Adult; Brain Mapping/methods*; Child; Electroencephalography/methods*; Female; Humans; Male; Middle Aged; Preoperative Care/methods*; Retrospective Studies; Sensitivity and Specificity; Reproducibility of Results; Surgery, Computer-Assisted/methods*; Young Adult
2. Pure spinal multiple sclerosis: A possible novel entity within the multiple sclerosis disease spectrum

   Schee JP, Viswanathan S

   Mult. Scler., 2019 07;25(8):1189-1195.

   PMID: 29771191 DOI: 10.1177/1352458518775912

   Abstract

   We identified five female patients retrospectively with relapsing short-segment partial myelitis whose clinical and paraclinical features were suggestive of cord involvement of multiple sclerosis (MS)-type albeit not rigidly fulfilling the 2017 McDonald criteria. Notably, these patients had not developed any typical MS-like brain lesions despite repeated neuroimaging assessments over years. Comprehensive work-up for differential diagnoses of MS and other causes of transverse myelitis particularly neuromyelitis optica spectrum disorders had been consistently negative on longitudinal follow-up. Thus, we postulate a possible entity of pure spinal MS which may represent a novel forme fruste within the MS disease spectrum.

   MeSH terms: Brain; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Multiple Sclerosis; Myelitis, Transverse; Neoplasm Recurrence, Local; Neuromyelitis Optica; Retrospective Studies; Tuberous Sclerosis; Neuroimaging
3. Analysis of reactive astrocytes and NG2 proteoglycan in ex vivo rat models of spinal cord injury

   Patar A, Dockery P, Howard L, McMahon S

   J. Neurosci. Methods, 2019 01 01;311:418-425.

   PMID: 30267723 DOI: 10.1016/j.jneumeth.2018.09.027

   Abstract

   BACKGROUND: The use of animals to model spinal cord injury (SCI) requires extensive post-operative care and can be expensive, which makes an alternative model extremely attractive. The use ofex vivo slice cultures is an alternative way to study the pathophysiological changes that can mimic in vivo conditions and support the 3Rs (replacement, reduction and refinement) of animal use in SCI research models.

   NEW METHOD: In this study the presence of reactive astrocytes and NG2 proteoglycans was investigated in two ex vivo models of SCI; stab injury and transection injury. Stereological analysis to measure immunohistochemical staining was performed on the scar and injury zones to detect astrocytes and the chondroitin sulphate proteoglycan NG2.

   RESULTS: The volume fraction (Vv) of reactive astrocytes and NG2 proteoglycans increased significantly between day 3 and day 10 post injury in both ex vivo models. This data shows how ex vivo SCI models are a useful research tool allowing reduction of research cost and time involved in carrying out animal studies, as well as reducing the numbers of animals used.

   COMPARISON WITH EXISTING METHOD: This is the first evidence of an ex vivo stab injury model of SCI and also the first comparison of immunohistochemical staining for injury markers within stab injured and transection injured ex vivo slice cultures.

   CONCLUSIONS: The use of organotypic slice culture models provide a simple way to study the cellular consequences following SCI and they can also be used as a platform for potential therapeutics regimes for the treatment of SCI.

   MeSH terms: Animals; Antigens; Astrocytes; Cicatrix; Membrane Proteins; Chondroitin Sulfate Proteoglycans; Proteoglycans; Spinal Cord Injuries; Staining and Labeling
4. Enhanced nitrogen removal in an anoxic-oxic-anoxic process treating low COD/N tropical wastewater: Low-dissolved oxygen nitrification and utilization of slowly-biodegradable COD for denitrification

   How SW, Chua ASM, Ngoh GC, Nittami T, Curtis TP

   Sci. Total Environ., 2019 Nov 25;693:133526.

