Obesity and major depressive disorder (MDD) are highly prevalent and often comorbid health conditions. Both are associated with differences in brain structure and are genetically influenced. Yet, little is known about how obesity, MDD, and known risk genotypes might interact in the brain. Subjects were 81 patients with MDD (mean age 48.6 years) and 69 matched healthy controls (mean age 51.2 years). Subjects underwent 1.5T magnetic resonance imaging, genotyping for the fat mass and obesity associated (FTO) gene rs3751812 polymorphism, and measurements for body mass index (BMI). We conducted a whole brain voxelwise analysis using tensor-based morphometry (TBM) to examine the main and interaction effects of diagnosis, BMI and FTO genotype. Significant effects of BMI were observed across widespread brain regions, indicating reductions in predominantly subcortical and white matter areas associated with increased BMI, but there was no influence of MDD or FTO rs3751812 genotype. There were no significant interaction effects. Within MDD patients, there was no effect of current depressive symptoms; however the use of antidepressant medication was associated with reductions in brain volume in the frontal lobe and cerebellum. Obesity affects brain structure in both healthy participants and MDD patients; this influence may account for some of the brain changes previously associated with MDD. BMI and the use of medication should ideally be measured and controlled for when conducting structural brain imaging research in MDD.

Central nervous system (CNS) tuberculosis is a serious clinical problem, the treatment of which is sometimes hampered by delayed diagnosis. Clearly, prompt laboratory diagnosis is of vital importance as the spectrum of disease is wide and abnormalities of the cerebrospinal fluid (CSF) are incredibly variable. Since delayed hypersensitivity is the underlying immune response, bacterial load is very low. The conventional bacteriological methods rarely detect Mycobacterium tuberculosis in CSF and are of limited use in diagnosis of tuberculous meningitis (TBM). This double blind study was, therefore, directed to the molecular analysis of CNS tuberculosis by an in-house-developed PCR targeted for amplification of a 240bp nucleotide sequence coding for MPB64 protein specific for Mycobacterium tuberculosis. Based on the clinical criteria, 47 patients with CNS tuberculosis and a control group of 10 patients having non-tubercular lesions of the CNS were included in the study. Analyses were done in three groups; one group consisting of 27 patients of TBM, a second group of 20 patients with intracranial tuberculomas and a third group of 10 patients having nontubercular lesions of the CNS acted as control. There were no false positive results by PCR and the specificity worked out to be 100%. In the three study groups, routine CSF analysis (cells and chemistry), CSF for AFB smear and culture were negative in all cases. PCR was positive for 21/27 patients (77.7% sensitivity) of the first group of TBM patients, 6/20 patients (30% sensitivity) of the second group with intracranial tuberculomas were positive by PCR and none was PCR-positive (100% specificity) in the third group. Thus, PCR was found to be more sensitive than any other conventional method in the diagnosis of clinically suspected tubercular meningitis.

OBJECTIVE

Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer's disease (AD).

METHODS

We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3 month scans, 628 subjects with baseline and 6 month scans and 464 subjects with baseline and 12 month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain tensor based morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial.

RESULTS

We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar.

CONCLUSIONS

Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration.

Tracheobronchomalacia (TBM) is defined as an excessive collapse of the intrathoracic trachea. Bronchoscopy is the gold standard for diagnosing TBM; however it has major disadvantages, such as general anaesthesia. Cine computed tomography (CT) is a noninvasive alternative used to diagnose TBM, but its use in children is restricted by ionising radiation. Our aim was to evaluate the feasibility of spirometer-controlled cine magnetic resonance imaging (MRI) as an alternative to cine-CT in a retrospective study. 12 children with a mean age (range) of 12 years (7-17 years), suspected of having TBM, underwent cine-MRI. Static scans were acquired at end-inspiration and expiration covering the thorax using a three-dimensional spoiled gradient echo sequence. Three-dimensional dynamic scans were performed covering only the central airways. TBM was defined as a decrease of the trachea or bronchi diameter >50% at end-expiration in the static and dynamic scans. The success rate of the cine-MRI protocol was 92%. Cine-MRI was compared with bronchoscopy or chest CT in seven subjects. TBM was diagnosed by cine-MRI in seven (58%) out of 12 children and was confirmed by bronchoscopy or CT. In four patients, cine-MRI demonstrated tracheal narrowing that was not present in the static scans. Spirometer controlled cine-MRI is a promising technique to assess TBM in children and has the potential to replace bronchoscopy.

