Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge.

BACKGROUND: Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma. METHODS: We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation. RESULTS: IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure. CONCLUSIONS: In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.

The radiation biology of radioimmunotherapy.

The treatment of cancer is a wide and varied field, encompassing many methods and modalities. Radioimmunotherapy is a technique which utilizes the ablative properties of radiation by delivering radioactive particles directly to the tumour cells. This paper presents a summary of the research evidence that relates to the optimization of the effect of radioimmunotherapy. It includes discussion on the appropriate choice of radionuclide and monoclonal antibody; methods of increasing the radiation dose absorbed by the tumour; techniques available to increase the effect that the absorbed dose has on the tumour; and methods of protecting critical healthy tissue, particularly the bone marrow, from the effects of the radiation administered.

Determining the influence of biocompatible oxygenators during cardiopulmonary bypass by 99m Tc-DTPA aerosol assessment of pulmonary permeability.

Changes in pulmonary permeability provide a partial measure of the clinical impact of biocompatible oxygenator use during cardiopulmonary bypass surgery. Previous research has shown that the clearance rate of 99mTc-labelled diethylene triamine penta-acetic acid (99mTc-DTPA) aerosol from the lungs is increased following cardiopulmonary bypass, resulting from an increase in pulmonary permeability. The aerosol clearance rate has been shown to return to normal after a period of 7 days. A blind trial was set up to assess the clinical impact of a biocompatible, Trillium-coated oxygenator compared with a standard oxygenator. In a group of 25 patients 99mTc-DTPA aerosol studies were carried out prior to cardiopulmonary bypass surgery for mitral valve surgery. Repeat studies were undertaken 3-4 h and 24-28 h after surgery. Analysis of the rates of pulmonary clearance reproduced the trends seen in earlier research. There was however no statistically significant difference in the variation of serial clearance times between the groups of patients undergoing surgery using the Trillium-coated oxygenators and those using the standard oxygenators.

A role for smad6 in development and homeostasis of the cardiovascular system.

Smad proteins are intracellular mediators of signalling initiated by Tgf-betasuperfamily ligands (Tgf-betas, activins and bone morphogenetic proteins (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific type I receptors, and associate with the common partner Smad4 to trigger transcriptional responses. The inhibitory Smads (6 and 7) are transcriptionally induced in cultured cells treated with Tgf-beta superfamily ligands, and downregulate signalling in in vitro assays. Gene disruption in mice has begun to reveal specific developmental and physiological functions of the signal-transducing Smads. Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities. Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants. These defects highlight the importance of Smad6 in the tissue-specific modulation of Tgf-beta superfamily signalling pathways in vivo.

Use of clonidine in hernia patients: intramuscular versus surgical site.

BACKGROUND AND OBJECTIVES: This study was designed to determine if administration of clonidine in hernia patients enhances analgesia. It was also designed to determine whether administration directly in the surgical site further improves the analgesia. METHODS: A randomized, double-blinded study was undertaken at a tertiary care hospital. Forty-five outpatients undergoing unilateral inguinal hernia repair by one of two surgeons (D.P. or M.A.) under local anesthesia with monitored anesthesia care were evaluated. Patients were invited to participate in this investigation at the time of the preoperative surgical visit. Patients who had a contraindication to the use of clonidine or who refused repair under local anesthesia with sedation were excluded. Patients were randomized to one of three groups: (a) clonidine 0.5 microg/kg intramuscularly and saline in the surgical site (mixed with the local anesthetic); (b) clonidine 0.5 microg/kg in the surgical site and saline intramuscularly; or (c) saline in both the surgical site and intramuscularly. The outcome measures included visual analog pain scores twice in the hospital, pain scores at rest and with movement 24 hours postoperatively, the time to first analgesic, and total analgesic requirement. RESULTS: The pain scores were lower in both clonidine groups at 2 hours postoperatively than in the control group (P < .03). No difference was observed with respect to the time to first analgesic, 24-hour analgesic use, or 24-hour pain scores among the groups. CONCLUSIONS: When clonidine is administered to patients undergoing hernia repair, the 2-hour pain scores are lowered. No difference was exhibited when clonidine was administered intramuscularly or directly into the hernia site.

Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol.

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50-70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may influence the development of coronary artery disease.

Determining the conditions for measurement of spatial-peak temporal-averaged intensity in scanned ultrasound beams.

This paper describes a new three stage approach which simplifies the process of measurement of spatial-peak temporal-averaged intensity for scanned ultrasound beams. Firstly, the conditions delivering the maximum total acoustic power are determined. Secondly, out-of-plane beam-widths are measured which, together with knowledge of the in-plane scan widths, are used to locate the depth at which the scanned area is at a minimum. Finally, the spatial-peak temporal-average intensity is measured using the conditions and depth identified in the first two stages. Experimental results justify the use of this new procedure.

6-Nitrocholesterol inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase and tumor cell growth.

6-Nitrocholesterol has been shown to cause a 50% reduction in the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in animal cells in culture at 1.9 microM and it has relative binding affinity for the cytosolic oxysterol binding protein of 357 nM in cell-free extracts from the same cell line. In addition, significant cytotoxicity was observed when this sterol was incubated with hepatoma and lymphoma cells in culture.