   PMID: 31376760 DOI: 10.1016/j.scitotenv.2019.07.332

   Abstract

   Many wastewater treatment plants (WWTPs) operating in biological nitrogen removal activated sludge process in the tropics are facing the pressure of increasingly stringent effluent standards while seeking solutions to reduce the plants' energy consumption and operating cost. This study investigated the feasibility of applying low-dissolved oxygen (low-DO) nitrification and utilizing slowly-biodegradable chemical oxygen demand (sbCOD) for denitrification, which helps to reduce energy usage and operating cost in treating low soluble COD-to-nitrogen tropical wastewater. The tropical wastewater was first characterized using wastewater fractionation and respirometry batch tests. Then, a lab-scale sequencing batch reactor (SBR) was operated to evaluate the long-term stability of low-DO nitrification and utilizing sbCOD for denitrification in an anoxic-oxic (AO) process treating tropical wastewater. The wastewater fractionation experiment revealed that particulate settleable solids (PSS) in the wastewater provided slowly-biodegradable COD (sbCOD), which made up the major part (51 ± 10%) of the total COD. The PSS hydrolysis rate constant at tropical temperature (30 °C) was 2.5 times higher than that at 20 °C, suggesting that sbCOD may be utilized for denitrification. During the SBR operation, high nitrification efficiency (93 ± 6%) was attained at low-DO condition (0.9 ± 0.1 mg O2/L). Utilizing sbCOD for post-anoxic denitrification in the SBR reduced the effluent nitrate concentration. Quantitative polymerase chain reaction, 16S rRNA amplicon sequencing and fluorescence in-situ hybridization revealed that the genus Nitrospira was a dominant nitrifier. 16S rRNA amplicon sequencing result suggested that 50% of the Nitrospira-related operational taxonomic units were affiliated with comammox, which may imply that the low-DO condition and the warm wastewater promoted their growth. The nitrogen removal in a tropical AO process was enhanced by incorporating low-DO nitrification and utilizing sbCOD for post-anoxic denitrification, which contributes to an improved energy sustainability of WWTPs.

   MeSH terms: Fluorescence; Hydrolysis; Nitrates; Nitrogen; Oxygen; RNA, Ribosomal, 16S; Sewage; Temperature; Waste Disposal, Fluid; Polymerase Chain Reaction; Biological Oxygen Demand Analysis; Denitrification; Nitrification; Waste Water
5. Antibiotic resistance, putative virulence factors and curli fimbrination among Cronobacter species

   Odeyemi OA, Abdullah Sani N

   Microb. Pathog., 2019 Aug 09;136:103665.

   PMID: 31404630 DOI: 10.1016/j.micpath.2019.103665

   Abstract

   This study aimed to investigate antibiotic resistance and putative virulence factors among Cronobacter sakazakii isolated from powdered infant formula and other sources. The following 9 cultures (CR1-9) were collected from our culture collection: C. sakazakii and 3 Cronobacter species: C. sakazakii ATCC® 29544™, C. muytjensii ATCC® 51329™, C. turicensis E866 were used in this study. Isolates were subjected to antibiotic susceptibility and the following virulence factors (protease, DNase, haemolysin, gelatinase, motility and biofilm formation) using phenotypic methods. All the bacteria were able to form biofilm on agar at 37 °C and were resistant to ampicillin, erythromycin, fosfomycin and sulphamethoxazole. It was observed from this study that tested strains formed weak and strong biofilm with violet dry and rough (rdar), brown dry and rough (bdar), red mucoid and smooth (rmas) colony morphotypes on Congo red agar. Rdar expresses curli and fimbriae, while bdar expresses curli. Both biofilm colony morphotypes are commonly found in Enterobacteriaceae including Salmonella species. This study also reveals a new colony morphotypes in Cronobacter species. Conclusively, there was correlation between putative virulence factors and antibiotic resistance among the tested bacteria. Further study on virulence and antibiotic resistance genes is hereby encouraged.

   MeSH terms: Agar; Ampicillin; Anti-Bacterial Agents; Congo Red; Deoxyribonucleases; Drug Resistance, Microbial; Enterobacteriaceae; Erythromycin; Fosfomycin; Hemolysin Proteins; Humans; Infant; Fimbriae, Bacterial; Salmonella; Sulfamethoxazole; Virulence; Gelatinases; Biofilms; Virulence Factors; Infant Formula; Cronobacter sakazakii; Cronobacter
6. Small molecule grp94 inhibitors block dengue and Zika virus replication

   Rothan HA, Zhong Y, Sanborn MA, Teoh TC, Ruan J, Yusof R, et al.

   Antiviral Res., 2019 Nov;171:104590.

   PMID: 31421166 DOI: 10.1016/j.antiviral.2019.104590

   Abstract

   Two major flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), cause severe health and economic burdens worldwide. Recently, genome-wide screenings have uncovered the importance of regulators of the Hrd1 ubiquitin ligase-mediated endoplasmic reticulum (ER)-associated degradation (ERAD) pathway for flavivirus replication in host cells. Here we report the identification of the compound Bardoxolone methyl (CDDO-me) as a potent inhibitor of the Hrd1 ubiquitin ligase-mediated ERAD, which possesses a broad-spectrum activity against both DENV and ZIKV. Cellular thermal shift assay (CETSA) suggested that CDDO-me binds to grp94, a key component of the Hrd1 pathway, at a low nanomolar concentration, whereas interaction was not detected with its paralog Hsp90. CDDO-me and the grp94 inhibitor PU-WS13 substantially suppressed DENV2 replication and the cytopathic effects caused by DENV and ZIKV infection. The antiviral activities of both compounds were demonstrated for all four DENV serotypes and four ZIKV strains in multiple human cell lines. This study defines grp94 as a crucial host factor for flavivirus replication and identified CDDO-me as a potent small molecule inhibitor of flavivirus infection. Inhibition of grp94 may contribute to the antiviral activity of CDDO-me. Further investigation of grp94 inhibitors may lead to a new class of broad-spectrum anti-flaviviral medications.