Experimental tubulointerstitial nephritis (TIN), induced in Brown Norway rats, is an autoimmune disorder in which afflicted animals display high levels of serum autoantibodies directed against antigens present on the tubular basement membrane (TBM). Serious functional damage, due to lesions of the kidney cortex, is evident 10 days after disease initiation. In an earlier study, we could show that cyclosporin A (CsA), an immunosuppressive drug, effectively prevented the onset of this illness, although it did not inhibit the formation of TBM autoantibodies. In the present study, the protective effects of CsA in autoimmune TIN was compared to those of drugs currently used to combat inflammatory ailments (i.e. prednisolone, indomethacin, naproxen, azathioprine) and a novel immunomodulating agent, leflunomide (HWA 486). Leflunomide is known to specifically inhibit the formation of T-dependent antibodies and is effective in preventing and curing animal autoimmune diseases, i.e. adjuvant arthritis disease of rats and murine lupus-like disorders. We found that not only could leflunomide inhibit TIN, but the drug-effects seemed to be more effective than those of CsA. Further, leflunomide was extremely effective in inhibiting the formation of autoantibodies to TBM, whereas CsA displayed only partial suppression. Neither prednisolone, indomethacin nor naproxen were effective in reducing the autoantibody titer, and did not offer any protection to the development of this disease. Together with the known effects on other autoimmune diseases we conclude that leflunomide is a novel immunointerventive drug protecting against several types of autoimmunity.

OBJECTIVE

Glomerular basement membranes (GBM) and tubular basement membranes (TBM) consist of a fine meshwork composed mainly of type IV collagen. Each segment of tubules has specialized physiologic functions, and thus we investigated the ultrastructure of various basement membranes in rat kidneys.

METHODS

Since purifying basement membranes from different tubule segments is technically challenging, we employed tissue negative staining rather than conventional negative staining to compare the ultrastructures of proximal and distal TBM and GBM in normal rats. We also assessed the distribution of extracellular matrix components including type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin in the basement membranes by immunohistochemistry.

RESULTS

TBM and GBM of normal rats showed a fine meshwork structure consisting of fibrils forming small round to oval pores. Short- and long-pore diameters in proximal tubules were 3.3 +/- 0.5 and 3.9 +/- 0.6 nm, respectively, and in distal tubules 3.5 +/- 0.7 and 4.3 +/- 0.8 nm, respectively. For GBM the respective diameters were 2.5 +/- 0.5 and 3.0 +/- 0.5 nm. Immunohistochemical analysis showed no significant difference in distribution of extracellular matrix components between proximal and distal TBM. However, immunofluorescence scores of alpha1 chain of type IV collagen, fibronectin, and laminin were higher in the TBM than in the GBM. On the other hand, heparan sulfate proteoglycan was higher in the GBM.

CONCLUSIONS

Ultrastructural differences in renal basement membranes may be related to differences in physiologic function in each segment.

We present two cases of tuberculous meningitis (TBM) in adults complicated by focal neurological deficits which showed progression whilst on steroids. In case 1 an MRI demonstrated multiple ring-enhancing lesions compressing the optic chiasm leading to a bitemporal hemianopia. After the introduction of thalidomide serial imaging and field perimetry at 6, 9, 12 and 24 months into treatment showed progressive improvement. In case 2, two months into anti-tuberculous treatment with steroids, the patient developed fluctuating right sided paralysis with the MRI demonstrating a large ring-enhancing mass encasing the left internal carotid and middle cerebral arteries. Thalidomide was introduced as an immunomodulatory adjunct and subsequently the patient made a complete neurological recovery. The immunomodulatory effects of thalidomide may have a role in the acute and chronic management of TBM complicated by intracranial tuberculomas.

