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Tuberculous meningitis (TBM) has a high mortality, possibly due to suboptimal therapy. Drug exposure data of antituberculosis agents in the central nervous system (CNS) are required to develop more effective regimens. Rifabutin is a rifamycin equivalently potent to rifampin in human pulmonary tuberculosis. Here, we show that human-equivalent doses of rifabutin achieved potentially therapeutic exposure in relevant CNS tissues in a rabbit model of TBM, supporting further evaluation in clinical trials.
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Modelos Animales de Enfermedad , Rifabutina , Tuberculosis Meníngea , Animales , Conejos , Rifabutina/uso terapéutico , Rifabutina/farmacología , Tuberculosis Meníngea/tratamiento farmacológico , Sistema Nervioso Central/efectos de los fármacos , Antituberculosos/uso terapéutico , Antituberculosos/farmacología , Rifampin/uso terapéutico , Rifampin/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Antibióticos Antituberculosos/uso terapéutico , Antibióticos Antituberculosos/farmacologíaRESUMEN
Background: To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in people with human immunodeficiency virus type 1 (HIV-1) with latent TB infection (LTBI), pulmonary TB (PTB), or PCTB. Methods: Using Luminex, we measured the concentration of 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB participants. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mycobacterium tuberculosis-specific CD4 T cells was measured in baseline samples using flow cytometry. Results: Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (25/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to that observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusions: Our results show that the inflammatory profile in blood was comparable between PTB and PCTB. However, at the site of infection (PCF), inflammation was significantly elevated compared to blood. Additionally, our data emphasize the potential role of HLA-DR expression as a biomarker for TB diagnosis.
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[This corrects the article DOI: 10.3389/fimmu.2022.1009016.].
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Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-α producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFNγ, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1ß production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtb-specific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB.
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Mycobacterium tuberculosis , Tuberculosis Ganglionar , Humanos , Linfocitos T CD4-Positivos , Interleucina-2/metabolismo , FenotipoRESUMEN
Intracranial schwannoma accounts for between 5 and 8% of intracranial tumors, whereas intracerebral schwannoma, a rare disease, accounts for <1% of intracranial schwannomas. In addition to the present case report, a total of 84 cases reported within China and elsewhere were reviewed and summarized, and the age of the tumor onset, the site of disease, imaging results, clinical presentation, pathological classification and prognosis were analyzed. The present case report described a 12-year-old female with an intracerebral schwannoma in the brainstem, who was followed-up for 5 years using magnetic resonance imaging after a surgical resection without recurrence, and clinical symptoms were reported to have completely resolved. The incidence of intracerebral schwannoma was low among cases, and the correct diagnosis was not able to be made preoperatively, and the majority of cases were diagnosed on the basis of postoperative pathology. The majority of cases analyzed were supratentorial, occurring at an age ≤40 according to previous literature. In addition, 33% of patients presented with subtentorial schwannoma, occurring at an age >40. The prognosis was classified as good (patient can live independently) for the majority of patients if surgery was able to completely resect the lesion.
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OBJECTIVE: We evaluated the clinical outcome and prognostic factors for post-relapse survival (PRS) in a large retrospective series of ovarian cancer patients with localized relapse. PATIENTS AND METHODS: The following radiological inclusion criteria were adopted: relapse in single anatomic site and ≤ 3 nodules. All cases were followed for at least 24 months after recurrent disease. RESULTS: Two hundred twenty ovarian cancer patients met the inclusion criteria. Serous histotype and G3 tumors were observed in 173 (78.6%) and 151 (77.4%) cases, respectively. All women received platinum-based first-line chemotherapy. Overall, the median follow-up was 46 (8-249) months, and platinum-resistant relapse was documented in 51 women (23.2%). Eighty-one patients (36.8%) recurred in the peritoneum (LPeR), 76 patients (34.5%) in the abdominal lymph nodes (LLNR), and 63 patients (28.7%) in parenchymal organs (LPaR); 142 patients (64.5%) recurred with a single nodule; and 78 patients (35.5%) recurred with 2-3 nodules. Secondary cytoreductive surgery (SCS) was attempted in 73 cases (33.2%), and complete debulking was achieved in all patients. On multivariate analysis, platinum-free interval (PFI, χ(2)=13.457, p value=0.001), complete SCS (median PRS, 69 months vs 25 months, p=0.001), anatomic site of relapse (median PRS, 41months in LPeRs, 63 months in LLNRs and 24 months in LPaRs, p=0.001), and number of nodules (median PRS, 58months in patients with one nodule, 24months in patients with 2-3 nodules, p=0.001) were identified as predictors of PRS. CONCLUSIONS: Beside the duration of PFI, the complete SCS, the anatomic site of relapse, and the number of nodules were independent prognostic factor for duration of PRS.