   MeSH terms: Zika Virus Infection; Zika Virus; Animals; Antiviral Agents; Cell Division; Cell Line; Dengue Virus; Endoplasmic Reticulum; Flavivirus; Humans; Ligases; Oleanolic Acid; Flavivirus Infections; Ubiquitin; Endoplasmic Reticulum-Associated Degradation; Serogroup
7. Modelling the immunopathophysiology of Brucella melitensis and its lipopolysaccharide in mice infected via oral route of exposure

   Osman AY, Kadir AA, Jesse FF, Saharee AA

   Microb. Pathog., 2019 Aug 21;136:103669.

   PMID: 31445124 DOI: 10.1016/j.micpath.2019.103669

   Abstract

   Brucella melitensis is one of the leading zoonotic pathogens with significant economic implications in animal industry worldwide. Lipopolysaccharide, however, remains by far the major virulence with substantial role in diseases pathogenesis. Nonetheless, the effect of B. melitensis and its lipopolysaccharide on immunopathophysiological aspects largely remains an enigma. This study examines the effect of B.melitensis and its lipopolysaccharide on immunopathophysiological parameters following experimental infection using mouse model. Eighty four (n = 84) mice, BALB/c, both sexes with equal gender distribution and 6-8 weeks-old were randomly assigned into three groups. Group 1-2 (n = 72) were orally inoculated with 0.4 mL containing 109 CFU/mL of B. melitensis and its LPS, respectively. Group 3 (n = 12) was challenged orally with phosphate buffered saline and served as a control group. Animals were observed for clinical signs, haematological and histopathological analysis for a period of 24 days post-infection. We hereby report that B.melitensis infected group demonstrated significant clinical signs and histopathological changes than LPS infected group. However, both infected groups showed elevated levels of interleukins (IL-1β and IL-6) and antibody levels (IgM and IgG) with varying degrees of predominance in LPS infected group than B. melitensis infected group. For hormone analysis, low levels of progesterone, estradiol and testosterone were observed in both B. melitensis and LPS groups throughout the study period. Moreover, in B. melitensis infected group, the organism was re-isolated from the organs and tissues of gastrointestinal, respiratory and reproductive systems thereby confirming the infection and transmission dynamics. This report is the first detailed investigation comparing the infection progression and host responses in relation to the immunopathophysiological aspects in a mouse model after oral inoculation with B. melitensis and its lipopolysaccharide.

   MeSH terms: Animals; Estradiol; Female; Genitalia; Immunoglobulin G; Immunoglobulin M; Interleukins; Lipopolysaccharides; Male; Mice, Inbred BALB C; Phosphates; Progesterone; Testosterone; Virulence; Interleukin-6; Brucella melitensis; Control Groups; Mice; Interleukin-1beta
8. Ultrasound mediated efficient synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamides as potent tyrosinase inhibitors: Mechanistic approach through chemoinformatics and molecular docking studies

   Dige NC, Mahajan PG, Raza H, Hassan M, Vanjare BD, Hong H, et al.

   Bioorg. Chem., 2019 Nov;92:103201.

   PMID: 31445195 DOI: 10.1016/j.bioorg.2019.103201

   Abstract

   We have carried out the synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamide derivatives by the reaction between isatoic anhydride, 2-furoic hydrazide and substituted salicylaldehydes in ethanol: water (5:5 v/v) solvent system using p-TSA as a catalyst under ultrasound irradiation at room temperature. The structures of newly synthesized compounds were confirmed through spectral techniques such as IR, 1H NMR, 13C NMR, and LCMS. The important features of this protocol include simple and easy workup procedure, reaction carried out at ambient temperature, use of ultrasound and high yield of oxoquinazolin-3(4H)-yl)furan-2-carboxamides in short reaction time. The synthesized compounds 4a-4j were screened against tyrosinase enzyme and all these compounds found to be potent inhibitors with much lower IC50 value of 0.028 ± 0.016 to 1.775 ± 0.947 µM than the standard kojic acid (16.832 ± 1.162 µM). The kinetics mechanism for compound 4e was analyzed by Lineweaver-Burk plots which revealed that compound inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. Along with this all the synthesized compounds (4a-4j) were scanned for their DPPH free radical scavenging ability. The outputs received through in vitro and in silico analysis are coherent to the each other with good binding energy values (kcal/mol) posed by synthesized ligands.

