OBJECTIVE

Clinicians often perform follow-up lumbar punctures (LPs) on patients with tuberculous meningitis (TBM) to document changes occurring in the cerebrospinal fluid (CSF). Normalisation of the CSF then serves as indirect confirmation of the diagnosis. However, changes occurring in CSF following the initiation of anti-tuberculosis (TB) treatment are not well described. We undertook a retrospective study to determine the temporal evolution of CSF in patients with TBM on anti-TB treatment in an attempt to provide a more rational basis for the interpretation of repeat LPs.

METHODS

Patients diagnosed with TBM at King George V Hospital in Durban from 1994 to 2003 were identified. Demographic, clinical, laboratory and radiological data were recorded. We examined the change in CSF lymphocyte cell count, polymorphonuclear (PMN) cell count, glucose concentration and protein concentration. Initially, scatter plots of the data modelled over time were produced and random effects models were then used to model the predicted changes in CSF over time.

RESULTS

Ninety-nine patients were identified, and a total of 327 LPs were done. The average number of LPs per patient was 3 (range 3 - 9). Statistically significant changes in all four variables (lymphocytes, PMN cells, glucose and protein) were demonstrated, with a p value < 0.001. The predicted models showed that lymphocyte count and protein concentration change slowly over time. PMN cells and glucose concentration changed rapidly in an exponential manner.

CONCLUSIONS

Our results demonstrate the tendency for CSF to normalise over time. The slow change in lymphocyte count and protein concentration limits clinical use. The rapid change in PMN cells and glucose concentration allows us to make reasonable clinical decisions. If a repeat LP does not show definite improvement in these two parameters, it should be considered atypical for TBM.

Central nervous system (CNS) tuberculosis, particularly tuberculous meningitis (TBM), is one of the severest forms of tuberculosis. At present, the diagnosis of CNS tuberculosis remains a complex issue because the most widely used conventional "gold standard" based on bacteriological detection methods, such as direct smear and culture identification, cannot rapidly detect Mycobacterium tuberculosis (M.Tb) bacilli in CSF specimens with sufficient sensitivity in the acute phase of TBM. Recently, instead of the conventional "gold standard", the various molecular-based methods, such as polymerase chain reaction (PCR) assay, has emerged as a promising new method for the diagnosis of TBM. Moreover, nested PCR assay has been reported as a key method that drastically increases the sensitivity and specificity of DNA amplification compared with conventional single-step PCR. Currently, a novel assay technique, which is internally controlled and combines the high sensitivity of nested PCR with the accurate quantification of real-time PCR, namely, Wide Range Quantitative Nested Real-time PCR (WR-QNRT-PCR) assay, has been developed. This novel assay technique is useful for the rapid diagnosis and the assessment of anti-tuberculosis treatment during clinical course of TBM. Therefore, in actual clinical practice, its wider use for diagnosis of TBM is expected in the future.

One-hundred-and-thirty-six children below 12 years of age hospitalized with a diagnosis of tuberculous meningitis (TBM) have been investigated to identify the underlying cause of convulsions. One-hundred-and-one children (74 per cent) presented with seizures before and/or during hospitalization. Generalized tonic and clonic seizures (GTCS) were the commonest (58 per cent) type of seizures followed by focal seizures (FS) (38 per cent) and tonic spasms (TS) (4 per cent). EEG changes were more frequently observed in cases with FS and in those children with GTCS who presented after first week of hospitalization. EEG findings included generalized dysrythmia with paroxysmal slow activity (38 per cent), interhemispheric asymmetry (23 per cent), multiple spike and wave pattern (10 per cent), and focal spike and wave pattern (15 per cent). CT scan findings were more common in those children with GTCS and TS who presented with recurrent seizures and/or seizures manifesting after first week of hospitalization. FS presenting at any stage of the disease were associated with CT scan abnormalities. Abnormalities detected in CT scan of brain included meningeal enhancement (55 per cent), hydrocephalus (32 per cent), tuberculomas (27 per cent), and cerebral infarctions (13 per cent). Clinical presentation and investigations indicate that the probable cause of convulsions could be attributed to cerebral edema (57 per cent), syndrome of inappropriate secretion of antidiuretic hormone (35 per cent), hydrocephalus (32 per cent), tuberculoma (27 per cent), abnormal electric focus (25 per cent), and cerebral infarction (13 per cent).

