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SummaryThis paper describes a controlled study of the effects of a fish supplement on haemostasis. This was evaluated by measuring bleeding times from skin incisions, the volume of the emerging blood, the number of platelets taking part in the formation of the haemostatic plug (platelet retention), and the release of thromboxane B2 and β-thromboglobulin in volunteers, before and after consuming a daily supplement of 100 g of fish (n = 20) or meat (n = 20) paste for 6 weeks. The fish supplement decreased the amount of thromboxane B2 released per platelet incorporated into the plug. Despite this, the skin bleeding times were hardly changed. There was also no difference in platelet retention, which was consistent with there being no difference in the release of β-thromboglobulin.These results suggest that in the effect of marine diets on haemostasis, a reduced vascular reactivity plays a more important role than decreased plug formation.

A breadboard called PODI (Prototype Optical Diagnostic Instrument) was developed following a study on a general facility for experimental research on fluid physics in a space laboratory. This breadboard has been extended to TelePODI, for the study of telescience and image processing in “microgee related instrumentation”, and has been integrated in the Telescience Test Bed, phase 1, at ESTEC. Some results of the integration, the telescience experiment preparation and execution are reported here. The experiments are related to ground simulations, which resulted in emphasis on data handling aspects.

Recently, fatigability and muscle oxygen consumption (mVO(2)) during sustained isometric contractions were found to be less at shorter (30 degrees knee angle; 0 degrees = full extension) compared to longer knee extensor muscle lengths (90 degrees ) and, at low torques, less in the rectus femoris (RF) muscle than in the vastus lateralis and medialis. In the present study we hypothesized that these findings could be accounted for by a knee angle- and a muscle-dependent activation respectively. On two experimental days rectified surface EMG (rsEMG) was obtained as a measure of muscle activation in nine healthy young males. In addition, on day 1 maximal torque capacity (MTC) was carefully determined using superimposed nerve stimulation on brief high intensity contractions (> 70%MVC) at 30, 60 and 90 degrees knee angles. On day 2, subjects performed longer lasting isometric contractions (10-70%MTC) while mVO(2) was measured using near-infrared spectroscopy (NIRS). At 30 degrees , maximal mVO(2) was reached significantly later (11.0 s +/- 6.5 s) and was 57.9 +/- 8.3% less (average +/- SD, across intensities and muscles) than mVO(2) at 60 and 90 degrees (p < 0.05). However, rsEMG was on average only 18.0 +/- 11.8% (p = 0.062) less at the start of the contraction at 30 degrees . At 10%MTC at all knee angles, maximal mVO(2) of the RF occurred significantly later (28.8 +/- 36.0 s) and showed a significantly smaller increase in rsEMG compared to both vasti. In conclusion, it is unlikely that the tendency for less intense muscle activation could fully account for the approximately 60% lower oxygen consumption at 30 degrees , but the later increase in RFmVO(2) seemed to be caused by a less strong activation of the RF.

A complete biological integration into the surrounding tissues (bone, gingiva) is a critical step for clinical success of a dental implant. In this work biomimetic coatings consisting either of collagen type I (for the gingiva region) and hydroxyapatite (HAP) or mineralized collagen (for the bone interface) have been developed as suitable surfaces regarding the interfaces. Additionally, using these biomimetic coatings as a matrix, adhesion peptides were bound to further increase the specificity of titanium implant surfaces. To enhance cell attachment in the gingiva region, a linear adhesion peptide developed from a laminin sequence (TWYKIAFQRNRK) was bound to collagen, whereas for the bone interface, a cyclic RGD peptide was bound to HAP and mineralized collagen using adequate anchor systems. The biological potential of these coatings deduced from cell attachment experiments with HaCaT human keratinocytes and MC3T3-E1 mouse osteoblasts showed the best results for collagen and laminin sequence coating for the gingiva region and mineralized collagen and RGD peptide coatings for regions with bone contact. Our concept opens promising approaches to improve the biological integration of dental implants.

No Abstract Available.© (2003) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

An electrochemical method for the deposition of calcium phosphate phases on titanium surfaces using the galvanostatic mode is presented. Deposition was performed in a (Ca(2+) / H(x)PO(4) ((3-x)-))-containing electrolyte near physiological conditions with regard to pH (6.4) and temperature (36 degrees C). Cathodic alkalization leads first to the formation of a thin homogeneous layer that shows a nanoscale surface topography of alternating wall-like elevations and channels. It is thought that these channels in the calcium phosphate prelayer are formed as pathways for hydroxyl ions and hydrogen. Upon this layer, spheres of amorphous calcium phosphate (ACP) are formed as indicated by Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy. According to transmission electron microscopy images, these spheres consist of small clusters of calcium phosphate (approximately 30 nm) and can grow up to 300 nm in diameter. Characteristic for this ACP is a high water content as seen by FTIR. As a function of current density, the ACP is then transformed into crystalline hydroxyapatite (HAP), which was identified using FTIR and X-ray diffraction. The morphology of the HAP crystals can be described as needles with dimensions of500-nm length and60-nm width. By choice of different electrochemical parameters, a homogeneous coating of either ACP, HAP, or the intermediate phase can be achieved, as shown in a kinetic phase diagram, thus allowing the formation of coatings with different properties in solubility and morphology.

