Due to inconsistent clinical presentations and the lack of a rapid, sensitive and specific test, tuberculous meningitis (TBM) is particularly difficult to diagnose. The present study was carried out to determine the utility of the polymerase chain reaction (PCR) using INS primers in the diagnosis of TBM and to compare the efficacy of two different DNA extraction protocols. Fifty-seven cerebrospinal fluid (CSF) samples from suspected cases of meningitis -- 30 definitive/possible TBM and 27 non-TBM -- were processed for microscopy, culture and PCR. Results of computer tomographic (CT) scan findings were noted. The results of smear, culture and PCR were compared using culture and/or clinical response to treatment as the gold standard. The sensitivity of microscopy, culture, CT scan and PCR was 3.3%, 26.7%, 60.0% and 66.7%, respectively. PCR following QIAmp DNA extraction had a sensitivity of 66.7% compared to PCR following a DNA extraction protocol based on the use of cetyl trimethyl ammonium bromide (CTAB) (50%). PCR was positive in all culture-positive CSF samples using either extraction method. PCR is a rapid and sensitive technique; above all, it can diagnose tuberculous meningitis at a very early stage.

Tubeimoside I (TBMS I), an extract from Chinese herbal medicine Bolbostemma paniculatum (MAXIM.) FRANQUET (Cucurbitaceae) has been shown as a potent anti-tumor agent for a variety of human cancers, but yet to be evaluated for hepatoma that is highly prevalent in Eastern Asian countries including China. Here, we examined in vitro the cytotoxic effects of TBMS I on human hepatoma (HepG2) and normal liver (L-02) cell lines. We also investigated TBMS I-induced molecular events related to apoptosis in HepG2 cells. The results show that TBMS I inhibited the proliferation of both HepG2 and L-02 cells in a dose- and time-dependent manner, but HepG2 cells appeared more sensitive to the agent. When exposed to TBMS I for 24, 48 and 72 h, IC₅₀ for HepG2 cells versus L-02 cells were 15.5 vs. 23.1, 11.7 vs. 16.2, 9.2 vs. 13.1 (µM, p<0.01), respectively. TBMS I induced cell shrinkage, nuclear condensation and fragmentation, cell cycle arrest at the G2/M phase, mitochondrial membrane disruption, release of cytochrome c from the mitochondria, activation of caspase 3 and 9, and shifting Bax/Bcl-2 ratio from being anti-apoptotic to pro-apoptotic, all indicative of initiation and progression of apoptosis involving mitochondrial dysfunction. Taken together, these results indicate for the first time that TBMS I potently inhibited growth in HepG2 cells by mediating a cascade of apoptosis signaling pathways. Considering its sensitivity of HepG2 cells, preferential distribution in the liver and natural product origin, TBMS I therefore may have a great potential as a chemotherapeutic drug candidate for hepatoma.

BACKGROUND

The management of granulomatous mastitis depends on the causative factor, and accurate diagnosis in distinguishing between idiopathic granulomatous mastitis (IGM) and tuberculous mastitis (TBM) is indispensable. This is particularly problematic in the cases of granulomatous mastitis in which the microbiological studies are negative. In this study, in a large cohort, the histological features for IGM and TBM were compared.

METHODS

The histopathology files from the two participating hospitals were searched for cases of granulomatous inflammation of the breast over an 8-year period. The parameters assessed included age of patient, lesional size, systemic and local symptoms, and histological findings of inflammatory cells, granulomas, necrosis, multinucleated giant cells, fibrosis and calcifications.

RESULTS

29 cases of IGM and 33 cases of TBM were included in this study. A significant difference was seen between the two groups with regard to patient age (t=2.52, p<0.05) and lesional size (t=-5.56, p<0.01). TBM occurred in a significantly younger population, and demonstrated larger lesional sizes than IGM. There was no difference between the number of cases showing mass, local and systemic symptoms. Comparing the different histological features, the TBM group showed significantly more fibrosis, eosinophils and necrosis, whereas the IGM group showed significantly more plasma cells. Taking all the cases together as one group to evaluate the relationship between the histological parameters, there was significant positive correlation between eosinophils and fibrosis (r(s)=0.39, p<0.01), and negative correlation between vague and well-formed granulomas (r(s)=-0.38, p<0.01).

