In silico modeling of interstitial lung mechanics: implications for disease development and repair

In this perspective, we first review some of the published literature on structural modeling of the mechanical properties of the lung parenchyma. Based on a recent study, we demonstrate why mechanical dysfunction accompanying parenchymal diseases such as pulmonary fibrosis and emphysema can follow a very different course from the progression of the underlying microscopic pathophysiology itself, particularly in the early stages. The key idea is related to the concept of percolation on elastic networks where the bulk modulus of the network suddenly changes when the fibrotic stiff regions or the emphysematous holes become suddenly connected across the network. We also introduce the concept of depercolation as a basis for the rational optimization of tissue repair. Specifically, we use these network models to predict the functional improvements that a hypothetical biological or tissue engineering repair could achieve. We find that rational targeted repair can have significant benefits over generic random repair. This concept may find application in the treatment of lung fibrosis, surgical, bronchoscopic, or biological lung volume reduction, or any future alveolar regeneration or tissue engineering solution to the repair of connective tissue damage of the lung.     

Clinicohistological disparity in leprosy

A healthy elderly man presented with localized isolated erythematous tender, anesthetic, oval plaque with little scaling near the medial angle of right eye, of 3 years' duration without any obvious nerve thickening, treated irregularly with WHO MDT for 3 months, clinically simulating BT leprosy with downgrading reversal reaction. Histology showed a BL granuloma with plenty of solid staining AFB within the foamy macrophages. Lepromin test was very weakly positive. The case is discussed in the light of clinicohistological disparity in leprosy cases with review of relevant literatures. A stress is laid on the importance of newer MDT in such cases to prevent drug-resistance, relapse and recurrence.     

In vitro activity of ertapenem against common clinical isolates in relation to human pharmacokinetics

The in vitro activity of ertapenem against bacterial pathogens isolated from patients with moderate to severe complicated intra-abdominal, complicated skin/skin structure, acute pelvic, or complicated urinary tract infection or community acquired pneumonia was compared to ceftriaxone and piperacillin-tazobactam and related to known plasma concentrations of the three agents. Ertapenem was more potent against methicillin-susceptible Staphylococcus aureus (MSSA) than ceftriaxone and piperacillin-tazobactam and was more potent and more active than both of these agents against Enterobacteriaceae and anaerobes. Piperacillin-tazobactam was the most active agent against enterococci and Pseudomonas aeruginosa. All isolates of Enterobacteriaceae (n=1088), Streptococcus pyogenes (n=37), Streptococcus agalactiae (n=48), MSSA (n=187), Haemophilus influenzae (n=59), and Moraxella catarrhalis (n=9) were susceptible to ertapenem; < 1% of 1284 anaerobes and only 1 of 113 Streptococcus pneumoniae (a penicillin-resistant isolate) were resistant to ertapenem. The MIC value at which 90% of all Enterobacteriaceae, streptococci, MSSA, H. influenzae, M. catarrhalis, and anaerobes were inhibited (MIC90) was < or = 1 microg/ml and below the mean plasma concentration of total ertapenem following a 1 g intravenous infusion for at least 24 hours, i.e., the entire recommended dosing interval, and below the free drug concentration for at least 8 h.     

Local differences in the trabecular bone structure of the proximal femur depicted with high-spatial-resolution MR imaging and multisection CT

RATIONALE AND OBJECTIVES: The authors performed this study to investigate structural variations in the trabecular bone of the proximal femur at high-resolution magnetic resonance (MR) imaging and high-resolution multisection computed tomography (CT). MATERIALS AND METHODS: Bone mineral density (BMD) was measured in 36 proximal human femur specimens by using dual x-ray absorptiometry. High-resolution MR imaging was performed at 1.5 T with an in-plane spatial resolution of 0.195 x 0.195 mm and a section thickness of 0.3 and 0.9 mm. Multisection CT was performed with an ultra-high-resolution protocol; images were obtained with an in-plane spatial resolution of 0.25 mm and a section thickness of 1 mm. In a subset of these specimens, micro CT was performed with an isotropic spatial resolution of 30 microm. Identical regions of interest (ROIs) were used to analyze images obtained with MR imaging, multisection CT, and micro CT. Trabecular bone structural parameters were obtained, and the parameters from the individual imaging modalities and BMD were correlated. RESULTS: Significant differences concerning the trabecular microarchitecture between the individual ROIs were demonstrated with multisection CT and MR imaging. A number of the correlations between structural parameters derived with multisection CT, MR imaging, micro CT, and BMD measurements were significant. For MR imaging, threshold technique and section thickness had an effect on structural parameters. CONCLUSION: Structural parameters obtained in the proximal femur with multisection CT and high-resolution MR imaging show regional differences. These techniques may be useful for depicting the trabecular architecture in the diagnosis of osteoporosis.     

Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model

Immunotherapy in combination with suicide gene therapy for breast cancer was tested using a metastatic animal model. Subcutaneous injection of the nonimmunogenic breast cancer cell line 4T1 in BALB/C mice gave rise to tumors in 100% of mice with both micrometastases and macrometastases in the lung. We used the herpes simplex virus thymidine kinase (HSV-TK) gene along with the cytokine genes granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) to determine their effect on tumor regression and inhibition of lung metastasis. Adenoviral (AV) vectors carrying these transgenes, in separate constructs, were used in this study. Intratumoral administration of AV-TK followed by 10 days of ganciclovir treatment resulted in a delay in tumor growth and, in some cases, in a low to moderate reduction in tumor volume. Inclusion of either GM-CSF or IL-2 gene with HSV-TK resulted in a slightly greater reduction in tumor volume, although these data were not significantly different from those obtained for TK treatment alone. However, when both cytokine genes were combined with TK, a substantial reduction in tumor growth was observed compared with HSV-TK alone (P < .02). Tumor weight data also exhibited superior efficacy of TK/GM-CSF/IL-2 treatment when compared with animals treated with TK gene only (P < .01). More importantly, TK/GM-CSF/IL-2 combination gene therapy induced a significant reduction in lung metastasis compared with any other treatment groups in the 4T1 model (P < .001 between TK GM-CSF/IL-2 versus TK only). Surgical excision of primary tumors after TK/GM-CSF/IL-2 plus ganciclovir treatment resulted in anti-metastatic activity that was similar to that observed for animals in which no surgery was performed. Survival analysis showed a significant difference between animals treated with AV-TK/GM-CSF/IL-2 and animals treated with TK only at 35 days after virus injection (P < .01). Immunophenotypic data suggest infiltration of lymphocytes within the tumor microenvironment in TK- and cytokine gene-treated animals. Thus, the overall data presented here demonstrate that TK gene therapy in combination with GM-CSF and IL-2 gene-mediated immunotherapy strategies have important implications in the treatment of breast cancer.