Choosing information technology (IT) is a high-risk guessing game to some extent because of its strategic nature within organizations and the threat of obsolescence as it turns over rapidly. Because the course of enterprise computing has been dictated by prevailing technologies and expedited by competitive pressures and its strategic significance, complex heterogeneous architectures have become wide spread. The typical enterprise utilizes centralized legacy mainframe and midrange, distributed client server, and is quickly adapting the newest to the mix, Internet/intranet. Moving into each strategy has presented enormous investments in time and new technologies, for which the unsuspecting executive has witnessed ever-shrinking periods of investment payback. Going forward the successful enterprise-computing model will be based on integrated applications and systems, a more manageable architecture that is complemented rather than disturbed by new technologies, and a simplified client device that is independent of the enterprise operating environment. This paper presents server-based computing as a strategy that facilitates simplifying the desktop by migrating its complexities and liabilities into a more effectively managed centralized location, while delivering the same level of functionality and familiar user interface. This approach isolates the dependency of the desktop, and fosters time-to-value, quality of service and administrative effectiveness, universal accessibility, high security, long-term growth and adaptability, and relatively low cost of ownership.

The effects of administering reserpine (0.1 mg/kg) or 17alpha-ethinyloestradiol (2.5 mg/kg) to New Zealand White rabbits on low density lipoprotein receptors in liver, on plasma low density lipoprotein and fibrinogen and on plasma and tissue lipids were determined. Blood pressure and heart rate were also followed. The drugs were injected subcutaneously into conscious unrestrained rabbits for 5 days. On the 6th day homologous 125I-tyramine cellobiose labelled low density lipoprotein (125I-TC-LDL) was injected intravenously and 24 h later the animals were killed. Compared to controls, reserpine significantly increased LDL receptor expression in the liver by about threefold, and reduced total cholesterol in plasma, aorta and heart, without affecting plasma triglycerides. The reductions in plasma cholesterol and heart were due to decreases in both unesterified and esterified cholesterol. Similar effects were observed with oestrogen, except that there was no change in esterified cholesterol in aorta. In liver, a decrease of 24% in total cholesterol was due mainly to decreased esterified cholesterol. In adrenal glands total cholesterol increased by 25%. Reserpine significantly accelerated the plasma clearance of intravenously injected homologous 125I-TC-LDL and reduced its accumulation in aortic wall. Neither reserpine nor oestradiol affected blood pressure, haematocrit or plasma fibrinogen. The results suggest that reserpine is an affective anti-atherogenic drug capable of decreasing cholesterol in plasma, arteries and heart by increasing high affinity LDL receptors in the liver.

An unusual fracture of the trapezium was found on computed tomography examination after plain radiographs failed to demonstrate any bony pathology. This coronal fracture has not been previously mentioned in the literature. Management included open reduction and internal fixation with 2 lag screws.

