We conducted a retrospective cohort study of patients with MRC grade II/III tuberculous meningitis (TBM) who accepted a background antitubercular regimen (BR) with or without linezolid (LZD). At the 4th week, the LZD-BR group achieved a faster and higher percentage of Glasgow coma scale recovery and temperature recovery, a higher cerebrospinal fluid (CSF)/blood glucose ratio, and lower CSF white blood cell counts than did the BR group. Short-term linezolid supplementation may be a more effective treatment for life-threatening TBM.

OBJECTIVE

Does in vitro maturation (IVM) of cumulus-enclosed germinal vesicle (GV) stage oocytes retrieved from small antral follicles in minimally stimulated cycles without an ovulatory hCG dose induce imprinting errors at LIT1, SNRPN, PEG3 and GTL2 in human oocytes?

CONCLUSIONS

There is no significant increase in imprinting mutations at LIT1, SNRPN, PEG3 and GTL2 after IVM of cumulus-enclosed GV oocytes from small antral follicles in minimally stimulated cycles without hCG priming.

BACKGROUND

Animal models have generally demonstrated correct methylation imprint establishment for in vitro grown and matured oocytes. For human IVM, well-designed studies allowing conclusions on imprint establishment are currently not available.

METHODS

Immature oocyte-cumulus complexes from 2 to 9 mm follicles were retrieved in polycystic ovary syndrome (PCOS) subjects in minimally stimulated cycles without hCG priming and matured in vitro. In vivo grown oocytes were retrieved after conventional ovarian stimulation for IVF/ICSI or after ovulation induction. Imprinting error rates at three maternally methylated (LIT1, SNRPN and PEG3) and one paternally methylated (GTL2) imprinted genes were compared in 71 in vitro and 38 in vivo matured oocytes.

METHODS

The limiting dilution bisulfite sequencing technique was applied, allowing increased sensitivity based on multiplex PCR for the imprinted genes and the inclusion of non-imprinted marker genes for cumulus cell DNA contamination.

RESULTS

In vitro as well as in vivo matured oocytes showed only a few abnormal alleles, consistent with epimutations. The abnormalities were more frequent in immature than in mature oocytes for both groups, although no significant difference was reached. There was no statistically significant increase in imprinting errors in IVM oocytes.

CONCLUSIONS

This single cell methylation analysis was restricted to a number of well-selected imprinted genes. Genome-wide methylation analysis of single human oocytes is currently not possible.

CONCLUSIONS

IVM is a patient-friendly alternative to conventional ovarian stimulation in PCOS patients and is associated with reduced gonadotrophin costs and avoidance of OHSS. The results of this study show for the first time that optimized human IVM procedures have no significant effects on the establishment of maternal DNA methylation patterns at LIT1, SNRPN, PEG3 and GTL2.

BACKGROUND

This study was supported by research funds from Agentschap voor Innovatie door Wetenschap en Technologie (IWT-TBM 110680), Wetenschappelijk Fonds Willy Gepts (WFWG 2011) and German Research Foundation (HA 1374/12-2). There are no competing interests.

BACKGROUND

Tuberculoma and cerebral infarctions are serious complications of central nervous system (CNS) tuberculosis. However, there are no studies comparing prognostic value of tuberculoma and infarcts alone and in patients diagnosed with CNS tuberculosis.

OBJECTIVE

The objective of this study was to identify frequency and prognostic value of tuberculoma and cerebral infarcts in a large sample of CNS tuberculosis patients.

METHODS

Retrospective chart review of patients diagnosed with CNS tuberculosis in a tertiary care hospital in Pakistan over 10-year period was carried out.

RESULTS

There were 404 patients included in this study (mean age of 43 years). There were 209 (52%) men and 195 (48%) women. Tuberculoma were present in 202 subjects (50%) while infarcts were present in 25% patients. 147 (36%) had tuberculous meningitis (TBM) without tuberculoma or infarction on CT or MRI, 158 (39%) had TBM with intracranial tuberculomas, 60 (15%) had TBM with cerebral infarction while 39 (10%) had TBM with both tuberculoma and infarction. At discharge, 249 patients (62%) were either normal (Modified Rankin Score (MRS)=0) or mild to moderately disabled (MRS=1-3) while 82 patients (20%) had severe disability (MRS=4-5). 73 (18%) patients died (MRS=6) during hospitalisation. Using logistic regression analysis, significant predictors of poor outcome included old age, high TBM grading, presence of infarction and presence of hydrocephalus.