BACKGROUND

Pediatric tuberculosis of the central nervous system (CNS-TB) is a severe form of extrapulmonary TB. It is most common in children between 6 months and 4 years of age. CNS-TB can present as meningitis and/or tuberculoma. In both situations, brain damage results from a cytokine-mediated inflammatory response, which causes vasculitis, obstructive hydrocephalus and cranial nerve palsy. Tumor necrosis factor alpha (TNF-alpha) is an important cytokine in this response. The prognosis of tuberculous meningitis (TBM) correlates most closely with the clinical stage of illness at the time treatment is started. Most patients in the 1st stage have a good outcome, whereas the management of patients in the 2nd and 3rd stage is still a clinical challenge, and the few patients who survive have permanent severe disabilities. Due to the important role of inflammation in CNS-TB pathogenesis, corticosteroids are routinely used in TBM or tuberculomas, in order to reduce death and disabling residual neurological deficits among survivors. Nevertheless, not all patients show a good response to standard anti-inflammatory treatment. Thalidomide is a drug with pleiotropic effects: it appears to downregulate production of TNF-alpha and other proinflammatory cytokines. Due to its anti-inflammatory effects, thalidomide has been evaluated as an adjunctive drug in the management of difficult-to-treat CNS-TB.

METHODS

A literature review was carried out based on MEDLINE/pubmed database (1997/2010) searching for the following descriptors: corticosteroids and tuberculous meningitis (limits: review, all child); thalidomide and tuberculosis treatment; and tuberculous meningitis; and CNS-TB; and brain abscess; and TB clinical trial.

OBJECTIVE

Literature review on the use of corticosteroids and thalidomide in the treatment of CNS-TB.

RESULTS

The Cochrane review for randomized-controlled trials evaluating the use of steroids in TBM showed significantly reduced overall mortality, reduced death and severe residual disability in children. Regarding the use of thalidomide, a randomized controlled trial published in 2004 do not support the use of adjunctive high-dose thalidomide therapy in the treatment of TBM in children, but results from four case reports, one clinical trial and one placebo-controlled trial suggest the use of thalidomide in CNS-TB not responding to standard therapy.

CONCLUSIONS

"Adjuvant" treatment with dexamethasone improves survival in patients with TBM but probably does not prevent disability. Thalidomide should not be used for the routine treatment, but it may be helpful as a "salvage therapy" in patients with TBM and tuberculomas not responding to anti-TB drugs and high dose corticosteroids. More studies should evaluate its not completely conclusive role.

BACKGROUND

Tuberculous meningitis (TBM) research is hampered by low numbers of microbiologically confirmed TBM cases and the fact that they may represent a select part of the disease spectrum. A uniform TBM research case definition was developed to address these limitations, but its ability to differentiate TBM from bacterial meningitis has not been evaluated.

METHODS

We assessed all children treated for TBM from 1985 to 2005 at Tygerberg Children's Hospital, Cape Town, South Africa. For comparative purposes, a group of children with culture-confirmed bacterial meningitis, diagnosed between 2003 and 2009, was identified from the National Health Laboratory Service database. The performance of the proposed case definition was evaluated in culture-confirmed TBM and bacterial meningitis cases.

RESULTS

Of 554 children treated for TBM, 66 (11.9%) were classified as "definite TBM," 408 (73.6%) as "probable TBM," and 72 (13.0%) as "possible TBM." "Probable TBM" criteria identified culture-confirmed TBM with a sensitivity of 86% and specificity of 100%; sensitivity was increased but specificity reduced when using "possible TBM" criteria (sensitivity 100%, specificity 56%).

CONCLUSIONS

"Probable TBM" criteria accurately differentiated TBM from bacterial meningitis and could be considered for use in clinical trials; reduced sensitivity in children with early TBM (stage 1 disease) remains a concern.

OBJECTIVE

The laboratory diagnosis of pulmonary tuberculosis (TB) and tuberculous meningitis (TBM) is particularly challenging. The aim of the present work is to develop an immunoassay for the diagnosis of TB infection, using synthetic peptides of antigen (Ag) 85 complex of M. tuberculosis (Mtb) H37Rv.

METHODS

Four peptides (7-10 amino acids long) corresponding to group-specific epitopes of Ag 85 complex of Mtb were synthesized. All peptides were evaluated by enzyme-linked immunosorbent assay (ELISA) for immunoreactivity with sera and CSF samples of TB and TBM patients respectively. The diagnostic value of the four peptides was evaluated in both the samples.

