Ethanol consumption leads to bone alterations, mainly osteoporosis. Ethanol itself may directly alter bone synthesis, but other factors, such as accompanying protein malnutrition--frequently observed in alcoholics, chronic alcoholic myopathy with muscle atrophy, alcohol induced hypogonadism or hypercortisolism, or liver damage, may all contribute to altered bone metabolism. Some data suggest that zinc may exert beneficial effects on bone growth. Based on these facts, we analyzed the relative and combined effects of ethanol, protein malnutrition and treatment with zinc, 227 mg/l in the form of zinc sulphate, on bone histology, biochemical markers of bone formation (osteocalcin) and resorption (urinary hydroxyproline excretion), and hormones involved in bone homeostasis (insulin growth factor 1 (IGF-1), vitamin D, parathormone (PTH), free testosterone and corticosterone), as well as the association between these parameters and muscle fiber area and liver fibrosis, in eight groups of adult Sprague Dawley rats fed following the Lieber de Carli model during 5 weeks. Ethanol showed an independent effect on TBV (F=14.5, p<0.001), causing it to decrease, whereas a low protein diet caused a reduction in osteoid area (F=8.9, p<0.001). Treatment with zinc increased osteoid area (F=11.2, p<0.001) and serum vitamin D levels (F=3.74, p=0.057). Both ethanol (F=45, p<0.001) and low protein diet (F=46.8, p<0.01) decreased serum osteocalcin levels. Ethanol was the only factor independently related with serum IGF-1 (F=130.24, p<0.001), and also showed a synergistic interaction with protein deficiency (p=0.027). In contrast, no change was observed in hydroxyproline excretion and serum PTH levels. No correlation was found between TBM and muscle atrophy, liver fibrosis, corticosterone, or free testosterone levels, but a significant relationship was observed between type II-b muscle fiber area and osteoid area (rho=0.34, p<0.01). Osteoporosis is, therefore, present in alcohol treated rats. Both alcohol and protein deficiency lead to reduced bone formation. Muscle atrophy is related to osteoid area, suggesting a role for chronic alcoholic myopathy in decreased bone mass. Treatment with zinc increases osteoid area, but has no effect on TBV.

The cortical collecting tubule (CCT) of the mammalian kidney reabsorbs sodium and potassium, processes that are mediated by Na/K-ATPase and H/K-ATPase. CCT is also an important site for proton secretion, which is driven, in part, by H/K-ATPase. Na/K-ATPase and H/K-ATPase are members of the ion-motive P-ATPase gene family. They are closely related plasma membrane proteins which consist of alpha beta heterodimers. The urinary bladder of the toad Bufo marinus is the amphibian counterpart of mammalian CCT. We have previously characterized a ouabain-resistant Na/K-ATPase [see ref. 17], from TBM cells, a clonal cell line derived from the toad bladder, which expresses transepithelial sodium transport. In the present study, we report the primary sequence and functional expression of a novel beta subunit (beta bladder = beta b1) isolated from a toad bladder epithelial cell cDNA library. The deduced polypeptide is 299 amino acids in length and has a predicted molecular mass of 33 kDa. The beta b1 protein exhibits 35% amino acid identity to the previously characterized beta 1 of B. marinus Na/K-ATPase and 39% identity with beta 3 of B. marinus Na/K-ATPase. It shares 38% identity with the mammalian beta gastric H/K-ATPase and 52% with the mammalian beta 2 Na/K-ATPase. Northern blot analysis shows that a 1.4 x 10(3)-base mRNA is expressed at a high level in bladder epithelial cells and eye and at a trace level in kidney; it is not detectable in significant amounts in the stomach, colon and small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

A comprehensive training program to develop tobacco-specific standardized patient instructors (SPIs) was implemented and evaluated at Wake Forest University.

METHODS

Descriptive statistics were used to assess SPIs' experience with the training program and medical students' perceptions of the SPI-student interaction. Two standardized scales, used to assess student performance on counseling (Tobacco Intervention Risk Factor Interview Scale [TIRFIS]) and cultural competency (Tobacco Beliefs Management Scale-Tobacco Cultural Concerns Scale [TBMS-TCCS]), were tested for internal and interrater reliability and sensitivity to varied student performance. Costs of the program were measured.

