Follicular dendritic cells (FDCs) were originally identified by their specific morphology and by their ability to trap immune-complexed antigen in B cell follicles. By virtue of the latter as well as the provision of chemokines, adhesion molecules, and trophic factors, FDCs participate in the shaping of B cell responses. Importantly, FDCs also supply tingible body macrophages (TBMs) with the eat-me-signaling molecule milk fat globule-EGF factor 8 (Mfge8), thereby enabling the disposal of apoptotic B cells. Recent studies have provided fundamental insights into the multiple functions of FDCs in both physiological and pathophysiological contexts and into their origin. Here we review these findings, and discuss current concepts related to FDC histogenesis both in lymphoid organs and in inflammatory lymphoneogenesis.

Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the beta-lactamase/beta-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Delta) in fibroblasts from a patient with HH syndrome. Apollo-Delta generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor.

Hydrocephalus is a common complication of tuberculous meningitis (TBM) in children. In this study, 217 patients with stage II and III TBM and hydrocephalus (TBMH) were reviewed. Ventriculoperitoneal shunting (VPS) was performed in the acute stage if the hydrocephalus was non-communicating or following failed medical therapy if the hydrocephalus was communicating. Following this protocol only 65 of 217 (29.9%) patients eventually required VPS. Non-communicating hydrocephalus was present in 38 of 65 (58.5%) and communicating hydrocephalus in 27 of 65 (41.5%) of the shunted cases. These 65 cases were followed for 6 months and their outcome assessed. Good outcome or moderate disability was seen in 55.4% and 12.3% died. Different factors relating to outcome are discussed. The shunted patients in this study had a high complication rate of 32.3%, with shunt infection and shunt obstruction each occurring in 9 of 65 (13.5%) of cases. TBM complicated by hydrocephalus remains a devastating condition and VPS in these patients has a high complication rate. Identifying those patients who may be managed without shunting will save costs and reduce complications, however early VPS in patients with non-communicating hydrocephalus is still indicated.

Chronic unilateral ureteral obstruction (UUO) results in interstitial fibrosis of the affected kidney. In this study we determined that enalapril ameliorates the increased production of extracellular matrix (ECM) protein in the tubulointerstitium during UUO. The relative volume (Vv) of the tubulointerstitium measured by a point-counting method increased significantly at three or five days of UUO as compared to the contralateral kidney. Enalapril significantly blunted this increase at either three or five days. Immunofluorescence studies revealed that collagen type IV increased remarkably in both the tubular basement membrane (TBM) and the interstitial space at three or five days of UUO. Glomeruli did not show any change. Collagen types I and III were faintly stained in the control kidneys while they were obviously increased in the interstitial space of the obstructed kidney. We examined the expression of collagen type IV (COL IV) because this basement membrane matrix protein appeared to be a major ECM protein deposited in the tubulointerstitium of the obstructed kidney. Semiquantitative analysis of COL IV by immunofluorescence microscopy revealed that enalapril reduced slightly (21%) but significantly (P < 0.01) the deposition of COL IV in the obstructed kidney. Measurement of cyanogen bromide peptides from the obstructed kidney by Western blotting showed an increase of COL IV. This increase was reduced slightly (20%) by enalapril. The level of COL IV mRNA measured by reverse transcription-PCR was very low or undetectable in the control and contralateral kidneys, while it was significantly increased in the obstructed kidney at three or five days of UUO. COL IV mRNA was abundant in glomeruli while it was almost undetectable in renal tubules in the control and contralateral kidneys. However, COL IV mRNA was increased in renal tubules but not in the glomeruli of the obstructed kidney. Enalapril treatment resulted in a 42% decrease (P < 0.01) in COL IV mRNA in the cortex and a remarkable decrease in the renal tubules of the obstructed kidney at five days. Enalapril treatment resulted in an 89% decrease in the number of infiltrating ED-1 positive monocytes/macrophages. These results indicate that enalapril treatment ameliorates the tubulointerstitial fibrosis of the affected kidney in UUO. This effect of enalapril on fibrosis may be due to the severe reduction in monocytes/macrophages capable of secreting the profibrotic factor TGF-beta 1.

BACKGROUND

Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altogether, accounting for the progressive decline in renal function. The mechanisms which link glomerular injury to tubulo-interstitial fibrosis are controversial. The present study describes the step-by-step sequence of histopathological events, i.e. the evolution of the injury from the initial lesion in the glomerulus to total nephron destruction.