RESULTS

It was observed that Ag 85 peptide 1, 3 and 4 had the highest positive rates in the pulmonary patients; however, Ag 85 peptide 1 and 2 had shown good positivity in the TBM subjects.

CONCLUSIONS

The synthetic peptide based ELISA using Ag 85 complex peptides is a sensitive, specific, rapid and cost effective immunoassay for early diagnosis of pulmonary and extrapulmonary TB. In addition, these synthetic peptides are comparatively easy to produce in a reproducible manner compared with the whole antigen.

OBJECTIVE

To investigate the prognostic factors of tuberculous meningitis (TBM) and develop strategies for the improvement of clinical efficacy.

METHODS

A total of 156 TBM patients were retrospectively reviewed. The demographic characteristics, underlying diseases, clinical features, laboratory findings, bacteriologic test, images, use of steroids, mannitol and anti-TB drugs, surgery or drainage, and clinical outcomes were collected and analyzed.

RESULTS

Patients with tubercle bacillus in the cerebrospinal fluid had significantly higher rate of consciousness disturbance (78.8%) and greater proportion of Glasgow coma scale (GCS) score of 3 (37.9%) when compared with the possible TBM patients (51.1% and 13.3%, respectively). Patients with definite TBM had a poor outcome and their mortality was significantly higher than in possible TBM patients (42.4% vs. 17.8%, P < 0.05). Univariate regression analysis showed that the advanced age, concomitant hematogenous disseminated pulmonary tuberculosis, change in consciousness, low GCS score on admission and hydrocephalus were associated with a poor prognosis; timely anti-TB treatment and reasonable hormone applications predicted a favorable outcome. Multivariate regression analysis showed that advanced age, change in consciousness, low GSC score and concomitant hydrocephalus were independent risk factors of TBM, and use of prednisone at ≥ 60 mg/d was protective factor for TBM (P=0.003, OR=0.013).

CONCLUSIONS

The advanced age, changes in consciousness, low GCS score on admission and concomitant hydrocephalus are independent risk factors of TBM. For patients with risk factors, diagnostic anti-TB therapy and reasonable hormone therapy should be performed timely to reduce mortality and disability.

Natural compounds are important sources of anticancer drugs. Rhizoma Bolbostemmatis (Chinese name "Tu Bei Mu") is the dry tuber of Bolbostemma paniculatum (Maxim.) Franquet (Cucurbitaceae). It has long been widely used for treating various ailments including cancer in traditional Chinese medicine. Its major pharmacologically active components are the triterpenoid saponins tubeimosides (TBMs) including tubeimoside (TBM) I, II and III. Extensive researches have provided evidences of the anticancer activities of TBMs in different stages of carcinogenesis both in vitro and in vivo model. TBMs could inhibit cell growth and proliferation, induce cell differentiation, apoptosis, autophagy and, inhibit inflammation, and suppress angiogenesis, invasion and metastasis via various signaling pathways. They are effective in combination therapies, particularly at targeting drug-resistant cancer cells. This mini-review aims to summarize and analyze the current knowledge on the pre-clinical studies of anti-tumor effects, the underlying molecular mechanisms and discuss the prospects of the application of TBMs in cancer prevention and treatment. The potential of TBMs as pertinent candidates could be appropriately developed and designed into an efficacious anticancer drug.

Intracranial pressure (ICP) monitored shortly after admission over a period of 1 h in 31 children with tuberculous meningitis (TBM) was significantly higher (median 22.5 mmHg, range 8.4-50.9 mmHg) in 19 children with laboratory evidence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) than in 12 children without such evidence (median 16.2 mmHg, range 5.8-42.5 mmHg; P = 0.027). Neither plasma nor cerebrospinal fluid arginine vasopressin (AVP) was related to ICP (r = 0.33 and 0.13 respectively). Mean arterial pressure (MAP) was measured in 23 children and a moderate correlation was found with plasma AVP (r = 0.62; P = 0.0019). In TBM, plasma AVP may be secreted as a response to raised ICP in an effort to raise MAP and maintain cerebral perfusion pressure. In this setting excess fluid may be inappropriately retained, leading to hyponatremia and hypo-osmolemia.