RESULTS

SPIs highly rated the content, organization, and presenters of the training program. Medical students positively evaluated their experience with the SPIs. The TIRFIS and TBMS-TCCS subscales demonstrated good internal reliability, and inconsistencies in ratings by different SPIs were minimal. In addition, a range of scores on both measures attest to the sensitivity of the instruments to assess variations in student performance. Significant start-up costs are associated with developing this training program, although costs decline when SPIs are retained long term.

CONCLUSIONS

The SPI training program was effective in developing a cohort of knowledgeable and reliable SPIs to train medical students in ways to improve their tobacco intervention counseling skills. Retaining SPIs long term should be a primary goal of implementing a cost-effective, successful training program.

BACKGROUND

Acute rejection is a major risk factor for chronic allograft nephropathy, although the link(s) between these events is not understood. The hypothesis of this study is that alterations in tubular basement membranes (TBMs) that occur during acute rejection may be irreversible and thereby play a role in the development of chronic allograft nephropathy.

METHODS

Fourteen renal transplant patients were selected, each having had two or more biopsies performed (42 total). All biopsies were scored for acute and chronic rejection using Banff 1997 criteria. The initial biopsy showed only acute interstitial rejection (type I rejection). No biopsies contained significant chronic arterial lesions of chronic vascular rejection. The entire cortex was examined on Jones methenamine silver-stained sections at x400 for interruption in TBM staining. The number of tubules with TBM abnormalities was counted, and the renal cortical area was measured by image analysis. Periodic acid-Schiff/immunoperoxidase stain was performed on 12 acute rejection biopsies stained for laminin, cytokeratin 7, CD3, CD20, and CD68. Controls consisted of 11 biopsies (8 negative for rejection and 3 acute tubular necrosis).

RESULTS

Numerous TBM alterations in silver staining were identified as being associated with acute rejection and tubulitis, consisting of abrupt TBM discontinuities and/or extreme attenuation with segmental or complete absence of TBM. A loss of TBM matrix proteins was confirmed by absent laminin staining in areas of acute rejection and tubulitis. There was herniation of tubular cells into the interstitium through TBM defects confirmed by cytokeratin staining. The TBM defects were spatially associated with inflammatory cells, particularly macrophages. When the biopsies were divided into two groups, <10 and> 10 TBM breaks/mm2, there were statistically significant morphologic and clinical correlations. The number of TBM disruptions correlated with the serum creatinine at the time of biopsy, a combined Banff t + i score, the difference in tubular atrophy between the initial and most recent biopsy and the difference between the nadir creatinine and most recent creatinine.

CONCLUSIONS

Damage to TBM develops in acute rejection as a consequence of interstitial inflammation and tubulitis. These lytic events correlate with the later development of clinical and morphologic evidence of chronic injury in the absence of arterial injury of chronic rejection. We suggest that chronic allograft nephropathy may have an inflammatory interstitial origin.

Tuberculous meningitis may rarely be followed by the development of a syrinx even after apparently successful chemotherapy. There are only six previously reported cases of this unusual complication; these are reviewed. A case is described of syringomyelia which developed 1 year after TBM. One year later magnetic resonance imaging demonstrated not only the spontaneous resolution of the syringomyelia but also the appearance of a new cavity within the brain stem. This surprising sequence of events illustrates the need for extensive studies of the natural history of syrinxes of differing aetiologies.

Toxicological studies showed that trihalomethanes (THMs), the most abundant classes of disinfection by-products (DBPs) in drinking water, impaired male reproductive health, but epidemiological evidence is limited and inconsistent. This study aimed to examine the associations of baseline blood THMs with semen parameters and serum total testosterone in a Chinese population. We recruited 401 men seeking semen examination from the Reproductive Center of Tongji Hospital in Wuhan, China between April 2011 and May 2012. Baseline blood concentrations of THMs, including chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM) were measured using SPME-GC/ECD method. Semen quality and serum total testosterone were analyzed. Multivariable linear regressions were used to assess the associations of baseline blood THM concentrations with semen parameters and serum total testosterone levels. We found that baseline blood THM concentrations were not associated with decrements in sperm motility, sperm straight-line and curvilinear velocity. However, moderate levels of BDCM (β=-0.13 million; 95% CI: -0.22, -0.03) and DBCM (β=-4.74%; 95% CI: -8.07, -1.42) were associated with decreased sperm count and declined sperm linearity compared with low levels, respectively. Suggestive dose-response relationships were also observed between elevated blood TCM or ∑ THMs (sum of TCM, BDCM, DBCM and TBM) concentration and decreased sperm concentration (both p for trend=0.07), and between elevated blood DBCM concentration and decreased serum total testosterone (p for trend=0.07). Our results indicate that elevated THM exposure may lead to decreased sperm concentration and serum total testosterone. However, the effects of THM exposure on male reproductive health still warrant further studies in humans.

Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV). Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid.

Tubulointerstitial injury is found frequently in lupus nephritis. Immune complex deposits can occur in the tubular basement membranes (TBMs), although its significance in lupus nephritis patients remains unclear. This study assessed the clinical and prognostic features of lupus nephritis patients with TBM deposits in a large Chinese multicenter cohort. Complete data were collected from 195 patients with renal biopsy-proven lupus nephritis diagnosed in the Peking University First Hospital as the discovery cohort. A total of 102 lupus nephritis patients were enrolled from another four centers as the validation cohort. The status of TBM deposits was retrospectively assessed using electron microscopy, and the associations of the deposits with clinical data, pathological characteristics and renal outcomes were further analyzed. The percentage of positive TBM deposits was nearly 30% in the lupus nephritis patients. Using immuno-gold labeling, we found that 10/10 patients were positive for IgG, 7/10 were C3d positive, 6/10 were C1q positive, and 1/10 were C4d positive. Patients with TBM deposits presented with more active features, including a higher SLEDAI score (SLE Disease Activity Index) ( p < 0.001), higher serum creatinine level ( p = 0.001) and lower serum C3 level ( p < 0.001). These patients also presented with higher scores for most renal pathological indices, including the total activity indices score ( p < 0.001) and total chronicity indices score ( p = 0.001). TBM deposits affected renal outcomes in the univariate Cox hazards regression analysis (HR = 4.2, 95% CI = 1.3-14.3, p = 0.02). In conclusion, TBM deposits were common in lupus nephritis patients and correlated closely with the clinical disease activity and renal outcome.

BACKGROUND

Tuberculosis (TB) remains one of the leading infectious diseases throughout the world. Among various forms of extrapulmonary TB, tuberculous meningitis (TBM) is the most severe form and remains a major global health problem with a high mortality rate. Our study was designed to evaluate tuberculous polymerase chain reaction (PCR) positive rate in patients who present with fairly long symptoms of meningitis.

METHODS

The 162 Patients with an indolent onset of symptoms compatible with central nervous system infection were admitted. Sample of cerebrospinal fluid (CSF) was evaluated for biochemistry and tuberculous real-time PCR. Data analyzed by Student's t-test and Fisher's test.

RESULTS

Patients were mostly male (69.8%), with a median age of 43.69 ± 22.67 years. CSF real-time PCR results in 6 patients (3.7%) were positive for tuberculous DNA. Of these 6 patients, 4 of whom were men and two of whom were women. In other words, the frequency of positive tuberculous DNA was in male 5.3% and female 1.4%, respectively.

CONCLUSIONS

Given that we live in Iran and in the vicinity of the tuberculous endemic countries, if we face a meningitis case with lasting symptoms and tendency to be chronic, TBM should be considered.

Tracheobronchomalacia (TBM) is frequently present in infants and children with congenital heart disease (CHD). Infants with CHD and TBM appear to do worse than those without TBM. The principle of operative intervention for TBM is to improve function of the airway and clinical status. When indicated, conventional surgical options include tracheostomy, aortopexy, tracheoplasty, and anterior tracheal suspension. There is no consensus on the optimal treatment of severe tracheobonchomalacia, which can be associated with a mortality rate as high as 80%. Congenital tracheal stenosis is also frequently associated with CHD (vascular rings, atrioventricular canal defects, and septal defects) and may require concomitant repair. Repair of tracheal stenosis is often associated with distal TBM. This article addresses new techniques that can be performed in corrective surgery for both TBM and congenital tracheal stenosis.