METHODS

The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive rats. The kidneys were fixed by in vivo perfusion and processed for structural investigation. Autopsy materials from human cases of focal segmental glomerulosclerosis and diabetic nephropathy were also examined.

RESULTS

FSGS as seen in rat models consists of collapsed and hyalinized capillaries and mesangial portions which are included within a synechia between the glomerular tuft and Bowman's capsule. In addition, a synechia generally contains glomerular capillaries which are perfused and continue to filter with the filtrate being delivered into the interstitium rather than into Bowman's capsular space. Such filtration creates a paraglomerular space on the outer aspect of the parietal epithelium. This space becomes separated from the interstitium by a dense layer of sheet-like fibroblast processes. Associated with the progression to global sclerosis, this space spreads around the entire circumference of a glomerulus; all 'sclerotic' tuft portions are eventually contained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basement membrane (TBM) and later, by separating the TBM from its epithelium, thus creating a peritubular space by misdirected filtrate spreading. Similar to the situation observed at the glomerulus this space becomes separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathway I whereby development to global sclerosis is dominant or develops concurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abundant fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glomerular cysts.

CONCLUSIONS

The present study suggests that severely injured glomeruli may continue to filter with the filtrate spreading along interstitial routes. Fluid added locally to the interstitium from such 'extraterritorial' glomerular capillaries probably is quite different in quantity and composition compared to that from interstitial capillaries. We propose that this kind of abnormal addition of fluid to the interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in human kidneys with focal segmental glomerulosclerosis suggest that the pathogenetic pathways defined in the rat models operate in human disease as well.

BACKGROUND

It is postulated that in patients with severe tracheobronchomalacia (TBM), airway stabilization with stents may relieve symptoms.

OBJECTIVE

To evaluate the effect of silicone stents (tracheal, mainstem bronchus, or both) on symptoms, quality of life, lung function, and exercise capacity in these patients.

METHODS

A prospective observational study in which baseline measurements were compared to those obtained 10 to 14 days after stent placement.

RESULTS

Of 75 referred patients, 58 had severe disease and underwent therapeutic rigid bronchoscopy with stent placement. Mean age was 69 years (range, 39 to 91 years), 34 were men, 33 had COPD, and 13 had asthma. Almost all patients (n = 57) had dyspnea as a sole symptom or in combination with cough and recurrent infections; four patients required mechanical ventilation for respiratory failure. In 45 of 58 patients, there was reported symptomatic improvement; quality of life scores improved in 19 of 27 patients (p = 0.002); dyspnea scores improved in 22 of 24 patients (p = 0.001); functional status scores improved in 18 of 26 patients (p = 0.002); and mean exercise capacity improved from baseline, although not significantly. The 49 complications included mainly 21 partial stent obstructions, 14 infections, and 10 stent migrations. Most patients with concomitant COPD also improved on most measures.

CONCLUSIONS

In the short term, airway stabilization with silicone stents in patients with severe TBM can improve respiratory symptoms, quality of life, and functional status. Coexisting COPD is not an absolute contraindication to a stenting trial in this population. Stenting is associated with a high number of short-term and long-term but generally reversible complications.

The Critical assessment of protein structure prediction round 9 (CASP9) aimed to evaluate predictions for 129 experimentally determined protein structures. To assess tertiary structure predictions, these target structures were divided into domain-based evaluation units that were then classified into two assessment categories: template based modeling (TBM) and template free modeling (FM). CASP9 targets were split into domains of structurally compact evolutionary modules. For the targets with more than one defined domain, the decision to split structures into domains for evaluation was based on server performance. Target domains were categorized based on their evolutionary relatedness to existing templates as well as their difficulty levels indicated by server performance. Those target domains with sequence-related templates and high server prediction performance were classified as TMB, whereas those targets without identifiable templates and low server performance were classified as FM. However, using these generalizations for classification resulted in a blurred boundary between CASP9 assessment categories. Thus, the FM category included those domains without sequence detectable templates (25 target domains) as well as some domains with difficult to detect templates whose predictions were as poor as those without templates (five target domains). Several interesting examples are discussed, including targets with sequence related templates that exhibit unusual structural differences, targets with homologous or analogous structure templates that are not detectable by sequence, and targets with new folds.

BACKGROUND

Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to 1 or more antituberculosis drugs is an increasingly common clinical problem, although the impact on outcome is uncertain.