OBJECTIVE

Early diabetic kidney disease (DKD) is characterized by renal hypertrophy and albuminuria. The mTOR signal pathway is closely related to DKD. This study was performed to determine the renal protection of niclosamide ethanolamine salt (NEN) which was identified as mTOR inhibitor.

METHODS

Type 2 diabetes (T2D) db/db mice were used and divided into db/db and db/db + NEN groups. Lean wild type mice served as T2D-control. NEN treatment lasted for 12 weeks. The kidney morphological changes, urine indices, blood glucose and metabolic symptoms were evaluated. In addition, the effects of NEN on kidney mitochondria and mTOR/4E-BP pathway were also measured.

RESULTS

NEN could prevent diabetic kidney hypertrophy and alleviate glomerular mesangial expansion, attenuate GBM and TBM thickening in db/db mice. It also restored podocyte dysfunction, reduced urinary albumin, NAG, NGAL, and TGF-β1 excretion. Specifically, it could uncouple kidney mitochondria and significantly inhibit renal cortical activation of mTOR/4E-BP1 pathway.

CONCLUSIONS

This study demonstrated that NEN could improve kidney injury in db/db mice and has the potential to translate to future clinical studies.

OBJECTIVE

Development of dentotropic (tooth-binding) micelle formulations to improved efficacy and safety of antimicrobial therapy for dental plaque prevention and treatment.

METHODS

Because of their excellent biocompatibility and biodegradability, diphosphoserine peptide and pyrophosphate were selected as the tooth-binding moieties to replace alendronate, which was used previously. Diphosphoserine peptide was conjugated to Pluronic P123 using "click" chemistry, whereas pyrophosphate was attached to P123 through an ester bond. The tooth-binding micelles (TBMs) were prepared by self-assembly of the modified P123 with the antimicrobial agent triclosan. The influence of human saliva and/or its components on TBMs' drug-releasing profile, tooth-binding potential and binding stability was evaluated in vitro. S. mutans UA159 biofilm formed on hydroxyapatite (HA) discs was used to evaluate the TBMs' therapeutic potential.

RESULTS

Saliva does not affect triclosan release from TBMs. More than 60% of TBMs' HA binding capacity was maintained in the presence of saliva. Less than 5% of TBMs bound to HA was released over 24 h in human saliva, protease or phosphatase, suggesting the retention properties of the TBMs will not be compromised due to the biodegradable nature of the binding moieties. In both in vitro biofilm prevention and treatment studies, the TBM treated group showed significantly lower CFU per HA disc compared to the controls (2-log reduction, p < 0.05).

CONCLUSIONS

The data from these studies suggest that the novel dentotropic micelle formulations bearing biodegradable tooth-binding moieties can be used as an effective and safe delivery tool for antimicrobials to improve dental plaque prevention and treatment.

Linezolid serves as an important component for the treatment of drug-resistant tuberculosis although there is little published data about linezolid use in children, especially in childhood tuberculous meningitis (TBM).

In this study, we retrospectively reviewed records of childhood TBM patients who started treatment between January 2012 and August 2014. A total of 86 childhood TBM patients younger than 15 years old were enrolled. Out of 86 children, 36 (41.9%) received the regimen containing linezolid.

Thirty-two (88.9%) of 36 linezolid-treated cases had favorable outcomes, and 35 (70.0%) cases were successfully treated in the control group. The frequency of favorable outcome of linezolid group was significantly higher than that of control group (P = 0.037). In addition, compared with cases with fever clearance time of <1 week, the control group had more cases with fever clearance time of 1-4 weeks (P = 0.010) and >4 weeks (P = 0.000) than linezolid group. Furthermore, there was no significant difference in the frequency of adverse events between the two regimens (P = 0.896). In addition, the patients with adverse events were more likely to have treatment failure, the P value of which was 0.008.

Our data demonstrate that linezolid improves early outcome of childhood TBM. The low frequency of linezolid-associated adverse effects highlights the promising prospects of its use for treatment of childhood TBM.

