BACKGROUND

Tracheobronchomalacia (TBM) refers to a condition in which structural integrity of cartilaginous wall of trachea is lost. Excessive dynamic airway collapse (EDAC) is characterized by excessive invagination of posterior wall of trachea. In both these conditions, airway lumen gets compromised, especially during expiration, which can lead to symptoms such as breathlessness, cough, and wheezing. Both these conditions can be present in obstructive lung diseases; TBM due to chronic airway inflammation and EDAC due to dynamic compressive forces during expiration. The present study was planned with the hypothesis that TBM/EDAC could also produce expiratory wheeze in patients with obstructive airway disorders. Hence, prevalence and factors affecting presence of this entity in patients with obstructive airway diseases were the aims and objectives of this study.

METHODS

Twenty-five patients with obstructive airway disorders (chronic obstructive pulmonary disease [COPD] or bronchial asthma), who were stable on medical management, but having persistent expiratory wheezing, were included in the study. They were evaluated for TBM/EDAC by bronchoscopy and computed tomographic scan of chest. The presence of TBM/EDAC was correlated with variables including age, sex, body mass index (BMI), smoking index, level of dyspnea, and severity of disease.

RESULTS

Mean age of the patients was 62.7 ± 7.81 years. Out of 25 patients, 14 were males. TBM/EDAC was found in 40% of study subjects. Age, sex, BMI, severity of disease, frequency of exacerbations and radiological findings etc., were not found to have any association with presence of TBM/EDAC.

CONCLUSIONS

TBM/EDAC is common in patients with obstructive airway disorders and should be evaluated in these patients, especially with persistent expiratory wheezing as diagnosis of this entity could provide another treatment option in these patients with persistent symptoms despite medical management.

OBJECTIVE

Tuberculous meningitis (TBM) frequently is complicated by hydrocephalus and cerebral infarction. Previous studies have shown radiologic evidence of cerebral infarction in TBM to be an indicator of poor outcome in both adults and children. Our objective was to assess short-term mortality in adult patients with TBM and hydrocephalus treated with an external ventricular drain and to assess the prognostic value of cerebral infarction on admission computed tomography imaging within this cohort.

METHODS

This was a retrospective case series based on an adult intensive care unit admissions database, analyzing demographic, clinical, diagnostic, and radiologic data against short-term mortality.

RESULTS

A total of 25 patients managed from 2005 to 2011 were identified. Three patients were excluded. Mean age was 31 years. British Medical Research Council clinical severity grading was grade I in 9.1%, grade II in 31.8%, and grade III in 59.1%. Short-term mortality was 68.2% overall. Cerebral infarction on admission scanning was seen in 10 patients (45.5%). Prevalence of infarcts was not significantly higher in HIV-positive patients (50.0% vs. 42.9%). Mortality in the group with infarcts was 100%, compared with 41.7% in the group without infarcts. Mortality in patients with an admission Glasgow Coma Scale of 8 or less was 91.7%. Mortality in the HIV-positive group was slightly greater, but this increase did not reach statistical significance (71.4% vs. 57.1% P = 0.6). Univariate analysis showed presence of infarcts at admission, Glasgow Coma Scale ≤8 at admission and age of 30 years or more to be significantly related to mortality. There was also a statistically significantly increased mortality according to British Medical Research Council grade.

CONCLUSIONS

TBM with hydrocephalus requiring cerebrospinal diversion carries a significant short-term mortality. Within this cohort, the group of patients who have computed tomography-evident cerebral infarcts at admission has an even worse outcome, with a significantly greater short-term mortality prevalence.

Tuberculosis is prevalent in China, which is the second greatest contributor to the global tuberculosis burden. Tuberculosis meningitis (TBM) is the most severe disease form but few reports describe long-term clinical outcomes and prognostic factors. Thus, we studied these features in Chinese TBM patients.

