Project description:There is currently no convenient way to effectively evaluate whether a miliary tuberculosis patient is complicated with central nervous system (CNS) tuberculosis. We aimed to find such a way by analyzing the clinical data of these patients. Fifty patients with confirmed miliary tuberculosis and 31 patients with confirmed miliary tuberculosis complicated with CNS tuberculosis from 2010 to 2014 were selected. Their general conditions, clinical features and laboratory tests were analyzed. Factors that were significantly different between them were chosen to performed multivariate and univariate logistic regression analyses, and factors with significant P values were used to establish a scoring system. Eight factors, i.e., age, cough, nausea, headache, hemoglobin (HGB), serum albumin (ALB), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were significantly different (P < 0.05). Multivariate logistic regression analysis showed that ALB was the independent risk predictor (HR = 1.29, 95% CI 1.09-1.52, P < 0.01), whereas the others were non-independent predictors except age (P < 0.05). The scoring system was based on a summation of the scores of the assigned values of the seven predictors and had an area under the curve (AUC) of 0.86 to confirm CNS tuberculosis, with a sensitivity of 81.5% and a specificity of 81.4% at a score of 0.75 and with a specificity of 95.3% at a score of 2.75. In contrast, a score below -0.75 excluded CNS tuberculosis, with a sensitivity of 88.9% and a specificity of 62.7%. The scoring system should be useful to evaluate whether a miliary tuberculosis patient is complicated with CNS tuberculosis and could help doctors avoid excessive investigation.
Project description:Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis.
Project description:BACKGROUND:Central nervous system disease is the most serious form of tuberculosis, and is associated with high mortality and severe neurological sequelae. Though recent clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with central nervous system disease, the microbial virulence factors required have not been described previously. RESULTS:We screened 398 unique M. tuberculosis mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found M. tuberculosis pknD (Rv0931c) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that pknD is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. M. tuberculosis pknD encodes a "eukaryotic-like" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the M. tuberculosis PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum. CONCLUSIONS:Our findings demonstrate a novel in vivo role for M. tuberculosis pknD and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children.
Project description:This study aimed to define the genes associated with PCNSL patient survival. Expression profiling was performed on 34 PCNSLs. A gene classifier was developed. Thirty-four PCNSL patients were selected for RNA extraction and hybridization on Affymetrix microarrays.
Project description:BACKGROUND:Ocular morbidity associated with systemic tuberculosis is common. The clinical picture varies from anterior uveitis, intermediate uveitis and posterior uveitis to even panuveitis. There is little data on the correlation between specific systemic presentations and the ocular inflammation. We conducted a retrospective review of the ocular findings in the case records of patients admitted with a diagnosis of miliary tuberculosis. These patients were then referred for a more detailed ophthalmic evaluation. METHODS:We analysed the case records of patients with a clinical diagnosis of miliary tuberculosis over a 10-year period at Lilavati Hospital and Research Center, Mumbai. RESULTS:In total, 11 immunocompetent patients were identified. All 22 eyes showed normal findings on slit lamp examination. Dilated fundus examination showed single or multiple tubercles. In our cohort, the ocular findings were exclusively in the form of choroidal tuberculosis, either unilaterally or bilaterally. Slit lamp examination revealed no anterior segment inflammation Conclusions: We suggest that this pattern of choroidal/retinal tuberculosis in the absence of anterior and intermediate segment inflammation is specific for miliary tuberculosis and may be related to a specific immune response.
Project description:Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.
Project description:Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis-immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.
Project description:This study aimed to define the genes associated with PCNSL patient survival. Expression profiling was performed on 34 PCNSLs. A gene classifier was developed.
Project description:ObjectiveCentral nervous system tuberculosis is the most serious form of extrapulmonary tuberculosis. We aim to discover potential biomarkers involved in the development of the disease.MethodsThrough gene difference analysis, construction of a protein interaction network and tissue specific analysis and other bioinformatics analysis methods, we found out the relatively high expression of important substances in the central nervous system, interferon induced protein with tetratricopeptide repeats 1. Subsequently, the lesion tissue and the resection margin tissue away from the lesion were collected from the 6 cases of central nervous system tuberculosis patients diagnosed from 2019 to 2020, and the pathological manifestations were observed by Hematoxylin and Eosin (H&E) staining, and the expression of IFIT1 was verified by immunohistochemistry.ResultsA total of 101 differential genes were analyzed between extrapulmonary tuberculosis patients and normal people, and they were mainly enriched in the interferon pathway. The protein interaction network unearthed 34 key genes. Through tissue specific analysis, it was found that IFIT1 is relatively high in the central nervous system. H&E staining showed the expression of multinucleated macrophages, and immunohistochemistry showed that IFIT1 was significantly positively expressed in the lesion tissue.ConclusionIFIT1 is an important substance involved in central nervous system tuberculosis.