To clarify the morphological changes in renal proximal tubules at the onset of diabetic nephropathy, we observed 177 biopsy samples from patients with Non-Insulin-Dependent Diabetics (NIDDM) using light and electron microscopy. Group I had no proteinuria (p.u.), group II had p.u. < or = 0.5 g/day, group III had p.u.>> 0.5 g/day, group IV had serum creatine level (Cr)>> 1.5 mg/dl. Twenty age-matched normal patients and 80 patients with IgA nephropathy were used as controls. In groups I and II, the following features were significantly different from those in the controls: spherical enlargement of mitochondria (MT) in proximal tubule cells, hypertrophy of proximal tubule cells and their nuclei, and thickening of both the proximal tubule basement membrane (TBM) and the glomerular basement membrane (GBM). Among the histological changes observed in group I, the thickness of the GBM and TBM indicated that the disease would lead to diabetic nephropathy. MT enlargement was positively correlated with nuclear and cytoplasmic enlargement of the proximal tubule cells in diabetic patients (p < 0.05), but was not correlated with other morphological changes or disease prognosis. Glomerular nodular lesions, glomerular sclerotic change, and cortical tubulointerstitial fibrosis became evident in groups III and IV. From the above, we concluded that MT enlargement and thickening of the TBM are possible causes of reduced active transport in the proximal tubules, causing microalbuminuria in diabetics, and initial impairment of post-tubule transport.

BACKGROUND

Patients with tuberculous meningitis (TBM) have been frequently observed to have excessive sleep during the day and frequent awakenings during night. We undertook this study to evaluate sleep related abnormalities in patients with TBM since there is no published literature pertaining to the same.

OBJECTIVE

To study sleep wake cycles in patients with tuberculous meningitis by actigraphy and sleep logs and compare these with age and sex matched controls.

METHODS

Consecutive patients admitted with tuberculous meningitis were studied clinically and with three days of continuous wrist actigraphy and sleep/wake parameters were compared to those of age and gender matched normal healthy controls.

RESULTS

Forty three patients with tuberculous meningitis were enrolled in the study. Of these, twenty-eight patients (15 females, 13 males; mean age 31.64 years) who were able to complete adequate actigraphy were compared with an equal number of controls (15 females, 13 males; mean age 30.93 years). Patients were found to have greater sleep time (p<0.0005) and more sleep episodes (p<0.0005) during the day while during the night they had less sleep (p<0.0005) with more frequent (p=0.019) and longer (p<0.0005) awakenings as compared to normal controls. Majority of the patients had reversal of sleep/wake cycles. There was poor co-relation between sleep parameters measured by actigraphy and sleep logs.

CONCLUSIONS

Tuberculous meningitis is associated with significant alteration of sleep-wake circadian cycles. This needs to be further characterized through studies involving polysomnography. There is a need to address these specific sleep difficulties to improve the quality of life of the patient as well as the care-giver.

Primary productivity of terrestrial vegetation is expected to increase under the influence of increasing atmospheric carbon dioxide concentrations ([CO2]). Depending on the fate of such additionally fixed carbon, this could lead to an increase in terrestrial carbon storage, and thus a net terrestrial sink of atmospheric carbon. Such a mechanism is generally believed to be the primary global driver behind the observed large net uptake of anthropogenic CO2 emissions by the biosphere. Mechanisms driving CO2 uptake in the Terrestrial Biosphere Models (TBMs) used to attribute and project terrestrial carbon sinks, including that from increased [CO2], remain in large parts unchanged since those models were conceived two decades ago. However, there exists a large body of new data and understanding providing an opportunity to update these models, and directing towards important topics for further research. In this review we highlight recent developments in understanding of the effects of elevated [CO2] on photosynthesis, and in particular on the fate of additionally fixed carbon within the plant with its implications for carbon turnover rates, on the regulation of photosynthesis in response to environmental limitations on in-plant carbon sinks, and on emergent ecosystem responses. We recommend possible avenues for model improvement and identify requirements for better data on core processes relevant to the understanding and modelling of the effect of increasing [CO2] on the global terrestrial carbon sink.