A retrospective follow-up study was used to collect clinical features and outcomes of adult TB meningitis at the First Affiliated Hospital of Chongqing Medical University from June 2012 to August 2015. Univariate analysis and multivariate analysis were used to identify predictive factors associated with outcomes at discharge and follow-up.

TBM patients (N = 154) were a median age of 41 years (range: 16-82 years). Median time to follow-up was 26.4 months (range: 9.3-46.5 months) and 31% had poor outcomes at follow-up and limb weakness (p = 0.016), lower GCS scores (p < 0.001), cranial-nerve palsy (p = 0.024), and hydrocephalus (p = 0.009) were closely associated with these poor outcomes. Furthermore, a high neutrophil to lymphocytes ratio, high D-dimer, a low albumin to globulin ratio and slow background of EEG associated with poor outcomes as well.

Mortality and disability associated with TBM are high in China. Limb weakness, GCS scores, cranial-nerve palsy and hydrocephalus were independent predictors of poor outcomes, and AGR, NLR, D-dimer, and EEG abnormalities may be prognostic factors of TBM.

OBJECTIVE

There is paucity of information about the outcome of tuberculous meningitis (TBM) patients on mechanical ventilation (MV). In this communication, we report the clinical characteristics, predictors of MV, and outcome of TBM patients requiring MV.

METHODS

Thirty-eight (18%) of 205 patients with TBM requiring MV were included; and their demographic, clinical, cerebrospinal fluid, and magnetic resonance imaging finding at admission and follow-up were noted. The ventilator-related and systemic complications, hospital death, and 3-month functional outcome were noted. The predictors of need of MV were derived by multivariate regression analysis.

RESULTS

There were 38 MV and 36 non-MV TBM patients who were matched for age, sex, and stage of meningitis on admission. The requirement of MV was independently related to leukocytosis, seizure, and cerebrospinal fluid pleocytosis on admission. Patients on MV had higher frequency of septicemia (9 vs 2), bedsores (6 vs 0), and gastric hemorrhage (4 vs 0) compared with non-MV patients. Only 29% of MV patients survived and had poor outcome at 3 months; but in the non-MV group, all the patients survived, and only 11% had poor outcome.

CONCLUSIONS

Mechanical ventilation was needed in 18% TBM patients because of TBM-related or systemic complications. Those requiring MV had high mortality and may be categorized separately.

Mild Cognitive Impairment (MCI) is a transitional stage between normal age-related cognitive decline and Alzheimer's disease (AD). Here we introduce a hyperbolic space sparse coding method to predict impending decline of MCI patients to dementia using surface measures of ventricular enlargement. First, we compute diffeomorphic mappings between ventricular surfaces using a canonical hyperbolic parameter space with consistent boundary conditions and surface tensor-based morphometry is computed to measure local surface deformations. Second, ring-shaped patches of TBM features are selected according to the geometric structure of the hyperbolic parameter space to initialize a dictionary. Sparse coding is then applied on the patch features to learn sparse codes and update the dictionary. Finally, we adopt max-pooling to reduce the feature dimensions and apply Adaboost to predict AD in MCI patients (N = 133) from the Alzheimer's Disease Neuroimaging Initiative baseline dataset. Our work achieved an accuracy rate of 96.7% and outperformed some other morphometry measures. The hyperbolic space sparse coding method may offer a more sensitive tool to study AD and its early symptom.

Ethnopharmacological relevance: Tubeimoside I (TBM) is a triterpenoid saponin purified from tubeimu (tuber of Bolbostemma paniculatum (Maxim.) Franquet). In traditional Chinese medicine, tubeimu had been used to treat acute mastitis, snake bites, detoxication, inflammatory diseases, and tumors for over 1000 years.

Aim of the study: This study aimed to investigate whether TBM could promote angiogenesis and how to promote angiogenesis.