Con el fin de comparar dos concentraciones de sulfato debario, 60 y 30% pv, mediante el método broncográfico "dederrame", se trabajó con dos grupos de 8 perros adultos, de ambossexos, clínicamente sanos, de 7 a 18 kg de peso, anestesiados contiopental sódico (2%) en dosis de 20 mg/kg vía iv. El mediode contraste se aplicó previa intubación del paciente, conun catéter conectado a una jeringa en dosis de 9 ml para cada perro.Se tomaron dos series radiográficas por animal, a los 3 y 6 minde aplicado el medio de contraste, en proyección lateral izquierday luego ventrodorsal 30 seg después. Las radiografías obtenidasfueron analizadas y comparadas intra e intergrupo, considerando la velocidadde avance del medio de contraste, densidad y contorno radiográfico,así como la presentación de reacciones adversas. Los resultadosindican que la velocidad de avance fue mayor con la concentraciónal 30%, ya que alcanzó a los 3 min en ambas proyecciones las estructurasanatómicas terminales del árbol bronquial, provocando alveolarizacióndel medio de contraste, lo que aumentó a los 6 min. Por esto seconsideró más adecuada la concentración al 60% yaque avanza hasta los bronquios, sin alcanzar el nivel alveolar. La densidadradiográfica media predominó en los diferentes segmentosen ambas concentraciones, presentándose en mayor proporciónpara la concentración al 60% la densidad media a alta, y para laconcentración al 30% la densidad media a baja. El contorno radiográficodel árbol bronquial se observó mayoritariamente liso conla concentración al 60%, en ambos tiempos para ambas proyecciones.En la concentración al 30% los contornos irregulares se presentaronen similar proporción que los contornos lisos en ambas series radiográficas.No se registró reacción adversa posterior a la realizacióndel método broncográfico Two solutions of barium sulphate, 60 and 30% w/v, were compared with the "overflow" Bronchographic method. Two groups of eight healthy adult dogs of both sexes, weighing 7 to 18 kg were used for the study. The dogs were anaesthetised with thiopentone sodium 2% (20 mg/kg iv). After intubation, each dog received contrast medium by a catheter connected to a syringe, in a 9 ml dose. Two series of two x-rays plates were taken in left lateral recumbent, 3 and 6 min after administering the contrast medium and in ventrodorsal projection, 30 sec. later. The x-ray plates obtained were analysed and compared intra and inter group considering the advance speed of the contrast medium, the radiographic density and outlines. Adverse reactions were controlled

It is gratifying that the editors of the Journal of Physiology wish to make available on-line a paper published by the late Michael Cross and myself more than 40 years ago (Born & Cross, 1963). The paper is based on the first method – optical aggregometry – permitting reproducible and rapid measurements of platelet aggregation in vitro, and reports some basic results. The method had been presented to the Physiological Society and published in Nature the year before (Born, 1962). The introduction of the simple, rather obvious method presumably accounts for the popularity of these papers, as with other papers introducing novel techniques (e.g. Lowry's for protein determination). The publications initiated a long series of papers reporting extensive new information about platelets and their doings. At the time the Journal of Physiology paper appeared the only known physiological function of platelets was haemostasis, in which individually circulating platelets rapidly adhere and aggregate in injured blood vessels, the resulting plug slowing and arresting the bleeding. The aggregation process is induced by changes in the normal haemodynamic and/or biochemical environment of circulating platelets. Although intravascular aggregation of platelets was recognized when they were discovered by Bizzozero in 1882, elucidation of the process made little progress until it could be investigated ex vivo by optical aggregometry. The urgency increased when it became clear that platelet aggregation in arterial, e.g. coronary, thrombosis is induced in essentially the same way as a consequence of haemorrhage through fissures in atheromatous plaques (Davies & Thomas, 1983; Richardson et al. 1989). I first became properly aware of platelets as an Army Medical Officer posted close to atom-bombed Hiroshima in defeated Japan in 1946, where many people were still dying from thrombocytopenic haemhorrages induced by radiation. My interest in the mechanism of platelet aggregation was awakened through the coming together of two observations. One was the exceptionally large concentrations of ATP in platelets, discovered while providing evidence that 5-hydroxytryptamine or serotonin, the vasoconstrictor factor in platelets, is bound ionically to ATP (Born et al. 1956). The other was the platelet-aggregating effect of ADP (Gaarder et al. 1961). I suggested that these findings are connected through the formation of ADP from ATP released from platelets and from other cells involved in vascular injury (Born, 1962). This turned out to be an oversimplification as far as the platelets themselves are concerned, which release ADP from both the same and a different pool from that containing most of the ATP. Nevertheless, the hypothesis that ADP contributes significantly to haemostatic and thrombotic platelet aggregation has been supported experimentally (Begent et al. 1982; Begent & Born, 1983; McClure et al. 1988) and by clinical trials (CAPRIE Steering Committee, 1996). The idea of optical aggregometry occurred to me from making so-called turbidimetric measurements of ribonuclease activity in Streptomyces culture filtrates for the Oxford D.Phil. In this method, a light beam is passed through platelet-rich, anticoagulated plasma, the optical density of which decreases, that is, light transmission increases, when the platelets are induced to aggregate. The only interpretable parameter is the initial rate of aggregation, which is proportional to the logarithm of the added aggregating agent, in that paper ADP. This method permitted ex vivo/in vitro quantification and analysis of determinants and inhibitors of platelet aggregation. This work has been extensively reviewed (see Born, 2002; Born & Patrono, 2005; Reynolds & Tansey (eds) 2005 for references). Aggregate formation was related to the optical changes and accounted for by classical light-scattering theory. Essential cofactors, viz. calcium and fibrinogen, were discovered; and the suggestion that fibrinogen forms ‘bridges’ linking aggregating platelets was later confirmed by electronmicroscopy and by the characterization of fibrinogen receptors. The first aggregation inhibitors were discovered, viz. ATP and adenosine, looked at initially because of their chemical relationship to pro-aggregatory ADP. A second phase of aggregation was discovered (by Macmillan & Oliver, 1965) and shown to be caused by the release of aggregating agents, viz. ADP and thromboxane A2, from the platelets themselves. The discovery (by Weiss & Aledort, 1967; Evans et al. 1968) that this release reaction is inhibited by Aspirin initiated its highly successful ‘second life’ for the prevention of arterial thromboses responsible for myocardial infarction and stroke. The main avenue of platelet research was followed with more than 40 co-workers for over 20 years. During that time several intriguing side roads presented themselves for investigation. Here are two of them. First, the non-adherence of platelets in normal vessels was shown to be due to electrostatic repulsion (rather than to prostacyclin). This led to the finding that the surface of vascular endothelium has a much greater density of free negative charges (from sialoproteins and proteoglycans) than the surfaces of other cells including erythrocytes; and that electrostatic repulsion contributes significantly to the ability of red cells to flow through capillaries (Born & Palinksi, 1989). Secondly, the inhibitory action of adenosine on platelet aggregation is potentiated by dipyridamole, which inhibits adenosine uptake by platelets. The trypanosome parasite responsible for African sleeping sickness is incapable of synthesizing nucleotides de novo but only from nucleosides like adenosine taken up from surrounding tissue fluids. This brought up the idea of developing trypanocidal drugs to act as inhibitors of adenosine uptake by these organisms. The demonstration that dipyridamole has a weak effect of this kind on Trypanosoma brucei (James & Born, 1980) initiated extensive research on purine acquisition by these organisms, with the discovery of many transporters with different substrate specificities. Differences between mammalian and trypanosome transporters are being exploited to find agents blocking the latter but not the former (for review see el Kouni, 2003). The 1963 Journal of Physiology paper ended as follows: ‘There are reasons for believing that red cells and platelets end their existence in the spleen. It is therefore possible that ADP released from red cells disintegrating in the spleen causes the circulating platelets to aggregate there and so to become trapped and to disintegrate in their turn.’ This suggestion for a physiological function of aggregation remains possible. As it has turned out, a much more important suggestion was made in the 1962 Nature paper: ‘If it can be shown that ADP takes part in the aggregation of platelets in blood vessels it is conceivable that AMP or some other substance could be used to inhibit or reverse platelet aggregation in thrombosis.’ Indeed, inhibition of aggregation was the most important discovery made with optical aggregometry because it established the therapeutic possibility of preventing arterial thrombosis by antiplatelet drugs and initiated the era of their beneficial use against myocardial infarction and stroke.

