Platelet Membrane and Calcium Control Abnormalities in Essential Hypertension

The mechanisms whereby intracellular calcium concentration is controlled are briefly reviewed. With the current knowledge of both calcium homeostasis and the function and properties of cellular Ca2+-target proteins / signal transduction systems, a dysfunction of cellular calcium metabolism is considered in relation to the pathogenesis of hypertension. Although the enhanced peripheral vascular resistance characteristic of hypertension is ultimately a function of Ca2+ availability for smooth muscle cell contraction, the platelet possesses many parallel biochemical and physiologic properties. Therefore, we have utilized the platelet as the cell model for investigating the role of Ca2+ in hypertension disorders. An overview of Ca2+-linked platelet processes altered in essential hypertension is presented, and an attempt is made to integrate these multiple aberrations in a fundamental membrane lesion. Am J Hypertens 1:42-46, 198

Endorthelium-modulated proliferation of medial smooth muscle cells: influence of angiotensin II and converting enzyme inhibition

This study investigated the role of the endothelium and angiotensin II (Ang II) in regulating medial smooth muscle cell (SMC) proliferation. [3II]-thymidine incorporation into medial SMC of rat arteries was examined in vivo, using ballooned rat carotid arteries, as well as in vitro, using cultures of aortic tissue rings (organoids). In vivo, maximal medial [3H]-thymidine incorporation occurred within 3 days post-ballooning. In endothelium-denuded organoids, maximum medial DNA synthesis was achieved after 7 days of culture. [3H]-thymidine-labelling of SMC in intact organoids (with endothelium) increased minimally during culture, indicating that the endothelium provided protection with respect to medial proliferation under basal conditions (culture in the presence of 1% plasma-derived serum). Inclusion of 10−7 M Ang-II significantly elevated medial [3H] thymidine incorporation above that in control cultures. The stimulatory effect of Ang II was much more pronounced in intact organoids than in endothelium-denuded organoids, indicating synergistic growth regulation by Ang II and endothelium-derived factors. When organoids were cultured in the combined presence of Ang II and the ACE inhibitor cilazaprilat, labelling indices of intact organoids were also significantly increased above control, but to a lower level than those obtained in the presence of Ang II alone. However, for endothelium-denuded organoids, medial [3H]-thymidine incorporation in the combined presence of Ang II and cilazaprilat was not significantly different from that in untreated controls. Thus, cilazaprilat exerts both endothelium-dependent and endothelium-independent negative regulatory effects on medial SMC proliferatio

DIII-D data for modeling the scrape-off-layer plasma

We are in the process of assembling a database of edge and divertor plasma parameters suitable for use in benchmarking tious 2D models of the scrape-off- layer (SOL) plasma. Also, we are using the Braams B2 code to derive transport coefficients for the edge plssma. In parallel, work is starting on an upgrade to the B2 code that includes padlel current flow and EXB drifts. These efforts are directed at increasing the confidence level of models of the tokamak edge plasma so that we can predict the effect of planned upgrades to DIII-D (e.g., the Advanced Divertor Program) and the performance of next generation machines such as CIT or ITER, where initial design studies show that plasma conditions at the divertor targets can have a large impact on the lifetime and cost of the machine. This report summarizes our recent progress in characterizing the DIII-D SOL plasma and in modeling these data with the the B2 code. Section I contains a brief description of the diagnostics available for characterizing the SOL plasma. In Section II we present our measurements of the SOL parameters for H-mode plasmas. This includes data showing how the divertor plasma parameters (n{sub e}(r), T{sub e}(r), and Q(r)) vary from ohmic to L-mode to H-mode, and power balance for quasi-stationary H-mode plasmas. Section III covers divertor-target heat-flux asymmetries for double and single null operation with forward and reversed toroidal field. In Section IV we show the scaling of L-mode parameters with neutral beam power, and Section V concludes with a summary of the results obtained from the Braams B2 SOL simulation code

Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents

Fluorescence imaging through dynamic scattering media with speckle-encoded ultrasound-modulated light correlation

Fluorescence imaging is indispensable to biomedical research, and yet it remains challenging to image through dynamic scattering samples. Techniques that combine ultrasound and light as exemplified by ultrasound-assisted wavefront shaping have enabled fluorescence imaging through scattering media. However, the translation of these techniques into in vivo applications has been hindered by the lack of high-speed solutions to counter the fast speckle decorrelation of dynamic tissue. Here, we report an ultrasound-enabled optical imaging method that instead leverages the dynamic nature to perform imaging. The method utilizes the correlation between the dynamic speckle-encoded fluorescence and ultrasound-modulated light signal that originate from the same location within a sample. We image fluorescent targets with an improved resolution of ≤75 µm (versus a resolution of 1.3 mm with direct optical imaging) within a scattering medium with 17 ms decorrelation time. This new imaging modality paves the way for fluorescence imaging in highly scattering tissue in vivo