Materials and methods: In vivo, the pro-angiogenic effects of TBM were examined using the hindlimb ischemia model. After the ischemia operation, 1 mg/kg/day TBM was given via intraperitoneal injection for 28 days and the recovery of blood flow was monitored by Doppler scanner every 7 days. The capillary density in gastrocnemius muscle was detected by immunofluorescence. Expression of related proteins were determined by western blotting. In vitro, the pro-angiogenic effects of TBM on HUVECs were examined by Cell Counting Kit-8, scratch assay, endothelial cell tube formation assay and western blotting.

Results: TBM improved recovery from hindlimb ischemia in C57BL/6 mice. TBM promoted endothelial cell viability, migration and tube formation in HUVECs. TBM could activate eNOS-VEGF signaling pathway by enhancing expression of eNOS. And TBM's pro-angiogenesis effects could be abolished by L-NAME (an inhibitor of eNOS).

Conclusions: TBM promoted angiogenesis via the activation of eNOS-VEGF signaling pathway and TBM could be a novel agent for therapeutic angiogenesis in ischemic diseases.

Keywords: Tubeimoside I; angiogenesis; endothelial nitric oxide synthase; endothelium; vascular endothelial growth factor.

BACKGROUND

Tuberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis infection. Our aim was to analyze the epidemiology, clinical features, diagnostic approach, and outcome of tuberculous meningitis in childhood.

METHODS

During a 25-y period (1984-2008), 43 children, aged 7 months to 13 y, were hospitalized in the Paediatric Department of the referral centre for infectious diseases in Thessaloniki, Greece with the diagnosis of TBM. The patients were classified according to the clinical findings on admission as per the UK Medical Research Council (MRC) staging: stage I, 16/43 (37.2%) children; stage II, 16/43 (37.2%); and stage III 11/43 (25.6%).

RESULTS

Twenty-seven of the 43 patients were Greek (63%) and none had been BCG-vaccinated. A family history of tuberculosis was identified in 18 cases (42%). 35 patients (81%) had a positive tuberculin skin test. An extrameningeal site of infection was identified in 14 children (33%); pulmonary tuberculosis in 14/43 patients (5/13 miliary tuberculosis) and spondylitis in 1. All patients were treated with anti-tuberculous drugs and 36 (84%) also received corticosteroids. Complications during hospitalization (coma, seizures, cranial nerve palsy, hydrocephalus) presented in 26 patients (60%). Two patients died (5%) and 6 (14%) had permanent neurological sequelae.

CONCLUSIONS

TBM, although rare, remains a disease with significant morbidity and mortality. Early clinical diagnosis and appropriate treatment initiation are important for the prognosis.

Metastatic triple-negative breast cancer (TNBC) has poor outcome with conventional chemotherapy regimens due to its aggressive behavior. The acquisition of anoikis resistance, a programmed cell death process triggered by substratum detachment, is an important mechanism in TNBC metastasis. Therefore, agents that can restore the sensitivity of cancer cells to anoikis may be helpful for the treatment of metastatic TNBC. In this study, we investigated the inhibitory effect of Tubeimosides V (TBMS-V), a cyclic bisdesmoside isolated from the ethanol extracts of tubers of B. paniculatum., on anoikis resistance and the involvement of caveolin-1(CAV-1)-related signaling pathways in such process in MDA-MB-231 cells. The results showed that the treatment of TBMS-V could sensitize cancer cells to anoikis, which was associated with suppression of anchorage-independent culture-induced CAV-1 overexpression, EGFR activation as well as ITGB1-FAK activation. The data from this study might contribute to providing a potential therapeutic target for metastatic TNBC and suggest the possibility of TBMS-V and its derivatives for metastatic TNBC therapy.

UNASSIGNED

Both stroke and cerebral salt wasting (CSW) are common in tuberculous meningitis (TBM), but there is paucity of studies evaluating their combined effect.

UNASSIGNED

The present study has been undertaken to evaluate the spectrum of stroke in TBM and its relation to CSW.

UNASSIGNED

Hospital-based prospective cohort study.

