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1.
J Physiol Pharmacol ; 75(3)2024 Jun.
Article in English | MEDLINE | ID: mdl-39042385

ABSTRACT

Pentylenetetrazole- (PTZ)-induced kindling is a broadly used experimental model to evaluate the impact of antiseizure drugs and their novel combination on seizure progression. The current study aimed to evaluate the anti-kindling effects of ivermectin (IVM) and rufinamide (RUFI) alone and their combination with vitamin E. The mice were administered 11 injections of PTZ (40 mg/kg) followed by assessment for anxiety-like behavior and cognitive abilities in a series of behavior tests with subsequent brain isolation for biochemical and histopathological evaluation. The outcomes showed a marked protection by IVM + RUFI (P<0.001) from kindling progression, anxiety-like behavior and cognitive deficit. However, additional supplementation with vitamin E worked superior to duo therapy as these mice were noted to be most fearless to visiting open, illuminated and elevated zones of open field, light/dark and elevated-plus maze (P<0.0001). Further, they showed marked remembrance of the familiar milieu in y-maze (P<0.01) and novel objection recognition (P<0.05) tests. Additionally, their recollection of aversive stimuli in passive avoidance and spatial memory in Morris water maze were evident (P<0.0001), in comparison to kindled mice. The IVM + RUFI duo therapy and its co-administration with vitamin E prevented kindling-triggered oxidative stress in brains and neuronal damage in hippocampus. We conclude that the benefits of the co-administration of vitamin E might be the results of antioxidant and anti-inflammatory effects of vitamin E which might be potentiating the antiseizure effects of RUFI and GABA-A modulating potential by ivermectin.


Subject(s)
Anticonvulsants , Behavior, Animal , Ivermectin , Kindling, Neurologic , Pentylenetetrazole , Seizures , Triazoles , Vitamin E , Animals , Kindling, Neurologic/drug effects , Vitamin E/pharmacology , Vitamin E/administration & dosage , Mice , Ivermectin/pharmacology , Ivermectin/administration & dosage , Anticonvulsants/pharmacology , Anticonvulsants/administration & dosage , Male , Seizures/drug therapy , Behavior, Animal/drug effects , Triazoles/pharmacology , Triazoles/administration & dosage , Drug Therapy, Combination , Anxiety/drug therapy , Maze Learning/drug effects , Brain/drug effects , Brain/pathology , Brain/metabolism
2.
Biomedicines ; 12(4)2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38672273

ABSTRACT

Cell therapy is at the forefront of biomedicine in oncology and regenerative medicine. However, there are still significant challenges to their wider clinical application such as limited efficacy, side effects, and logistical difficulties. One of the potential approaches that could overcome these problems is based on extracellular vesicles (EVs) as a cell-free therapy modality. One of the major obstacles in the translation of EVs into practice is their low yield of production, which is insufficient to achieve therapeutic amounts. Here, we evaluated two primary approaches of artificial vesicle induction in primary T cells and the SupT1 cell line-cytochalasin B as a chemical inducer and ultrasonication as a physical inducer. We found that both methods are capable of producing artificial vesicles, but cytochalasin B induction leads to vesicle yield compared to natural secretion, while ultrasonication leads to a three-fold increase in particle yield. Cytochalasin B induces the formation of vesicles full of cytoplasmic compartments without nuclear fraction, while ultrasonication induces the formation of particles rich in membranes and membrane-related components such as CD3 or HLAII proteins. The most effective approach for T-cell induction in terms of the number of vesicles seems to be the combination of anti-CD3/CD28 antibody activation with ultrasonication, which leads to a seven-fold yield increase in particles with a high content of functionally important proteins (CD3, granzyme B, and HLA II).

3.
Cureus ; 15(6): e39814, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37397679

ABSTRACT

Renal lymphangiectasia is one of the rarest surgical complications in post-transplant kidney patients. A few patients may clinically complain of nonspecific symptoms, and the other few might be diagnosed incidentally. We report the case of a 32-year-old female patient with a known case of Joubert syndrome who presented with nonspecific clinical manifestations. The patient underwent ultrasound, magnetic resonance imaging (MRI), and nuclear medicine (NM) imaging to confirm the diagnosis, which showed radiologic features of renal lymphangiectasia. Conservative medical management was delivered to the patient.