Delayed reproductive death, the appearance of colonies with a reduced cell density (impaired colonies) and the number of giant cells per colony were investigated in murine fibrosarcoma cells after irradiation with 3 to 9 Gy of x-rays. Radiation survivors were replated after reaching confluence, which occurred after 13 to 15 doublings; this procedure was repeated three times. The replating efficiency decreased in a dose-dependent manner, the survivors of 9 Gy achieving only 30% of the plating efficiency of unirradiated cells. After the third replating, i.e. after 40 to 45 doublings, the plating efficiency of the survivors approached that of the controls. The median colony size of the survivors showed a similar dose-dependent decrease, which was pronounced after the first replating but still remained significant after the third replating. The fraction of impaired colonies was increased to more than 30% in 9-Gy survivors, and though abating, the increase was still significant even after the third replating. Evidence of residual damage was also provided by the presence of giant cells. For instance, after 6 Gy irradiation and 13 to 15 doublings, the proportion of colonies with giant cells was 60%, decreasing only to 45% after 40 to 45 doublings. The number of giant cells per colony was 1.4 in colonies arising immediately after 6 Gy, decreasing to 0.9 after the third replating. These results suggest that the proliferative capacity of surviving cells is depressed even longer than their clonogenic capacity.

Atherosclerotic disease begins with the accumulation of atherogenic plasma proteins, predominantly low-density lipoprotein (LDL), in susceptible arteries. One determinant of this is the LDL concentration in the blood (4). We are investigating other factors which may influence the uptake of LDL and of fibrinogen, another atherogenic plasma protein, by artery walls, as well as the mechanism(s) of this uptake. In order to model human atherogenesis as closely as possible, the experiments are mostly in vivo, using rabbits and rats.