UNASSIGNED

Eighty-one patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid and magnetic resonance imaging (MRI) criteria were prospectively included. Stroke was diagnosed on the basis of clinical, MRI findings or both. Stroke risk factors were noted. Patients with hyponatremia were categorized into CSW and other causes. Three and 6 months outcome was defined using modified Rankin Scale (mRS) as good (<2) or poor (≥2).

UNASSIGNED

Out of 81 patients with TBM, 32 (39.5%) had ischemic stroke. CSW was the commonest cause of hyponatremia and occurred in 34 (42%) patients. Stroke occurred in tubercular zone in 10, ischemic zone in 15 and both in 7 patients. The patients with ischemic zone infarction were older and had stroke risk factors such as diabetes mellitus, hypertension and hyperlipidemia. Out of 16 (47%) patients with CSW, 10 (62.5%) had stroke during the polyuric phase. The patients with CSW had more frequent deep white matter infarcts (P = 0.01) which were in internal border zone in 4 (40%).

UNASSIGNED

In TBM, stroke occurred in 39.5% of the patients, 50% of whom had CSW. Volume contraction due to CSW may contribute to stroke.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children. Methods: We collected serum samples from children in whom TBM was suspected at a tertiary hospital in Cape Town, South Africa. Children were subsequently classified as having TBM or no TBM using a published uniform research case-definition. Using a multiplex cytokine array platform, we investigated the concentrations of serum biomarkers comprising biomarkers that were previously found to be of value in the diagnosis of adult pulmonary TB (CRP, SAA, CFH, IFN-γ, IP-10, Apo-AI, and transthyretin) plus other potentially useful host biomarkers as diagnostic candidates for TBM. Findings: Out of 47 children included in the study, 23 (48.9%) had a final diagnosis of TBM and six were HIV infected. A modified version of the adult 7-marker biosignature in which transthyretin was replaced by NCAM1, diagnosed TBM in children with AUC of 0.80 (95% CI, 0.67-0.92), sensitivity of 73.9% (95% CI, 51.6-89.8%) and specificity of 66.7% (95% CI, 44.7-84.4%), with the other six proteins in the signature (CRP, IFN-γ, IP-10, CFH, Apo-A1, and SAA) only achieving and AUC of 0.75 (95% CI, 0.61-0.90) when used in combination. A new childhood TBM specific 3-marker biosignature (adipsin, Aβ42, and IL-10) showed potential in the diagnosis of TBM, with AUC of 0.84 (95% CI, 0.73-0.96), sensitivity of 82.6% (95 CI, 61.2-95.0%) and specificity of 75.0% (95% CI, 53.3-90.2%) after leave-one-out cross validation. Conclusion: A previously described adult 7-marker serum protein biosignature showed potential in the diagnosis of TBM in children. However, a smaller childhood TBM-specific 3-marker signature demonstrated improved performance characteristics. Our data indicates that blood-based biomarkers may be useful in the diagnosis of childhood TBM and requires further validation in larger cohort studies.

OBJECTIVE

To report atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels in patients with tuberculous meningitis (TBM) and acute encephalitis syndrome (AES), and evaluate their relationship with hyponatraemia.

METHODS

Consecutive patients with TBM and AES were included in the study. Hyponatraemia was categorised as cerebral salt wasting (CSW), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and a miscellaneous group based on clinical and laboratory criteria. Serum ANP and BNP levels were measured upon hospital admission, at the time of diagnosis of hyponatraemia and upon correction of hyponatraemia. Outcome at 3 months was assessed using the modified Rankin scale (mRS) as good (mRS 2) and poor (mRS >2).

RESULTS

There were 67 patients with TBM and 77 with AES. Hyponatraemia was more common in TBM than in AES (65.7% vs. 27%, P < 0.01). Forty-one (63.1%) patients had CSW, 6 (9.2%) SIADH and 18 (27.7%) had miscellaneous causes of hyponatraemia. During hyponatraemia, ANP (180 ± 45 vs. 106 ± 32 pg/ml, P < 0.01) and BNP (263 ± 118 vs. 163 ± 91 pg/ml, P  0.01) levels were significantly increased compared with baseline, and remained high even after Na+ correction.