CONCLUSIONS

Tuberculomas were present in 50% of patients, while infarcts were present in 25%. Old age, TBM grading, presence of infarction and hydrocephalus were all predictors of poor outcome.

This study compares the velocity and motility of boar sperm under capacitating and non-capacitating incubation conditions. Aliquots of pooled, washed boar sperm were incubated in either Tyrode's complete medium (TCM; a capacitating medium), Ca2+-free TCM (TCM-Ca2+), or Ca2+ and NaHCO3-free TCM (Tyrode's basal medium [TBM]; a non-capacitating medium). Motility patterns were determined every hour over a 3h period of incubation at 38 degrees C. Capacitation status was assessed by the chlortetracycline assay after 1 and 3h of incubation. Experiments were repeated five times. Compared to the TBM control, a significant increase was seen in the percentage of capacitated sperm after 1h of incubation in TCM: the kinematics of these sperm cells were favorably modified. However, the motility patterns of sperm cells incubated in TCM and TCM-Ca2+ were very similar. Under capacitating conditions (TCM), the coefficients of linearity (LIN) and straightness (STR) significantly increased over time (LIN values were significantly different after 3h of incubation, while STR values were significantly different after only 2 h). Significant correlations were seen between LIN and the percentage of cells showing the B pattern (r = 0.334, P < 0.05) and the number of acrosome reacted spermatozoa (r = 0.301, P < 0.05). This suggests that capacitated boar spermatozoa may have a species-specific motility pattern.

Tuberculomas may present with meningitis, may lead to meningitis, or may develop during the treatment of TBM. In this study, we report a series of 22 adult cases of symptomatic central nervous system tuberculomas, in eight of them tuberculomas were coexisting with TBM on admission and in 14 of them symptomatic tuberculomas developed during anti-tuberculosis therapy. We also aimed to compare the clinical, laboratory and outcome data of the 14 TBM patients that developed symptomatic tuberculomas, with the data of 41 TBM that did not, under the same treatment regimen. Most of the patients developed symptomatic tuberculomas in the first 6 weeks of treatment. Five patients developed late tuberculomas. The characteristics of tuberculomas and the role of corticosteroids in TBM patients are discussed. In conclusion, although steroids may diminish neurologic symptoms and improve outcome, tuberculomas may appear during the course of anti-tuberculosis and steroid treatment. Because of the possibility of late development of tuberculomas after initial successful treatment, all TBM patients need to be followed-up carefully for a long period.

UNASSIGNED

Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection.

UNASSIGNED

We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/).

UNASSIGNED

951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone.

UNASSIGNED

The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.

OBJECTIVE

Tuberculous meningitis (TBM) is a global health problem. In this review, we systematically evaluate the evidence for current and emerging antimicrobials, host-directed therapies and supportive managements.

RESULTS

Current antimicrobial regimes do not factor the differing ability of drugs to cross the blood-brain barrier. Rifampicin may be more effective at higher doses yet the most recent clinical trial failed to demonstrate survival benefit at 15 mg/kg/day. Dose finding studies suggest that higher doses still may be safe and more effective. Fluoroquinolones are currently listed as important second-line agents in drug-resistant TBM; however, a survival benefit as a first-line agent has yet to be shown. Linezolid may be a promising antimicrobial with good central nervous system penetrance. Dexamethasone reduces mortality in HIV-uninfected individuals yet evidence for its use in HIV co-infection is lacking. Aspirin has anti-inflammatory and anti-thrombotic properties. Small studies have demonstrated efficacy in reducing stroke but further research is required to better understand its effect on controlling the host inflammatory response. Discovery of genetic polymorphisms may direct individualized immune therapies and mediators of the innate immune response may provide targets for the development of novel therapies. There is at present no significant evidence base to guide management of hydrocephalus in HIV co-infection. Further clinical trial data is required to improve treatment outcomes in TBM in particularly in regard to the value of high-dose rifampicin, newer antimicrobials with improved central nervous system penetration and host-directed therapies. Supportive measures in particular the management of hydrocephalus in HIV co-infection should be an area for future research.