4.
J Org Chem ; 88(14): 9657-9667, 2023 Jul 21.
Article in English | MEDLINE | ID: mdl-37379249

ABSTRACT

A verity of α,ß-ketoepoxides was synthesized using a CuII-catalyzed oxidative C-C/O-C coupled cyclization strategy with high yield and cis-selectivity. Water is used as the source of oxygen and phenacyl bromide as the carbon in the valuable epoxides. The self-coupling method was extended to cross-coupling between phenacyl bromides with benzyl bromides. A high cis-diastereoselectivity was observed in all the synthesized ketoepoxides. Control experiments and density functional theory (DFT) study were performed to understand the CuII-CuI transition mechanism.

5.
Int J Mol Sci ; 24(10)2023 May 22.
Article in English | MEDLINE | ID: mdl-37240445

ABSTRACT

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: -136.48, -130.08, -130.99, and -140.81 kJ mol-1, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states.


Subject(s)
Electrons , Nitrogen Oxides , Models, Molecular , Cycloaddition Reaction
6.
Chem Commun (Camb) ; 59(31): 4664-4667, 2023 Apr 13.
Article in English | MEDLINE | ID: mdl-36994605

ABSTRACT

In this study, we have devised a new method for synthesizing highly valuable 5,6,7,8a-tetrahydropyrrolo[2,1-b]thiazoles using a decarboxylative C-N coupling reaction between phenyl glyoxal and proline or its analogue, which is catalyzed by CuI in the presence of K2CO3. This reaction is followed by a regiospecific C-C and C-S coupling cyclization with dialkyl trithiocarbonate. Furthermore, we have demonstrated that this cross-coupling method can also be extended to imines, leading to the formation of fused symmetrical and unsymmetrical 6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles. This finding greatly expands the scope and versatility of the synthetic approach. Therefore, this work represents a significant contribution to the field of organic synthesis, providing a novel and efficient method for the preparation of fused N-heterocyclic compounds that could have useful applications in areas such as material science and pharmaceuticals.

7.
J Epidemiol Glob Health ; 13(1): 47-54, 2023 03.
Article in English | MEDLINE | ID: mdl-36626091

ABSTRACT

The outcome of transplant recipients is variable depending on the study population, vaccination status and COVID-19 variants. Our aim was to study the impact of Omicron subvariants on the mortality of transplant recipients. We reviewed the results of SARS-CoV-2 whole genome sequence of random isolates collected from 29 December 2021 until 17 May 2022 in King Faisal Specialist Hospital and Research center, Jeddah (KFSHRC-J), Saudi Arabia performed as hospital genomic surveillance program for COVID-19 variants. We included 25 transplant patients infected with confirmed Omicron variants.17 (68%) and 8 (32%) patients had Omicron BA.1 and BA.2, respectively. 12 (68%) patients had renal transplants. Only 36% of patients received three doses of COVID-19 vaccines. 23 (92%) patients required hospitalization. 20 (80%) patients survived and 6 (25%) required intensive care unit (ICU) admission. Among ICU patients, 66.7% were more than 50 years, 50% had two to three comorbidities and 5 out of 6 (83%) died. The mortality of transplant patients infected with Omicron variants in our cohort was higher than other centers as a limited number of patients received booster vaccines. Optimizing booster vaccination is the most efficient method to improve the mortality of COVID-19 in transplant recipients recognizing the inefficacy of monoclonal antibodies in the presence of SARS-CoV-2 emerging variants. We did not show a difference in mortality in transplant patients infected with Omicron BA.1 and BA.2 knowing the limitation of our sample size.