CONCLUSIONS

ANP and BNP levels were increased during hyponatraemia and remained high even after correction of hyponatraemia in TBM and AES, especially in patients with CSW. However, ANP and BNP levels could not be used to differentiate CSW from SIADH.

Unlike in pulmonary multidrug-resistant (MDR) tuberculosis, the clinical outcome of MDR tuberculous meningitis (TBM) in children, including extensively drug-resistant tuberculosis, is poor and management is challenging. We report the successful treatment of a case of extensively drug-resistant TBM in a 4-year-old girl, and we discuss implications for tuberculosis diagnosis and chemotherapy.

OBJECTIVE

Chemoradiation for the treatment of anal cancer is known to cause significant hematologic toxicity (HT). We sought to investigate if radiation dose to specific pelvic subsites is associated with increased HT risk.

METHODS

Forty-five patients with nonmetastatic anal cancer who received definitive chemoradiation with intensity modulated radiation therapy and concurrent mitomycin-C and 5-fluorouracil were studied. Total pelvic bone marrow (TBM) was divided into 3 subsites: lumbosacral bone marrow (LSBM), including the entire sacrum and L5 vertebral body; iliac bone marrow (IBM) extending from the iliac crests to the superior border of the femoral head; and lower pelvic bone marrow, including the pubic bones, ischia, acetabula, and proximal femurs. The primary endpoint was absolute neutrophil count (ANC) nadir during or within 2 weeks of treatment completion. Generalized linear modeling was used to analyze the correlation between the equivalent uniform dose (with an "a" value of 0.5) to the individual pelvic subsites and the various hematologic endpoints. Age, body mass index, sex, baseline blood counts, and immunosuppression were analyzed as potential covariates.

RESULTS

Mean ± standard deviation ANC nadir was 0.77 × 109/L (±0.66 × 109/L). Grades 3+ and 4+ neutropenia occurred in 71.1% and 44.4% of patients, respectively. In addition to radiation dose to pelvic bone marrow, baseline ANC was the only significant predictor of hematologic toxicity on multivariable analysis and was included in all models. The equivalent uniform doses of TBM, LSBM, and IBM were each significantly associated with neutropenia. The model performance of TBM (adjusted R2 = 0.226) was similar to both LSBM (adjusted R2 = 0.206) and IBM (adjusted R2 = 0.249).

CONCLUSIONS

Radiation doses to TBM, LSBM, and IBM were individually associated with HT, suggesting that sparing just a portion of pelvic bone marrow is insufficient to decrease rates of clinically significant bone marrow suppression.

To improve margin revision, this study characterizes the number, fragmentation, and orientation of tumor bed margins (TBM) in patients with pT1-2 pN0 squamous cell carcinoma (SCC) of the oral tongue.

Pathology reports (n=346) were reviewed. TBM parameters were indexed. In Group 1 patients all margins were obtained from the glossectomy specimen and there were no TBM. In Revision Group/Group 2 (n=103), tumor bed was sampled to revise suboptimal margins identified by examination of the glossectomy specimen. In Group 3 (n=124), TBM were obtained before examination of the glossectomy specimen.

Fewer TBMs were obtained per patient in Group 2 compared to Group 3 (57/103, 55% of patients with <3 vs. 117/124, 94%, ≥3 TBMs, respectively). The new margin surface was more frequently indicated in Group 2 compared to Group 3 (59/103, 57%, vs. 19/124, 15%, p<.001). If glossectomy specimen margins are accepted as the reference standard, then the TBM was 15% sensitive in Group 2 (95% confidence interval [CI], 7-29) and 32% sensitive in Group 3 (95% CI, 15-55). TBM fragmentation (23/103, 22% vs. 42/124, 34%) and frozen vs. permanent discrepancies (8/103, 3% vs. 3/124, 2%) were similar between Groups 2 and 3. The new margin surface was not indicated in 6 of 11 cases with discrepant frozen vs. permanent pathology findings, precluding judgment on final margin status. To facilitate the assessment of final margins, TBM should be represented by one tissue fragment with a marked new margin surface.

