Biomedical subjects
D Tobias
Publications and source records attributed to D Tobias.
First-principles determination of hybrid bilayer membrane structure by phase-sensitive neutron reflectometry.
The application of a new, phase-sensitive neutron reflectometry method to reveal the compositional depth profiles of biomimetic membranes is reported. Determination of the complex reflection amplitude allows the related scattering length density (SLD) profile to be obtained by a first-principles inversion without the need for fitting or adjustable parameters. The SLD profile so obtained is unique for most membranes and can therefore be directly compared with the SLD profile corresponding to the chemical compositional profile of the film, as predicted, for example, by a molecular dynamics simulation. Knowledge of the real part of the reflection amplitude, in addition to enabling the inversion, makes it possible to assign a spatial resolution to the profile for a given range of wavevector transfer over which the reflectivity data are collected. Furthermore, the imaginary part of the reflection amplitude can be used as a sensitive diagnostic tool for recognizing the existence of certain in-plane inhomogeneities in the sample. Measurements demonstrating the practical realization of this phase-sensitive technique were performed on a hybrid bilayer membrane (self-assembled monolayer of thiahexa (ethylene oxide) alkane on gold and a phospholipid layer) in intimate contact with an aqueous reservoir. Analysis of the experimental results shows that accurate compositional depth profiles can now be obtained with a spatial resolution in the subnanometer range, primarily limited by the background originating from the reservoir and the roughness of the film's supporting substrate.
Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma.
Previous in vitro studies have demonstrated that endogenously produced human interleukin-8 (IL-8) can act as an important growth factor for human melanoma cells in vitro. The present study, has investigated whether IL-8 mRNA expression in primary melanomas may be of prognostic relevance with regard to melanoma progression and metastatic spread. In order to evaluate the clinical significance of IL-8 mRNA expression of melanoma cells in vivo, 59 melanocytic tissue specimens (37 primary melanomas and 22 melanocytic naevi) were studied using a semiquantitative in situ hybridization technique. Significant mRNA expression of IL-8 was found in 59 per cent (22/37) of melanomas. In 19 per cent (7/37) of the malignant melanomas, additional hybridization signals were noted within keratinocytes of the overlying epidermis. In contrast, paralesional normal-appearing epidermis and melanocytes in non-malignant lesions (melanocytic naevi) showed no IL-8 mRNA. Analysis of the relationship between IL-8 expression and clinico-histopathological features showed a significant association between IL-8 mRNA expression and the histological melanoma subtype (IL-8 mRNA: 14/19 in superficial spreading melanoma versus 4/12 in nodular melanoma, p< 0.05). Furthermore, IL-8 expression in primary tumours could be correlated with the patients' clinical course, with time to progression being significantly reduced in primary tumours expressing IL-8 in either the tumour cells or keratinocytes of the overlying epidermis. These results demonstrate for the first time that IL-8 expression, as detected by in situ hybridization in primary tumours, may serve as a significant prognostic factor for tumour progression in human malignant melanoma.
Cervical Neoplasia and Cigarette Smoking: Are They Linked?
The presence of tobacco-specific carcinogens in the cervical mucus of smokers and their effect on the local immune system strongly suggest that smoking has an etiologic role in the development of cervical neoplasia. However, it remains unclear whether smoking can affect the initiation of high-grade cervical neoplasia independently from human papillomavirus (HPV) infection. Studies that control for HPV infection may not entirely resolve the issue of the role of smoking in cervical neoplasia. Cigarette smoking may be causative through its effect on oncogenic HPV infection or by altering the immune response system. This article reviews the currently available data assessing the relationship between cigarette smoking and cervical neoplasia.
Human facet cartilage: swelling and some physico-chemical characteristics as a function of age. Part 1: Swelling of human facet joint cartilage.
The hydration of cartilage from human facet joints was measured after the joints had been subjected to different treatments. One group of facets was opened and directly exposed to physiologic saline solution before extraction of cartilage plugs. The plugs were weighed, re-equilibrated in fluid, and weighed again. The swelling results obtained under these conditions were compared with those when similar plugs of cartilage were excised from joints that had not been exposed to solution or had been exposed to solution while still closed. It was found that swelling was least (and similar in value to hip cartilage) for joints that had been exposed open to saline solution, highest for joints that had not been exposed to solution, and intermediate for joints that had been exposed to solution while still closed. The same trends were observed whether the cartilage on the joint was intact or fibrillated, although in each group the swelling and the final hydration were higher for fibrillated than for intact tissue. It was concluded that facet cartilage, unlike human hip or knee cartilage, is underhydrated when excised from the joint. This underhydration is thought to reflect the permanent presence of stresses in vivo on some part of the facet joints, the position of the loaded site changing with time. The authors attempted to distinguish between the swelling caused by this underhydration and that from disruption of the collagen network in the case of fibrillated specimens.
Effects of different angiotensin-converting enzyme (ACE) inhibitors on ischemic isolated rat hearts: relationship between cardiac ACE inhibition and cardioprotection.
We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs, zofenopril and S-benzoylcaptopril, hydrolyzed rapidly by cardiac esterase, were more effective than their component ACE-inhibitors, whereas fosinopril, ramipril and enalapril were poorly active. For studies in ischemic rat hearts, vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity, only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid, ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations, despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril, however, had any effect on coronary flow before or after ischemia. Thus, it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or, at least, that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and, thus, this group appears to be important in mediating their cardioprotective actions.
Characteristics of lung pericytes in culture including their growth inhibition by endothelial substrate.
Pericytes and endothelial cells from the same sample of adult rat lung have been separately established in culture by use of selective growth media. The endothelial cells are positive and the pericytes negative for angiotensin-converting enzyme activity and tissue plasminogen activator. Morphologically in culture, the pericytes are similar to pericytes from bovine retina and other sites and show positive immunofluorescence to both human platelet (non-muscle) myosin and smooth muscle myosin. In this respect they resemble smooth muscle cells grown from the rat main pulmonary artery, but lack the myofilaments and dense bodies characteristic of muscle cells. Lung endothelial cells and fibroblasts are positive only for platelet myosin. Pericytes in culture demonstrate an unusual growth response to endothelial substrate, obtained by removing confluent endothelial monolayers with nonionic detergent or alkali. When plated onto this material at low density, pericyte growth is inhibited. By contrast, the substrate stimulates the growth of endothelial cells and has no effect on smooth muscle cells. Initial attachment of endothelial cells and pericytes to the substrate is similar.