Tracheomalacia or tracheobronchomalacia (TM or TBM) is a common problem especially for elderly patients often unfit for surgical techniques. Several surgical or minimally invasive techniques have already been described. Stenting is one option but in general long-time stenting is accompanied by a high complication rate. Stent removal is more difficult in case of self-expandable nitinol stents or metallic stents in general in comparison to silicone stents. The main disadvantage of silicone stents in comparison to uncovered metallic stents is migration and plugging. We compared the operation time and in particular the duration of a sufficient Dumon stent fixation with different techniques in a patient with severe posttracheotomy TM and strongly reduced mobility of the vocal cords due to Parkinson's disease. The combined approach with simultaneous Dumon stenting and endoluminal transtracheal externalized suture under cone-beam computer tomography guidance with the Berci needle was by far the fastest approach compared to a (not performed) surgical intervention, or even purely endoluminal suturing through the rigid bronchoscope. The duration of the endoluminal transtracheal externalized suture was between 5 minutes and 9 minutes with the Berci needle; the pure endoluminal approach needed 51 minutes. The alternative of tracheobronchoplasty was refused by the patient. In general, 180 minutes for this surgical approach is calculated. The costs of the different approaches are supposed to vary widely due to the fact that in Germany 1 minute in an operation room costs on average approximately 50-60€ inclusive of taxes. In our own hospital (tertiary level), it is nearly 30€ per minute in an operation room for a surgical approach. Calculating an additional 15 minutes for patient preparation and transfer to wake-up room, therefore a total duration inside the investigation room of 30 minutes, the cost per flexible bronchoscopy is per minute on average less than 6€. Although the Dumon stenting requires a set-up with more expensive anesthesiology accompaniment, which takes longer than a flexible investigation estimated at 1 hour in an operation room, still without calculation of the costs of the materials and specialized staff that the surgical approach would consume at least 3,000€ more than a minimally invasive approach performed with the Berci needle. This difference is due to the longer time of the surgical intervention which is calculated at approximately 180 minutes in comparison to the achieved non-surgical approach of 60 minutes in the operation suite.

OBJECTIVE

To study the clinical and pathological characteristics of aristolochic acid nephropathy (AAN).

METHODS

86 patients with AAN during 2001 and 2009 in our department were recruited in this retrospective study. The clinical and pathological features were analyzed.

RESULTS

There were 47 males and 39 females, aging from 12 to 69 years old. Abnormal urine analysis and gastro-intestinal diseases were two main underlying causes for patients taking aristolochic acid (AA) containing drugs. All patients suffered from renal function impairment. 19 patients (22.0%) presented with acute kidney injury (AKI), while 67 patients (78%) presented as chronic cases. Among them, 31 patients (36.0%) lacked symptoms, 30 patients (34.8%) were accompanied with hypertension, and 26 patients (30.2%) presented with gastrointestinal symptoms. Laboratory examination revealed elevated urine retinol-binding protein (RBP) (90.7%) and urine N-acetyl-β-glucosaminidase (NAG) (80.2%). Anemia and glucosuria accounted for 64.0% and 58.1%, respectively. Renal biopsy showed prominent tubular brush border ablation (84.2%) in acute cases, while obvious tubular basement membrane (TBM) thickening (81.4%) and interstitial fibrosis were present in chronic cases. During the follow- up, 11 (57.9%) acute cases gained renal function recovery. They had lower urine RBP level and lower incidence of hypokalemia than the non-recovery acute cases. In the chronic group, 27 patients (40.2%) progressed to endstage renal disease (ESRD), with 11 dialysis and 5 renal transplantation cases.

CONCLUSIONS

AAN patients usually suffered from renal impairment with an associated history of taking AA containing drugs. Proximal renal tubular dysfunction and structure destroying would be the main positive findings in laboratory tests and renal biopsy. Urine RBP and hypokalemia might determine the outcome of acute AAN patients.

The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study.

In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples.

Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities.

These results provide experimental evidence to support our conceptual astrocyte-microglia lactate shuttle model formulated from our previous NMR-based metabolomics study - highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers.

The value of cerebrospinal fluid (CSF) lactate and lactate dehydrogenase (LD) values as aids in differentiating tuberculous meningitis (TBM) from aseptic meningitis has been investigated. Using an upper limit of normal for CSF lactate levels of 2,75 mmol/l resulted in detection of 24 out of 26 cases of TBM (a sensitivity of 92%). If, however, a level of 3,85 mmol/l was taken as the upper limit of normal, then 18 out of 26 cases were detected (a sensitivity of 69%). Using 40 U/l as the upper limit of normal for LD levels detected 21 out of 38 cases of TBM (a sensitivity of 55%). Both tests may give normal values in the presence of TBM, but this should not cause specific antituberculosis therapy to be withheld. Neither test appears to hold marked advantages over conventional chemical analysis of CSF in differentiating TBM from aseptic meningitis.