Tuberculosis remains to be an endemic infectious disease in developing countries. With the increasing incidence of HIV and AIDS, there is further increase in the incidence of tuberculosis. Although CNS involvement by tuberculosis is seen in all age groups, there is a predilection for younger patients. Central nervous system tuberculosis may present as tuberculoma, cerebral abscess or tuberculous meningitis (TBM). Vasculitis secondary to TBM can cause infarcts and rarely aneurysm formation. In TBM there is a thick, gelatinous exudate around the sylvian fissures, basal cisterns. There is a border zone reaction occurring in the surrounding brain tissue. Inflammatory changes occur in the vessel wall of the arteries bathed in the exudate leading to narrowing of the lumen or occlusion by thrombus formation. The vessels at the base of the brain are most severely affected, including the internal carotid artery, proximal middle cerebral artery and perforating vessels of the basal ganglion. In these cases, the infection probably spreads from the adventitia towards the internal elastic lamina, weakening the vessel wall, with subsequent formation of an infectious aneurysm. Intracranial tuberculomas are space-occupying masses of granulomatous tissue that result from haematogenous spread from a distant focus of tuberculous infection. In endemic regions, tuberculomas account for as many as 50% of all intracranial space-occupying lesions. Inflammation in the vessels surrounding the tuberculoma may lead to formation of aneurysms. This case report illustrates an unusual case of intracranial tuberculomas complicated by intralesional haemorrhage due to an infective tubercular aneurysm in its vicinity. The endovascular treatment of these infectious aneurysms is safe, effective and durable. To the best of our knowledge, this is the first case report of a tuberculoma having intracranial haemorrhage on anti-tubercular treatment due to an infectious aneurysm developing in an artery in the vicinity of the tuberculoma and managed end.

Central nervous system (CNS) tuberculosis may manifest as meningitis, meningoencephalitis, tuberculoma, tubercular abscess, stroke due to tuberculous vasculitis and tuberculous encephalopathy. Occasionally, tubercular meningitis (TBM) can predispose to cerebral venous sinus thrombosis (CVST). We report a young man, who developed CVST as a complication of TBM. Worsening of pre-existing headache, impairment of consciousness and seizures should raise suspicion of CVST in any patient with CNS infection. Early diagnosis and appropriate clinical management are important for good outcome.

OBJECTIVE

Tuberculous Meningitis is associated with a high morbidity and mortality if there is a delay in diagnosis. The diagnosis is based on clinical evaluation since the bacteriological diagnosis takes time and has a low yield. This study attempts to validate these criteria in children with TBM.

METHODS

Forty-two children clinically suspected to have TBM were enrolled in the study. History, examination, CT scan and CSF findings were utilized to categorize patients into "definite", "highly probable", "probable" and "possible" TBM based on the criteria laid down by Ahuja et al. The validity of these criteria was tested against bacterial isolation and response to treatment.

RESULTS

Thirty one children, with complete data, were included for analysis. Using "improvement on therapy as a criterion for definite TBM, we analyzed the sensitivity and specificity of the Ahuja criteria in diagnosing TBM. Using the criteria of "highly probable" TBM, the sensitivity was 65% with a specificity of 75%. When the criteria of "probable" TBM were used, the sensitivity increased to 96% while the specificity dropped to 38%. In an attempt to make these criteria more appropriate for children, we modified the criteria by including mantoux reaction, and family history of exposure in the criteria. The modified criteria gave a sensitivity of 83% and a specificity of 63%.

CONCLUSIONS

A sensitivity of 65% (highly probable group) implies that 35% of TBM patients will be missed, while the probable criteria gave a 63% false positive rate suggesting that the trade-off for a higher sensitivity makes the criteria very unreliable. Our modification of the criteria gave us a reasonable sensitivity of 83% with a higher specificity of 63%. The false positive rate was also reduced to 38%. Thus the modified Ahuja criteria worked better for children with TBM.

CONCLUSIONS

The modified Ahuja criteria are better applicable for use in pediatric patients with TBM . Since the number of patients was small in this study, the study needs to be validated with a larger sample size.

Hydrocephalus is one of the commonest complications of tuberculous meningitis (TBM). It can be purely obstructive, purely communicating, or due to combinations of obstruction in addition to defective absorption of cerebrospinal fluid (CSF). Endoscopic third ventriculostomy (ETV) as an alternative to shunt procedures is an established treatment for obstructive hydrocephalus in TBM. ETV in TBM hydrocephalus can be technically very difficult, especially in acute stage of disease due to inflamed, thick, and opaque third ventricle floor. Water jet dissection can be helpful in thick and opaque ventricular floor patients, while simple blunt perforation is possible in thin and transparent floor. Lumbar peritoneal shunt is a better option for communicating hydrocephalus as compared to VP shunt or ETV. Intraoperative Doppler or neuronavigation can help in proper planning of the perforation to prevent neurovascular complications. Choroid plexus coagulation with ETV can improve success rate in infants. Results of ETV are better in good grade patients. Poor results are observed in cisternal exudates, thick and opaque third ventricle floor, acute phase, malnourished patients as compared to patients without cisternal exudates, thin and transparent third ventricle floor, chronic phase, well-nourished patients. Some of the patients, especially in poor grade, can show delayed recovery. Failure to improve after ETV can be due to blocked stoma, complex hydrocephalus, or vascular compromise. Repeated lumbar puncture can help faster normalization of the raised intracranial pressure after ETV in patients with temporary defect in CSF absorption, whereas lumbar peritoneal shunt is required in permanent defect. Repeat ETV is recommended if the stoma is blocked. ETV should be considered as treatment of choice in chronic phase of the disease in obstructive hydrocephalus.

