Analysis of ADAR gene variant in a Chinese pedigree affected with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical features and genetic basis for a Chinese pedigree affected with hereditary dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#Peripheral blood samples of the proband and his mother were collected and subjected to PCR and Sanger sequencing.@*RESULTS@#The patient has conformed to the typical pattern of DSH and manifested with hyperpigmentation, hypo- and hyperpigmentation spots on the back of hands, feet and face. Sanger sequencing confirmed that the proband and his mother have both harbored heterozygous splicing variant c.2762+1G>T in exon 9 of the ADAR gene, which was unreported previously. The same variant was not detected among 100 healthy controls. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP4).@*CONCLUSION@#The c.2762+1G>T variant of the ADAR gene probably underlay the DSH in this pedigree. Above finding has enriched the spectrum of ADAR gene mutations.

Analysis of a Chinese pedigree affected with dyschromatosis symmetrica hereditaria due to a novel variant of ADAR gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#PCR and Sanger sequencing were carried out for the proband, and suspected variant was validated by Sanger sequencing in the pedigree.@*RESULTS@#The proband was found to harbor a novel variant of c.1352delA (p.N451Mfs*13) of the ADAR (NM_001111) gene. The same variant was found in her affected mother and sister, but not in her unaffected father, uncle, and 100 healthy individual.@*CONCLUSION@#The novel variant of the ADAR gene probably underlay the pathogenesis of DSH in this pedigree.

CRISPR-mediated base editing in mice using cytosine deaminase base editor 4

BACKGROUND: Many human genetic diseases arise from point mutations. These genetic diseases can theoretically be corrected through gene therapy. However, gene therapy in clinical application is still far from mature. Nearly half of the pathogenic single-nucleotide polymorphisms (SNPs) are caused by G:C>A:T or T:A>C:G base changes and the ideal approaches to correct these mutations are base editing. These CRISPR-Cas9-mediated base editing does not leave any footprint in genome and does not require donor DNA sequences for homologous recombination. These base editing methods have been successfully applied to cultured mammalian cells with high precision and efficiency, but BE4 has not been confirmed in mice. Animal models are important for dissecting pathogenic mechanism of human genetic diseases and testing of base correction efficacy in vivo. Cytidine base editor BE4 is a newly developed version of cytidine base editing system that converts cytidine (C) to uridine (U). RESULTS: In this study, BE4 system was tested in cells to inactivate GFP gene and in mice to introduce single-base substitution that would lead to a stop codon in tyrosinase gene. High percentage albino coat-colored mice were obtained from black coat-colored donor zygotes after pronuclei microinjection. Sequencing results showed that expected base changes were obtained with high precision and efficiency (56.25%). There are no off-targeting events identified in predicted potential off-target sites. CONCLUSIONS: Results confirm BE4 system can work in vivo with high precision and efficacy, and has great potentials in clinic to repair human genetic mutations.

Role of cancer ratio and other new parameters in the differential diagnosis of malignant pleural effusion

OBJECTIVES: We compared the diagnostic potential of cancer ratio (CR, serum lactate dehydrogenase [LDH]/pleural fluid adenosine deaminase [pfADA]), cancer ratio plus (CR plus, cancer ratio/pleural lymphocyte percentage), and age/pfADA ratio with pfADA in malignant pleural effusion. METHODS: Data from 100 patients with malignant pleural effusion (MPE) and 119 patients with tuberculous pleural effusion (TPE) were retrospectively collected. PfADA, age/pfADA ratio, CR, and CR plus were compared between patients with MPE and those with TPE in two age groups (≤50 and >50 years). The best cut-off value was determined, and the diagnostic performance was evaluated according to the receiver operating characteristic curve. RESULTS: PfADA was statistically significantly lower while age/pfADA ratio, CR, and CR plus were significantly higher in the MPE group than in the TPE group in both age groups (p<0.05). For patients aged ≤50 years, the differential diagnostic value of pfADA for MPE was better than those of age/pfADA ratio, CR, and CR plus. At a cut-off value of 13.0 U/L, the sensitivity, specificity, and accuracy were 88.9%, 100.0%, and 98.9%, respectively. For patients aged >50 years, the diagnostic performance of CR plus was superior to those of pfADA, age/pfADA ratio, and CR. At a cut-off value of 22.6, the sensitivity, specificity, and accuracy of CR plus for the diagnosis of MPE were 86.8%, 84.6%, and 86.2%, respectively. CONCLUSIONS: The best parameter for diagnosing MPE was different for patients aged ≤50 years and >50 years. For patients aged >50 years, CR plus was a good parameter for the differential diagnosis of MPE. For patients aged ≤50 years, pfADA was better.