The effect of 5 days of oral nifedipine treatment (approximately 1 mg/kg per day in drinking water) on low density lipoprotein (LDL) and cholesterol accumulation in rabbit arteries was determined. Compared with control aortas, nifedipine treatment (n = 5) significantly reduced homologous 125I-tyramine cellobiose-LDL accumulation (control versus nifedipine: 45.93 +/- 4.3 versus 20.14 +/- 3.1 ng LDL per milligram dry weight x10(-3), p = 0.001) while the reduction of human LDL accumulation (n = 5) was not significant (49.1 +/- 6.1 versus 35.5 +/- 4.1 ng LDL per milligram dry weight x10(-3)). Aortic accumulation of orally administered [3H]cholesterol was also inhibited by nifedipine (352 +/- 34 versus 257 +/- 16 ng cholesterol per milligram dry weight x10(-3), n = 10, p = 0.022). These findings suggest a possible mechanism for the antiatherosclerotic effect of nifedipine.

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

Die Bedeutung von Lipidablagerungen in der Gefaswand fur die Atherosklerose ergibt sich aus dem seit langem bekannten Lipidanteil atherosklerotischer Plaques. Aus zahllosen Untersuchungen hat sich ein detaillierteres Verstandnis der an der Lipiddeposition beteiligten biochemischen Prozesse und der Bedeutung verschiedener atherogener Plasmalipide ableiten lassen. Durch spezielle Markierung von Lipiden [5] ist es moglich, spezifisch Einlagerung und Abbau von Lipiden in der Gefaswand experimentell zu untersuchen und neben den Auswirkungen physiologischer Faktoren [6] auch Effekte pharmakologischer Intervention zu prufen. Imanixil (INN), 4-Amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-pyrimidin-5-carbonsaure-N-(3-trifluoromethyl-phenyl)-amid-monohydrochlorid (HOE 402) ist eine neue Entwicklungssubstanz mit lipidsenkenden, antiatherosklerotischen und antithrombotischen Eigenschaften [2, 3], deren Wirkung auf die Lipideinlagerung in die Gefaswand uberpruft wurde. Nach 8tagiger Vorbehandlung mit Imanixil (10 mg/kg) wurde bei Ratten eine signifikante Abnahme der Einlagerung nativer bzw. durch Makrophagen modifizierter Low density lipoproteins (LDL) um 45% bzw. 65% festgestellt (p < 0.0075 bzw. p < 0.0001). Bei Kaninchen fuhrte eine 7tagige Vorbehandlung mit Imanixil sogar in deutlich niedrigerer Dosierung (3 bzw. 1 mg/kg) noch zu einer Abnahme der Einlagerung nativer LDL um 70% bzw. 37%(p

The aim of this study was to evaluate the effects of a preparation of low molecular weight heparan sulphate (LMW-HS) on the fibrinolytic system. Twenty-five healthy volunteers received LMW-HS by mouth in three separate experiments. In the first experiment, 10 volunteers received either 80 mg LMW-HS or placebo in a single-blind cross-over study; blood samples were taken before and 1, 2, 3 and 6 h after treatment. LMW-HS caused an increase in global fibrinolysis, the effect being greatest after 2-3 h and disappearing by 6 h. However, neither plasminogen activator activity nor tissue-type plasminogen activator (tPA) antigen levels were changed. In the second experiment, daily doses of 80 mg LMW-HS were administered to 10 volunteers for 7 days; this regimen did not produce a statistically significant increase in fibrinolytic activity for the whole group although some individuals did respond markedly. In the third experiment, 160 mg LMW-HS administered to five volunteers did not affect ADP- and collagen-induced platelet aggregation. In vitro, LMW-HS added to plasma at concentrations of 20 and 30 micrograms/ml, brought about a significant increase in apparent plasminogen activator activity. These results suggest that the increased fibrinolytic activity seen after LMW-HS is due to the recruitment of additional amounts of tPA in the ex vivo test system. LMW-HS had no effect on plasminogen activator inhibitor.

Atherosclerotic disease begins with the accumulation of atherogenic plasma proteins, predominantly low-density lipoprotein (LDL), in the walls of susceptible arteries. One determinant of this accumulation is the LDL concentration in the blood. We are investigating other factors which may influence the uptake of LDL and of fibrinogen, another atherogenic plasma protein, by artery walls from the circulating blood; the mechanism(s) of this uptake; and the rate and magnitude of the accumulation of the atherogenic plasma components in arteries. In order to model human atherogenesis as closely as possible, the experiments are in vivo using rabbits in which the initial stages of atherogenesis appear to be similar to those in man.