OBJECTIVE

The involvement of the central nervous system in the form of meningitis or meningoencephalitis is common in scrub typhus and is an important differential diagnosis of other lymphocytic meningitis like tuberculous meningitis (TBM). The aim of this study was to identify the clinical and laboratory parameters that may be helpful in differentiating scrub typhus meningitis from TBM.

METHODS

We compared of the clinical and laboratory features of 57 patients admitted with scrub typhus meningitis or TBM during a 3-year period. Patients who had abnormal cerebrospinal fluid (CSF) and positive scrub typhus enzyme-linked immunosorbent assay serology (n=28) were included in the scrub typhus meningitis group, while the TBM group included those who satisfied the consensus diagnostic criteria of TBM (n=29).

RESULTS

Compared with the TBM group, the mean duration of symptoms was less in patients with scrub typhus meningitis, who also had a lower magnitude of neurological deficits, such as altered mental status and cranial nerve and motor deficits. Patients with scrub typhus meningitis had a lower CSF white blood-cell count (WBC) than the TBM group (130.8±213 195±175 cells/mm3, P=0.002), lower CSF protein elevation (125±120 vs. 195.2±108.2mg/dl, P=0.002), and higher CSF sugar (70.1±32.4 vs. 48.7±23.4mg/dl, P=0.006). Features predictive of the diagnosis of scrub typhus meningitis included the absence of neurological impairment at presentation, blood serum glutamic-oxaloacetic transaminase>40 international units (IU)/L, serum glutamic-pyruvic transaminase>60 IU/L, total blood leukocyte count>10,000/mm3, CSF protein<100mg/dl, CSF sugar>50mg/dl, CSF WBC<100 cells/mm3. All patients with scrub typhus meningitis recovered completely following doxycycline therapy CONCLUSIONS: This study suggests that, clinical features, including duration of fever, neurological deficits at presentation and laboratory parameters such as CSF pleocytosis,CSF protein elevation, CSF sugar levels and liver enzyme values are helpful in differentiating scrub typhus meningitis from tuberculous meningits. These features with scrub IgM serology may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis.

Tubulointerstitial nephritis antigen (TIN-ag) is an extracellular matrix (ECM) glycoprotein that has been recently isolated and cloned from the rabbit kidney. It is an integral component of the basal lamina, and unlike other basement membrane proteins it is exclusively expressed in the tubular basement membranes (TBMs). Since other ECM glycoproteins have been shown to regulate development of various organ systems, studies were initiated to ascertain its developmental regulation in renal tubulogenesis and glomerulogenesis. Embryonic (day-13 and -17 of gestation), newborn and one-week-old mice kidneys were harvested for expression of TIN-ag as well as cDNA cloning studies. Immunostaining with polyclonal anti-TIN-ag antibody revealed its localization to the basal lamina of ureteric bud branches and epithelial elements of developing nephrons in day-13 embryonic kidneys. Interestingly, it was heavily expressed at the tips of the ureteric bud branches, and was not expressed in the distal convolutions of the S-shaped body stage of the nephrons, the region which forms the future glomerulus. At day-17, TIN-ag expression was less, and the immuno-reactivity was mainly localized to the cortex. In the newborn and one-week-old mice kidneys, the cortical expression of TIN-ag increased progressively, but was absent in the glomeruli. The TIN-ag expression was confined to the cortical TBMs, while absent in the medullary tubules, the latter included segments of the collecting ducts and loop of Henle. Immunoprecipitation studies on [35S]methionine-labeled metanephroi revealed a single band of approximately 58 kDa at day-13, and the incorporated radioactivity decreased at day-17. No high molecular weight isoforms were observed. A partial-length mouse TIN-ag cDNA of approximately 530 bp PCR product was generated, and it had approximately 88% and approximately 93% nucleotide and amino acid sequence homolgy, respectively, with rabbit TIN-ag. Utilizing this cDNA, Northern blot analyses revealed a single transcript of approximately 2 Kb in fetal and postnatal mice kidneys. mRNA expression initially decreased at day-17, and then progressively increased by one week. Utilizing a mouse TIN-ag riboprobe, in situ hybridization studies revealed a generalized diffuse expression of TIN-ag in the epithelial clements of developing nephrons and ureteric bud branches at day-13. Gene expression decreased by day-17, and became confined to the renal cortex, and then progressively increased during the neo- and post-natal periods, but remained absent in the renal medulla and glomeruli. These data indicate that TIN-ag is expressed in the metanephros early in embryonic life in the absence of any detectable isoforms, and it exhibits spatio-temporal characteristics during metanephric development. Being concentrated at the tips of the ureteric bud branches, it is conceivably involved in epithelial:mesenchymal interactions which are highly prevalent during renal organogenesis, and its role in tubulogenesis diverges from glomerulogenesis at the S-shaped body stage of the nephron.