Performance of the quantification of adenosine deaminase and determination of the lactate dehydrogenase/adenosine deaminase ratio for the diagnosis of pleural tuberculosis in children and adolescents / Desempenho da quantificação de adenosina desaminase e determinação da relação lactato desidrogenase/adenosina desaminase para o diagnóstico de tuberculose pleural em crianças e adolescentes

ABSTRACT Objective: To evaluate the accuracy of determining the adenosine deaminase (ADA) level, the 2'-deoxyadenosine/ADA ratio, and the LDH/ADA ratio in pleural fluid for the diagnosis of pleural tuberculosis (PT) in children and adolescents. Methods: This was a retrospective cross-sectional study conducted at a tertiary hospital in a high-tuberculosis-incidence area, between 2001 and 2018. All patients with ADA in pleural fluid and a confirmed diagnosis of PT (cPT) or parapneumonic effusion (PPE) were included. Results: The cPT and PPE groups comprised 25 and 68 individuals, respectively. At a cutoff of 40 U/L, ADA measurement showed the following: sensitivity, 88%; specificity, 31%; positive predictive value (PPV), 32%; negative predictive value (NPV), 88%; and overall accuracy, 46%. The best cutoffs were an ADA level of 125 U/L, a 2'-deoxyadenosine/ADA ratio of 0.5, and an LDH/ADA ratio of 8.3, with AUC of 0.67, 0.75, and 0.82, respectively. The sensitivity, specificity, PPV, NPV, and overall accuracy of the 125 U/L ADA cutoff were 84%, 65%, 47%, 92%, and 70%, respectively, compared with 79%, 79%, 59%, 91%, and 79%, respectively, for the 8.3 LDH/ADA ratio cutoff. Changing the LDH/ADA ratio cutoff to 3.0 increased the specificity to 98%. Conclusions: The ADA level and the 2'-deoxyadenosine/ADA ratio are not good biomarkers for the diagnosis of PT in pediatric patients. Determination of the LDH/ADA ratio provides the best overall accuracy for the diagnosis of PT in such patients.

RESUMO Objetivo: Avaliar a acurácia da determinação do nível de adenosina desaminase (ADA), da relação 2'-desoxiadenosina/ADA e da relação LDH/ADA no líquido pleural para o diagnóstico de tuberculose pleural (TP) em crianças e adolescentes. Métodos: Estudo transversal retrospectivo realizado em um hospital terciário em uma área de alta incidência de tuberculose entre 2001 e 2018. Todos os pacientes com determinação de ADA no líquido pleural e com diagnóstico confirmado de TP (TPc) ou de derrame parapneumônico (DPP) foram incluídos. Resultados: Os grupos TPc e DPP foram compostos por 25 e 68 indivíduos, respectivamente. Num ponto de corte de 40 U/L, a medida de ADA mostrou o seguinte: sensibilidade, 88%; especificidade, 31%; valor preditivo positivo (VPP), 32%; valor preditivo negativo (VPN), 88%; e acurácia geral, 46%. Os melhores pontos de corte foram ADA de 125 U/L, relação 2'-desoxiadenosina/ADA de 0,5 e relação LDH/ADA de 8,3, com ASC de 0,67, 0,75 e 0,82, respectivamente. A sensibilidade, especificidade, VPP, VPN e acurácia geral do ponto de corte de 125 U/L para ADA foram de 84%, 65%, 47%, 92% e 70%, respectivamente, em comparação com 79%, 79%, 59%, 91% e 79%, respectivamente, para o ponto de corte de 8,3 para a relação LDH/ADA. Ao alterar o ponto de corte da relação LDH/ADA para 3,0 a especificidade aumentou para 98%. Conclusões: O nível de ADA e a relação 2'-desoxiadenosina/ADA não são bons biomarcadores para o diagnóstico de PT em pacientes pediátricos. A determinação da relação LDH/ADA fornece a melhor acurácia geral para o diagnóstico de PT nesses pacientes.

