Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Dominant components of the Thoroughbred metabolome characterised by (1) H-nuclear magnetic resonance spectroscopy: A metabolite atlas of common biofluids.

REASONS FOR PERFORMING STUDY: Metabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu. OBJECTIVES: To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution (1) H-nuclear magnetic resonance (NMR) spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area. STUDY DESIGN: This study was performed using 7 Thoroughbreds in race training at a single time point. Urine and faecal samples were collected noninvasively and plasma was obtained from samples taken for routine clinical chemistry purposes. METHODS: Biofluids were analysed using (1) H-NMR spectroscopy. Metabolite assignment was achieved via a range of one- and 2-dimensional experiments. RESULTS: A total of 102 metabolites were assigned across the 3 biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host cometabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short-chain fatty acids were the predominant features identified within this biofluid by (1) H-NMR spectroscopy. CONCLUSIONS: Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis.

Model system studies of the influence of bacterial biofilm formation on mineral surface reactivity.

Biofilm development on mineral surfaces and related changes in surface reactivity were studied using batch and flow through experiments. An artificial groundwater was used as the primary nutrient medium, Pseudomonas aeruginosa (PAO1) was the model microbial organism and 'mineral' surfaces were kept as simple as possible by using glass or a polished quartz tile. Experiments were also completed with very low concentrations (100 mg l(-1)) of iron, Fe(2+ ), in the solution. In situ confocal laser scanning microscopy of developing colonies during the live growth phase, and of thick, mature biofilms, revealed only sporadic coverage of biofilm cells and associated polymers at the 'mineral-microbe interface'. Imaging and analysis of biofilm-conditioned surfaces doped with Fe(2+ )-rich solutions allowed the locus and form of Fe-rich mineral precipitation to be determined and show that biological surface components can cause mineral precipitation from dilute dissolved species which might otherwise remain in solution.

Annexin 2 has an essential role in actin-based macropinocytic rocketing.

Annexin 2 is a Ca(2+) binding protein that binds to and aggregates secretory vesicles at physiological Ca(2+) levels [1] and that also associates Ca(2+) independently with early endosomes [2, 3]. These properties suggest roles in both exocytosis and endocytosis, but little is known of the dynamics of Annexin 2 distribution in live cells during these processes. We have used evanescent field microscopy to image Annexin 2-GFP in live, secreting rat basophilic leukemia cells and in cells performing pinocytosis. Although we found no evidence of Annexin 2 involvement in exocytosis, we observed an enrichment of Annexin 2-GFP in actin tails propeling macropinosomes. The association of Annexin 2-GFP with rocketing macropinosomes was specific because Annexin 2-GFP was absent from the actin tails of rocketing Listeria. This finding suggests that the association of Annexin 2 with macropinocytic rockets requires native pinosomal membrane. Annexin 2 is necessary for the formation of macropinocytic rockets since overexpression of a dominant-negative Annexin 2 construct abolished the formation of these structures. The same construct did not prevent the movement of Listeria in infected cells. These results show that recruitment of Annexin 2 to nascent macropinosome membranes 16656is an essential prerequisite for actin polymerization-dependent vesicle locomotion.

Calcium signaling and annexins.

The annexins, are a family of calcium ion (Ca2+)-binding proteins whose physiological functions are poorly understood. Although many diverse functions have been proposed for these proteins, such as in vesicle trafficking, this review focuses on their proposed roles as Ca2+ or other ion channels, or as intracellular ion channel regulators. Such ideas are founded mainly on in vitro and structural analyses, but there is increasing evidence that at least some members of this protein family may indeed play a part in intracellular Ca2+ signaling by acting both as atypical ion channels and as modulators of ion channel activity. This review first introduces the annexin family, then discusses intracellular localization, developmental regulation, and modes of membrane association of annexins, which suggest roles in Ca2+ homeostasis. Finally, it examines the structural and electrophysiological data that argue for key roles for annexins in the control of ion fluxes.

High-resolution CT in the evaluation of clinically suspected Pneumocystis carinii pneumonia in AIDS patients with normal, equivocal, or nonspecific radiographic findings.

OBJECTIVE: We prospectively studied AIDS patients with a high clinical pretest probability of Pneumocystis carinii pneumonia (PCP) in whom chest radiographic findings were normal, equivocal, or nonspecific with high-resolution CT (HRCT) to determine the incidence of PCP in these patients, to assess the diagnostic accuracy of HRCT for the presence or absence of PCP, to evaluate the role of HRCT in patient management, and to determine the clinical outcome of all patients 1 month after evaluation. SUBJECTS AND METHODS: All patients were referred to the Division of Pulmonary and Critical Care Medicine for diagnosis of clinically suspected PCP. Thirty-three patients were prospectively evaluated with HRCT within 24 hr of diagnostic bronchoalveolar lavage; 18 other patients who underwent HRCT were managed according to the HRCT interpretation and followed up clinically. All HRCT scans were independently reviewed by three chest radiologists; patchy or nodular ground-glass attenuation was considered to indicate "possible PCP." RESULTS: The incidence of PCP was 12% (6/51). The sensitivity of HRCT was 100%; specificity, 89%; and accuracy, 90% (p < .005). We had five false-positive and no false-negative interpretations. Some form of "airways disease" (n = 23) was the single most common HRCT interpretation. CONCLUSION: HRCT may allow exclusion of PCP in patients with findings that are normal, equivocal, or nonspecific on chest radiographs. Empiric therapy or immediate bronchoscopy can be avoided in many patients on the basis of the HRCT findings.

Impact of Streptococcus pneumoniae bacteremia and human immunodeficiency virus type 1 on oral mucosal immunity.

To determine whether defects in mucosal immunity were associated with invasive disease caused by a mucosal pathogen, Streptococcus pneumoniae, levels of salivary immunoglobulins and nonspecific immune factors were compared in subjects with human immunodeficiency virus type 1 (HIV-1) infection and in HIV-1-seronegative subjects with and without pneumococcal bacteremia. The IgA2 subclass may be of particular importance because S. pneumoniae produces IgA1 protease, which cleaves IgA1 but not IgA2. Levels (37-56 micrograms/mL) and proportions (11%-17%) of IgA2 were similar among groups. Serotype-specific capsular salivary IgA was present in a minority of patients with acute bacteremia. Levels of lactoferrin were increased with bacteremia. Neither selective mucosal IgA2 deficiency nor impaired nonspecific upper respiratory mucosal responses were associated with invasive pneumococcal disease during HIV-1 infection; thus, other defects in mucosal cellular responses and systemic immunity may predispose HIV-1-infected patients to invasive pneumococcal disease.