BACKGROUND

With high short-term mortality and substantial excess morbidity among survivors, tuberculous meningitis (TBM) is the most severe manifestation of extra-pulmonary tuberculosis (TB). The objective of this study was to assess the long-term mortality and causes of death in a TBM patient population compared to the background population.

METHODS

A nationwide cohort study was conducted enrolling patients notified with TBM in Denmark from 1972-2008 and alive one year after TBM diagnosis. Data was extracted from national registries. From the background population we identified a control cohort of individuals matched on gender and date of birth. Kaplan-Meier survival curves and Cox regression analysis were used to estimate mortality rate ratios (MRR) and analyse causes of death.

RESULTS

A total of 55 TBM patients and 550 individuals from the background population were included in the study. Eighteen patients (32.7%) and 107 population controls (19.5%) died during the observation period. The overall MRR was 1.79 (95%CI: 1.09-2.95) for TBM patients compared to the population control cohort. TBM patients in the age group 31-60 years at time of diagnosis had the highest relative risk of death (MRR 2.68; 95%CI 1.34-5.34). The TBM patients had a higher risk of death due to infectious disease, but not from other causes of death.

CONCLUSIONS

Adult TBM patients have an almost two-fold increased long-term mortality and the excess mortality stems from infectious disease related causes of death.

Tuberculous meningitis (TBM) is a severe complication of tuberculosis and occurs mainly during early childhood. The incidence rate of TBM varies with season, and serum vitamin D levels, which are dependent on sunlight, might play a role. We studied the association between TBM incidence rate and hours of sunshine in Cape Town, South Africa and found a significant association between the incidence rate of TBM and hours of sunshine 3 months earlier (incidence rate ratio per 100 sunshine hours 0·69, 95% confidence interval 0·54-0·88, P = 0·002). The association supports the hypothesis that vitamin D might play a role in the pathophysiology of TBM. Further prospective studies in which vitamin D status is measured are necessary to determine causality.

BACKGROUND

Various serological techniques have been developed to detect antibodies and antigens in the cerebrospinal fluid (CSF) for diagnosis of tubercular meningitis. Most of the serological assays are ELISA based. Attempts have been made to use much simpler antigen detection techniques like the reverse passive haemagglutination (RPHA)which is simple and cost-effective.

OBJECTIVE

To evaluate the reverse passive haemagglutination (RPHA) test for detection of mycobacterial antigens in the CSF for diagnosis of tubercular meningitis.

METHODS

In the present study, we have made the use of polyclonal antiserum against heat killed whole Mycobacterium tuberculosis bacilli to sensitize the RBCs in RPHA to detect antigens in clinically suspected cases. A total of 46 cases (clinically suspected TBM 24, culture proven TBM 2, non- TBM cases 20) were included in the present study for detecting M. tuberculosis antigen in the CSF specimens.

RESULTS

Of the 26 test CSF specimens, 13 CSF specimens were positive by RPHA while 4 of the 20 control CSF specimens were also reactive. Two culture positive specimens included in the study were positive by RPHA. Of the 4 control CSF specimens positive by RPHA, 3 were culture proven cases of pneumococcal meningitis and 1 was a case of cryptococcal meningitis. The RPHA is found to be 50% sensitive and 80% specific; and showed a 76.4 % positive predictive value and a 55.2 % negative predictive value.

CONCLUSIONS

The RPHA is a simple test that could be used as an adjunct in diagnosing TBM. It does not require any special equipment or technically trained or skilled manpower. It is economical and can be afforded for use in community where TBM is more prevalent. Even though the present study showed a poor sensitivity and specificity, further identification, characterization and evaluation of better immuno-dominant and specific antigens or epitopes, and the usage of antibodies developed against such mycobacterial antigens might improve the sensitivity and specificity of this test.

