Endotoxin-induced organ injury.
To review the effects of endotoxemia on the major organ systems of the body and discuss potential mechanisms of tissue injury.



Appraisal of 60 articles representing a cross section of studies relating to in vivo and in vitro responses to endotoxin.



Cell cultures, isolated tissue preparations, animal and human studies.



Endotoxemia results in the activation of numerous cellular and hematogenous mediators. These mediators range from prostaglandins, thromboxanes, and leukotrienes, to complement components. Tumor necrosis factor may be responsible for initiating many of the observed responses to endotoxin. Species and tissue specificity are a prominent feature of the response to endotoxin.



No single agent can yet be implicated as the common mediator of endotoxin-induced organ injury. Endotoxin initiates the elaboration of a cascade of secondary mediators that amplify the response to the initial insult. The relative importance of individual agents as mediators of the response to endotoxin varies with the experimental model studied.

title: Management of donors for heart and heart-lung transplantation.
abstract: The quality of donor organs will determine the quality of life for the recipient and the importance of optimal management of the multi-organ donor is that the organs may benefit up to five, critically ill, patients. The basic principle is to maintain sufficient preload to minimise the need for inotropic support and it is recommended that all multiple organ donors should have central venous and arterial pressure monitoring in addition to adequate venous access. The importance of the choice of fluid for volume expansion and the management of the hormonal disturbances which follow brain death are considered.

title: The Papworth BiVent tube: a new device for lung isolation.
abstract: Provision of one lung ventilation can be technically challenging, particularly for anaesthetists who are only occasionally required to isolate one lung from the other. A new double lumen endotracheal tube, the Papworth BiVent Tube, has been designed to enable rapid and reliable lung isolation using any bronchus blocker without the need for fibreoptic endoscopic guidance. In this study, an airway-training manikin was used to assess ease of tracheal intubation and lung isolation using the Papworth BiVent tube. Ease of intubation was compared to a single lumen endotracheal tube and a conventional double lumen endobronchial tube. Ease of lung isolation when using a bronchus blocker was compared to a single lumen tube combined with a bronchial blocker. Tracheal intubation using the Papworth BiVent tube was found to be easier than when using a conventional double lumen endobronchial tube. Lung isolation using the Papworth BiVent tube used in combination with a bronchus blocker was achieved more reliably and rapidly than when using a single lumen tube and bronchus blocker.

title: Glycogen content & structure & some enzymes of glycogen metabolism in human foetal organs.
abstract: The glycogen content, and its structure and the enzymes involved in glycogenolysis in human foetal organs were studied at different periods of gestation. Of all the tissues studied glycogen content was found to be the highest in cardiac muscle. Very little glycogen was present in the foetal liver at 9-12 wk of gestation, this increased progressively to nearly 2 per cent at 24 wk. Glycogen content of placenta was lower than that of skeletal muscle and liver. The level of glycogen in adipose tissue, placenta and cerebrum was not high enough to play any role in glucose homeostasis of the foetus. Human foetal liver and skeletal muscle glycogen showed the normal branched structure while the liver glycogen was found to be unusually stable. Glycogen phosphorylase activity in the foetal liver and muscle was found to be low, i.e., about a fifth and a fourth of adult liver and muscle activity respectively. The stability of foetal liver glycogen and phosphorolytic activity in the liver and muscle indicate negligible glycogenolysis during foetal development. Glucose-6-phosphatase activity in foetal liver was undetectable below 12 wk of gestation, the activity increasing progressively up to 24 wk.

title: Clearance of acanthosis nigricans associated with insulinoma following surgical resection.
abstract: Acanthosis nigricans is said to be a marker of insulin resistance. It is known to occur in patients with insulinoma where there is marked hyperinsulinaemia. We report a case wherein the acanthosis disappeared following surgical resection of insulinoma and this strengthens the hypothesis that hyperinsulinaemia is responsible for acanthosis.