Lactate levels in the cerebrospinal fluid (CSF) were determined in 21 patients with culture-proved tuberculous meningitis (TBM). All patients showed uniformly high lactate level (greater than or equal to 3.9 mmol/l). Neither the clinical stage of TBM nor the prognosis was related to the CSF lactate concentration. Repeated CSF studies demonstrated persistently high lactate levels in the early stage of illness despite adequate antituberculous therapy.

The assessment and management of tuberculous meningitis (TBM) is often complex, yet no standardised approach exists, and evidence for the clinical care of patients, including those with critical illness, is limited. The roles of proformas and checklists are increasing in medicine; proformas provide a framework for a thorough approach to patient care, whereas checklists offer a priority-based approach that may be applied to deteriorating patients in time-critical situations. We aimed to develop a comprehensive assessment proforma and an accompanying 'priorities' checklist for patients with TBM, with the overriding goal being to improve patient outcomes. The proforma outlines what should be asked, checked, or tested at initial evaluation and daily inpatient review to assist supportive clinical care for patients, with an adapted list for patients in critical care. It is accompanied by a supporting document describing why these points are relevant to TBM. Our priorities checklist offers a useful and easy reminder of important issues to review during a time-critical period of acute patient deterioration. The benefit of these documents to patient outcomes would require investigation; however, we hope they will promote standardisation of patient assessment and care, particularly of critically unwell individuals, in whom morbidity and mortality remains unacceptably high.

BACKGROUND

Tuberculous meningitis (TBM) is the most severe and frequent form of central nervous system tuberculosis. The current lack of efficient diagnostic tests makes it difficult to differentiate TBM from other common types of meningitis, especially viral meningitis (VM). Metabolomics is an important tool to identify disease-specific biomarkers. However, little metabolomic information is available on adult TBM.

METHODS

We used 1H nuclear magnetic resonance-based metabolomics to investigate the metabolic features of the CSF from 18 TBM and 20 VM patients. Principal component analysis and orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) were applied to analyze profiling data. Metabolites were identified using the Human Metabolome Database and pathway analysis was performed with MetaboAnalyst 3.0.

RESULTS

The OSC-PLS-DA model could distinguish TBM from VM with high reliability. A total of 25 key metabolites that contributed to their discrimination were identified, including some, such as betaine and cyclohexane, rarely reported before in TBM. Pathway analysis indicated that amino acid and energy metabolism was significantly different in the CSF of TBM compared with VM.

CONCLUSIONS

Twenty-five key metabolites identified in our study may be potential biomarkers for TBM differential diagnosis and are worthy of further investigation.

Background: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.

In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.