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Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4⁺ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4⁺ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.

Cerebrovascular complications of central nervous system tuberculosis (TB) are predictors of poor prognosis and adverse outcomes. These complications are mainly intracranial arterial involvement, with occasional venous involvement. Here, we present a 67-year-old woman with concurrent cerebral infarction and intracranial tuberculoma induced by the carotid plaque complicated by miliary tuberculosis. Mycobacterium tuberculosis was observed on the luminal side of the carotid plaques in pathological specimens. Treatment with anti-TB drugs alone would likely not cure the patient, as M. tuberculosis would continue to disseminate. Endarterectomy could directly remove the embolic source, and a complete cure was achieved.

Intracranial tuberculomas are infrequent with a lower morbidity and mortality compared to tubercular meningitis. Giant intracranial tuberculomas are rarer but important differentials for intracranial space-occupying lesions causing focal neurological deficits depending on anatomical location and size. Histopathologically confirmed giant intracranial tuberculomas selected based on institutional size criteria (<12 Years-old: ≥25 mm; 12–18 Years-old: ≥35 mm; ≥18 Years-old: ≥40 mm) were retrospectively reviewed and analyzed for clinical features, radiology, surgical management, and outcomes in patients admitted from 2015 to 2022. Ten patients were included (Males:Females = 3:7; Age: 8–68 Years, Average: 30.1 Years). Mean duration of symptoms was 2.84 months. Two patients demonstrated active systemic tuberculosis. Previous tubercular infections included pulmonary involvement in four, meningeal in three, and a cerebellar tuberculoma in one patient. Cerebrospinal fluid analysis in five patients demonstrated no tubercle bacilli. Seven lesions were supratentorial and three infratentorial. Giant tuberculomas demonstrated profound T2 hypointensity, sub-marginal T2 hyperintense crescents, and significant perilesional vasogenic edema. Craniotomy and excision were mainstay except in one case treated only with ventriculoperitoneal shunting. Three additional patients underwent ventriculoperitoneal shunting for hydrocephalus. One patient died from aspiration pneumonia and sepsis following a postoperative seizure. Anti-Tubercular Therapy (ATT) was advised for 18 months. Follow up ranged from 4 to 18 months. One patient was medically managed for ATT-induced hepatitis, hepatic encephalopathy, and coincidental paradoxical reaction. Remainder of patients showed complete resolution of symptomatology and absence of new symptoms till latest follow up. Clinical course of giant tuberculomas differ from non-giant variants in characteristic radiology, more intensive ATT, and possibility for partial debulking/excision. •Giant tuberculomas can constitute ∼50% of Neurosurgical tuberculoma presentations.•“Giantness” of tuberculomas may not enhance sensitivity of CSF tubercular detection.•Profound T2 hypointensity & submarginal crescent hyperintensity are characteristic.•Excision forms mainstay followed by 18 months of Anti-Tubercular Therapy (ATT).•Partial excision & ATT can engender clinical resolution with giant tuberculomas.

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis -infected mice at cellular resolution. Colocalizing transcript networks at <10 μm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis . Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression ( Foxp3 , Il10 ), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined. Granulomas are a hallmark and focus of infective and immunological processes during infection with Mycobacterium tuberculosis . Here, Carow and colleagues show distinct spatial and temporal arrangement of immunological transcripts in tuberculosis granulomas.