Cerebral ischaemia is a serious complication of tuberculous meningitis (TBM) with the anterior circulation most commonly affected. Acute syringomyelia is a very rare complication of TBM. Here, we report an unusual presentation of TBM with a third nerve palsy as a result of posterior circulation stroke as well as a syringomyelia.

It has been shown in experimental models that cell-mediated immunologic mechanisms can lead to glomerular as well as tubulointerstitial renal injury, with or without concomitant antibody-mediated effects. The glomerular lesions are characterized by varying combinations of monocyte and, to a lesser extent, lymphocyte influx, necrosis, and proliferation of intrinsic glomerular cells. The tubulointerstitial lesions have generally been characterized by interstitial infiltrates containing numerous T lymphocytes and, often, numerous macrophages, sometimes with invasion of tubules and tubular cell damage. Although similar renal abnormalities are seen in several human renal diseases, further evidence is obviously required to establish a pathogenetic role for cellular immunity. Analyses of infiltrating mononuclear cells by immunohistochemical methods, with monoclonal antibodies that identify subsets of T cells, have indirectly supported a role for delayed hypersensitivity reactions in tubulointerstitial nephritis resulting from drugs or associated with anti-TBM antibodies, as well as a role for both delayed hypersensitivity and cytolytic lymphocyte effects in renal allografts. However, only with the development of methods that permit the identification of subsets of lymphocytes with unique functions, as well as the identification of the antigen specificity of the cells, will it be possible to understand fully the renal lesions that are now suspected of being cell-mediated.

Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx).

Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation.

Lung graft survivals in the 2 non-survival animals were 48 and >72 hours, while survivals in the other 9 were 25 and 28 hours, at 5, 5, 6, 7, >7, 9, and 10 days. One baboon with graft survival >7 days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10 days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss.

To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.

BACKGROUND

Tuberculous and cryptococcal meningitis (TBM and CM) are the most common causes of opportunistic meningitis in HIVinfected patients from resource-limited settings, and the differential diagnosis is challenging.

OBJECTIVE

To compare clinical and basic cerebrospinal fluid (CSF) characteristics between TBM and CM in HIV-infected patients.

METHODS

A retrospective analysis was conducted of clinical, radiological and laboratory records of 108 and 98 HIV-infected patients with culture-proven diagnosis of TBM and CM, respectively. The patients were admitted at a tertiary centre in São Paulo, Brazil. A logistic regression model was used to distinguish TBM from CM and derive a diagnostic index based on the adjusted odds ratio (OR) to differentiate these two diseases.

RESULTS

In multivariate analysis, TBM was independently associated with: CSF with neutrophil predominance (odds ratio (OR) 35.81, 95% confidence interval (CI) 3.80 - 341.30, p=0.002), CSF pleocytosis (OR 9.43, 95% CI 1.30 - 68.70, p=0.027), CSF protein >1.0 g/L (OR 5.13, 95% CI 1.38 - 19.04, p=0.032) and Glasgow Coma Scale <15 (OR 3.10, 95% CI 1.03 - 9.34, p=0.044). Nausea and vomiting (OR 0.27, 95% CI 0.08 - 0.90, p=0.033) were associated with CM. Algorithm-related area under the receiver operating characteristics curve was 0.815 (95% CI 0.758 - 0.873, p<0.0001), but an accurate cut-off was not derived.

CONCLUSIONS

Although some clinical and basic CSF characteristics appear useful in the differential diagnosis of TBM and CM in HIVinfected patients, an accurate algorithm was not identified. Optimised access to rapid, sensitive and specific laboratory tests is essential.

The transferable belief model (TBM) is a model to represent quantified uncertainties based on belief functions, unrelated to any underlying probability model. In this framework, two main approaches to pattern classification have been developed: the TBM model-based classifier, relying on the general Bayesian theorem (GBT), and the TBM case-based classifier, built on the concept of similarity of a pattern to be classified with training patterns. Until now, these two methods seemed unrelated, and their connection with standard classification methods was unclear. This paper shows that both methods actually proceed from the same underlying principle, i.e., the GBT, and that they essentially differ by the nature of the assumed available information. This paper also shows that both methods collapse to a kernel rule in the case of precise and categorical learning data and for certain initial assumptions, and a simple relationship between basic belief assignments produced by the two methods is exhibited in a special case. These results shed new light on the issues of classification and supervised learning in the TBM. They also suggest new research directions and may help users in selecting the most appropriate method for each particular application, depending on the nature of the information at hand.

