Endothelin-1 causes luminal constrictions in rat cochlear veins

Serum levels of the vasoconstrictor endothelin-1 (ET-1) increase in ischemia and systemic hypertension. We examined the effects of ET-1 on the cochlear microvasculature. Blood vessels were cast with methacrylate in adult male Wistar Kyoto rats, 10 min after intravenous injection of ET-1 (1.0 microg/kg); control animals received saline. Systemic blood pressure was recorded continuously. ET-1 increased the average systolic pressure by 18% and average diastolic pressure by 22% (P < 0.01). Scanning electron microscopy of cast vessels showed multiple circumscribed luminal constrictions on: (1) postcapillary venules; (2) collecting veins; (3) where collecting veins merged with the spiral modiolar vein; (4) on the spiral modiolar vein itself. Circumscribed constrictions in arteries were not observed. In ET-1 injected animals focal contractions of collecting veins reduced luminal width by 13.4% +/- 2.9 (P < 0.01). In control rats, constrictions on venous casts were minimal and constrictions on arteries were not observed. The present study shows that ET-1 is involved in local control of cochlear blood flow in that it focally contracts cochlear veins. It is suggested that this might be due to the high affinity of ET-1 receptors and/or the large number of ET-1 receptors on contractile cells in venous walls.     

Dynamic and geometric error assessment of an XYC axis subset on five-axis high-speed machine tools using programmed end point constraint measurements

This paper presents a technique for assessing the volumetric errors on a five-axis machine tool for motion involving two linear axes and one rotary axis at selected feed rates using data from two sources. The first source of data is obtained through a programmed end point constraint procedure with measurement of the 3D volumetric positioning errors between a point on the tool holder and another fixed to the machine table reference frame. The tests involve maintaining the nominal coincidence of these two points whilst exercising the three axes. The second source of data is the position feedback signal from the encoder provided by the machine controller. Tests were carried out at low and high feed rates to evaluate the effect of geometric and dynamic errors. Polynomial functions are used to represent and then predict the geometric errors. The predicted geometric errors are then added to the dynamic errors provided by the servo errors from position feedback signals and propagated to the tool centre point and are compared with the measured volumetric errors. It shows that the influence of the geometric errors are dominant at low feed, whereas the effects of the servo errors of the linear axes become dominant as the feed increases, reaching 80% of the total error at a feed of 10,000 mm/min.     

Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF). PlGF is a member of the vascular endothelial growth factor (VEGF) family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.     

Identification of fenestrated capillary segments in microvascular corrosion casts of the rat exocrine pancreas

The capillary bed of the rat exocrine pancreas was studied by scanning and transmission electron microscopy of corrosion casts and tissue sections. Two types of capillaries were distinguished in corrosion casts. First, there were straight capillaries of relatively constant width (mean diameter 4.79±0.87 μm), which were characterized by numerous circular constrictions on their surface. About 37% of the capillaries belonged to this type. Second, there were undulating capillaries which showed smooth surfaced eccentric dilatations defined by similar surface constrictions. The bulging areas measured 8.43 ± 1.33 μm, the constrictions next to the bulges figured for 6.45 ± 1.53 μm. About 63% of the capillaries belonged to the second type. Two types of capillaries were also identified in tissue sections. First, there were capillaries with continuous endothelial lining (26% of capillary profiles; mean diameter 5.48 ± 1.67 μm); 27% of their endothelial lining was provided with underlying pericytes. Second, there were capillaries with fenestrated endothelium (64% of capillary profiles; mean diameter 6.16 ± 1.75 μm); 12% of their endothelial lining was accompanied by pericytes. According to frequency and dimension of these two types of capillaries, we conclude that bulged and undulating capillary casts correspond to fenestrated capillaries and straight capillary casts of constant width correspond to nonfenestrated capillaries. The frequency of crests on the surface of capillary casts correlates with the different frequency of pericyte processes on fenestrated and nonfenestrated capillaries. It is concluded that pericyte processes beneath the endothelium hold resistance against luminal pressure. Bulging areas of capillary casts correlate with fenestrated areas of endothelial lining, that is, areas which are not reinforced by pericyte processes.     

Pulmonary venous sphincters in cattle

Formulation difficulties prevented the otherwise promising clinical development of the anti-tumour agent trimelamol (TM; tris-[hydroxymethyl]trimethylmelamine]). A synthetic analogue programme resulted in the identification of CB 7646 (bis N-[hydroxymethyl]trimethylmelamine) as a compound with improved stability and favourable formulation characteristics. The in vitro and in vivo activity of CB 7646 was shown to be very similar to that of TM. In addition, curative activities were shown in the PXN/65 human ovarian cancer xenograft and the MX-1 and T-61 human breast cancer xenograft models. The effectiveness of the N-(hydroxymethyl)melamines against platinum-refractory disease was noted in the phase I clinical trial of TM. In line with this finding, the present study confirmed the effective activity of both TM and CB 7646 against various forms of platinum resistance in in vitro models. Curative activity for TM and CB 7646 was seen in the HX110P human ovarian cancer xenograft with acquired carboplatin resistance. Animal studies indicated less neurotoxicity for CB 7646 than for TM. The pharmacokinetic profile of CB 7646 indicated a decreased plasma elimination, indicative of slower in vivo degradation than for TM. CB 7646, therefore, represents a promising candidate for clinical development, designed to supersede TM.