Subject(s)
COVID-19 , Transplant Recipients , Humans , Saudi Arabia , Retrospective Studies , COVID-19 Vaccines , SARS-CoV-2
8.
Int J Surg Case Rep ; 96: 107329, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35792407

ABSTRACT

INTRODUCTION: We report a case of subacute thyroiditis (SAT) in a 29 -year-old female who presented with painful thyroid swelling. PRESENTATION OF CASE: Patient presented with neck pain, tender neck swelling and generalized fatigue. She had no history of neck or chest radiation or compressive symptoms. Ultrasound (US) imaging reveled bilateral nodules of the thyroid gland. Lymph nodes were unremarkable. FNAC was suspicious for papillary thyroid carcinoma. The patient was discussed at the thyroid multidisciplinary meeting, and after deliberation the decision was to offer the patient the choice of repeating FNAC of the bilateral nodules in one month or to proceed with total thyroidectomy. DISCUSSION: Despite being aware of the possibility that the final pathology could be benign, the patient insisted on total thyroidectomy, given that her FNAC results were suspicious of papillary thyroid carcinoma, and in order to avoid recurrence of the condition and the pain. Following the patient's preference, total thyroidectomy was performed, and surgery was not straightforward as intraoperatively, there was a diffusely inflamed gland. Histopathology findings revealed benign pathology. Follow up until 1.5 years showed that the patient was satisfied, and with normal voice. CONCLUSION: SAT is a painful but potentially self-limiting. In some cases, FNAC findings might be suspicious for papillary thyroid carcinoma. Treatment is mostly conservative, but if the pain is severe and the patient insists on surgery as in our case despite the possibility of the condition being of benign pathology, then surgery should be undertaken.

9.
Int J Cardiol Heart Vasc ; 40: 101029, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35434258

ABSTRACT

Background: Cardiovascular magnetic resonance (CMR) is the test of choice for diagnosis and risk stratification of myocardial inflammation in acute viral myocarditis. The objective of this study was to assess patterns of CMR inflammation in a cohort of acute myocarditis patients from Northern Africa, Asia, and the Middle East using unsupervised machine learning. Methods: A total of 169 racially and ethnically diverse adults ( ≥ 18 years of age) with CMR confirmed acute myocarditis were studied. The primary outcome was a combined clinical endpoint of cardiac death, arrhythmia, and dilated cardiomyopathy. Machine learning was used for exploratory analysis to identify patterns of CMR inflammation. Results: Our cohort was diverse with 25% from Northern Africa, 33% from Southern Asia, and 28% from Western Asia/the Middle East. Twelve patients met the combined clinical endpoint - 3 had arrythmia, 8 had dilated cardiomyopathy, and 1 died. Patients who met the combined endpoint had increased anterior (p = 0.034) and septal (p = 0.042) late gadolinium enhancement (LGE). Multivariable logistic regression, adjusted for age, gender, and BMI, found that patients from Southern Asia (p = 0.041) and the Middle East (p = 0.043) were independently associated with lateral LGE. Unsupervised machine learning and factor analysis identified two distinct CMR patterns of inflammation, one with increased LGE and the other with increased myocardial T1/T2. Conclusions: We found that anteroseptal inflammation is associated with worsened outcomes. Using machine learning, we identified two patterns of myocardial inflammation in acute myocarditis from CMR in a racially and ethnically diverse group of patients from Southern Asia, Northern Africa, and the Middle East.

10.
J Tradit Complement Med ; 11(6): 481-492, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34765512

ABSTRACT

BACKGROUND AND AIM: Epithelial ovarian cancer has the deadliest prognosis amongst gynaecological cancers, warranting an unmet need for newer drug targets. Based on its anticancer as well as abortifacient potential, Moringa oleifera Lam. root was hypothesized to have some implications in follicle stimulating hormone receptor (FSHR) dependent cancers like epithelial ovarian cancer. EXPERIMENTAL PROCEDURE: Effect of Moringa oleifera Lam. root extract (MRE) was studied in epithelial ovarian cancer cell line through in vitro studies viz. MTT assay, clonogenic assay, cell cycle analysis, flow cytometry, western blot analysis, immunocytochemical analysis of FSHRand c-Myc expression and in vivo studies viz. effect of MRE in mice model of ovarian carcinoma. The structure of the active compound of MRE was elucidated following solvent extraction, purification through column chromatography, preparative TLC and bioactivity guided structural identification through 1H-NMR, 13C-NMR, DEPT-135, ESIMS,FT-IR spectrophotometry, UV-vis-NIR spectrophotometry and DFT study. RESULTS AND CONCLUSION: Crude MRE displayed cytotoxic activity, induced apoptosis, and attenuated expression of FSHR and c-Myc in ovarian cancer cell line OAW42. MRE also attenuated expression of CD31, FSHR, and c-Myc in tumour xenograft mouse model. Finally, the active compound purified from ethyl acetate-n-hexane subfraction ofMRE, that attenuated viability of ovarian carcinoma cell lines and reduced FSHR and c-Myc expression, was identified as a naturally hydrated-trifattyglyceride, showing aDFT-optimized folded amphipathic structure for easy transportation through hydrophilic and hydrophobic regions in a biological system, indicating its immense therapeutic relevance in epithelial ovarian carcinoma.