   MeSH terms: Ethanol; Aldehydes; Free Radicals; Furans; Kinetics; Ligands; Oxazines; Pyrones; Reaction Time; Solvents; Temperature; Monophenol Monooxygenase; Water; Inhibitory Concentration 50; Carbon-13 Magnetic Resonance Spectroscopy; Proton Magnetic Resonance Spectroscopy
9. Enhanced paracellular delivery of vaccine by hydrogel microparticles-mediated reversible tight junction opening for effective oral immunization

   Chen XY, Butt AM, Mohd Amin MCI

   J Control Release, 2019 Aug 26;311-312:50-64.

   PMID: 31465827 DOI: 10.1016/j.jconrel.2019.08.031

   Abstract

   The current conventional injectable vaccines face several drawbacks such as inconvenience and ineffectiveness in mucosal immunization. Therefore, the current development of effective oral vaccines is vital to enable the generation of dual systemic and mucosal immunity. In the present study, we examine the potential of pH-responsive bacterial nanocellulose/polyacrylic acid (BNC/PAA) hydrogel microparticles (MPs) as an oral vaccine carrier. In-vitro entrapment efficiency and release study of Ovalbumin (Ova) demonstrated that as high as 72% of Ova were entrapped in the hydrogel, and the release of loaded Ova was pH-dependent. The released Ova remained structurally conserved as evident by Western blot and circular dichroism. Hydrogel MPs reduced the TEER measurement of HT29MTX/Caco2/Raji B triple co-culture monolayer by reversibly opening the tight junctions (TJs) as shown in the TEM images. The ligated ileal loop assay revealed that hydrogel MPs could facilitate the penetration of FITC-Ova into the Peyer's patches in small intestine. Ova and cholera toxin B (CTB) were utilized in in-vivo oral immunization as model antigen and mucosal adjuvant. The in-vivo immunization revealed mice orally administered with Ova and CTB-loaded hydrogel MPs generated significantly higher level of serum anti-Ova IgG and mucosal anti-Ova IgA in the intestinal washes, compared to intramuscular administrated Ova. These results conclude that BNC/PAA hydrogel MPs is a potential oral vaccine carrier for effective oral immunization.

   MeSH terms: Acrylic Resins; Animals; Cholera Toxin; Circular Dichroism; Humans; Immunoglobulin A; Immunoglobulin G; Immunization; Intestine, Small; Ovalbumin; Peyer's Patches; Vaccination; Vaccines; Blotting, Western; Fluorescein-5-isothiocyanate; Coculture Techniques; Immunity, Mucosal; Caco-2 Cells; Tight Junctions; Mice
10. Fulltext Phosphoinositide 3-kinase δ inactivation prevents vitreous-induced activation of AKT/MDM2/p53 and migration of retinal pigment epithelial cells

    Han H, Chen N, Huang X, Liu B, Tian J, Lei H

    J. Biol. Chem., 2019 Oct 18;294(42):15408-15417.

    PMID: 31467081 DOI: 10.1074/jbc.RA119.010130

    Abstract

    Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cell-surface molecules to intracellular protein effectors. Key PI3Ks include PI3Kα, PI3Kβ, and PI3Kδ, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. However, which PI3K isoforms are involved in PVR is unknown. A major characteristic of PVR is the formation of epi (or sub)-retinal membranes that consist of extracellular matrix and cells, including retinal pigment epithelium (RPE) cells, glial cells, and macrophages. RPE cells are considered key players in PVR pathogenesis. Using immunoblotting and immunofluorescence analyses, we herein provide the evidence that PI3Kδ is highly expressed in human RPEs when it is primarily expressed in leukocytes. We also found that PI3Kδ inactivation through two approaches, CRISPR/Cas9-mediated depletion and a PI3Kδ-specific inhibitor (idelalisib), not only blocks vitreous-induced activation of AKT and MDM2 but also abrogates a vitreous-stimulated decrease in p53. Furthermore, we demonstrate that PI3Kδ inactivation prevents vitreous-induced proliferation, migration, and contraction of human RPEs. These results suggest that PI3Kδ may represent a potential therapeutic target for RPE-related eye diseases, including PVR.

    MeSH terms: Animals; Extracellular Matrix; Fluorescent Antibody Technique; Humans; Leukocytes; Lipids; Macrophages; Neuroglia; Proto-Oncogenes; Purines; Immunoblotting; Tumor Suppressor Protein p53; Vitreoretinopathy, Proliferative; Phosphatidylinositol 3-Kinases; Protein Isoforms; Cell Proliferation; Proto-Oncogene Proteins c-akt; Mice; Quinazolinones; Retinal Pigment Epithelium; Class I Phosphatidylinositol 3-Kinases; CRISPR-Cas Systems