Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.

Tuberculous pericarditis is one of the most severe forms of extrapulmonary tuberculosis, causing death or disability in a substantial proportion of affected people.1,2 In Africa, the incidence of tuberculous pericarditis is rising as a result of the HIV epidemic.3 The effect of HIV infection on survival in patients with tuberculous pericarditis is unknown.2,4 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have a similar outcome to non-infected cases,5 others have shown that there may be an increase in mortality in HIV associated with tuberculous pericarditis.2,6,7 We established a prospective observational study, the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry, to obtain current information on the diagnosis, management and outcome of patients with presumed tuberculous pericarditis living in sub-Saharan Africa, where the burden of HIV infection is the greatest in the world.4,8-10 In this paper, we report the mortality rate and its predictors during the 6 months of antituberculosis treatment among patients enrolled in the regis

Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry

BACKGROUND: The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease

Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa

Objective: To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. Design: Between 1 March 2004 and 31 October 2004, we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon, Nigeria, and South Africa, and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study, with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression, we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. Results: We obtained the vital status of 174 (94%) patients (median age 33; range 14-87 years). The overall mortality rate was 26%. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40% versus 17%, P=0.001). Independent predictors of death during follow-up were: (1) a proven non-tuberculosis final diagnosis (hazard ratio [HR] 5.35, 95% confidence interval 1.76 to 16.25), (2) the presence of clinical signs of HIV infection (HR 2.28, 1.14-4.56), (3) co-existent pulmonary tuberculosis (HR 2.33, 1.20-4.54), and (4) older age (HR 1.02, 1.01-1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80, 0.90-3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34, 0.10-1.19). Conclusion: A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africans. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease

The importance of nerve microenvironment for schwannoma development

Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation-emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas

Mortality in patients treated for tuberculous pericarditis in Sub-Saharan Africa

BibliographyObjective. To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. Design. Between 1 March 2004 and 31 October 2004, we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon, Nigeria and South Africa, and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study, with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression, we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. Results. We obtained the vital status of 174 (94%) patients (median age 33; range 14-87 years). The overall mortality rate was 26%. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40% v. 17%, p=0.001). Independent predictors of death during follow-up were: (i) a proven non-tuberculosis final diagnosis (hazard ratio (HR) 5.35, 95% confidence interval (CI) 1.76-16.25), (ii) the presence of clinical signs of HIV infection (HR 2.28, CI 1.14-4.56), (iii) coexistent pulmonary tuberculosis (HR 2.33, CI 1.20-4.54), and (iv) older age (HR 1.02, CI 1.01-1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80, CI 0.90-3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34, CI 0.10-1.19). Conclusion. A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africa. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease.The IMPI Africa Registry was sponsored by the South African Medical Research Council and National Research Foundation (through the 2004 - 2006 Africa Fellowship to Dr C S Wiysonge); the University of Cape Town’s Cardiac Clinic Research Fund; and the MESAB (Medical Education for South African Blacks) (through the 2003 Don Kennedy Scholarship to Dr M Ntsekhe)

Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes

<div><p>Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.</p></div

Relationship between cluster extension and HCV RNA content.

<p>(<b>A</b>) The maximal extension of the clusters, , characterized on the different grids in relation to the maximal cellular HCV RNA content in the cells belonging to this cluster. For each grid, only the clusters including the cell with the highest amount of intracellular HCV RNA were considered. Different patients are indicated by different symbols and colors. The radius is given on a continuous scale, as well as converted into number of cells assuming radial spread. (<b>B</b>) The level of the HCV RNA content in hepatocytes with increasing cluster extension as characterized by Fig. 2. Dots correspond to the radii estimated during the iterative process of cluster determination. The individual results for all patients and all different sections per patient (grid 1 <i>red</i>, grid 2 <i>blue</i>, grid 3 <i>green</i>) are shown. Lines indicate the best fit of a model assuming a biphasic linear decrease of the intracellular HCV RNA content with increasing cluster extension (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003934#pcbi-1003934-t004" target="_blank">Table 4</a>). (<b>C</b>) The total HCV RNA content in an inferred cluster, i.e., the sum of the HCV RNA content in all hepatocytes belonging to a cluster versus the square root of the cluster size measured in number of cells. Each point is the result of 10,000 simulated clusters based on the characteristics for each of the different clusters per patient per grid as described in <i><a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003934#s4" target="_blank">Materials & Methods</a></i>. Symbols indicate the mean of total HCV RNA content and cluster size, arrows determine the 2.5% and 97.5% percentiles of the 10,000 bootstrap replicates. Corresponding values are given in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003934#pcbi-1003934-t001" target="_blank">Table 1</a>.</p

HCV RNA and age of infection.

<p>HCV RNA and age of infection.</p