In vitro and in vivo activities of ruthenium(II) phosphine/diimine/picolinate complexes (SCAR) against Mycobacterium tuberculosis.

Rifampicin, discovered more than 50 years ago, represents the last novel class of antibiotics introduced for the first-line treatment of tuberculosis. Drugs in this class form part of a 6-month regimen that is ineffective against MDR and XDR TB, and incompatible with many antiretroviral drugs. Investments in R&D strategies have increased substantially in the last decades. However, the number of new drugs approved by drug regulatory agencies worldwide does not increase correspondingly. Ruthenium complexes (SCAR) have been tested in our laboratory and showed promising activity against Mycobacterium tuberculosis. These complexes showed up to 150 times higher activity against MTB than its organic molecule without the metal (free ligand), with low cytotoxicity and high selectivity. In this study, promising results inspired us to seek a better understanding of the biological activity of these complexes. The in vitro biological results obtained with the SCAR compounds were extremely promising, comparable to or better than those for first-line drugs and drugs in development. Moreover, SCAR 1 and 4, which presented low acute toxicity, were assessed by Ames test, and results demonstrated absence of mutagenicity.

Relationship between asthma control status, the Asthma Control Test™ and urgent health-care utilization in Asia.

BACKGROUND AND OBJECTIVE: Accurate assessment of control is an integral part of asthma management. We investigated the relationship between control status derived from the Global Initiative for Asthma (GINA), the Asthma Control Test (ACT) and urgent health-care utilization. METHODS: Asthma Insights and Reality in Asia-Pacific Phase 2 (AIRIAP 2) was a cross-sectional, community-based survey of 4805 subjects with asthma from urban centres across Asia. A symptom control index was derived from the AIRIAP 2 questionnaire using the GINA control criteria for day- and night-time symptoms, need for rescue medication, activity limitation and exacerbations; lung function was excluded. The main outcomes were asthma control, based on these GINA criteria and the ACT, and the relationship between control and self-reported urgent health-care utilization (hospitalization, emergency room visits or other unscheduled urgent visits) related to asthma over the previous 12months. RESULTS: Each of the symptom criteria was significantly associated with urgent health-care utilization, with odds ratios (ORs) ranging from 2.25 (95% confidence interval (CI): 1.94-2.61) for daytime symptoms to 2.57 (95% CI: 2.29-2.90) for nocturnal awakening. Similarly, control status was significantly associated with urgent health-care utilization, with ORs of 0.19 (95% CI: 0.13-0.28), 0.70 (95% CI: 0.65-0.76) and 1.00 for controlled, partly controlled and uncontrolled, respectively. The optimal ACT cut-off score for identifying uncontrolled asthma was ≤19 for subjects aged ≥12years. Urgent health-care utilization was reported by 57.2% versus 28.7% of patients scoring ≤19 versus >19 (P<0.001). CONCLUSIONS: The GINA control classification and the ACT are valid symptom-based measures that are significantly associated with urgent health-care utilization.

Prognostic effect of pathologic fracture in localized osteosarcoma: a cohort/case controlled study at a single institute.

BACKGROUND: The negative prognostic role of pathologic fracture in osteosarcoma is not determined, as previous case-control and retrospective cohort studies have produced contradictory results. METHODS: We conducted both cohort (n = 384) and case-control (n = 111) studies on 37 pathologically fractured localized osteosarcoma of extremity. RESULTS: In cohort study, patients with a fracture showed a tendency of poorer survival, but the difference did not reach the level of significance (5-year metastasis-free survival rates; 48% for cases vs. 61% for controls; P = 0.06). A case-control study on 37 fractured and 74 control recruited from 347 patients matched for tumor size and location showed no survival difference between the cases and controls (P = 0.12). CONCLUSIONS: Reported negative prognostic effect of a pathologic fracture is likely to be due to confounding by tumor size and location. The present study suggests that the presence of a pathologic fracture has no prognostic relevance.

Vaccination with Bacille-Calmette Guérin promotes mycobacterial control in guinea pig macrophages infected in vivo.

Tuberculosis pleurisy was induced by inoculation of virulent (H37Rv strain or Erdman strain) or attenuated (H37Ra strain) green-fluorescent protein-expressing Mycobacterium tuberculosis into guinea pigs that had or had not been vaccinated with Bacille-Calmette Guérin (BCG). Pleural fluid and cells were analyzed for phagosome-lysosome (P-L) fusion, on the basis of confocal microscopy, intracellular and extracellular bacterial survival, and production of cytokine mRNA. BCG vaccination increased fluid volume and cellular accumulation, significantly enhanced P-L fusion, and significantly decreased intracellular bacterial survival in pleural-effusion macrophages of the guinea pigs infected with the 2 virulent strains. Furthermore, significant increases in interferon-gamma, transforming growth factor-beta, tumor necrosis factor-alpha, and interleukin-12p40 cytokine mRNA were seen in the pleural cells of the BCG-vaccinated guinea pigs.

Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascular-focused hyperthermia: characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy.

We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.

In Vivo Detection of Gold Nanoshells in Tumors Using Diffuse Optical Spectroscopy.

This study demonstrates the use of diffuse optical spectroscopy (DOS) for the noninvasive measurement of gold nanoshell concentrations in tumors of live mice. We measured the diffuse optical spectra (500-800 nm) using an optical fiber probe placed in contact with the tissue surface. We performed in vitro studies on tissue phantoms illustrating an accurate measurement of gold-silica nanoshell concentration within 12.6% of the known concentration. In vivo studies were performed on a mouse xenograft tumor model. DOS spectra were measured at preinjection, immediately postinjection, 1 and 24 h postinjection times, and the nanoshell concentrations were verified using neutron activation analysis.

Monte Carlo calculations of the dose distribution around a commercial gynecologic tandem applicator.

BACKGROUND AND PURPOSE: Dose rate distributions around Fletcher Suit Delclos (FSD) tandem applicators used for intracavitary brachytherapy are usually calculated by assuming each source is a point source and summing the contributions from each of the sources. Consequently, interpellet attenuation and scattering are ignored. Additional error may be introduced because the applicator walls and tip screw are not considered. The focus of this study was a Monte Carlo simulation of a Selectron tandem, verification of the calculations, and presentation of the implications of the point-source approximation for treatment planning. MATERIALS AND METHODS: MCNPX 2.4.k was used to calculate dose rate distributions around straight and curved tandems. The Monte Carlo calculations were verified with radiochromic film. RESULTS: MCNPX calculated dose to within +/-2% or +/-2 mm for 97% of the points on the film parallel to the long axis and 98% on a film perpendicular to the long axis of the straight portion of the tandem. The point source approximation overestimated dose by as much as 33% superior to the tip of the tandem as compared to MCNPX. The point source approximation overestimated dose when photons passed through multiple pellets by as much as 18% as compared to MCNPX. Laterally, the dose distribution was not affected greatly. CONCLUSIONS: Interpellet attenuation was a dominant factor in determining the distribution along the length of the pellet train. MCNPX calculated doses accurately when the pellets and applicator walls were included in the geometry. The point source approximation is adequate lateral to the tandem. The point source approximation does not calculate dose accurately superior to the tandem or when photons pass through multiple pellets.