Since Shankar et al used polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis (M. tuberculosis) in cerebrospinal fluid (CSF), there have been numerous reports on PCR assay for diagnosis of tuberculosis meningitis (TBM). The PCR assay have been recognized to be a rapid method for diagnosis of TBM, however there are problems of PCR sensitivity when dealing with CSF samples containing small amount of M. tuberculosis DNA. Comparing direct PCR with nested PCR, we studied on the evaluation of PCR for diagnosis of TBM. In present study the nested PCR were positive in all CSF specimens from 4 patients with TBM, but we could not detect M. tuberculosis DNA by only the direct PCR. Because nested PCR amplification improved the sensitivity and specificity, the nested PCR assay will be necessary for rapid diagnosis of TBM on the clinical laboratory.

OBJECTIVE

Irradiation of pelvic bone marrow (BM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. We hypothesized that irradiation of hematologically active bone marrow (ABM) subregions defined by fluorodeoxyglucose (FDG) positron emission tomography (PET) is a principal cause of radiation-associated HT.

METHODS

The cohort included 45 patients with nonmetastatic anal cancer who underwent FDG-PET imaging prior to definitive chemoradiation with mitomycin-C and 5-fluorouracil. Total bone marrow (TBM) was defined as the external contour of the pelvic bones from the top of lumbar 5 (L5) to the bottom of the ischial tuberosity. Standardized uptake values (SUV) for all voxels within the TBM were quantified and normalized by comparison to normal liver SUV. Subvolumes of the TBM that exhibited the highest and lowest 50% of the SUVs were designated ABM50 and IBM50, respectively. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2 weeks of completion of treatment. Multivariate linear modeling was used to analyze the correlation between the equivalent uniform doses (EUD) with an a value of 0.5, 1 (equivalent to mean dose), 3, 7, and 12 to the BM structures and the ANC.

RESULTS

Mean ± SD ANC nadir was 0.77 × 10(9)/L (±0.66 × 10(9)/L). Grades 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. The EUD a parameter of 0.5 was optimal for all BM models indicating high radiation sensitivity. EUD of TBM and ABM50 and IBM50 were all significantly associated with ANC nadir. However, model performance for ABM50 was not superior to that of the TBM and IBM50 models.

CONCLUSIONS

Irradiation of pelvic BM was associated with HT. However, FDG-PET-defined ABM models failed to improve model performance compared to the TBM model.

BACKGROUND

Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 30% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcome. Areas covered: In this review we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance and children; and optimal research strategies. Expert commentary: There is good evidence from preclinical, clinical and modelling studies to support use of high-dose rifampicin in TBM, likely to be at least 30mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate use of molecular pharmacological approaches, physiologically-based pharmacokinetic (PBPK) modelling and pharmacokinetic-pharmacodynamic (PK-PD) studies to define optimal regimens to be tested in clinical trials. Fortunately, exciting data from recent studies hold promise for improved regimens and better outcome of TBM patients.

One of the adjunctive modes of diagnosing tuberculous meningitis (TBM) is to detect immune responses in the cerebrospinal fluid (CSF) to the Mycobacterium tuberculosis antigen. Up to 70% of clinical TBM reveal the presence of antimycobacterial antibody by the enzyme-linked immunosorbant assay. Defining the specificity of this immune response by Western blotting on separated M. tuberculosis antigen has been attempted in this study. Only antimycobacterial antibody-positive TBM cases were included in the study. An analysis of 30 such TBM cases showed a major immune reactivity to the 30- to 40-kDa region (93%) while a lower degree of immune reactivity was seen to the 14-kDa region (87%) and to the 18- to 25-kDa region (60%). Grossly the antibody reactivity on Western blot correlated with the ELISA results. Assessment of antimycobacterial antibody in the neurologic control CSF samples of pyogenic meningitis [n = 10], cryptococcal meningitis [6], neurocysticercosis [28], neurosyphilis [8], viral meningoencephalitis [8], carcinomatous meningitis [8], iatrogenic meningitis [6], and nonneurological control CSF samples from patients undergoing spinal anesthesia [20] revealed the presence of antibody in the CSF of 2 of the 10 pyogenic meningitis and 5 of the 28 neurocysticercosis cases. A Western blot analysis of these 7 cases revealed immune reactivity to 30- to 40-kDa regions only in 2 cases (1 of pyogenic and 1 of neurocysticercosis). The remaining 5 CSF samples did not reveal any immune reactivity on Western blotting, although ELISA demonstrated antimycobacterial antibodies. The antibody response to M. tuberculosis lipoarabinomannan and 38-kDa antigen by ELISA revealed 70.58 and 41.17% positivity, respectively. Thus this study has demonstrated that, by Western blotting, the major immune response is to the 30- to 40-kDa region, namely, lipoarabinomannan. Further, this finding will be useful for specific immunodiagnosis of the TBM.