BACKGROUND

Foreign-born mothers have been reported to have better pregnancy outcomes as measured by the preterm birth rate, neonatal mortality, and birth weight compared with native-born mothers in Belgium, France, Taiwan, and the United States. However, little is known about the association between maternal nationality and the prevalence of orofacial clefts in Asian countries.

METHODS

Taiwan Birth Registry data from 2004 to 2006 were analyzed for an association between maternal nationality and orofacial clefts. Singleton live births with a gestational age ≥24 weeks were included in this study.

RESULTS

The overall estimated prevalence percentages of orofacial clefts were 0.11 (95% confidence interval [CI] = 0.03 to 0.12) among newborns of Taiwan-born mothers (TBMs) and 0.13 (95% CI = 0.04 to 0.16) among newborns of foreign-born mothers (FBMs), respectively. The estimated prevalence of orofacial clefts of all live births of FBMs in Taiwan was similar to that of the FBMs from Southeast Asian countries.

CONCLUSIONS

There was a slightly higher but no significant difference of estimated prevalence of orofacial clefts between newborns of TBMs and newborns of FBMs in Taiwan.

Oxidative stress is implicated in the etiopathogenesis of a variety of human diseases. Therefore, in the present study, erythrocyte lipid peroxidation, percentage hemolysis, antioxidant enzymes viz., glutathione reductase, glutathione peroxidase, superoxide dismutase and plasma antioxidants viz., ceruloplasmin, vitamins A,E and C have been determined in 19 patients with tubercular meningitis (TBM) and 50 normals. Six patients who were treated with antibiotics were considered for the follow up. The statistical analysis was carried out by Mann Whitney U test and Wilcoxon rank sum test. Lipid peroxidation (P<0.02), percentage hemolysis (P<0.001) and plasma ceruloplasmin (P<0.0001) of TBM patients were significantly higher, whereas erythrocyte glutathione reductase (P<0.05) and plasma antioxidant vitamins A, E and C (P<0.01, P<0.05 respectively) were significantly lower than those of the controls. In the follow up patients the glutathione reductase and catalase levels were significantly high (P<0.05) compared to their pre-treated condition. Vitamin C and E levels have attained normal range. This study indicated that the blood antioxidant status of TBM patients which was low compared to controls improved after treatment, suggesting the role of free radicals in TBM.

The purpose of the study was to investigate child behaviour in children who recovered from tuberculous meningitis (TBM) and to compare behaviour profiles of stage II and stage III patients. The mean age of the cohort of 74 children at the time of evaluation was 10 years and 7 months. At follow-up all patients underwent a thorough neurological examination and a psychometric test battery, which included intellectual assessment and evaluation of behaviour by means of the CBCL/6-18. Results indicated elevated mean scores (T>> 60) on CBCL/6-18 scales which measure problems with anxiety, depression, attention, social relationships, disruptive and rule-breaking behaviour. Mean CBCL scores of stage III patients were significantly higher than the mean scores of stage II patients on scales which measure social problems, disruptive and rule-breaking behaviour. In addition, problems with conduct, attention, attention-deficit/hyperactivity problems, affective problems as well as the total problem scores were more pronounced in the patients with stage III TBM. We conclude that general behavioural disinhibitions as well as internalized emotional disorder probably are long-term complications in more than 10% of the survivors of TBM.