Central nervous system (CNS) tuberculosis (TB) is the most severe form of TB, characterized morphologically by brain granulomas and tuberculous meningitis (TBM). Experimental strategies for the study of the host-pathogen interaction through the analysis of granulomas and its intrinsic molecular mechanisms could provide new insights into the neuropathology of TB. To verify whether cerebellar mycobacterial infection induces the main features of the disease in human CNS and better understand the physiological mechanisms underlying the disease, we injected bacillus Calmette-Guerin (BCG) into the mouse cerebellum. BCG-induced CNS-TB is characterized by the formation of granulomas and TBM, a build up of bacterial loads in these lesions, and microglial recruitment into the lesion sites. In addition, there is an enhanced expression of signaling molecules such as nuclear factor-κB (NF-κB) and there is a presence of inducible nitric oxide synthase (iNOS) in the lesions and surrounding areas. This murine model of cerebellar CNS-TB was characterized by cellular and biochemical immune responses typically found in the human disease. This model could expand our knowledge about granulomas in TB infection of the cerebellum, and help characterize the physiological mechanisms involved with the progression of this serious illness that is responsible for killing millions people every year.

BACKGROUND

Endoscopic third ventriculostomy (ETV) is increasingly being used as an alternative treatment in tubercular meningitis (TBM) hydrocephalus. This study is aimed to evaluate the role of ETV in TBM hydrocephalus.

METHODS

This is a prospective study of 59 patients with TBM and obstructive hydrocephalus. The diagnosis was confirmed by a computed tomography scan and/or magnetic resonance imaging scan preoperatively. The procedure was performed using the standard technique or water jet dissection.

RESULTS

Three (5.1%) patients had blocked stoma, 31 (53%) had associated malnutrition, and 13 (22%) had complex hydrocephalus. Clinical improvement was seen in 34 (58%) after ETV and in 47 (80%) patients after ETV with lumber peritoneal shunt. Thirteen patients with patent stoma and complex hydrocephalus did not improve after ETV alone; an additional lumber peritoneal shunt was required. Clinical outcome was significantly better in good grade. Early recovery was observed in 81%. Results of ETV were better in patients without cisternal exudates, good nutritional status, thin and identifiable floor of third ventricle compared to cases with cisternal exudates, malnourished, thick and unidentifiable floor respectively, although the difference was statistically insignificant. There was no operative death. Three patients with normal ICP did not show any improvement. The radiological recovery after 3 weeks of surgery was 52%; follow-up ranged between 7 and 54 months. Six patients developed CSF leak.

CONCLUSIONS

Endoscopic third ventriculostomy was safe and effective in TBM hydrocephalus. Complex hydrocephalus and associated cerebral infarcts were the major causes of failure to improve. Good results were observed in better grades.

OBJECTIVE

We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM).

METHODS

In this open-label, randomized controlled trial from India, patients with TBM diagnosed on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ transplantation, malignancy, pregnancy, lactation, allergy, seizure, age <15 years and antitubercular treatment ≥1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat MRI changes and serious adverse events (SAEs).

RESULTS

The median age of the patients was 34.5 (16-75) years. The baseline clinical and MRI findings were similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23 out of 60 (38.3%) patients in the rifampicin arm had died (P = 0.07). On Cox regression analysis, survival in the levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04-4.34, P = 0.04). The functional outcome (P = 0.47) was, however, not significantly different between the two groups. On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P = 0.01).

CONCLUSIONS

Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability. Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure.

Tuberculous meningitis (TBM) causes significant morbidity and mortality. The primary objective was to re-examine the concept of "TB zone" and "ischaemic zone" in cerebral infarction in patients with tuberculous meningitis. The secondary objective was to evaluate cerebral infarction, vasculitis and vasospasm in tuberculous meningitis infections. Between 2009 and 2014, TBM patients were recruited. Neuroimaging was performed and findings of cerebral infarction, vasculitis and vasospasm were recorded. Infarcts were classified based on arterial supply and Hsieh's classification. Fifty-one TBM patients were recruited of whom 34 patients (67%) had cerebral infarction. Based on Hsieh's classification, 20 patients (59%) had infarcts in both "TB zone" and "ischaemic zones". 12 patients (35%) had infarcts in "ischaemic zone" and two (6%) patients had infarcts in "TB zone". In terms of vascular supply, almost all patients (35/36) had infarcts involving perforators and cortical branches. 25 patients (73%) and 14 patients (41%) had infarcts supplied by lateral lenticulostriate and medial lenticulostriate arteries respectively. 15 patients (37%) had vasculitis. Vasospasm was present in six patients (15%). 29 patients (85%) with cerebral infarction also had leptomeningeal enhancement (p = 0.002). In summary, infarcts involved mainly perforators and cortical branches, rather than "TB zone" versus "ischaemic zone".