CONCLUSIONS

TBM was more likely to occur in younger patients, with a larger clinical mass at presentation. Histologically, TBM tends to show more eosinophils and necrosis, and IGM is associated with more plasma cells. The characteristics of the granulomas and giant cells were not distinguishing features.

Concentrations of interferon gamma (IFN-gamma) in the lumbar cerebrospinal fluid (CSF) of 30 children (mean age, 27 months) being treated for stage III (16 children) and stage II (14 children) tuberculosis meningitis (TBM) were determined by ELISA. Nine children with stage III TBM and six with stage II TBM received prednisone (4 mg/kg). Concentrations of IFN-gamma in 73 CSF specimens (18 from the first week of therapy, 20 from the second, 19 from the third, and 16 from the fourth) were determined. The mean concentrations were 780 pg/mL in the first week of therapy and 554 pg/mL, 529 pg/mL, and 269 pg/mL in the second, third, and fourth weeks, respectively. Tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) concentrations in 56 specimens from 23 of these same children were determined by ELISA. The mean CSF TNF-alpha concentration in 12 specimens obtained during the first week of therapy was 17 pg/mL, and the mean was 11 pg/mL during each of the subsequent weeks (14 specimens were evaluated in the second week and 15 specimens in the third and fourth weeks of therapy). Mean IL-1beta concentrations in these same groups of specimens were 52 pg/mL, 43 pg/mL, 42 pg/mL, and 18 pg/mL. No correlation could be shown between cytokine concentration and stage of disease, and no differences existed between those who did and those who did not receive prednisone. A significant decline in IL-1beta concentrations was shown during the 4-week period, but none in TNF-alpha or IFN-gamma concentrations was noted. Persistently high CSF INF-gamma concentrations in cases of TBM (as in cases of aseptic meningitis but not bacterial meningitis) at the time of diagnosis suggest an immune response fundamentally different from that in bacterial meningitis.

BACKGROUND

Diagnosis of tuberculous meningitis (TBM) is difficult. Rapid confirmatory diagnosis is essential to initiate required therapy. There are very few published reports about the diagnostic significance of 65 kD heat shock protein (hsp) in TBM patients, which is present in a wide range of Mycobacterium tuberculosis species and elicits a cellular and humoral immune response. In the present study we have conducted a prospective evaluation for the demonstration of 65 kD hsp antigen in cerebrospinal fluid (CSF) of TBM patients, by indirect ELISA method using monoclonal antibodies (mAb) against the 65 kD hsp antigen, for the diagnosis of TBM.

METHODS

A total of 160 CSF samples of different groups of patients (confirmed TBM {n = 18}, clinically suspected TBM {n = 62}, non TBM infectious meningitis {n = 35} and non-infectious neurological diseases {n = 45}) were analyzed by indirect ELISA method using mAb to 65 kD hsp antigen. The Kruskal Wallis test (Non-Parametric ANOVA) with the Dunnett post test was used for statistical analysis.

RESULTS

The indirect ELISA method yielded 84% sensitivity and 90% specificity for the diagnosis of TBM using mAb to 65 kD hsp antigen. The mean absorbance value of 65 kD hsp antigen in TBM patients was [0.70 +/- 0.23 (0.23-1.29)], significantly higher than the non-TBM infectious meningitis group [0.32 +/- 0.14 (0.12-0.78), P < 0.001] and also higher than the non-infectious neurological disorders group [0.32 +/- 0.13 (0.20-0.78), P < 0.001]. A significant difference in the mean absorbance of 65 kD hsp antigen was noted in the CSF of culture-positive TBM patients [0.94 +/- 0.18 (0.54-1.29)] when compared with clinically suspected TBM patients [0.64 +/- 0.20 (0.23-0.98), P < 0.05].

CONCLUSIONS

The presence of 65 kD hsp antigen in the CSF of confirmed and suspected cases of TBM would indicate that the selected protein is specific to M. tuberculosis and could be considered as a diagnostic marker for TBM.

OBJECTIVE

To evaluate the spectrum of aetiologies, and distinguishing clinical and laboratory features, of meningeal infection in a community with a high prevalence of tuberculosis (TB) and HIV infection.