Biochemical characterization of adenosine deaminase (CD26 EC 3. 5. 4. 4) activity in human lymphocyte-rich peripheral blood mononuclear cells

The conversion of adenosine to inosine is catalyzed by adenosine deaminase (ADA) (EC 3.5.4.4), which has two isoforms in humans (ADA1 and ADA2) and belongs to the zinc-dependent hydrolase family. ADA modulates lymphocyte function and differentiation, and regulates inflammatory and immune responses. This study investigated ADA activity in lymphocyte-rich peripheral blood mononuclear cells (PBMCs) in the absence of disease. The viability of lymphocyte-rich PBMCs isolated from humans and kept in 0.9% saline solution at 4-8°C was analyzed over 20 h. The incubation time and biochemical properties of the enzyme, such as its Michaelis-Menten constant (Km) and maximum velocity (Vmax), were characterized through the liberation of ammonia from the adenosine substrate. Additionally, the presence of ADA protein on the lymphocyte surface was determined by flow cytometry using an anti-CD26 monoclonal human antibody, and the PBMCs showed long-term viability after 20 h. The ADA enzymatic activity was linear from 15 to 120 min of incubation, from 2.5 to 12.5 µg of protein, and pH 6.0 to 7.4. The Km and Vmax values were 0.103±0.051 mM and 0.025±0.001 nmol NH3·mg-1·s-1, respectively. Zinc and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) inhibited enzymatic activity, and substrate preference was given to adenosine over 2′-deoxyadenosine and guanosine. The present study provides the biochemical characterization of ADA in human lymphocyte-rich PBMCs, and indicates the appropriate conditions for enzyme activity quantification.

The Auxiliary Diagnostic Value of Serum Adenosine Deaminase in Acute Leukemia at Clinical Test / 中国实验血液学杂志

OBJECTIVE@#To investigate the auxiliary diagnostic value of serum adenosine deaminase (ADA) in acute leukemia (AL) at clinical test.@*METHODS@#123 AL patients hospitalized in Zhejiang hospital from November 2018 to March 2020 were enrolled as the observation group, and 98 healthy people in the same period were randomly enrolled as the control group. AL patients were divided into two groups: 77 acute myeloid leukemia (AML) patients for AML group and 46 acute lymphoblastic leukemia (ALL) patients for ALL group. The levels of adenosine deaminase (ADA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and homocysteine (Hcy) in serum of the patients were detected, and the correlation of ADA with these items was analyzed. Receiver operating characteristic curve (ROC) was used to analyze the clinical diagnostic value of ADA, Yoden index was used to confirm the best cut-off point.@*RESULTS@#The serum ADA level in AL patients was significant higher than that in control group (P < 0.05). The results of Pearson correlation analysis showed that there was a significant positive correlation of ADA with Hcy, ALT, AST, GGT, LDH in AML group (r = 0.47, r = 0.28, r = 0.37, r = 0.22, r = 0.55); and also there was a significant positive correlation of ADA with GGT in ALL group (r = 0.54). In AML group, the maximum area under ROC curve was 0.761 (P = 0.00), 95% confidence interval was 0.682-0.841, sensitivity was 54.50%, specificity was 98.90%, and the best cut-off point was 17.1 U/L. In ALL group, the maximum area under ROC curve was 0.785, 95% confidence interval was 0.694-0.877, sensitivity was 65.90%, specificity was 84.00%, and the best cut-off point was 13.45 U/L.@*CONCLUSION@#The detection of ADA in serum can be used as an auxiliary examination in patients with AL, which can provide a certain value for the diagnosis of the disease.