METHODS

We performed a prospective study of 180 Vietnamese adults admitted consecutively for TBM. M. tuberculosis was cultured from the cerebrospinal fluid (CSF) of all patients and was tested for susceptibility to first-line antituberculosis drugs. Presenting clinical features, time to CSF bacterial clearance, clinical response to treatment, and 9-month morbidity and mortality were compared between adults infected with susceptible and those infected with drug-resistant organisms.

RESULTS

Of 180 isolates, 72 (40.0%) were resistant to at least 1 antituberculosis drug, and 10 (5.6%) were resistant to at least isoniazid and rifampicin. Isoniazid and/or streptomycin resistance was associated with slower CSF bacterial clearance but not with any differences in clinical response or outcome. Combined isoniazid and rifampicin resistance was strongly predictive of death (relative risk of death, 11.63 [95% confidence interval, 5.21-26.32]) and was independently associated with human immunodeficiency virus infection.

CONCLUSIONS

Isoniazid and/or streptomycin resistance probably has no detrimental effect on the outcome of TBM when patients are treated with first-line antituberculosis drugs, but combined isoniazid and rifampicin resistance is strongly predictive of death.

BACKGROUND

Very high levels of prenatal maternal mercury have adverse effects on the developing fetal brain. It has been suggested that all possible sources of mercury should be avoided. However, although seafood is a known source of mercury, little is known about other dietary components that contribute to the overall levels of blood mercury.

OBJECTIVE

Our goal was to quantify the contribution of components of maternal diet to prenatal blood mercury level.

METHODS

Whole blood samples and information on diet and sociodemographic factors were collected from pregnant women (n = 4,484) enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). The blood samples were assayed for total mercury using inductively coupled plasma dynamic reaction cell mass spectrometry. Linear regression was used to estimate the relative contributions of 103 dietary variables and 6 sociodemographic characteristics to whole blood total mercury levels (TBM; untransformed and log-transformed) based on R2 values.

RESULTS

We estimated that maternal diet accounted for 19.8% of the total variation in ln-TBM, with 44% of diet-associated variability (8.75% of the total variation) associated with seafood consumption (white fish, oily fish, and shellfish). Other dietary components positively associated with TBM included wine and herbal teas, and components with significant negative associations included white bread, meat pies or pasties, and french fries.

CONCLUSIONS

Although seafood is a source of dietary mercury, seafood appeared to explain a relatively small proportion of the variation in TBM in our UK study population. Our findings require confirmation, but suggest that limiting seafood intake during pregnancy may have a limited impact on prenatal blood mercury levels.

Matrix metalloproteinase-9 (MMP-9) is one of the major components of the matrix proteolytic network, and its role in the pathogenesis of renal interstitial fibrosis remains largely unknown. Here, we demonstrate that ablation of MMP-9 attenuated renal interstitial fibrotic lesions in obstructive nephropathy. Mice lacking MMP-9 were less likely to develop morphological injury, which was characterized by a reduced disruption of tubular basement membrane (TBM) and expression of fibronectin as well as deposition of total tissue collagen in the kidneys after sustained ureteral obstruction compared with their wild-type counterparts. Deficiency of MMP-9 blocked tubular epithelial-to-myofibroblast transition (EMT) but did not alter the induction of transforming growth factor (TGF)-β1 axis expression in the obstructed kidneys. In vitro, TBM, which was digested by MMP-9 instead of MMP-9 itself, induces EMT and enhances migration of transformed cells. Thus increased MMP-9 is detrimental in renal interstitial fibrogenesis through a cascade of events that leads to TBM destruction and in turn to promotion of EMT. Our findings establish a crucial and definite importance of MMP-9 in the pathogenesis of renal interstitial fibrosis at the whole-animal level.

Transcriptional activation in eukaryotes involves protein-protein interactions between regulatory transcription factors and components of the basal transcription machinery. Here we show that c-Fos, but not a related protein, Fra-1, can bind the TATA-box-binding protein (TBP) both in vitro and in vivo and that c-Fos can also interact with the transcription factor IID complex. High-affinity binding to TBP requires c-Fos activation modules which cooperate to activate transcription. One of these activation modules contains a TBP-binding motif (TBM) which was identified through its homology to TBP-binding viral activators. This motif is required for transcriptional activation, as well as TBP binding. Domain swap experiments indicate that a domain containing the TBM can confer TBP binding on Fra-1 both in vitro and in vivo. In vivo activation experiments indicate that a GAL4-Fos fusion can activate a promoter bearing a GAL4 site linked to a TATA box but that this activity does not occur at high concentrations of GAL4-Fos. This inhibition (squelching) of c-Fos activity is relieved by the presence of excess TBP, indicating that TBP is a direct functional target of c-Fos. Removing the TBM from c-Fos severely abrogates activation of a promoter containing a TATA box but does not affect activation of a promoter driven only by an initiator element. Collectively, these results suggest that c-Fos is able to activate via two distinct mechanisms, only one of which requires contact with TBP. Since TBP binding is not exhibited by Fra-1, TBP-mediated activation may be one characteristic that discriminates the function of Fos-related proteins.

Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer's disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy "younger elderly" volunteers, aged 55-75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively "normal" at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.

BACKGROUND

Template selection and target-template alignment are critical steps for template-based modeling (TBM) methods. To identify the template for the twilight zone of 15~25% sequence similarity between targets and templates is still difficulty for template-based protein structure prediction. This study presents the (PS)2-v2 server, based on our original server with numerous enhancements and modifications, to improve reliability and applicability.

RESULTS

To detect homologous proteins with remote similarity, the (PS)2-v2 server utilizes the S2A2 matrix, which is a 60 x 60 substitution matrix using the secondary structure propensities of 20 amino acids, and the position-specific sequence profile (PSSM) generated by PSI-BLAST. In addition, our server uses multiple templates and multiple models to build and assess models. Our method was evaluated on the Lindahl benchmark for fold recognition and ProSup benchmark for sequence alignment. Evaluation results indicated that our method outperforms sequence-profile approaches, and had comparable performance to that of structure-based methods on these benchmarks. Finally, we tested our method using the 154 TBM targets of the CASP8 (Critical Assessment of Techniques for Protein Structure Prediction) dataset. Experimental results show that (PS)2-v2 is ranked 6th among 72 severs and is faster than the top-rank five serves, which utilize ab initio methods.

CONCLUSIONS

Experimental results demonstrate that (PS)2-v2 with the S2A2 matrix is useful for template selections and target-template alignments by blending the amino acid and structural propensities. The multiple-template and multiple-model strategies are able to significantly improve the accuracies for target-template alignments in the twilight zone. We believe that this server is useful in structure prediction and modeling, especially in detecting homologous templates with sequence similarity in the twilight zone.

Twenty-eight patients with cerebral infarction secondary to chronic meningitis were retrospectively identified at our institution over a period of 5 years. They accounted for 47% (17/36) of tuberculous meningitis (TBM) and 32% (11/34) of cryptococcal meningitis cases. Single infarctions were found in 15 patients and multiple infarctions in 13. The distribution of single infarctions was: basal ganglia 7; internal capsule 3; thalamus 1; cerebellum 1; and cortical infarct 3. Therapeutic outcomes at 3 months were determined using a modified Barthel INDEX: At follow-up of 3 months or more, 10 had good outcomes while the other 18 had poor outcomes. The 18 with poor outcomes included six who died, and 12 who had severe neurological sequelae. TBM and cryptococcal meningitis shared similar clinical features, both being frequently associated with other neurological complications, including hydrocephalus, cranial nerve palsy, and seizures in our patients. However, extracranial involvement, such as spinal and pulmonary involvement, was more commonly found in TBM patients. Cerebral infarction can occur in both the acute stage and later stages of treatment. Mortality and morbidity are high, and early diagnosis and appropriate antimicrobial treatment are essential. If hydrocephalus is demonstrated, early ventricular decompression is needed to prevent further cerebral ischaemia.

Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies - including corticosteroids, aspirin and thalidomide - has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.

Hydrocephalus is one of the commonest complications of tuberculous meningitis (TBM) occurring in up to 85% of children with the disease. It is more severe in children than in adults. It could be either of the communicating type or the obstructive type with the former being more frequently seen. The Vellore grading system for clinical grading of patients with TBM and hydrocephalus with grade I being the best grade and grade IV being the worst grade has been validated by several authors. The management of hydrocephalus can include medical therapy with dehydrating agents and steroids for patients in good grades and those with communicating hydrocephalus. However, surgery is required for patients with obstructive hydrocephalus and those in poor grades. Surgery can involve either a ventriculo-peritoneal shunt or endoscopic third ventriculostomy (ETV). Complications of shunt surgery in patients with TBM and hydrocephalus are high with frequent shunt obstructions and shunt infections requiring repeated revisions. ETV has variable success in these patients and is generally not advisable in patients in the acute stages of the disease. Mortality on long-term follow up has been reported to vary from 10.5% to 57.1% in those with altered sensorium prior to surgery and 0 to 12.5% in patients with normal sensorium. Surgery for patients in Vellore grade IV is usually associated with a poor outcome and high mortality and therefore, its utility in these patients is debatable.

Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r=-0.51, p=3.85 x 10(-7); caudate nucleus: r=-0.43, p=2.35 x 10(-5); putamen: r=-0.36, p=6.12 x 10(-6)). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r=-0.56, p=9.96 x 10(-9); caudate nucleus: r=-0.31, p=3.10 x 10(-3); putamen: r=-0.50, p=6.06 x 10(-7)), 2) T1 hypointense lesion volumes (thalamus: r=-0.61, p=2.29 x 10(-10); caudate nucleus: r=-0.35, p=9.51 x 10(-4); putamen: r=-0.43, p=3.51 x 10(-5)), and 3) normalized CSF volume (thalamus: r=-0.66, p=3.55 x 10(-12); caudate nucleus: r=-0.52, p=2.31 x 10(-7), and putamen: r=-0.66, r=2.13 x 10(-12)). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS.

In order to understand the molecular mechanism of ouabain resistance in the toad Bufo marinus, Na,K-ATPase alpha and beta subunits have been cloned and their functional properties tested in the Xenopus laevis oocyte expression system. According to sequence comparison between species, alpha 1, beta 1, and beta 3 isoforms were identified in a clonal toad urinary bladder cell line (TBM 18-23). The sequence of the alpha 1 isoform is characterized by two positively charged amino acids (Arg, Lys) at the N-terminal border of the H1-H2 extracellular loop and no charged amino acid at the C terminus, a pattern distinct from the ouabain-resistant rat alpha 1 isoform. The coexpression of alpha 1 beta 1 or alpha 1 beta 3 TBM subunits in the Xenopus oocyte resulted in the expression of identical maximum Na,K-pump currents with identical inhibition constant for ouabain (Ki) (alpha 1 beta 1: 53 +/- 3 microM; n = 7 vs. alpha 1 beta 3: 57 +/- 3.0 microM; n = 8) but distinct potassium half activation constant (K1/2) (alpha 1 beta 1: 0.87 +/- 0.08 mM, n = 16; alpha 1 beta 3: 1.29 +/- 0.07 mM, n = 17; p less than 0.005). We conclude that (i) the TBM alpha 1 isoform is necessary and sufficient to confer the ouabain resistant phenotype; (ii) the beta 3 or beta 1 subunit can associate with the alpha 1 equally well without affecting the ouabain-resistant phenotype; (iii) some specific sequence of the beta subunit can modulate the activation of the Na,K-pump by extracellular potassium ions.

Tuberculous meningitis (TBM) develops most often when a caseating meningeal or sub-cortical focus, the Rich focus, discharges its contents into the subarachnoid space. It is recognized that TBM is frequently accompanied by miliary tuberculosis, but the relationship between the development of the Rich focus and miliary tuberculosis remains controversial. The original descriptions of Arnold Rich and Howard McCordock are reviewed together with the work of other pathologists and the observations of the natural history of tuberculosis by astute clinicians such as Arvid Wallgren and Edith Lincoln. Rich and McCordock dissociated miliary tuberculosis from a role in the pathogenesis of TBM, and this view continues to appear in reviews and textbooks dealing with TBM. We suggest, particularly in childhood, that miliary tuberculosis is indeed directly involved in the pathogenesis of TBM in as much as that the overwhelming bacillaemia that accompanies miliary tuberculosis serves to increase the likelihood that a meningeal or sub-cortical Rich focus will be established, which may in its turn caseate and give rise to TBM.

In this paper methods for using multiple templates in tensor-based morphometry (TBM) are presented and compared to the conventional single-template approach. TBM analysis requires non-rigid registrations which are often subject to registration errors. When using multiple templates and, therefore, multiple registrations, it can be assumed that the registration errors are averaged and eventually compensated. Four different methods are proposed for multi-template TBM. The methods were evaluated using magnetic resonance (MR) images of healthy controls, patients with stable or progressive mild cognitive impairment (MCI), and patients with Alzheimer's disease (AD) from the ADNI database (N=772). The performance of TBM features in classifying images was evaluated both quantitatively and qualitatively. Classification results show that the multi-template methods are statistically significantly better than the single-template method. The overall classification accuracy was 86.0% for the classification of control and AD subjects, and 72.1% for the classification of stable and progressive MCI subjects. The statistical group-level difference maps produced using multi-template TBM were smoother, formed larger continuous regions, and had larger t-values than the maps obtained with single-template TBM.