OBJECTIVE

A retrospective analysis of 50 hydrocephalic children having a minimum follow-up of 6 months was carried out to see their etiology, clinical features, complications, incidence of shunt revisions, outcome and the variation from their Western counterparts.

METHODS

Clinical features, image findings and treatment of all the cases were recorded from their discharge summaries. Record of shunt revision complications and outcome was maintained by the principal author. The data of all the cases were analyzed.

RESULTS

The age of children varied from 1 month to 12 yr (mean 2.2 yr). The most common etiology of hydrocephalus was aqueductal stenosis in 18 (36%) children. Post infective hydrocephalus, either of post-tubercular meningitis (TBM) or following bacterial meningitis, remained the cause in 15 children (30%). Congenital TORCH infection was responsible for 3 cases of hydrocephalus making infective etiology as the cause in 18 (36%) cases. Intra 4th ventricular neurocysticercus cyst caused blockade of CSF pathway in 2 children. 15 out of 50 children required shunt revision, either due to infection (8,16%) or shunt obstruction (7, 14%). Multiple shunt revisions were required in 2 children only. These revisions were required due to infection, obstruction or malfunction of the shunt.

CONCLUSIONS

Infective etiology is responsible for hydrocephalus in significant number of children (36%). The possibility of TORCH infection, as a cause of hydrocephalus should be considered even amongst the children of screened mothers during antenatal check-up. Pure intra 4th ventricular neurocysticercus cysts (without intraparenchymal cyst), though rare, can manifest with outlet obstruction. Incidence of shunt revision using Chhabra's medium pressure shunt is very high in children at an average follow up of 1.6 yr. Post infective hydrocephalus is a major cause of delayed milestones, contributing to mental retardation.

The localization of C3d, a fragment produced by C3 activation and S-protein (vitronectin), a regulatory factor of C5b-9, was studied immunohistochemically in normal human kidney and renal biopsies from patients with several types of glomerulonephritis. Immunofluorescent staining of the normal kidneys showed that C3d was present along the glomerular basement membrane (GBM), tubular basement membrane (TBM) and arterioles, and that S-protein was present in the GBM, mesangium, TBM, and arterioles. Immunoelectron microscopy of isolated basement membranes showed that C3d was localized exclusively on the epithelial side of the GBM, and that S-protein was present along both the epithelial and endothelial sides. In nephritic tissues, glomerular staining of C3d, C5b-9, and S-protein was increased when compared with that in normal tissues. S-protein, frequently co-localized with C3d and C5b-9 neoantigen, was intensely positive in the immune deposits of glomerular capillaries and the mesangial area, overlapping the background staining of GBM and mesangial matrix. S-protein and its receptor were occasionally co-localized in the glomeruli. These findings indicate that C3d and S-protein are normally present in the glomeruli. Co-staining of C3d, C5b-9 neoantigen, and S-protein within the immune deposits of nephritic kidneys suggests in situ binding of S-protein to locally-formed C5b-9 complex, or merely co-distribution of S-protein with the complex, rather than trapping of large molecular SC5b-9 complex from the circulation.

Using a monoclonal anti-tubular basement membrane antibody (alpha TBM-Ab) affinity column, we isolated from collagenase-solubilized human renal tissue (HSRTA) a predominantly 48,000-mol-wt moiety (H3M-1) which is selectively recognized by antisera from two patients with alpha TBM-Ab-associated interstitial nephritis (alpha TBM disease). Whereas both antisera had alpha TBM-Ab titers of 1:64-1:128 by immunofluorescence on tissue sections, their reactivity with H3M-1 in a solid-phase radioimmunoassay was demonstrable at dilutions up to 1:10,000. While these sera displayed some reactivity with pre-column HSRTA, this was markedly less than with H3M-1. HSRTA depleted of H3M-1 by passage over the alpha TBM-Ab affinity column was almost completely depleted of reactivity. Neither pooled normal human sera nor sera from patients with a variety of renal lesions not associated with alpha TBM-Ab (including interstitial nephritis and antiglomerular basement membrane disease) were reactive with H3M-1. Both patient antisera containing alpha TBM-Ab were also highly reactive with R3M-1, the 48,000-mol-wt rabbit glycoprotein antigen of experimental alpha TBM disease. Furthermore, a competitive inhibition radioimmunoassay revealed that alpha TBM-Ab from rodents with experimental alpha TBM disease could inhibit 45-98% of the R3M-1 binding reactivity of patient antisera and 85% of the H3M-1 binding reactivity of patient antisera, thus suggesting paratypic cross-reactivity. We conclude, therefore, that tubular basement membrane target epitopes and their paratypic recognition are highly conserved among mammals.