Analysis of ADAR1 gene variants in two pedigrees affected with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

OBJECTIVE@#To detect variants of ADAR1 gene in two Chinese pedigrees affected with dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#Clinical data and peripheral blood samples of the pedigrees were collected. All exons of the ADAR1 gene were amplified by PCR and subjected to Sanger sequencing. Suspected pathogenic variants were validated among other members of the pedigrees and 100 unrelated healthy controls.@*RESULTS@#For pedigree 1, Sanger sequencing has identified a heterozygous missense variant c.3002G>C (p.Asp968His) in exon 11 of the ADAR1 gene in the proband and his father. For pedigree 2, a novel nonsense variant c.3145C>T (p.Gln1049Ter) was identified in exon 12 of the ADAR1 gene in the proband and his son, which were previously unreported and absent among the healthy controls.@*CONCLUSION@#The c.3002G>C (p.Asp968His) and c.3145C>T (p.Gln1049Ter)variants of the ADAR1 gene probably underlay the DSH in the two pedigrees.

Analysis of ADAR gene mutations in two pedigrees affected with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

OBJECTIVE@#To detect mutations of ADAR gene in two pedigrees affected with dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#Potential mutations of the ADAR gene were analyzed by Sanger sequencing of the probands from both pedigrees. Suspected mutations were validated by Sanger sequencing of other patients from both pedigrees as well as unrelated healthy individuals.@*RESULTS@#A heterozygous nonsense mutation c.1325C>G (p.Ser442Ter) and a novel nonsense mutation c.1498C>T (p.Gln500Ter) were respectively identified in the ADAR gene among all patients from the two pedigrees but not among 200 healthy individuals.@*CONCLUSION@#Mutations of the ADAR gene probably underlie the DSH in the two pedigrees. Above findings have enriched the spectrum of ADAR gene mutation.

Identification of a novel c.2633_2634del CT variant of the ADAR gene in a patient with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of two unrelated patients with dyschromatosis symmetrica hereditaria.@*METHODS@#Variant analysis of the ADAR gene was carried out by Sanger sequencing.@*RESULTS@#Patient 1 was found to harbor a c.2633_2634delCT (p.Ser878fs) in exon 8 of the ADAR gene. The same variant was not found among 100 unrelated individuals. No pathogenic variant of the ADAR gene was found in patient 2. Functional prediction of the ADAR c.2633_2634delCT (p.Ser878fs) variant indicated it to be pathogenic by losing a catalytic structural domain.@*CONCLUSION@#The c.2633_2634delCT (p.Ser878fs) variant of the ADAR gene probably underlies the pathogenesis of DSH in one of the patients.

Evolution of potential biomarkers of acute muscle injury after physical exercise

Skeletal muscle injury is a frequent event and diagnosis using the classical blood markers sometimes produces unsatisfactory results. Therefore, objective of the study was to detect new biomarkers in plasma, saliva and urine in response to acute muscle damage induced by physical exercise. A cross-sectional study was conducted with 27 American football players. Before the physical exercises (T0), 60 minutes (T1) and 24 hours (T2) after physical exercise, was determined the clinical, biochemical and molecular parameters, including ADA, TBARS, leukocytes, lymphocytes and comet assay. The serum ADA was significantly higher in T1 and T2, in the urine there was a significant increase in T1, in the saliva there was no significant differences. There was an increase in serum TBARS in T2, saliva and urine in T1. The leukocytes increased in T1 and decreased in T2. Through the comet assay was observed significant DNA damage in T1 and T2. Serum and urinary ADA activity, serum, urinary and salivary TBARS are robust and promising biomarkers of acute muscle injury and that the comet assay allows a quick and effective evaluation of DNA lesions induced by physical exercise and could be used to monitor athletes avoiding injuries that are more serious.