OBJECTIVE

To evaluate the efficacy and safety of aspirin in preventing stroke and mortality in tuberculous meningitis (TBM).

METHODS

Patients with TBM diagnosed on the basis of clinical, MRI and cerebrospinal fluid (CSF) criteria were randomized into aspirin 150 mg daily or placebo. All the patients received four drug antitubercular treatment- RHZE (rifampicin, isoniazide, pyrazinamide and ethambutol) with or without corticosteroid. The primary endpoint was MRI proven stroke at 3 months and secondary end points were mortality and functional outcome assessed by Barthel Index score at 3 months. The adverse drug reactions were also analyzed.

RESULTS

118 TBM patients were randomized into aspirin and placebo groups. The baseline demographic, clinical (severity of meningitis, MRI and CSF changes) were not significantly different between the two groups. 19 (16.1%) patients lost from follow up. 21 (33.3%) patients developed stroke after randomization which was insignificantly lesser in aspirin (24.2%) compared to the placebo group (43.3%; OR 0.42, 95%CI 0.12-1.39). Aspirin resulted in absolute risk reduction of stroke in 19.1% and significant reduction in mortality compared to placebo (21.7% Vs 43.4%, P=0.02). On binary logistic regression analysis, the age (OR 1.09, CI 1.03-1.14, P=0.001) was the only independent risk factor of stroke and aspirin was significantly related to survival (OR 3.17, 95% CI 1.21-8.31). Aspirin was well tolerated and was not withdrawn in any patient because of side effects.

CONCLUSIONS

Aspirin resulted in insignificantly lesser strokes and significantly reduced 3 month mortality in patients with TBM.

We retrospectively reviewed 56 adults with culture-proven tuberculous meningitis (TBM), investigating clinical signs, cerebrospinal fluid (CSF) findings and outcome. There were 50 patients, aged 18-59 years, 39 with and 11 without human immunodeficiency virus (HIV) infection. Six were aged 60 years or older. Neurological signs of TBM in 18-59-year-olds were unaffected by HIV serostatus while, compared to those>> or = 60 years of age, there were more patients with meningism (86.0% vs. 33.3%; p = 0.011) and fewer with seizures (12.0% vs. 50.0%; p = 0.046). The HIV-infected 18-59-year-olds had significantly more extrameningeal tuberculosis compared to the non-HIV-infected (76.9% vs. 9.1%; p = 0.0001) and 23.1% had 'breakthrough' TBM. CSF analysis revealed 12 patients (21.4%) with acellular fluid (more common in those>> or = 60 years of age, p = 0.016), of whom three had completely normal CSF. A neutrophil predominance was found in 22 patients (39.3%). Only three patients (5.4%) had a positive CSF smear for acid-fast bacilli. In-hospital mortality occurred in 39 patients (69.1%), was similar in all study groups, and was not related to neurological stage. The diagnosis of TBM can be masked by lack of meningism in the elderly and by atypical CSF findings.

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.

OBJECTIVE

To compare dynamic expiratory and end-expiratory computed tomography (CT) for depicting central airway collapse in patients with acquired tracheobronchomalacia (TBM).

METHODS

Institutional review board approval was obtained, and informed consent was not needed. Retrospective review was performed of all patients with a CT diagnosis of TBM in a 10-month period (n = 34) who underwent evaluation of airway disease by means of three different sequences at multi-detector row CT: end inspiration, dynamic expiration, and end expiration (the latter was performed only at the levels of the aortic arch, carina, and bronchus intermedius). Fourteen patients (11 men, three women; age range, 19-79 years) who had comparable images obtained with all three sequences at any of these three levels were included in the study. The degree of airway collapse was measured by two thoracic radiologists in consensus by calculating the percentage change in the area of the airway between inspiratory and expiratory scanning. Statistical analysis was performed by using the paired t test.

RESULTS

Dynamic expiratory CT elicited a significantly greater degree of airway collapse than end-expiratory CT at all three levels (P < .005). The mean percentages of airway collapse at each of the three levels were as follows: aortic arch, 53.9% with dynamic expiration versus 35.7% with end expiration (P = .0046); carina, 53.6% with dynamic expiration versus 30.9% with end expiration (P < .0001); and bronchus intermedius, 57.5% with dynamic expiration versus 28.6% with end expiration (P = .0022).

CONCLUSIONS

Dynamic expiratory CT elicits a significantly greater degree of airway collapse than standard end-expiratory CT in patients with TBM.