Autoimmune tubulointerstitial nephritis (TN) was induced in strain XIII and Hartley but not strain II guinea pigs after immunization with rabbit tubular basement membranes (TBM) in CFA. Strain XIII guinea pigs developed extensive autoimmune TN associated with high anti-TBM (aTBM) antibody titers and linear deposits of IgG along renal cortical TBM after immunization with 10 mug to 10 mg of TBM. In addition, autoimmune TN was passively transferred to strain XIII animals by the i.p. injection of aTBM sera obtained from actively immunized Hartley guinea pigs. In contrast, strain II guinea pigs did not develop autoimmune TN after active immunization (10 mug to 10 mg) with rabbit TBM in CFA, and only produced high aTBM antibody titers with the highest immunnizing antigen dose. At this dose (10 mg) the strain II animals demonstrated linear deposits of IgG along renal cortical TBM but did not develop autoimmune TN. Further, recipient strain II guines pigs did not develop autoimmune TN after passive transfer of aTBM antisera despite renal cortical tubular deposition of aTBM antibodies. Both inbred guinea pig strains produced antibodies reactive with rabbit and rat renal basement membranes. No evidence for differences in nephritogenic TBM antigens could be demonstrated betweed strain XIII and strain II TBM. These observations indicate that 1) genetic factor(s) influence the production of antibodies reactive to autologous TBM, 2) after the deposition of antibodies on the TBM, additional or related genetic factor(s) determine the full expression of this autoimmune renal disease, and 3) aTBM antibody deposition on renal TBM is not sufficient to elicit autoimmune TN.

The autoimmune B cell repertoire in anti-tubular basement membrane (alpha TBM) disease is focused on the nephritogenic P1 domain of the 3M-1 target Ag in kidney and normally expresses a disease-modifying cross-reactive Id (IdX). The molecular structure of this Id was determined from a library of rat mAb alpha TBM/alpha 3M-1 by using anchor polymerase chain reactions. Our findings provide the first alignment of V region sequences for rat IgG and reveal that specificity for the P1 domain among alpha 3M-1 antibodies is derived from several recurring germ-line VH genes which have not undergone somatic mutation. The IdX in this repertoire localizes to the H chain on Western blot, and to the CDR3 region as deduced from the cDNA encoding several informative clones. Computer modeling of the Id reveals a conformational structure largely dependent on hydroxyl groups in or near turn position 4 of the H chain CDR3 region. These findings demonstrate that regulatory elements protective of autoimmunity are not encoded in the germ line as IdX, but rather emerge from a recombinatorial diversity engaged by the recognition of parenchymal self.

Tensor-based morphometry (TBM) is an analysis technique where anatomical information is characterized by means of the spatial transformations mapping a customized template with the observed images. Therefore, accurate inter-subject non-rigid registration is an essential prerequisite for both template estimation and image warping. Subsequent statistical analysis on the spatial transformations is performed to highlight voxel-wise differences. Most of previous TBM studies did not explore the influence of the registration parameters, such as the parameters defining the deformation and the regularization models. In this work performance evaluation of TBM using stationary velocity field (SVF) diffeomorphic registration was performed in a subset of subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A wide range of values of the registration parameters that define the transformation smoothness and the balance between image matching and regularization were explored in the evaluation. The proposed methodology provided brain atrophy maps with very detailed anatomical resolution and with a high significance level compared with results recently published on the same data set using a non-linear elastic registration method.

Tandem-base mutations (TBM) are associated with ultraviolet light and other mutagens. Herein, we report an age- and tissue-specific difference in the frequency of spontaneous TBM in Big Blue transgenic mice. A total of 390 mutants from liver and adipose tissue contained 17 and 4 TBM, respectively, while no TBM were detected in 683 mutants from six other tissues. There was a proportional increase in the frequency of TBM in liver with age (29 days postconception to 25 months of age). Nine TBM (43%) were GG to TT transversions that preferentially occurred at specific sites. The remaining 12 mutants contained at least one transversion mutation each. We speculate that the increase of TBM in liver and adipose tissue with age is due to chronic mutagen exposure, perhaps derived from fat in the diet.