Tuberculosis abdominal: patología infrecuente en un paciente joven: reporte de un caso / Abdominal tuberculosis: an unusual disease in a young patient: a case report

Resumen Introducción: La tuberculosis abdominal es un problema reemergente, y es una de las enfermedades transmisibles más importante en todo el mundo. A pesar de las expectativas acerca de su erradicación en países en desarrollo, ha sido recientemente declarada de nuevo como una patología de emergencia mundial. Con el aumento de su incidencia y prevalencia, su forma abdominal es una de las presentaciones de afectación extrapulmonar más comunes. Objetivo: Dado que la tuberculosis puede afectar diversos órganos, tiene una amplia gama y gran espectro de signos y síntomas que dificultan su diagnóstico y retrasan el tratamiento. Por esto, se realiza esta revisión de tema, concentrándonos en que el alto índice de sospecha debe ser un factor importante en el diagnóstico precoz, para que una vez establecido, se pueda iniciar el tratamiento ayudando a prevenir y disminuir las altas tasas de morbilidad y mortalidad evidenciadas en la actualidad. Caso Clínico: Paciente joven con presencia de ascitis secundaria a tuberculosis abdominal confirmada por una biopsia y el aumento de la adenosin deaminasa en el líquido peritoneal. Se describen los principales hallazgos clínicos, paraclínicos, estudios imagenológicos y tratamiento.

Introduction: Abdominal tuberculosis is a reemerging problem and is one of the most important communicable diseases in the world. Despite expectations about the eradication in developing countries, it has recently been re-declared as a global emergency pathology. The increased incidence and prevalence shows an abdominal shape as one of the most common extrapulmonary involvement presentations. Objective: Since tuberculosis can affect various organs, it has a wide range and spectrum of signs and symptoms that make diagnosis difficult and delay treatment. Therefore, this review of the topic is done, concentrating on the fact that the high suspicion index should be an important factor in the early diagnosis. Treatment can be initiated helping to prevent and reduce high morbidity and mortality rates. Case Report: We present a case of a young patient with ascites secondary to abdominal tuberculosis confirmed by biopsy and increased adenosine deaminase in the peritoneal fluid. The main clinical findings, paraclinic, imaging studies and treatment are described.

Tuberculosis pleural en paciente pediátrico: reporte de un caso y revisión de la literatura / Pleural tuberculosis in a pediatric patient: case report and review

Tuberculosis (TB) is a common cause of pleural effusion in young people from endemic areas. Among the forms of extrapulmonary TB in people with immunodeficiencies, the most frequent localization is the pleura. The use of immunological and molecular biology tests for the diagnosis of TB in pleural fluid and other locations with high sensitivity and specificity is highlighted. We present a clinical case with the objective of giving an overview of the treatment of the patient with suspected pleural tuberculosis

La Tuberculosis (TB) es una causa común de derrame pleural en jóvenes en zonas endémicas. Dentro de las formas de TB extrapulmonar en personas que cursan con inmunodeficiencias, la localización más frecuente es la TB pleural. Se destaca el uso de las pruebas inmunológicas y de biología molecular para el diagnóstico de TB en líquido pleural y de otras localizaciones con una elevada sensibilidad y especificidad. Se presenta un caso clínico con el objetivo de describir una visión general del abordaje del paciente con sospecha de tuberculosis pleural

ADAR1-mediated RNA-editing of 3'UTRs in breast cancer

BACKGROUND: Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA ( ADAR ) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed. RESULTS: We characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3'UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3'UTRs. Interestingly, editing was particularly increased in the 3'UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1). CONCLUSIONS: Altogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.

Biological roles of adenosine deaminase acting on RNA and their relationship with human diseases / 中南大学学报(医学版)

RNA editing, especially A-to-I RNA editing, is a common post-transcriptional modification in mammals. Adenosine deaminase acting on RNA (ADAR) is a key protein for A-to-I editing, which converts the adenosine group of a double-stranded RNA to creatinine group by deaminating it, resulting in a change of nucleotide sequence. There are 3 types of ADARs (ADAR1, ADAR2, ADAR3) that have been found in recent years. The abnormalities of ADARs are closely related to many human diseases such as viral infections, metabolic diseases, nervous system diseases, and tumors.