11.
Ann Afr Med ; 20(2): 78-83, 2021.
Article in English | MEDLINE | ID: mdl-34213472

ABSTRACT

Background: There are variable reports of glycemic control and complications among patients living with diabetes mellitus (DM). Aim: The aim of this study was to determine the glycemic control and complications among patients with DM seen at the medical outpatient department of a tertiary health institution in Northwestern Nigeria. Methodology: This was a descriptive cross-sectional study of 236 patients attending DM Clinic at Federal Medical Centre Gusau. A questionnaire was administered that contains sociodemographic characteristics of the patients, duration of DM, adherence to management, and complications. Anthropometry, blood pressures, and fasting plasma glucose (FPG) were recorded. Data were analyzed using SPSS version 20.0. Results: Eighty-six (36%) males and 150 (64%) females patients with DM were evaluated. Their mean (standard deviation [SD]) age was 53.5 ± 12.3 years with mean (SD) duration of DM of 7.9 ± 6.2 years. The mean FPG was 8.85 ± 3.8 mmol/L (males 8.21 ± 3.6, females 9.49 ± 3.8). Forty-seven (20%), 75 (32%), 113 (48%) of the patients had good, fair, and poor glycemic control, respectively. The major complications observed were peripheral neuropathy (61%) and visual impairment (51%). Glycemic control was significantly better among males and those with good adherence to medications. There was a positive association between the longer duration of DM with complications. Conclusion: Only 20% of our patients achieved good glycemic control and many have complications. Majority of the patients adhered more with medications as compared to dietary management and exercise. There is a need for clinicians to educate patients more on the need for lifestyle modifications.


RésuméConcernant les origines de la situation: Il y a des variables rapports glycémie de contrôle et des complications parmi les patients qui vie avec le diabète mellitus(DM). BUT: Le but de cet étude était pour déterminer le contrôle et les complications glycémie parmi les patients avec le DM vue dans le service de consultation tertiaire dans l'établissement de santé au Nord-ouest du Nigéria. Méthodologie: C'était une description transversale d'étude de 236 patients qui ont assistait à l'événement clinique de la DM au centre médical fédérale à Gusau.Un questionnaire était gérer à contenu de socio démographe de trait de caractère des patients, durée de la DM, hypertension, et le FPG qui se lit "Fasting plasma glucose" en anglais ont été enregistré. Les données ont été analysé avec l'utilisation de la SPSS version 20.0. Résultat: Quatre-vingt huit(36%) mâles et 150(64%) femelles des patients avec la DM ont été évalué. Leurs âges (écart-type) [ET]) moyenne était 53.5±12.3 ans avec une moyenne (ET) et avec une durée de DM de 7.9±6.2 ans. La moyenne et pauvre contrôle du glycémie respectivement. Les complications majeur observé était les périphériques neuropathie(61%) et malvoyants(51%). Le contrôle glycémie était sensiblement mieux parmi les mâles et avec ceux de bonnes médications. Il y avait une association positive entre une longue durée de la DM avec complication. Conclusion: Seul 20% de nos patients ont obtenu un bon contrôle de glycémie et d'autre avec beaucoup de complications. La majorité des patients se sont adhérent plus avec la médication comparer à la gestion diététique et exercice. Il y a la nécessité des clinicien d'instruire ou éduquer les patients plus suis la mode de vie de modification.


Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Glycated Hemoglobin/analysis , Adult , Aged , Cross-Sectional Studies , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Male , Middle Aged , Nigeria/epidemiology , Risk Factors , Young Adult
12.
Sci Rep ; 11(1): 1806, 2021 01 19.
Article in English | MEDLINE | ID: mdl-33469047

ABSTRACT

This study investigates the removal of Pb(II) using polymer matrix membranes, cellulose acetate/vinyl triethoxysilane modified graphene oxide and gum Arabic (GuA) membranes. These complexation-NF membranes were successfully synthesized via dissolution casting method for better transport phenomenon. The varied concentrations of GuA were induced in the polymer matrix membrane. The prepared membranes M-GuA2-M-GuA10 were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, atomic force microscope and bio-fouling studies. Thermal stability of the membranes was determined by thermogravimetric analysis under nitrogen atmosphere. Dead end nanofiltration was carried out to study the perm- selectivity of all the membranes under varied pressure and concentration of Pb(NO3)2. The complexation-NF membrane performances were significantly improved after the addition of GuA in the polymer matrix membrane system. M-GuA8 membrane showed optimum result of permeation flux 8.6 l m-2 h-1. Rejection of Pb(II) ions was observed to be around 97.6% at pH 9 for all the membranes due to electrostatic interaction between CA and Gum Arabic. Moreover, with the passage of time, the rate of adsorption was also increased up to 15.7 mg g-1 until steady state was attained. Gum Arabic modified CA membranes can open up new possibilities in enhancing the permeability, hydrophilicity and anti-fouling properties.

13.
Int J Tuberc Lung Dis ; 24(7): 665-673, 2020 07 01.
Article in English | MEDLINE | ID: mdl-32718398

ABSTRACT

BACKGROUND: Systematic screening for TB using automated chest radiography (ACR) with computer-aided detection software (CAD4TB) has been implemented at scale in Karachi, Pakistan. Despite evidence supporting the use of ACR as a pre-screen prior to Xpert® MTB/RIF diagnostic testing in presumptive TB patients, there has been no data published on its use in mass screening in real-world settings.METHOD: Screening was undertaken using mobile digital X-ray vehicles at hospital facilities and community camps. Chest X-rays were offered to individuals aged ≥15 years, regardless of symptoms. Those with a CAD4TB score of ≥70 were offered Xpert testing. The association between Xpert positivity and CAD4TB scores was examined using data collected between 1 January and 30 June 2018 using a custom-built data collection tool.RESULTS: Of the 127 062 individuals screened, 97.2% had a valid CAD4TB score; 11 184 (9.1%) individuals had a CAD4TB score ≥70. Prevalence of Xpert positivity rose from 0.7% in the <50 category to 23.5% in the >90 category. The strong linear association between CAD4TB score and Xpert positivity was found in both community and hospital settings.CONCLUSION: The strong association between CAD4TB scores and Xpert positivity provide evidence that an ACR-based pre-screening performs well when implemented at scale in a high-burden setting.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Pulmonary , Tuberculosis , Aged , Humans , Mass Screening , Pakistan/epidemiology , Radiography , Sensitivity and Specificity , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Tuberculosis, Pulmonary/diagnostic imaging , Tuberculosis, Pulmonary/epidemiology
14.
Article in English | MEDLINE | ID: mdl-32266172

ABSTRACT

Mycobacterium kansasii is an important opportunistic pathogen of humans and has a close phylogenetic relationship with Mycobacterium tuberculosis. Seven subtypes (I-VII) have been identified using molecular biology approaches, of which subtype I is the most frequent causative agent of human disease. To investigate the genotypes and pathogenic components of M. kansasii, we sequenced and compared the complete base-perfect genomes of different M. kansasii subtypes. Our findings support the proposition that M. kansasii "subtypes" I-VI, whose assemblies are currently available, should be considered as different species. Furthermore, we identified the exclusive presence of the espACD operon in M. kansasii subtype I, and we confirmed its role in the pathogenicity of M. kansasii in a cell infection model. The espACD operon is exclusively present in mycobacterial species that induce phagosomal rupture in host phagocytes and is known to be a major determinant of ESX1-mediated virulence in pathogenic mycobacteria. Comparative transcriptome analysis of the M. kansasii I-V strains identified genes potentially associated with virulence. Using a comparative genomics approach, we designed primers for PCR genotyping of M. kansasii subtypes I-V and tested their efficacy using clinically relevant strains of M. kansasii.