title: Visualization and quantification of skin barrier perturbation induced by surfactant-humectant systems using two-photon fluorescence microscopy.
abstract: In order to visualize the effects of aqueous surfactant-humectant systems on the skin barrier, an in vitro two-photon fluorescence microscopy (TPM) study, including dual-channel visualization, was carried out. TPM is a non-invasive imaging technique based on two-photon induced nonlinear excitations of fluorophores, with the capability for deep-tissue imaging (up to several hundred micrometers). The following aqueous solutions of surfactants, a humectant, and a surfactant+humectant mixture that contacted pig full-thickness skin (p-FTS) were studied: (i) a harsh surfactant solution-sodium dodecyl sulfate (SDS) (1 wt%); (ii) a harsh surfactant+humectant solution-SDS (1 wt%) + glycerol (10 wt%); (iii) a mild surfactant solution-sodium cocoyl isethionate (SCI) (1 wt%); (iv) a control solution-phosphate-buffered saline (PBS); and (v) a humectant solution-glycerol (10 wt%). Sulforhodamine B (SRB), a hydrophilic fluorescent probe, was used to visualize the effects of aqueous contacting solutions i-v on the skin barrier morphology. The results of the TPM visualization study revealed that SDS induces corneocyte damage by denaturing keratins and creating intracorneocyte penetration pathways. On the other hand, SDS+glycerol did not significantly induce corneocyte damage. The dual-channel TPM images corresponding to aqueous contacting solutions iii-v showed low SRB penetration into the corneocytes, as well as localization of the SRB probe within the lipid bilayers surrounding the corneocytes of the SC. Through a quantification of the amount of SRB that penetrated into the skin as a function of skin depth, we found that adding glycerol to an SDS aqueous contacting solution can significantly reduce the SDS-induced penetration depth of SRB, which provides evidence of the ability of glycerol to mitigate SDS-induced skin barrier perturbation. The distribution of SRB in the p-FTS samples was analyzed using a theoretical model that quantified changes in the skin aqueous pore characteristics induced by aqueous contacting solutions i, ii, iii, and v, relative to aqueous contacting solution iv, the control. The results of the theoretical model indicate the following ranking order in the extent of perturbation to the skin aqueous pores (from the highest to the lowest): i > ii > iii > iv > v. The development of such an in vitro visual ranking methodology, including quantification using TPM, can potentially reduce many costly in vivo screening procedures, thereby significantly reducing the cost and time-to-market of new cosmetic formulations containing surfactants and humectants.

title: Cell density is a critical determinant of aromatase expression in adipose stromal cells
abstract: Obesity is associated with an increased risk of breast cancer among postmenopausal women. This is at least partly due to excessive estrogen production in adipose tissue of obese women. Aromatase, the key enzyme in estrogen biosynthesis, is an important target in endocrine therapy for estrogen receptor (ER)-positive postmenopausal breast cancer. In this study we show that high confluency of human adipose stromal cells (ASCs) cultured in vitro can significantly stimulate aromatase gene expression and reduce the expression of breast tumor suppressor BRCA1 and members of the NR4A orphan nuclear family. Furthermore, small interfering RNA (siRNA)-mediated knockdown of Nurr1, a member of the NR4A family, substantially increased aromatase expression. Lastly, we found that the cell density-triggered inducibility of aromatase expression varies in ASCs isolated from different disease-free individuals. Our finding highlights the impact of increased cell number on estrogen biosynthesis as in the case of excessive adiposity.

title: Mechanical phenotype is important for stromal aromatase expression
abstract: Evidence that aromatase expression in tumor-associated breast stroma is elevated, provides a rationale for use of aromatase inhibitors (AIs) in breast cancer treatment. However, regulation of local aromatase expression in cancer-free breast stroma is poorly understood. Recent clinical work indicates that stromal cells in dense breast tissue tend to express higher levels of aromatase than their counterpart from non-dense tissue. Consistent with the clinical observation, our cell culture-based study indicated that cell density, cell shape, and extracellular matrix (ECM) significantly induced stromal aromatase expression via a distinct signal transduction pathway. In addition, we identified a number of cell surface markers that are commonly associated with aromatase-expressing stromal cells. As mammographic density is one of the strongest and most prevalent risk factors for breast cancer, these findings provide a potential mechanistic link between alterations in tissue composition of dense breast tissue and increased stromal aromatase expression. Further exploration of the in vitro model system may advance understanding of an important problem in breast cancer biology.