Induction of autoimmune antibodies against antigens of glomerular basement membrane (GBM) was studied in nine inbred strains of rats each with a different major histocompatibility complex H-1. Brown-Norway (BN) (H-1n), Lewis (H-1(1)), PVG/c (H-1c), AS2 (H-1f), AVN (H-1a), BD V (H-1d), DA (H-1a) and F344 (H-1(1)) rats were immunized with bovine GBM and Freund's complete adjuvent (CFA). A pronounced linear deposition of host IgG (IgG1 and IgG2a) along the GBM was found in BN rats. No deposition of C3 could be detected in the glomeruli nor did the animals develop proteinuria. The quantity of autoimmune antibodies fixed to the GBM was low (48 microgram +/- 14) which could explain the absence of C3 deposition and proteinuria. The antigenic specificity of the antibodies deposited along the GBM in BN rats was shown by the fixation in vitro of the eluted antibodies to the GBM and tubular basement membrane (TBM) of normal kidneys. A much weaker and irregular deposition of host IgG along the GBM was observed in PVG/c, AS2. AVN, BD V, DA and F344 rats. Of these strains, eluates from the glomeruli of PVG/c, AVN, BD V and DA rats fixed very weakly to the GBM of normal kidneys whereas eluates from AS2 and F344 rats did not fix to GBM or TBM. No deposition of host IgG was found in Lewis rats, and the eluates did not fix to normal kidneys. Congenic L.BN rats with the BN H-1n haplotype and a Lewis background did not respond. This study shows a genetic predisposition in rats to an autoimmune anti-GBM response which is not, or not exclusively, controlled by genes linked to the H-1 histo-compatibility complex.

In the kidneys of anti-glomerular basement membrane (anti-GBM) antibody disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechanisms of binding of anti-GBM antibodies to TBM in vivo with special reference to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions of renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2Ag) was perfused in the left kidney and then blood circulation was restored. Mild proteinuria ( < 10 mg/16 hr) was observed during first several days. Five days later, there were tubulointerstitial injuries defined by tubular vimentin staining and leukocyte infiltration. Significant deposition of C3 was observed in the capillaries and in TBM. In rats intravenously injected with rabbit anti-rat GBM antibodies five minutes after kidney perfusion with 5I2, strong binding of rabbit IgG to TBM was observed at one and five days after injection. Although these rats showed mild proteinuria comparable to those perfused with 5I2 and those injected with normal rabbit serum, tubulointerstitial injury was significantly enhanced at Day 5. In contrast, rats perfused with irrelevant mAb and injected with anti-GBM antibodies did not show any significant binding of antibodies to TBM nor tubulointerstitial injury. Furthermore, rats which were made proteinuric by puromycin aminonucleoside and injected with anti-GBM antibodies did not show any significant binding of rabbit IgG to TBM. These results indicate that 5I2Ag, a rat membrane inhibitor of complement at the C3 convertase level, regulates vascular permeability in the living kidney, and that dysfunction or decreased expression of this molecule leads to increased accessibility of anti-GBM antibodies to TBM.

OBJECTIVE

Late diagnosis and treatment lead to high mortality and poor prognosis in tuberculous meningitis (TbM). A rapid and accurate diagnosis is necessary for a good prognosis. Neuron-specific enolase (NSE) has been investigated as a biochemical marker of nervous tissue damage. In the present study, the usefulness of NSE was evaluated, and a cut-off value for the differential diagnosis of TbM was proposed.

METHODS

Patient charts were reviewed for levels of serum and cerebrospinal fluid (CSF) NSE, obtained from a diagnostic CSF study of samples in age- and gender-matched TbM (n=15), aseptic meningitis (n=28) and control (n=37) patients.

RESULTS

CSF/serum NSE ratio was higher in the TbM group than those of the control and aseptic groups (p=0.001). In binary logistic regression, CSF white blood cell count and CSF/serum NSE ratio were significant factors for diagnosis of TbM. When the cut-off value of the CSF/serum NSE ratio was 1.21, the sensitivity was 86.7% and the specificity was 75.4%.

CONCLUSIONS

The CSF/serum NSE ratio could be a useful parameter for the early diagnosis of TbM. In addition, the authors of the present study suggest a cut-off value of 1.21 for CSF/serum NSE ratio.

METHODS

France, 1990.

OBJECTIVE

To measure the incidence and describe the characteristics of bacteriologically-confirmed tuberculous meningitis (TBM) and to estimate the protective efficacy of BCG vaccination in children aged less than 5 years.