Oxidative DNA damage triggers telomere erosion and cellular senescence. However, how repair is initiated at telomeres is largely unknown. Here, we found unlike PARP1-mediated Poly-ADP-Ribosylation (PARylation) at genomic damage sites, PARylation at telomeres is mainly dependent on tankyrase1 (TNKS1). TNKS1 is recruited to damaged telomeres via its interaction with TRF1, which subsequently facilitates the PARylation of TRF1 after damage. TNKS inhibition abolishes the recruitment of the repair proteins XRCC1 and polymerase β at damaged telomeres, while the PARP1/2 inhibitor only has such an effect at non-telomeric damage sites. The ANK domain of TNKS1 is essential for the telomeric damage response and TRF1 interaction. Mutation of the tankyrase-binding motif (TBM) on TRF1 (13R/18G to AA) disrupts its interaction with TNKS1 concomitant recruitment of TNKS1 and repair proteins after damage. Either TNKS1 inhibition or TBM mutated TRF1 expression markedly sensitizes cells to telomere oxidative damage as well as XRCC1 inhibition. Together, our data reveal a novel role of TNKS1 in facilitating SSBR at damaged telomeres through PARylation of TRF1, thereby protecting genome stability and cell viability.

METHODS

Tertiary referral hospitals in southern Vietnam.

OBJECTIVE

Molecular characterisation of multidrug-resistant (MDR) tuberculous meningitis (TBM).

METHODS

Mycobacterium tuberculosis isolates from the cerebrospinal fluid (CSF) of 198 Vietnamese adults were compared with 237 isolates from patients with pulmonary tuberculosis (PTB) matched for age, sex and residential district. Isolates resistant to isoniazid or rifampicin (RMP) were sequenced in the rpoB and katG genes, inhA promoter and oxyR-ahpC intergenic regions.

RESULTS

While drug resistance rates were lower in the CSF (2.5% MDR) than pulmonary isolates (5.9% MDR), the difference was not significant. The most commonly mutated codons were 531, 526 and 516 in rpoB and 315 in katG. Four novel triple mutants in rpoB were identified.

CONCLUSIONS

RMP resistance is a good surrogate marker for MDR-TBM in this setting. However, probes directed against these three codons would have a maximum sensitivity of only 65%. A rapid phenotypic detection test may be more applicable for the diagnosis of MDR-TBM.

BACKGROUND

Tuberculous meningitis (TBM) is a growing problem in HIV-infected patients in developing countries, where there is scarce data about this co-infection. Our objectives were to analyze the main features and outcomes of HIV-infected patients with TBM.

METHODS

This was a retrospective study of HIV-infected Brazilian patients admitted consecutively for TBM. All patients had Mycobacterium tuberculosis isolated from the cerebrospinal fluid (CSF). Presenting clinical and laboratory features were studied. Multivariate analysis was used to identify variables associated with death during hospitalization and at 9 months after diagnosis. Survival was estimated using the Kaplan-Meier method.

RESULTS

We included 108 cases (median age 36 years, 72% male). Only 15% had fever, headache, and meningeal signs simultaneously. Forty-eight percent had extrameningeal tuberculosis. The median CD4+ cell count was 65 cells/microl. Among 90 cases, 7% had primary resistance to isoniazid and 9% presented multidrug-resistant strains. The overall mortality during hospitalization was 29% and at 9 months was 41%. Tachycardia and prior highly active antiretroviral therapy (HAART) were associated with 9-month mortality. The 9-month survival rate was 22% (95% confidence interval 12-43%).

CONCLUSIONS

Clinical and laboratory manifestations were unspecific. Disseminated tuberculosis and severe immunosuppression were common. Mortality was high and the 9-month survival rate was low. Tachycardia and prior HAART were associated with death within 9 months of diagnosis.