Twenty two children, under 15 years of age, from southern Chile's Tenth Region, with advanced stages of Hodgkin's disease (8 III-A, 6 III-B and 8 IV-B) were treated with chemotherapy (modified COPP protocol) and radiotherapy between 1976 and 1985 at Valdivia's Regional Hospital. Overall survival rate was 77.3% and disease-free survival rate was 64.5% after a follow-up period from 3 to 13 years (median 70 months). Five patients died during the first two years. One relapsed 10 years after beginning of therapy, but achieved a second complete remission. The survival rate in patients with lymphocytic depletion type (5 cases) was 20.0%, whereas that of the mixed cellularity type (14 cases) was 92.9% (p less than 0.01). No cases of second neoplasms related to chemotherapy and radiotherapy were seen in this series.

Atherosclerosis has a long initial phase in which plaques form within the arterial intima, followed by a second episodic phase in which clinical symptoms occur. We are investigating the events that initiate the second phase. It has been established that a major proportion of the acute episodes are thrombotic and that the trigger is exposure to the blood of thrombogenic constituents of the intima when cracks of fissures develop in the cap of atheromatous plaques.

Most coronary thrombi large enough to be detected by angiography are associated with tears or fissures in the caps of atherosclerotic plaques. These fissures allow blood to penetrate into the arterial wall, whereupon thrombus forms within the intima; this may be followed by thrombosis in the lumen. This process was first described in 1926 (Benson, 1926; Constantinides, 1966); however, its pre-eminence in initiating acute clinical events was realized more recently after the microanatomy of coronary thrombi was established by serial histological sectioning (Fulton,1965; Davies and Thomas, 1981, 1985). Knowledge of post-mortem angiographic appearance of plaque fissures allowed them to be recognized in the angiograms of living patients with unstable angina (Ambrose, 1985, 1988; Lo et al., 1988) or with acute myocardial infarction, (Ambrose et al., 1985, 1986) and in patients resuscitated from sudden ischemic death. Angioscopy in living patients with unstable angina has also confirmed the presence of mural thrombi on torn atherosclerotic plaques in the coronary arteries (Sherman et al., 1986; Forrester et al., 1987).

Acute myocardial infarction is most commonly initiated by fissuring of an atheromatous plaque. Through such fissures the blood is exposed to thrombogenic constituents of the intima, causing thrombotic obstruction of the coronary artery. Why plaque fissuring occurs is not known. Our investigation is to establish which types of plaque undergo fissuring by relating their mechanical with their cellular and biochemical properties; and to quantify the distribution of fissures. Results so far indicate that fissures occur predominantly in plaques with lipid pools in one segment of intima, and that the commonest single site of fissuring is that of maximal stress concentration as predicted by computer modelling. The results also suggest that arterial spasm at the immediate site of fissuring is not involved, as more than half the fissures occur at sites where there is no residual medial smooth muscle. Obstructive coronary thrombosis is initiated in most cases by plaque fissure with local haemorrhage which induces intravascular platelet aggregation. Recent observations with novel techniques have provided evidence that platelet aggregation in vivo is initiated by ADP and potentiated by thromboxane A2 and thrombin, with actual contribution of exposed collagen still undetermined. These observations provide an explanation for the limited effectiveness of any simple platelet-inhibiting drug, including Aspirin, by itself whenever arterial, eg. coronary or cerebral thrombosis is initiated by haemorrhages into atheromatous plaques. On the other hand, Aspirin is significantly effective when myocardial infarction follows unstable angina and when strokes follow transient episodes of cerebral ischaemia. This partial effectiveness can be explained through an action of Aspirin on platelets by assuming that, in such cases, their thrombo-embolic aggregation is initiated by haemodynamic effects of atheromatous lesions. Recently we discovered that the uptake of atherogenic low-density lipoprotein is accelerated by noradrenaline at its physiological blood concentrations (Shafi, Cusack & Born, 1989: Proc. Roy. Soc. B., 235, 289). This may help to explain the increased incidence of coronary thrombosis in conditions associated with elevated blood noradrenaline, including cigarette smoking and stress; and it may open new therapeutic approaches.