OBJECTIVE

Lupus nephritis is characterized by glomerular and extraglomerular immune complex deposition in the kidney. It is unclear whether the same circulating immune complexes deposit in the glomeruli and in extraglomerular structures, or whether they are pathogenetically different. Differences in the IgG subclass composition may point towards different pathways in the formation of glomerular and extraglomerular immune complexes. Therefore we investigated IgG subclass distribution in the immune complex deposits at these anatomic sites.

METHODS

A total of 84 biopsies diagnosed as lupus nephritis and classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification, were examined by direct immunofluorescence staining for IgG subclasses. The IgG subclass composition in the glomerular, tubular basement membrane (TBM) and vascular wall deposits was compared. We also correlated the presence/absence of interstitial inflammation and IgG subclasses in the TBM and vascular deposits. Lastly, we looked for correlation between staining for IgG subclasses and complement C1q and C3 staining.

RESULTS

IgG staining was present in the TBM in 52/84 biopsies, and in the vascular walls in 40/84 biopsies. IgG subclass distribution was discrepant between glomerular and TBM deposits in 36/52 biopsies, and between glomerular and vascular deposits in 27/40 biopsies. Interstitial inflammation did not correlate with the presence of IgG staining or distribution of IgG subclasses in the TBM. Interstitial inflammation was more common in biopsies of African-American patients than Caucasian patients. The IgG subclass staining correlated with C1q staining in all the three compartments.

CONCLUSIONS

The antibody composition of the glomerular and extraglomerular immune complex deposits appear to differ from each other. They may not represent the same preformed immune complexes from the circulation. It is likely that their pathogenesis and site of formation are different.

The involvement of calcium ions in the mechanism of meiotic resumption has been studied in mouse oocytes made resistant to the lethal effects of calcium-free medium (CFM) by zona pellucida removal (De Felici et al., '89). We show here that such oocytes undergo meiotic resumption in CFM (as evaluated by germinal vesicle breakdown, GVBD) at a rate comparable to that shown by oocytes cultured in medium containing 1.7 mM Ca2+. The addition to CFM of 50 u M Quin2/AM (a membrane permeable, high affinity Ca2+ chelator) totally prevents GVBD, while purported antagonists of Ca2+ release from intracellular stores, such as 150 uM 8-(N,N-diethylamino)octyl-3-4-5 trimethoxybenzoate (TMB-8) or 300 uM chlortetracycline, only cause a slight meiotic delay. On the other hand, if the oocytes are pre-incubated for 30 min in CFM supplemented with 100 uM TBM-8 plus 0.2 mM dibutyryl-cyclic AMP (dbcAMP, a reversible inhibitor of GVBD), and then cultured in the same medium, without dbcAMP, a sustained inhibition of meiotic maturation is obtained. Our observations suggest that an increase in intracellular free Ca2+ is essential for meiotic resumption by mouse oocytes; in the experimental absence of external Ca2+, release of the cation from internal stores is sufficient to allow meiotic resumption.

Tracheobronchomalacia (TBM) is increasingly recognized in infants, children, and adults with acquired chronic lung diseases as the use of flexible bronchoscopy has become widely established in spontaneously breathing patients. However, the lack of a reliable method to quantify the severity of the airway collapse has made serial studies, evaluation of therapies, and comparisons between patients difficult. The purpose of this study was to describe a method of quantifying airway collapse in TBM. The degree of airway collapse was quantitated by measuring the ratio of the smallest to the largest airway area during a respiratory cycle. The videotape of flexible bronchoscopy was run through a video monitor and frozen at the appropriate times. The airway circumference was then traced onto plastic overlays and the area measured. The videotapes of seven infants and children with TBM and eight with normal airways were reviewed by investigators who did not know the diagnosis. Intra-observer variability was 2.2%, and inter-observer variability was 1.4%. The mean smallest/largest airway ratio was 0.34 + or - 0.14 (SD) in the subjects with known TBM, compared with a ratio of 0.82 + or - 0.08 (SD) in children with a normal airway (P< 0.0001). The range in the children with TBM was 0.22-0.61, whereas for the control children it was 0.73-0.93. In this series, there was no overlap in the ratios between affected and unaffected patients. In addition to the manual method of calculating airway area ratios, a computer-assisted method is described that could be adapted to real-time use. This way of analyzing the degree of airway collapse could be used to assess patients with TBM quantitatively and reproducibly.