METHODS

An active surveillance of TBM cases confirmed by positive cerebrospinal fluid (CSF) culture was conducted through a network of microbiology laboratories serving 99.8% of regional and district general hospitals and other large private hospitals.

RESULTS

A total of 70 cases were reported: 61% were adults over 44 years, 64% were males and 77% were born in France. 7 patients were known to be infected with HIV. 6 cases were observed in children aged less than 5 years, 2 of whom had been vaccinated with BCG. 3 of the 6 children died (one had been BCG-vaccinated). Given the 80% coverage of BCG in this age group, the protective efficacy of BCG vaccination was estimated to be 87.5% (95% CI: 30-98), which indicates that 14 TBM cases may have been prevented by BCG vaccination in 1990.

CONCLUSIONS

Results are consistent with the number of TBM cases expected on the basis of a 0.04% annual risk of infection. Current BCG vaccination policy in France still has a measurable impact on the incidence of tuberculous meningitis in children under 5 years of age. Given the probable continuous decrease of the annual risk of infection in future years, alternative policies should be considered.

Although many advanced and sophisticated ab initio approaches for modeling protein-protein complexes have been proposed in past decades, template-based modeling (TBM) remains the most accurate and widely used approach, given a reliable template is available. However, there are many different ways to exploit template information in the modeling process. Here, we systematically evaluate and benchmark a TBM method that uses conserved interfacial residue pairs as docking distance restraints [referred to as alpha carbon-alpha carbon (CA-CA)-guided docking]. We compare it with two other template-based protein-protein modeling approaches, including a conserved non-pairwise interfacial residue restrained docking approach [referred to as the ambiguous interaction restraint (AIR)-guided docking] and a simple superposition-based modeling approach. Our results show that, for most cases, the CA-CA-guided docking method outperforms both superposition with refinement and the AIR-guided docking method. We emphasize the superiority of the CA-CA-guided docking on cases with medium to large conformational changes, and interactions mediated through loops, tails or disordered regions. Our results also underscore the importance of a proper refinement of superimposition models to reduce steric clashes. In summary, we provide a benchmarked TBM protocol that uses conserved pairwise interface distance as restraints in generating realistic 3D protein-protein interaction models, when reliable templates are available. The described CA-CA-guided docking protocol is based on the HADDOCK platform, which allows users to incorporate additional prior knowledge of the target system to further improve the quality of the resulting models.

Tracheobronchomalacia (TBM) in adults is a disease defined by a reduction of more than 50% of the airway lumen during expiration. It encompasses many etiologies that differ in their morphologic aspects, pathophysiological mechanisms and histopathologies. TBM is encountered with increasing frequency, as it is more easily diagnosed with new imaging techniques and diagnostic bronchoscopy, as well as because of its frequent association with Chronic Obstructive Pulmonary Disease (COPD), which represents the most frequent etiology for acquired TBM in adults. A distinction between TBM in association with failure of the cartilaginous part of the airways and TBM affecting only the posterior membranous part is emerging since their physiopathology and treatment differ. The therapeutic management of TBM should be as conservative as possible. Priority should be given to identification and treatment of associated respiratory diseases, such as asthma or COPD. Surgery addressing extrinsic compression (thyroid goiter or tumor, for example) may be necessary. Noninvasive ventilation can be considered in patients with increasing symptoms. Endoscopic options, such as the placement of stents, should only be used as palliative or temporary solutions, because of the high complication rates. Symptomatic improvement after stenting might be helpful in selecting patients in whom a surgical management with tracheobronchoplasty can be useful.

OBJECTIVE

To evaluate the usefulness of serum and CSF adenosine deaminase (ADA) activity for the diagnosis of tuberculous meningitis (TBM) from other meningitis.

METHODS

We studied CSF and serum ADA activity for 83 cases of TBM, 148 of bacterial meningitis (BM), and 262 of viral or aseptic meningitis.

RESULTS

The mean ADA activities (IU/L) in CSF and serum were higher in TBM (11.80 ± 2.50, 30.28 ± 7.30) than in other types of meningitis (8.52 ± 3.60, 17.90 ± 9.20 in BM; 5.26 ± 1.90, 8.56 ± 5.9 in viral or aseptic meningitis). When we accepted a serum ADA activity cut-off value of 15 IU/L for the differential diagnosis of TBM and non-TBM with ROC analysis, the sensitivity was 84% and specificity was 82%. Combining CSF (≥ 10) and serum (≥ 15) ADA activity significantly increased overall specificity from 92% to 97% for the diagnosis of TBM.