METHODS

A hospital serving mineworkers, originating from rural areas of Southern Africa.

METHODS

Prospective cohort of 60 consecutive lumbar punctures (LPs), performed for suspected meningitis.

METHODS

Clinical history and examination; concurrent cerebrospinal fluid (CSF) and blood samples; mortality status six months after entry to study.

RESULTS

38 of 57 patients (66.7%) were HIV-1 positive, 59.5% of whom had a CD4 count <200 cells/mm3. Nine patients had tuberculous meningitis (TBM) and two had tuberculomas; four developed disease while on TB therapy. There was one case of multidrug, and two of isoniazid-resistant TBM. There were nine episodes of cryptococcal meningitis (seven patients), nine of aseptic meningitis, two of neurosyphilis and 20 normal LPs, including four with AIDS dementia complex (ADC). Ten patients with meningococcal infection, part of a larger outbreak, were significantly younger (p=0.004). All patients with tuberculous, cryptococcal (most immune-suppressed p<0.001) and aseptic meningitis were HIV-1 positive. Within six months, 19 patients had died. Death was associated with HIV positivity (p=0.004), low CD4 count (p<0.001) and a diagnosis of cryptococcal meningitis, CNS TB or ADC.

CONCLUSIONS

HIV has a major impact on the burden of disease and mortality, with a predominance of opportunistic chronic meningitides, despite a meningococcal outbreak, in this community. Of concern is the development of TBM despite therapy, and the emergence of drug-resistant strains.

BACKGROUND

Treatment of obstructive hydrocephalus in children with tuberculous meningitis (TBM) depends on the level of the cerebrospinal fluid (CSF) block. Air-encephalography is regarded as the gold standard for differentiating communicating and non-communicating hydrocephalus. Since air-encephalography involves a lumbar puncture, it carries the risk of cerebral herniation. AIM. The aim of this study was to determine whether communicating and non-communicating hydrocephalus in TBM can be differentiated by means of cranial computerised tomography (CT).

METHODS

A number of CT indices were measured in 50 children with communicating and 34 children with non-communicating hydrocephalus according to air-encephalographic findings.

RESULTS

The only CT finding that correlated with the type of hydrocephalus was the shape of the third ventricle. Significantly more children with non-communicating hydrocephalus had a rounded third ventricle than those with communicating hydrocephalus.

CONCLUSIONS

CT is therefore not useful in determining the level of CSF block in TBM. Air-encephalography remains the most reliable way of determining the level of CSF obstruction.

BACKGROUND

Ischemic complications are known to occur in tuberculous meningitis (TBM). They are usually seen in patients with TBM having a more severe disease. Diffusion weighted imaging (DWI) provides information regarding tissue ischemia at an early stage as compared to conventional magnetic resonance imaging (MRI).

METHODS

Ischemic complications in human immunodeficiency virus (HIV) negative TBM were evaluated using DWI and T2 weighted imaging in 30 patients in the present study. The imaging was performed at baseline within 7 days of admission and in case of any neurological deterioration during follow up. The outcome was assessed by the modified Barthel's index at 1 year follow up. A score of>>/=12 was taken as a poor outcome, while a score of <12 was considered as good outcome.

RESULTS

Seventeen of these 30 patients had infarcts, and the total number of infarcts seen was 42. Thirty eight lesions were acute/sub acute and four were chronic infarcts. Out of the 38 acute/sub acute infarcts 34 were visible both on T2 weighted imaging and on DWI, while four were seen only on DWI. The volume of infarcts as seen by DWI was significantly larger as compared to conventional T2 weighted imaging (p = 0.019). Six patients had a poor outcome, five from the infarct group and one from the non-infarct group.

CONCLUSIONS

DWI demonstrates a larger area of infarction and may also be useful in the early detection of infarction. It should be used as an additional sequence along with conventional imaging in patients with TBM while they are on a follow up on anti tuberculous treatment. The information obtained by DWI may be of value in explaining the clinical condition of the patient as well as in the management and prognostication.