Thank you for inviting me to provide a short commentary to the proceedings. As one who has had little experience in the field of platelet heterogeneity I am sure that I have learnt much more than anybody else at this meeting. I believe that it is the first of its kind. It raises fascinating questions all the way from molecular biology and the uniqueness of mammalian platelets to the possible role of platelet heterogeneity in disease. I would like to divide my commentary into technical and basic questions.

some observations were made also on smallarteries forcomparison. Thevenousvessels werecho-sen for quantification in preference to arteries becausethe comparative slowness ofbloodflow madeit easierto develop and control the new methods required.The results showed that the injection of hamsterplatelets, made fluorescent by labeling in vitro withfluorescein isothiocyanate, into thecirculationofotherhamsters makesit possible to quantifythe flowingandsticking ofplatelets in vivo. Theexperiments provideevidence that there is very little tendency for circulat-ing platelets to stick to the walls of small veins andarterioles, evenunderconditions in whichtheadhesionpropensities ofbothplatelets andvesselwallsmightbeexpectedtobeincreasedbypreparativemanipulations.In venules such

A new type of crystal spectrometer for elastic and inelastic neutron scattering has been set up by modifying an existing flat-cone diffractormeter at the BER II-reactor in Berlin (West). The main difference to conventional triple axis spectrometers is the analyser part. It consists of large crystal plates which reflect the neutrons out of the horizontal plane into a curved multicounter. This allows simultaneous measurements in a large and continuous range of scattering angles for a constant energy transfer. The resolution function has been calculated and compared with experimental results. There is the possibility to focus acoustical phonons. We present applications together with experimental results such as quasielastic diffuse scattering in orientationally disordered crystals and inelastic scattering due to acoustical phonons. In combination with the flat-cone technique all elastic and inelastic scattering events of a single crystal can be collected in a systematic and efficient way.

The intravascular adhesion and aggregation of platelets initiate hemostasis and arterial thrombosis. In vitro, platelet aggregation is induced by many different agents; which of these is responsible for aggregation in vivo is now under investigation. For this purpose, we have developed novel techniques for the reproducible determination of bleeding times in mesenteric arterioles of rats and rabbits. Local infusions of enzyme systems which remove adenosine diphosphate (ADP) greatly increase the bleeding time at arterial injuries distal to the site of infusion. These observations establish the involvement of ADP in the activation of platelets for primary hemostasis. Direct measurement of free adenosine triphosphate (ATP), as an indicator of ADP, at such injury sites indicates that enough ADP for activating platelets is released very rapidly from damaged vessel walls and much later from the platelets themselves. This bleeding-time technique has also shown that hemostatic platelet aggregation is delayed less by the inhibition of the production of thromboxane A2 than by that of ADP. These observations provide an explanation for the ineffectiveness of any simple platelet-inhibiting drug (including aspirin) by itself, whenever arterial (e.g., coronary or cerebral) thrombosis is initiated by hemorrhages into atheromatous plaques. On the other hand, aspirin is significantly effective when myocardial infarction follows unstable angina and when strokes follow transient episodes of cerebral ischemia. This partial effectiveness can be explained by an action of aspirin on platelets, assuming that, in such cases, their thromboembolic aggregation is initiated by hemodynamic effects of atheromatous lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

If blood passes through extracorporeal circuits, platelets are activated even if the patient is fully heparinized.1 These activated thrombocytes begin to adhere, cluster, release their granular constituents, and within minutes of the institution of cardio pulmonary bypass a sheath of platelet and fibrin aggregates will line all components of the extracorporeal circuit.2,3,4 This process endangers the patient in two ways: (1) The lining of aggregates on the "down side" to the arterial filter may fragment and cause a shower of microemboli. (2) Intra-bypass platelet aggregation depletes the number of circulating thrombocytes, thus increases the possibility of post-operative bleeding.5,6,7

Atherosclerosis is accelerated in hyperlipidaemias but, apart from the concentration of low-density lipoprotein (LDL) in the blood, very little is known about other influences on the disease process. We now provide evidence that in anaesthetized rabbits the atherogenic uptake of LDL by arterial walls is accelerated by noradrenaline at its physiological concen­trations in rabbit and human blood. The principle of the experiments was to compare the uptake of intra­venously injected, radioactively labelled LDL, methylated to prevent removal by high-affinity receptors, in the two carotid arteries of anaes­thetized rabbits after infusing low concentrations of noradrenaline into one carotid and saline as control into the other, the volume rates of infusion being about 1% of the carotid blood flows. Human LDL, which behaves sufficiently like rabbit LDL for these purposes, was prepared, methylated and radio-iodinated by standard methods. At the end of the infusions, the arteries were excised and their radio activities determined. Noradrenaline infused for 2 h to produce local blood concentrations of nominally 1, 10, 50 and 100 nM significantly increased the LDL radio­ activities of the walls of the noradrenaline-infused carotids. Concen­trations of nominally 100 nM also increased the LDL radioactivities of the walls of the saline-infused carotids; this was associated with significant increases in their blood noradrenaline concentrations. These results may contribute towards an explanation for the acceler­ated atherosclerosis and the increased incidence of its clinical manifes­tations in conditions associated with elevated blood noradrenaline concentrations, including the episodic increases associated with stress and cigarette smoking as well as the more persistent increases caused by phaeochromocytoma.