Subject(s)
Mycobacterium Infections, Nontuberculous , Mycobacterium kansasii , Gene Expression Profiling , Genomics , Humans , Mycobacterium kansasii/genetics , Phylogeny , Transcriptome , Virulence
15.
Stem Cell Reports ; 14(1): 60-74, 2020 01 14.
Article in English | MEDLINE | ID: mdl-31902705

ABSTRACT

In mammals, LINE-1 (L1) retrotransposons constitute between 15% and 20% of the genome. Although only a few copies have retained the ability to retrotranspose, evidence in brain and differentiating pluripotent cells indicates that L1 retrotransposition occurs and creates mosaics in normal somatic tissues. The function of de novo insertions remains to be understood. The transdifferentiation of mouse embryonic fibroblasts to dopaminergic neuronal fate provides a suitable model for studying L1 dynamics in a defined genomic and unaltered epigenomic background. We found that L1 elements are specifically re-expressed and mobilized during the initial stages of reprogramming and that their insertions into specific acceptor loci coincides with higher chromatin accessibility and creation of new transcribed units. Those events accompany the maturation of neuronal committed cells. We conclude that L1 retrotransposition is a non-random process correlating with chromatin opening and lncRNA production that accompanies direct somatic cell reprogramming.


Subject(s)
Cell Transdifferentiation/genetics , Dopaminergic Neurons/cytology , Dopaminergic Neurons/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Long Interspersed Nucleotide Elements , Animals , Biomarkers , Cell Culture Techniques , Cell Line , Computational Biology/methods , Fluorescent Antibody Technique , Gene Expression Profiling , Gene Expression Regulation, Developmental , Genome , Mice , Retroelements , Whole Genome Sequencing
16.
Infect Genet Evol ; 75: 103948, 2019 11.
Article in English | MEDLINE | ID: mdl-31276801

ABSTRACT

Recurrent tuberculosis (TB) after successful TB treatment occurs due to endogenous reactivation (relapse) or exogenous reinfection. We revisited the conclusions of relapse in a high TB incidence setting that were drawn on the basis of IS6110 restriction fragment length polymorphism (RFLP) analysis in a large retrospective cohort study in suburban Cape Town, South Africa. Using whole genome sequencing (WGS), we undertook pair-wise genome comparison of Mycobacterium tuberculosis strains cultured from diagnostic sputum samples collected at the index and recurrent TB episode for 25 recurrent TB cases who had been classified as relapse based on identical DNA fingerprint patterns in the earlier study. We found that paired strain genome sequences were identical or showed minimal variant differences in 22 of 25 recurrent TB cases, consistent with relapse. One showed 20 variant differences, suggestive of exogenous reinfection. Two of the 25 had mixed infections, each with the index episode strain detected as the dominant strain at recurrence in one of these patients, the minority strain harboured drug-resistance conferring mutations (rpoB, katG). In conclusion, our study highlights the additional value of WGS for investigating recurrent TB in settings with high infection pressure and closely related circulating strains, where the extent of re- and mixed infection may be underestimated.


Subject(s)
DNA Fingerprinting/methods , Tuberculosis/genetics , Whole Genome Sequencing/methods , Adult , Cohort Studies , Drug Resistance, Bacterial/genetics , Female , Humans , Male , Middle Aged , Recurrence
17.
PLoS One ; 14(1): e0211003, 2019.
Article in English | MEDLINE | ID: mdl-30673778

ABSTRACT

The mycobacterial type VII secretion system ESX-1 is responsible for the secretion of a number of proteins that play important roles during host infection. The regulation of the expression of secreted proteins is often essential to establish successful infection. Using transcriptome sequencing, we found that the abrogation of ESX-1 function in Mycobacterium marinum leads to a pronounced increase in gene expression levels of the espA operon during the infection of macrophages. In addition, the disruption of ESX-1-mediated protein secretion also leads to a specific down-regulation of the ESX-1 substrates, but not of the structural components of this system, during growth in culture medium. This effect is observed in both M. marinum and M. tuberculosis. We established that down-regulation of ESX-1 substrates is the result of a regulatory process that is influenced by the putative transcriptional regulator whib6, which is located adjacent to the esx-1 locus. In addition, the overexpression of the ESX-1-associated PE35/PPE68 protein pair resulted in a significantly increased secretion of the ESX-1 substrate EsxA, demonstrating a functional link between these proteins. Taken together, these data show that WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates and that ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion.