Tracheobronchomalacia (TBM) and excessive dynamic airway collapse (EDAC) are both dynamic forms of central airway obstruction characterized by a decrease of>>/=50% in the cross-sectional area of the tracheobronchial lumen. The differences between these two entities, however, are not uniformly accepted in the medical community. While TBM is characterized by a weakness of the tracheobronchial cartilaginous structures, EDAC is marked by excessive bulging of the posterior membrane into the airway lumen during exhalation. These disease entities are probably underdiagnosed because they present with a variety of nonspecific symptoms similar to patients with other obstructive ventilatory disorders such as asthma and COPD. Diagnosis is confirmed by dynamic radiologic imaging studies or bronchoscopy. Current therapeutic management depends on the extent, type, and severity of airway abnormalities noted and the clinical presentation. Proposed management alternatives include conservative medical therapy, and minimally invasive and open surgical interventions. Inhaled bronchodilators should be used only if symptoms and ventilatory function improve after use. Continuous positive airway pressure acts as a pneumatic stent and should be considered as an alternative or additional therapeutic modality. Endoluminal stent insertion can improve symptoms and pulmonary function in patients with central airway obstruction and should be considered for patients with symptoms refractory to conservative therapy. Several open surgical procedures have also been performed over the years, including tracheostomy, airway splinting, tracheal resection and, more recently, external tracheal stents. Endobronchial laser therapy, resorbable stents, application of grafting materials used to support the collapsed airway as well as the use of cartilage regeneration techniques are experimental, and their efficacy in humans remains to be determined. Future studies should compare therapeutic interventions and outcomes such as functional status, ventilatory function, and bronchoscopic and radiologic appearances in order to define the costs and benefits of individual and combined treatment modalities.

Here we introduce multivariate tensor-based surface morphometry using holomorphic one-forms to study brain anatomy. We computed new statistics from the Riemannian metric tensors that retain the full information in the deformation tensor fields. We introduce two different holomorphic one-forms that induce different surface conformal parameterizations. We applied this framework to 3D MRI data to analyze hippocampal surface morphometry in Alzheimer's Disease (AD; 26 subjects), lateral ventricular surface morphometry in HIV/AIDS (19 subjects) and cortical surface morphometry in Williams Syndrome (WS; 80 subjects). Experimental results demonstrated that our method powerfully detected brain surface abnormalities. Multivariate statistics on the local tensors outperformed other TBM methods including analysis of the Jacobian determinant, the largest eigenvalue, or the pair of eigenvalues, of the surface Jacobian matrix.

The localization of the membrane attack complex of complement (MAC) was examined in the normal human kidneys and in biopsy specimens from patients with primary IgA nephropathy by immunofluorescent and immunoelectron microscopies. Immunofluorescent staining for MAC was significantly more intense than in the normal kidneys, and was observed in the mesangium and occasionally along the glomerular capillary walls of 22 of 30 patients with IgA nephropathy. By dual-staining, the MAC deposits were generally concordant with the deposits of IgA, C3, C5 and C9, or of IgG, when present. C1q or C4 was infrequently observed in the glomeruli. Immunoelectron microscopy revealed various staining patterns of glomerular MAC deposition; homogeneous fine-granular staining beneath the glomerular basement membrane (GBM) in the paramesangial zone, patchy staining within the mesangial electron dense deposits (EDD), and ring-shaped or ribbon-like staining, associated with the striated membrane structures (SMS), in the matrix of the mesangium, GBM and tubular basement membrane (TBM). This study suggests that the terminal complement system is activated, mainly by an alternative complement pathway mechanism, in the mesangium of IgA nephropathy, and is associated with the paramesangial lesion and EDD. MAC deposition in glomerular SMS may also result from in situ activation rather than trapping from the circulation. There was little correlation between glomerular MAC deposition and proteinuria or renal histology of patients with IgA nephropathy.