SUMMARY. Platelets are activated in vitro by various chemical agents. It is not certain which if any of these is responsible for the haemostatic aggregation of platelets in living blood vessels. This report provides evidence that ADP is involved in activating platelets in vivo.

Adenosine inhibits the aggregation of human but not of rat platelets whereas both are inhibited by prostaglandin E1 or by the pyrimido-pyrimidine compound RA233. In human platelets all three agents increase adenosine-3'-5'-cyclic monophosphate (cAMP). If the inhibition of aggregation depended on this increase, adenosine might be expected not to increase cAMP in rat platelets. Under conditions in which adenosine inhibited aggregation and increased cAMP in human platelets, adenosine caused a similar increase in cAMP in rat platelets without inhibiting their aggregation. The aggregation of rat platelets was inhibited as effectively as that of human platelets by PGE1 or RA233 at concentrations which caused greater increases in cAMP than did the highest concentrations (2.8 X 10(-4) M) of adenosine it was possible to use. When the increase of cAMP in rat platelets by PGE1 was limited to that produced by adenosine, PGE1 like adenosine failed to inhibit aggregation. Therefore, the difference in the inhibitory effectiveness of adenosine on rat and human platelets was quantitative rather than qualitative and apparently depended on the inability of adenosine to increase cAMP sufficiently in rat platelets. When cAMP had been increased by adenosine, PGE1 or RA233, the addition of ADP caused cAMP to decrease rapidly in both human and rat platelets to between +22 and -18% of control values, except that the decrease in rat platelets was to +40% after RA233 had been present for 0.5 min before ADP. The increase in cAMP produced in rat platelets by adenosine at 5 X 10(-6) to 2.8 X 10(-4) M for 3 min was associated with a small increase in aggregation velocity. It is suggested that the comparative ineffectiveness of adenosine as an inhibitor of platelet aggregation, particularly with rat but less so also with human platelets, is because, unlike PGE1 or RA233, adenosine has two opposing actions on aggregation; one being inhibition by activating adenylate cyclase and increasing cAMP, and the other being potentiation by uptake. This hypothesis accounts for the present results as well as for the earlier observation that dipyridamole which prevents the uptake of adenosine potentiates its inhibitory effect on the aggregation of human platelets.

A new method for the evalution of neutron scattering data from semicrystalline polymers is proposed for small and intermiediate q [q = (4π/λ)sinθ/2]. It is based on the assumption that, in general, a molecule cryustallizes in various lamellae. Within one lamella the crystalline stems connected by loop or folds from intramolecular “clusters,” which are connected by tie molecules. Without further assumptions the method yields in a straightforward manner the following quantities: (i) the average number of clusters per molecule, from which the number of tie molecules can be estimated; (ii) the radius of gyration of the centers of the stems belonging to one cluster; and (iii) the radius of gyration of the cluster centers with respect to the center of the molecule the method was successfully tested using experimental data obtained from poly(ethylene oxide), polyethylene, and isotactic polypropylene.

We have successfully realized very short MESFET's with gatelengths down to 75nm. Maximum transconductances as high as 335 mS/mm were achieved, even for the smallest gatelengths. During device fabrication two different electron beam systems have been used in a mix&match mode.

Chronically hypoxic cells were 5 times more resistant to Adriamycin (ADR) than exponentially growing oxic cells. On reoxygenation, resistance decreased slowly to reach the ADR sensitivity of oxic cells after 24 h. With increasing pH, ADR efficiency increased more in oxic than in chronically hypoxic cells. With increasing cell density, ADR efficiency decreased linearly. The differences in ADR efficiency under the various conditions were accompanied by differences in intracellular ADR uptake. Chronically hypoxic cells incorporated 1.6 times less than oxic cells; the incorporation rate at pH 6.5 was half that at pH 7.4; and at a cell density of 5 X 10(5)/bottle the intracellular uptake was 6 times that at 5 X 10(6)/bottle. The observed differences in uptake of ADR were not, however, sufficient to explain the differences in cytotoxicity.

Elastic diffuse neutron scattering intensity due to orientational disorder in ND4Cl at room temperature, space group Pm3m, is studied with a single crystal. By a novel `vertical' energy analysis on the one hand and the `flat-cone' technique on the other, the intensity is obtained in a large three-dimensional region of reciprocal space in a reasonable time. The data are analysed with short-range-order and interaction-potential parameters. The two parameter sets are consistent. Local chlorine displacements of 0.16 Å, along 〈111〉 directions are determined.