CONCLUSIONS

The determination of CSF and serum ADA activity is a simple and reliable test for differentiating TBM from other types of meningitis.

Microvascular hyperpermeability to plasma proteins via vascular endothelial growth factor (VEGF) with endothelial nitric oxide synthase (eNOS) induction may contribute to wound healing through matrix remodeling. However, vascular hyperpermeability is not examined in acute renal failure (ARF), a unique form of wound healing. Subcutaneous injection of gentamicin (400 mg/kg per day for 2 days in divided doses every 8 h) in rats increased serum creatinine levels and induced tubular damage, which peaked at day 6, after the last gentamicin injection. Ki67-positive regenerating proximal tubules (PTs) peaked in number at day 6 and almost covered the bare tubular basement membrane (TBM) by day 10. Staining of fibrinogen and plasma fibronectin began to increase in the peritubular regions as early as day 0, steadily increased in TBM and tubular lumen until day 6 and then decreased. Hyperpermeable peritubular capillaries were identified by extravasation of perfused-fluoresceinated dextran (both 70 kDa and 250 kDa) into peritubular regions as early as day 0 and prominently into TBM and tubular lumen at day 6. Electron microscopy further suggested the intraendothelial pathway of dextran. Immunoreactive VEGF increased in the damaged and regenerating PTs. Immunoreactive VEGF receptors-1 and -2 did not change, but immunoreactive eNOS increased in the peritubular capillaries after induction of ARF. Western blotting for VEGF and eNOS supported the immunostaining findings. In addition, we assessed the effects of NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) on vascular hyperpermeability during the recovery phase of this model. Treatment with L-NAME (s.c. at a dose of 100 mg/kg/day from day 3 to day 6) decreased extravasation of perfused-250-kDa dextran and significantly inhibited the regenerative repair of PTs at day 6 when compared with vehicle-treated rats. In conclusion, plasma protein extravasation occurred, leading to matrix remodeling, such as the process of wound healing during the tubular repair in gentamicin-induced ARF. Since VEGF-induced vascular hyperpermeability may depend on NO production, VEGF/VEGF receptor system with eNOS induction might be responsible for this process.

UNASSIGNED

Mycobacterium tuberculosis (Mtb) bacillary load in the brain of those with tuberculous meningitis (TBM) may reflect the host ability to control the pathogen and determine disease severity and treatment outcomes.

UNASSIGNED

We measured pre-treatment cerebrospinal fluid (CSF) Mtb bacterial load by GeneXpert in 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes.

UNASSIGNED

Ten-fold higher Mtb load was associated with increased disease severity (Odds Ratio=1.59, p=0.001 for grade 1 versus grade 3), and increased CSF neutrophils (r=0.364, p<0.0001) and cytokine concentrations (r=0.438, p<0.0001). High Mtb load predicted new neurological events after starting treatment (Multinomial logistic regression, p=0.005), but not death. Death was previously associated with attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations compared to survivors. In contrast, patients with high pre-treatment CSF bacterial loads, cytokines, and neutrophils were more likely to subsequently suffer neurological events.

UNASSIGNED

Pre-treatment GeneXpert-derived Mtb load may be a useful predictor of neurological complications occurring during TBM treatment. Therapeutic strategies aimed at reducing neurological complications and deaths from TBM may need reassessment, given the evidence for their divergent pathogenesis.

Tuberculous meningitis (TBM) is a serious meningitic infection commonly found to occur in the developing countries endemic to tuberculosis. Based on the clinical features alone, the diagnosis of TBM can neither be made nor excluded with certainty. Unfortunately there is still no single diagnostic method that is both sufficiently rapid and sensitive. Most factors found to correlate with poor outcome can be directly traced to the stage of the disease at the time of diagnosis. The only way to reduce the mortality and morbidity is by early diagnosis and timely recognition of complications and institution of the appropriate treatment strategies.