We develop two complementary pipelines, "Zhang-Server" and "QUARK", based on I-TASSER and QUARK pipelines for template-based modeling (TBM) and free modeling (FM), and test them in the CASP12 experiment. The combination of I-TASSER and QUARK successfully folds three medium-size FM targets that have more than 150 residues, even though the interplay between the two pipelines still awaits further optimization. Newly developed sequence-based contact prediction by NeBcon plays a critical role to enhance the quality of models, particularly for FM targets, by the new pipelines. The inclusion of NeBcon predicted contacts as restraints in the QUARK simulations results in an average TM-score of 0.41 for the best in top five predicted models, which is 37% higher than that by the QUARK simulations without contacts. In particular, there are seven targets that are converted from non-foldable to foldable (TM-score >0.5) due to the use of contact restraints in the simulations. Another additional feature in the current pipelines is the local structure quality prediction by ResQ, which provides a robust residue-level modeling error estimation. Despite the success, significant challenges still remain in ab initio modeling of multi-domain proteins and folding of β-proteins with complicated topologies bound by long-range strand-strand interactions. Improvements on domain boundary and long-range contact prediction, as well as optimal use of the predicted contacts and multiple threading alignments, are critical to address these issues seen in the CASP12 experiment.

BACKGROUND

Tracheobronchomalacia (TBM) is characterized by excessive collapsibility of the central airways, typically during expiration. TBM may be present in as many as 50% of patients evaluated for COPD. The impact of central airway stabilization on symptom pattern and quality of life is poorly understood in this patient population.

METHODS

Patients with documented COPD were identified from a cohort of 238 patients assessed for TBM at our complex airway referral center. Pulmonary function testing, exercise tolerance, and health-related quality-of-life (HRQOL) measures were assessed at baseline and 2 to 4 weeks following tracheal stent placement/operative tracheobronchoplasty (TBP). Severity of COPD was classified according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) staging system.

RESULTS

One hundred three patients (48 women) with COPD and moderately severe to severe TBM were identified. Statistically and clinically significant improvements were seen in HRQOL measures, including the transitional dyspnea index (stent, P = .001; TBP, P = .008), the St. George Respiratory Questionnaire (stent, P = .002; TBP, P < .0001), and the Karnofsky performance score (stent, P = .163; TBP, P < .0001). The improvement appeared greatest following TBP and was seen in all GOLD stages. Clinical improvement was also seen in measured FEV(1) and exercise capacity as assessed by 6-min walk test.

CONCLUSIONS

Central airway stabilization may provide symptomatic benefit for patients with severe COPD and concomitant severe airway malacia. Operative airway stabilization appears to impart the greatest advantage. Long-term follow-up study is needed to fully ascertain the ultimate efficacy of both stenting and surgical airway stabilization in this patient group.

HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.

Improving the accuracy of estimates of forest carbon exchange is a central priority for understanding ecosystem response to increased atmospheric CO2 levels and improving carbon cycle modelling. However, the spatially continuous parameterization of photosynthetic capacity (Vcmax) at global scales and appropriate temporal intervals within terrestrial biosphere models (TBMs) remains unresolved. This research investigates the use of biochemical parameters for modelling leaf photosynthetic capacity within a deciduous forest. Particular attention is given to the impacts of seasonality on both leaf biophysical variables and physiological processes, and their interdependent relationships. Four deciduous tree species were sampled across three growing seasons (2013-2015), approximately every 10 days for leaf chlorophyll content (ChlLeaf ) and canopy structure. Leaf nitrogen (NArea ) was also measured during 2014. Leaf photosynthesis was measured during 2014-2015 using a Li-6400 gas-exchange system, with A-Ci curves to model Vcmax. Results showed that seasonality and variations between species resulted in weak relationships between Vcmax normalized to 25°C (Vcmax25) and NArea (R2 = 0.62, P < 0.001), whereas ChlLeaf demonstrated a much stronger correlation with Vcmax25 (R2 = 0.78, P < 0.001). The relationship between ChlLeaf and NArea was also weak (R2 = 0.47, P < 0.001), possibly due to the dynamic partitioning of nitrogen, between and within photosynthetic and nonphotosynthetic fractions. The spatial and temporal variability of Vcmax25 was mapped using Landsat TM/ETM satellite data across the forest site, using physical models to derive ChlLeaf . TBMs largely treat photosynthetic parameters as either fixed constants or varying according to leaf nitrogen content. This research challenges assumptions that simple NArea -Vcmax25 relationships can reliably be used to constrain photosynthetic capacity in TBMs, even within the same plant functional type. It is suggested that ChlLeaf provides a more accurate, direct proxy for Vcmax25 and is also more easily retrievable from satellite data. These results have important implications for carbon modelling within deciduous ecosystems.

Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment.

We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression.

Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM.

Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored.

ISRCTN61649292.

Post-tubercular meningitic hydrocephalus (TBMH) and post-traumatic hydrocephalus (PTH) is often considered a contraindication for endoscopic third ventriculostomy (ETV), as it is mostly of communicating type in these cases. The aim of the present study was to define the role of ETV in patients with communicating hydrocephalus. Ten consecutive patients of TBMH, PTH and postneurocysticercus (NCC) hydrocephalus were formed the study group. Diagnosis of communicating hydrocephalus was made using magnetic resonance ventriculography (MRV). If contrast was seen coming out from the ventricular system into the basal cisterns, it was considered as communicating hydrocephalus. Patients with clinical and imaging evidence of raised intracranial pressure and failed medical treatment were taken up for ETV. All patients were studied by preoperative and postoperative MRV. Success of the procedure was assessed by the improvement in clinical and imaging parameters on postprocedure follow-up in all these cases. Technically successful ETV was performed in all 10 patients. Overall success rate of ETV in communicating hydrocephalus was 70% (n = 7). The shunt surgery was performed in the remaining three patients with ETV failure. One patient developed complication following postoperative MRV and was managed conservatively. We conclude that ETV is effective in post-TBM, post-traumatic communicating and post-NCC communicating hydrocephalus and should be considered as initial surgical option for cerebrospinal fluid diversion in these patients. MRV is a relatively safe technique to ascertain the patency of subarachnoid space as well as ETV stoma.

Members of the large G protein-coupled receptor (GPCR) clan are implicated in many physiological and disease processes, making them important therapeutic drug targets. In the present study, we follow up on results of a pilot study suggesting a functional relationship between glucocorticoid (GC)-induced ocular hypertension and GPR158, one of three orphan members of the GPCR Family C. GC treatment increases levels of GPR158 mRNA and protein through transcriptional mechanisms, in cultured trabecular meshwork (TBM) cells derived from the eye's aqueous outflow pathway. Like treatment with GCs, transient overexpression of GPR158 stimulates cell proliferation, while siRNA knockdown of endogenous GPR158 has the opposite effect. Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. However, when cells are treated with inhibitors of clathrin-mediated endocytosis, GPR158 is shifted to the plasma membrane. Mutation of a bipartite nuclear localization signal (NLS) in the 8(th) helix also shifts GPR158 out of the nucleus, but in this case the protein is found in vesicles localized in the cytoplasm. These results suggest that newly synthesized GPR158 first traffics to the plasma membrane, where it rapidly undergoes endocytosis and translocation to the nucleus. Significantly, mutation of the NLS abrogates GPR158-mediated enhancement of cell proliferation, indicating a functional requirement for nuclear localization. GPR158 overexpression upregulates levels of the cell cycle regulator cyclin D1, but mutation of the NLS reverses this. Overexpression of GPR158 enhances the barrier function of a TBM cell monolayer, which is associated with an increase in the levels of tight junction proteins ZO-1 and occludin, similar to reported studies on GC treatment. Regulated paracellular permeability controls aqueous outflow facility in vivo. Since GCs stimulate GPR158 expression, the result is consistent with a role for elevation of GPR158 expression in GC-induced ocular hypertension.

Accurate representation of photosynthesis in terrestrial biosphere models (TBMs) is essential for robust projections of global change. However, current representations vary markedly between TBMs, contributing uncertainty to projections of global carbon fluxes. Here we compared the representation of photosynthesis in seven TBMs by examining leaf and canopy level responses of photosynthetic CO2 assimilation (A) to key environmental variables: light, temperature, CO2 concentration, vapor pressure deficit and soil water content. We identified research areas where limited process knowledge prevents inclusion of physiological phenomena in current TBMs and research areas where data are urgently needed for model parameterization or evaluation. We provide a roadmap for new science needed to improve the representation of photosynthesis in the next generation of terrestrial biosphere and Earth system models.