A retrospective study was performed to assess the epidemiology, diagnosis, clinic, and laboratory of the patients with tuberculous meningitis (TBM) in a multicentral study. The medical records of adult cases with TBM treated at 12 university hospitals throughout Turkey, between 1985 and 1998 were reviewed using a standardized protocol. The diagnosis of TMB was established with the clinical and laboratory findings and/or microbiological confirmation in cerebrospinal fluid (CSF). The non-microbiologically confirmed cases were diagnosed with five diagnostic sub-criteria which CSF findings, radiological findings, extra-neural tuberculosis, epidemiological findings and response to antituberculous therapy. A total of 469 patients were included in this study. Majority of the patients were from Southeast Anatolia (164 patients, 35.0%) and (108 patients, 23.0%) from East Anatolia regions. There was a close contact with a tuberculous patient in 88 of 341 patients (25.8%) and with a tuberculous family member in 53 of 288 patients (18.4%). BCG scar was positive in 161 of 392 patients (41.1%). Tuberculin skin test was done in 233 patients and was found to be negative in 75. Totally 115 patients died (24.5%) of whom 23 died in 24 hour after admittance. The diagnosis was confirmed with clinical findings and CSF culture and/or Ziehl-Nelson staining in 88 patients (18.8%). Besides clinical criteria, there were three or more diagnostic sub-criteria in 252 cases (53.7%), two diagnostic sub-criteria in 99 cases (21.1%), and any diagnostic sub-criteria in 30 patients (6.4%). Since TBM is a very critical disease, early diagnosis and treatment may reduce fatal outcome and morbidity.

BACKGROUND

The southeast region of Iran is an endemic area for tuberculosis. Tuberculous radiculomyelitis (TBRM) was considered a rare form of parenchymal neurotuberculosis.

OBJECTIVE

To analyze the clinical, laboratory and electrophysiological data of patients with TBRM. We report five patients and review the literature.

METHODS

We searched Medline since 1966 and reviewed all cases of TBRM, excluding those with Pott's disease. We then evaluated the clinical and electrophysiological data of our patients.

RESULTS

Five patients (two men), with a mean age of 25 years, were assessed. The mean duration of symptoms before diagnosis was 4.5 weeks. Three patients had clinical manifestation of tuberculous meningitis (TBM). Diagnosis was based on sputum smear and culture, cerebrospinal fluid (CSF) culture and polymerase chain reaction (PCR) gene amplification of Mycobacterium tuberculosis. Paraparesis or paraplegia, sphincter incontinence and Babinski sign were the main clinical features. CSF analysis was compatible with chronic meningitis. Electromyography showed radiculopathy in all patients and peripheral nerve disease secondary to axonal damage in only three, while myelography showed adhesive arachnoiditis in three.

CONCLUSIONS

Despite the rarity of TBRM, clinical features were well described. To prevent neurological sequelae, early diagnosis and treatment is mandatory. Electrophysiological study may predict the prognosis.

Tuberculous meningitis (TBM), the most devastating manifestation of tuberculosis, is often missed or overlooked because of nonspecific symptoms and difficulties in diagnosis. It continues to be an important cause of neurologic handicap in resource-poor countries. Owing to the suboptimal performance of diagnostic tests of TBM, diagnosis relies on thorough history, clinical examination, and relevant investigations. The development of affordable, accurate diagnostic tests for TBM in resource-poor settings remains a priority. Short intensified treatment is safe and effective in both human immunodeficiency virus (HIV)-infected and HIV-uninfected children. Treatment of tuberculous hydrocephalus depends on the level of the cerebrospinal fluid obstruction. Corticosteroids reduce risk of neurodisability and death in HIV-uninfected children. Thalidomide should be considered in children compromised by tuberculosis abscesses and tuberculous-related optochiasmic arachnoiditis. In resource-poor countries, home-based TBM treatment after initial in-hospital stabilization is feasible in carefully selected patients. Early diagnosis and treatment of TBM is the single most important factor determining outcome.