Background Isolated brainstem tuberculomas are rare lesions and account for up to 5% of all intracranial tuberculomas in endemic areas. The difficulties in diagnosis and management of this condition are sparsely reported. The aim of this study is to illustrate the nuances in managing brainstem tuberculomas, define prognosis, and demonstrate a shift in management strategies with newer imaging modalities. Method A retrospective review of 14 patients diagnosed and treated with a diagnosis of ‘isolated brainstem tuberculoma’ between 2011 and 2015 was done. Diagnosis was made after combining the findings at clinical history, examination, as well as imaging features. Patients were treated with steroids for 6 weeks or until they made a meaningful clinical recovery, and antitubercular therapy (ATT) for a minimum of 18 months or until there was resolution of the tuberculoma. Confirmation of tubercular pathology was done by observing if response to treatment resulted in clinical improvement, which happened in all of our cases. Results Mean age at diagnosis was 24.7 years and nine were males. Twelve patients had a combination of cranial nerve deficits with pyramidal weakness or sensory symptoms. Mean duration of symptoms was 4.7 months and tests for human immunodeficiency virus (HIV) infection were negative in all patients. Only two patients had a previous history of tubercular meningitis. Most lesions were located in the pons with size ranging from 1 to 22.2 cm 3 . Eight patients showed complete resolution of the lesion at latest follow-up and the rest were still on ATT. Mean duration of ATT received for resolution of the lesion was 22 months. Almost all of our patients improved clinically on steroids and ATT. Conclusions Intracranial tuberculomas may present with or without meningitis. A high index of suspicion is essential, especially in endemic areas. A combination of clinical symptoms, investigations, and imaging features help in coming to a diagnosis. Biopsy of a brainstem lesion is fraught with complications. Antitubercular therapy has a very good prognosis, though the duration of therapy required may be longer.

Adjunctive dexamethasone increases survival from tuberculous meningitis, but the underlying mechanism is unclear. We aimed to determine the effect of dexamethasone on cerebral MRI changes and their association with intracerebral inflammatory responses and clinical outcome in adults treated for tuberculous meningitis. Cerebral MRI was undertaken, when possible, at diagnosis and after 60 days and 270 days of treatment in adults with tuberculous meningitis admitted to two hospitals in Vietnam. Patients were randomly assigned either dexamethasone (n=24) or placebo (n=19) and received 9 months of treatment with standard first-line antituberculosis drugs. We assessed associations between MRI findings, treatment allocation, and resolution of fever, coma, cerebrospinal fluid inflammation, and neurological outcome. 83 scans were done for 43 patients: 19 given placebo, 24 given dexamethasone. Basal meningeal enhancement (82%) and hydrocephalus (77%) were the most common presenting findings. Fewer patients had hydrocephalus after 60 days of treatment with dexamethasone than after placebo treatment (p=0·217). Tuberculomas developed in 74% of patients during treatment and in equal proportions in the treatment groups; they were associated with long-term fever, but not relapse or poor clinical outcome. The basal ganglia were the most common site of infarction; the proportion with infarction after 60 days was halved in the dexamethasone group (27% vs 58%, p=0·130). Dexamethasone may affect outcome from tuberculous meningitis by reducing hydrocephalus and preventing infarction. The effect may have been under-estimated because the most severe patients could not be scanned.

PurposeTo investigate the clinical features and treatment outcomes of patients with choroidal tuberculoma.MethodsIn this retrospective, observational case series, the medical records of five patients with choroidal tuberculoma who were followed up at a university hospital for at least 6 months were analyzed.ResultsOf five patients, one was male and four were female. The overall mean age was 38.0 ± 9.4 years (mean follow-up: 41.2 ± 33.8 months). Tuberculin skin test was performed in three patients, and it was positive in two of them. Interferon-gamma assay was performed in two patients and was positive in all two. Three patients had systemic tuberculosis involving the lung or other organs. Five patients were treated with antitubercular therapy for a period of 9.6 ± 8.6 months. Systemic corticosteroid treatment was performed in 3 patients, with a period of 3.5 ± 0.7 months. One patient with a recurrent vascularized tuberculoma was successfully treated with single intravitreal bevacizumab injection.ConclusionChoroidal tuberculoma can develop without evidence of systemic tuberculosis and can recur despite antitubercular treatment. High index of suspicion is important in early detection, and management of choroidal tuberculoma. In cases of suspected choroidal tuberculoma, positive results on immunological tests would be sufficient to initiate antitubercular therapy even if radiological evidence of systemic tuberculosis is not found. Antitubercular therapy combined with systemic corticosteroids provided favorable results. Intravitreal injection of anti-vascular endothelial growth factor may be considered for highly vascularized choroidal tuberculoma.