This review focusses on paradoxical reactions occurring during the treatment of tuberculous meningitis (TBM) in human immunodeficiency virus-negative cases. A paradoxical reaction is defined as the worsening of a pre-existing lesion or the appearance of new lesion in a patient whose clinical symptoms initially improved with anti-tuberculosis treatment. A number of different paradoxical reactions have been reported in patients with TBM including expansion of existing cerebral tuberculomas, and appearance of new tuberculomas, hydrocephalus, and optochiasmatic and spinal arachnoiditis. While the exact mechanism of paradoxical reactions is uncertain, an exaggerated immune reaction against Mycobacterium tuberculosis-associated antigens is currently the most accepted theory for tuberculous paradoxical reaction. Corticosteroids are considered to have a beneficial effect in the management of paradoxical reactions. Immuno-modulatory drugs, including tumor necrosis factor-α antagonists, thalidomide and interferon-γ have been used in isolated cases with more severe forms of paradoxical reactions.

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM.

We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations.

LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype.

LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

The localization and distribution of complement components in term and pre-term normal human placentae have been studied by using haemadsorption and immunofluorescence experiments. The components Clq, C4, C5, C6 and C9 were identified in characteristic locations. Receptors for C3 and C4 were not found. Complement was associated with certain stromal cells, areas of fibrinoid necrosis within the trophoblastic mantle, and in the walls and endothelia of foetal stem vessels. Activation of the complement system on trophoblastic basement membranes (TBM) did not appear to involve the early reacting components of the classical pathway of complement activation, because C1q, C4 and C2 could not be identified on TBM. The C6 component was identified within cytoplasmic granules of foetal stem vessel endothelia, suggesting that it may be synthesized by these cells. These findings put forward the possibility that complement may play an immunobiological role in the materno-foetal relationship during normal human pregnancy.

Tuberculosis (TB) remains a leading cause of death globally. Dissemination of TB to the brain results in the most severe form of extrapulmonary TB, tuberculous meningitis (TBM), which represents a medical emergency associated with high rates of mortality and disability. Via various mechanisms the Mycobacterium tuberculosis (M.tb) bacillus disseminates from the primary site of infection and overcomes protective barriers to enter the CNS. There it induces an inflammatory response involving both the peripheral and resident immune cells, which initiates a cascade of pathologic mechanisms that may either contain the disease or result in significant brain injury. Here we review the steps from primary infection to cerebral disease, factors that contribute to the virulence of the organism and the vulnerability of the host and discuss the immune response and the clinical manifestations arising. Priorities for future research directions are suggested.

UNASSIGNED

Neuroimaging studies have revealed that disturbances in network organization of key brain regions may underlie cognitive and emotional dysfunction in posttraumatic stress disorder (PTSD). Examining both brain structure and function in the same population may further our understanding of network alterations in PTSD.

UNASSIGNED

We used tensor-based morphometry (TBM) and intrinsic connectivity distribution (ICD) to identify regions of altered volume and functional connectivity in unmedicated individuals with PTSD (n=21) and healthy comparison (HC) participants (n=18). These regions were then used as seeds for follow-up anatomical covariance and functional connectivity analyses.

UNASSIGNED

Smaller volume in the cerebellum and weaker structural covariance between the cerebellum seed and middle temporal gyrus were observed in the PTSD group. Individuals with PTSD also exhibited lower whole-brain connectivity in the cerebellum, dorsolateral prefrontal cortex (dlPFC) and medial prefrontal cortex (mPFC). Functional connectivity in the cerebellum and grey matter volume in the dlPFC were negatively correlated with PTSD severity as measured by the DSM-5 PTSD checklist (PCL-5; r= -.0.77, r=-0.79). Finally, seed connectivity revealed weaker connectivity within nodes of the central executive network (right and left dlPFC), and between nodes of the default mode network (mPFC and cerebellum) and the supramarginal gyrus, in the PTSD group.

UNASSIGNED

We demonstrate structural and functional alterations in PTSD converging on the PFC and cerebellum. Whilst PFC alterations are relatively well established in PTSD, the cerebellum has not generally been considered a key region in PTSD. Our findings add to a growing evidence base implicating cerebellar involvement in the pathophysiology of PTSD.