Acerca de la tuberculosis extrapulmonar / On extrapulmonary tuberculosis

La tuberculosis es una enfermedad infecciosa de gran prevalencia en países en vía de desarrollo como el nuestro. Aunque el compromiso pulmonar es el más frecuente y de impacto en la salud pública, existen varias formas extrapulmonares con diversas presentaciones clínicas y de difícil diagnóstico, recalcando la importancia de sospechar estas patologías para intervenciones oportunas y que impacten en la morbimortalidad. En este artículo se presentan cuatro casos clínicos donde se sospechó tuberculosis extrapulmonar (pericárdica, peritoneal, pleural y meníngea) en el Hospital de San José de Bogotá, describiendo la forma en que se realizó o se descartó la tuberculosis extrapulmonar y haciendo una breve descripción del rendimiento de diferentes pruebas diagnósticas.

Tuberculosis (TB) is an infectious disease with high-prevalence in developing countries as ours. Although pulmonary involvement is most common and is associated with greater impact on public health, there are various forms of extrapulmonary TB (EPTB) exhibiting various often difficult to diagnose clinical presentations, highlighting the importance of suspecting these pathologies in order to conduct timely interventions that impact their morbidity and mortality rates. This article presents four clinical cases at San José Hospital in Bogotá where EPTB disease was suspected (pericardium, peritoneum, pleura and meninges), describing the way EPTB disease was diagnosed or ruled out and briefly defining the diagnostic performance of various tests.

Qualitative and Quantitative Comparison of Contrast-Enhanced Fluid-Attenuated Inversion Recovery, Magnetization Transfer Spin Echo, and Fat-Saturation T1-Weighted Sequences in Infectious Meningitis

OBJECTIVE: To compare the contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR), the CE T1-weighted (CE-T1W) sequence with fat suppression (FS) and magnetization transfer (MT) for early detection and characterization of infectious meningitis. MATERIALS AND METHODS: Fifty patients and 10 control subjects were evaluated with the CE-FLAIR and the CE-T1W sequences with FS and MT. Qualitative assessment was done by two observers for presence and grading of abnormal leptomeningeal enhancement. Quantitative assessment included computation of net meningeal enhancement, using single pixel signal intensity software. A newly devised FLAIR based scoring system, based on certain imaging features including ventricular dilatation, ependymal enhancement, infarcts and subdural effusions was used to indicate the etiology. Data were analysed using the Student's t test, Cohen's Kappa coefficient, Pearson's correlation coefficient, the intraclass correlation coefficient, one way analysis of variance, and Fisher's exact test with Bonferroni correction as the post hoc test. RESULTS: The CE-FLAIR sequence demonstrated a better sensitivity (100%), diagnostic accuracy (95%), and a stronger correlation with the cerebrospinal fluid, total leukocyte count (r = 0.75), protein (r = 0.77), adenosine deaminase (r = 0.81) and blood glucose (r = -0.6) values compared to the CE-T1W sequences. Qualitative grades and quantitative meningeal enhancement on the CE-FLAIR sequence were also significantly greater than those on the other sequences. The FLAIR based scoring system yielded a diagnostic accuracy of 91.6% and a sensitivity of 96%. A strong inverse Pearson's correlation (r = -0.95) was found between the assigned score and patient's Glasgow Coma Scale at the time of admission. CONCLUSION: The CE-FLAIR sequence is better suited for evaluating infectious meningitis and could be included as a part of the routine MR imaging protocol.

Tuberculous Meningitis-Mimicking Varicella-Zoster Meningitis

BACKGROUND: Varicella-zoster virus (VZV) is one of the most common etiologies of aseptic meningitis. The severest manifestation of VZV meningitis is occasionally confused with tuberculous meningitis (TBM). Thus, we investigated the clinical manifestations of VZV meningitis as compared with those of TBM. MATERIALS AND METHODS: All adult patients who were diagnosed with VZV meningitis or TBM were enrolled at a tertiary hospital in Seoul, South Korea, during an 8-year period. The clinical characteristics and cerebrospinal fluid (CSF) profile of patients were analyzed. RESULTS: Seventy-nine patients with VZV meningitis and 24 patients with TBM were enrolled in this study. Of the 79 patients with VZV meningitis, 63 (80%) did not received empirical anti-tuberculous therapy (Group 1) and the remaining 16 (20%) received empirical anti-tuberculous therapy (Group 2), compared with 24 patients with TBM (Group 3). Altered mental status, intensive care unit (ICU) admission, neurologic sequelae, CSF protein levels, and CSF adenosine deaminase levels revealed a trend of being higher in Group 3 than Group 2, which was higher than Group 1. However, the CSF/serum glucose ratio was significantly lower in Group 3 than in Group 1 or Group 2. CONCLUSION: About one fifth of VZV meningitis cases presented as severe manifestations, mimicking TBM. The CSF/serum glucose ratio might be useful to differentiate VZV meningitis from TBM until definite diagnostic tests are available. Physicians should keep in mind that a differential diagnosis between severe VZV meningitis and TBM is needed.