Guidelines for the best steroid dose in children with tuberculous meningitis (TBM) have not been established. We enrolled 63 children with TBM and divided them into three steroid dose groups: Group 1 (prednisolone 2mg/kg/day over 4 weeks), Group 2 (prednisolone 4 mg/kg/day over 1 week and 2mg/kg/day for the next 3 weeks) and Group 3 (prednisolone 4 mg/kg/day over 4 weeks). All patients received standard antituberculous therapy. Optic atrophy, tuberculoma, hydrocephalus, mental retardation, spasticity, hearing impairment, vasculitis and mortality outcomes were compared. Optic atrophy was higher in Group 3 compared to Group 1 (odds ratio [OR]=2.8) and Group 2 (OR=2.8), although Group 3 had a high incidence of optic atrophy at diagnosis. Tuberculomas were more frequent in Group 1 (OR=2.4) and Group 3 (OR=3.0) as compared to Group 2. Infarcts were more common in Group 3 than in Group 1 (OR=1.9) and in Group 2 (OR=3.5). Hearing loss was higher in Group 2 as compared to Group 1 (OR=2.88) and Group 3 (OR=4.8). Evolving hydrocephalus was higher in Group 3 as compared to Group 2 (OR=2.8) and Group 1 (OR=3.1). Mental retardation was higher in children in Group 3 (OR=1.6) and in Group 2 (OR=1.9) as compared to Group 1. Spasticity was higher in Group 3 (OR=2.0) and in Group 2 (OR=1.4) as compared to Group 1. There was no difference in mortality between the groups. We conclude that prednisolone at a dose of 4 mg/kg/day for 1 week followed by 2mg/kg/day for 3 weeks is associated with fewer tuberculomas and infarcts but a higher incidence of hearing loss. A prolonged period of high dose steroids increases the risk of optic atrophy and hydrocephalus. Prednisolone at a dose of 2mg/kg/day is associated with lower risk of mental retardation and spasticity.

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.

The application of metagenomic next-generation sequencing (mNGS) in the diagnosis of tuberculous meningitis (TBM) remains poorly characterized. Here, we retrospectively analyzed data from patients with TBM who had taken both mNGS and conventional tests including culture of Mycobacterium tuberculosis (MTB), polymerase chain reaction (PCR) and acid-fast bacillus (AFB) stain, and the sensitivity and specificity of these methods were compared.

We retrospectively recruited TBM patients admitted to the hospital between December 2015 and October 2018. The first collection of cerebrospinal fluid (CSF) samples underwent both mNGS and conventional tests. In addition, patients with bacterial/cryptococcal meningitis or viral meningoencephalitis were mNGS positive controls, and a patient with auto-immune encephalitis was an mNGS negative control.

Results

Twenty three TBM patients were classified as 12 definite and 11 clinical diagnoses, which were based on clinical manifestations, pathogen evidence, CSF parameters, brain imaging, and treatment response. The mNGS method identified sequences of Mycobacterium tuberculosis complex (MBTC) from 18 samples (18/23, 78.26%). In patients with definite TBM, the sensitivity of mNGS, AFB, PCR, and culture to detect MTB in the first CSF samples were 66.67, 33.33, 25, and 8.33%, respectively. The specificity of each method was 100%. Among the four negative mNGS cases (4/23, 17.39%), three turned out positive by repeated AFB stain. The agreement of mNGS with the total of conventional methods was 44.44% (8/18). Combination of mNGS and conventional methods increased the detection rate to 95.65%. One patient was diagnosed as complex of TBM and cryptococcal meningitis, in which AFB stain and cryptococcal antigen enzyme immunoassay were positive and the DNA of Cryptococcus neoformans was detected by mNGS.

Our study indicates that mNGS is an alternative method to detect the presence of mycobacterial DNA in CSF samples from patients with TBM and deserves to be applied as a front-line CSF test.