Tuberculomas are the conglomeration of tuberculous granulomas into structurally organized three-dimensional (3D) masses that result from Mycobacterium tuberculosis infection and represent one of the more severe morphological forms of tuberculosis (TB). Several in vitro models that mimic human TB granulomas have been reported to decipher complex host-pathogen interactions and to discover new prophylactic and therapeutic interventions. They serve as ethical bridge approaches to human studies. However, these models need improvements in generating well-organized granuloma lesions, classic tuberculoma structures, and relevant microenvironments. They are impractical for screening extensive chemical and genetic libraries owing to their low throughput, limited scalability, batch-to-batch variability, and high costs. Here, we describe a ‘mycobacteria-in-spheroid’ co-culture workflow in a standard 96-well plate format that generates a robust 3D cell culture model. This model reproduces key attributes and microenvironments in human tuberculomas and can be scaled up as a high-throughput screening (HTS)-compatible bioplatform. The tuberculoma-like structures generated encompass organized, florid granulomatous foci and exhibit solid, necrotic, and cavitary morphologies. This model can be developed using freshly isolated human primary cells or a monocytic cell line with virulent mycobacteria. The platform combines the entire workflow, from generation to imaging of tuberculoma-like structures, in situ . It permits the serial quantitation of drug efficacy and monitoring of lesion resolution over several days to weeks following a single treatment. Additionally, we outline a methodology for adopting this workflow for cryo-preservation, enhancing its potential for commercial application. The ease of generation, pliability, cryo-shelf stability, and reproducibility of the bioplatform make it ideal for HTS applications and for implementation in discovery programs for TB and other granulomatous diseases.

Tuberculoma of medulla oblongata is a rare manifestation of central nervous system tuberculosis (CNS TB), which may manifest as intractable singultus as the initial symptom. It is almost impossible to obtain definite diagnosis through biopsy consider its location. Immediate thorough diagnostic workup is needed, and empirical treatment should be started. We report a case of medulla oblongata tuberculoma in an HIV-negative 38-year-old man with intractable singultus as one of the early symptoms. He was treated empirically with anti-tuberculosis therapy and his symptoms subsided within 2 weeks. •Tuberculoma of medulla oblongata is a rare manifestation of CNS TB.•Intractable singultus as the initial symptom of medulla oblongata tuberculoma.•Immediate diagnostic workup is needed and empirical treatment should be started.

Background Tuberculomas are prevalent in developing countries and demonstrate variable signals on MRI resulting in the overlap of the conventional imaging phenotype with other entities including glioma and brain metastasis. An accurate MRI diagnosis is important for the early institution of anti-tubercular therapy, decreased patient morbidity, mortality, and prevents unnecessary neurosurgical excision. This study aims to assess the potential of radiomics features of regular contrast images including T1W, T2W, T2W FLAIR, T1W post contrast images, and ADC maps, to differentiate between tuberculomas, high-grade-gliomas and metastasis, the commonest intra parenchymal mass lesions encountered in the clinical practice. Methods This retrospective study includes 185 subjects. Images were resampled, co-registered, skull-stripped, and zscore-normalized. Automated lesion segmentation was performed followed by radiomics feature extraction, train-test split, and features reduction. All machine learning algorithms that natively support multiclass classification were trained and assessed on features extracted from individual modalities as well as combined modalities. Model explainability of the best performing model was calculated using the summary plot obtained by SHAP values. Results Extra tree classifier trained on the features from ADC maps was the best classifier for the discrimination of tuberculoma from high-grade-glioma and metastasis with AUC-score of 0.96, accuracy-score of 0.923, Brier-score of 0.23. Conclusion This study demonstrates that radiomics features are effective in discriminating between tuberculoma, metastasis, and high-grade-glioma with notable accuracy and AUC scores. Features extracted from the ADC maps surfaced as the most robust predictors of the target variable.