Subject(s)
Antigens, Bacterial , Bacterial Proteins , Down-Regulation , Gene Expression Regulation, Bacterial , Mycobacterium marinum , Mycobacterium tuberculosis , Transcriptome , Antigens, Bacterial/genetics , Antigens, Bacterial/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Humans , Mutation , Mycobacterium marinum/genetics , Mycobacterium marinum/metabolism , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , THP-1 Cells
18.
Case Rep Genet ; 2019: 1398250, 2019.
Article in English | MEDLINE | ID: mdl-31976094

ABSTRACT

We present two half siblings with significant short stature who proved a diagnostic challenge for several years. Radiological findings included subtle epiphyseal changes. The diagnosis was made through whole genome sequencing via the 100,000 genome project. A maternally inherited pathogenic heterozygous CDKN1C variant was found in the PCNA (proliferating cell nuclear antigen) domain. Mutations of the PCNA domain of the CDKN1C gene are known to be associated with IMAGe syndrome thus with adrenal disease, although neither affected patient in our case had evidence of adrenal dysfunction. This report supports the previously reported findings of Russell-Silver syndrome (RSS) like phenotype caused by this unusual mechanism (CDKN1C mutations in the PCNA domain), highlights subtle radiological features not described previously and the phenotypic variability between two affected siblings. Additionally it reminds clinicians of the importance of considering associated adrenal disease/diabetes mellitus for variants within the PCNA domain. Finally it confirms RSS-like disorders should be considered in patients who have epiphyseal or metaphyseal changes and short stature, since CDKN1C PCNA domain mutations can result in this phenotype.

19.
Malays Orthop J ; 12(2): 15-19, 2018 Jul.
Article in English | MEDLINE | ID: mdl-30112123

ABSTRACT

Introduction: Non-operative management has successfully been practised for long in diaphyseal fractures of both bones of the leg. This study attempts to establish an acceptability criteria for plaster cast in order to predict future loss of reduction and its adequacy. Materials and Methods: A total of forty subjects were included as per inclusion-exclusion criteria. Gap and cast indices were calculated in the immediate post reduction phase and at third week follow-up visit. Results: The mean values of gap and cast indices in the immediate post-reduction phase were 0.35±0.220 and 0.99±0.08 respectively and at the third week follow-up the mean value for both the parameters in those without loss of reduction were 1.11±0.50 and 1.03±0.09 respectively and in those with loss of reduction were 0.84±0.44 and 1.01±0.06 respectively. Conclusion: Gap and cast indices are not informative in assessing adequacy of reduction in diaphyseal fractures of both bones of the leg.

20.
Article in English | WPRIM (Western Pacific) | ID: wpr-756918

ABSTRACT

@#Introduction: Non-operative management has successfully been practised for long in diaphyseal fractures of both bones of the leg. This study attempts to establish an acceptability criteria for plaster cast in order to predict future loss of reduction and its adequacy. Materials and Methods: A total of forty subjects were included as per inclusion-exclusion criteria. Gap and cast indices were calculated in the immediate post reduction phase and at third week follow-up visit. Results: The mean values of gap and cast indices in the immediate post-reduction phase were 0.35±0.220 and 0.99±0.08 respectively and at the third week follow-up the mean value for both the parameters in those without loss of reduction were 1.11±0.50 and 1.03±0.09 respectively and in those with loss of reduction were 0.84±0.44 and 1.01±0.06 respectively. Conclusion: Gap and cast indices are not informative in assessing adequacy of reduction in diaphyseal fractures of both bones of the leg.

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