Identification of Diverse Adenosine-to-Inosine RNA Editing Subtypes in Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: RNA editing generates protein diversity by altering RNA sequences in coding regions without changing the overall DNA sequence. Adenosine-to-inosine (A-to-I) RNA editing events have recently been reported in some types of cancer, but they are rare in human colorectal cancer (CRC). Therefore, this study was conducted to identify diverse RNA editing in CRC. MATERIALS AND METHODS: We compared transcriptome data of 39 CRC samples and paired adjacent tissues from The Cancer Genome Atlas database to identify RNA editing patterns in CRC, focusing on canonical A-to-I RNA edits in coding sequence regions. We investigated nonsynonymous RNA editing patterns by comparing tumor and normal tissue transcriptome data. RESULTS: The number of RNA edits varied from 12 to 42 per sample. We also observed that hypoand hyper-RNA editing patterns were distinguishable within the samples. We found 10 recurrent nonsynonymous RNA editing candidates in nine genes (PDLIM, NEIL1, SRP9, GLI1, APMAP, IGFBP7, ZNF358, COPA, and ZNF587B) and validated some by Sanger sequencing and the inosine chemical erasing assay. We further showed that editing at these positions was performed by the adenosine deaminase acting on RNA 1 enzyme. Most of these genes are hypoedited in CRC, but editing of GLI1 was increased in cancer tissues compared with normal tissues. CONCLUSION: Our results show that nonsynonymous RNA editing patterns can be used to identify CRC patients and could serve as novel biomarkers for CRC.

Mycobacterium tuberculosis ESAT6 and CPF10 Induce Adenosine Deaminase 2 mRNA Expression in Monocyte-Derived Macrophages / 결핵및호흡기질환

BACKGROUND: Delayed hypersensitivity plays a large role in the pathogenesis of tuberculous pleural effusion (TPE). Macrophages infected with live Mycobacterium tuberculosis (MTB) increase the levels of adenosine deaminase2 (ADA2) in the pleural fluid of TPE patients. However, it is as yet unclear whether ADA2 can be produced by macrophages when challenged with MTB antigens alone. This study therefore evaluated the levels of ADA2 mRNA expression, using monocyte-derived macrophages (MDMs) stimulated with MTB antigens. METHODS: Purified monocytes from the peripheral blood mononuclear cells of healthy volunteers were differentiated into macrophages using granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). The MDMs were stimulated with early secretory antigenic target protein 6 (ESAT6) and culture filtrate protein 10 (CFP10). The mRNA expression levels for the cat eye syndrome chromosome region, candidate 1 (CECR1) gene encoding ADA2 were then measured. RESULTS: CECR1 mRNA expression levels were significantly higher in MDMs stimulated with ESAT6 and CFP10, than in the unstimulated MDMs. When stimulated with ESAT6, M-CSF-treated MDMs showed more pronounced CECR1 mRNA expression than GM-CSF-treated MDMs. Interferon-γ decreased the ESAT6- and CFP10-induced CECR1 mRNA expression in MDMs. CECR1 mRNA expression levels were positively correlated with mRNA expression of tumor necrosis factor α and interleukin 10, respectively. CONCLUSION: ADA2 mRNA expression increased when MDMs were stimulated with MTB antigens alone. This partly indicates that pleural fluid ADA levels could increase in patients with culture-negative TPE. Our results may be helpful in improving the understanding of TPE pathogenesis.