Receptor‐targeted scintigraphy using radiolabeled somatostatin analogs such as octreotate is being used with great success to demonstrate the in vivo presence of somatostatin receptors on various tumors. A new and promising application for these analogs is radionuclide therapy. Radionuclides suitable for this application include the Auger electron‐emitter 111In and the β‐emitters 90Y (high energy) and 177Lu (low energy). We investigated [DOTA0,Tyr3]octreotate, labeled with the lanthanide 177Lu, in biodistribution and radionuclide therapy experiments using male Lewis rats bearing the somatostatin receptor‐positive rat CA20948 pancreatic tumor. Biodistribution studies in Lewis rats showed the highest uptake in the rat pancreatic CA20948 tumor and sst2‐positive organs, which include the adrenals, pituitary and pancreas, of [177Lu‐DOTA0,Tyr3]octreotate in comparison with 88Y‐ and 111In‐labeled analogs. Kidney uptake of [177Lu‐DOTA0,Tyr3]octreotate could be reduced by approximately 40% by co‐injection of 400 mg/kg D‐lysine. In radionuclide therapy studies, a 100% cure rate was achieved in the groups of rats bearing small (≤1 cm2) CA20948 tumors after 2 doses of 277.5 MBq or after a single dose of 555 MBq [177Lu‐DOTA0,Tyr3]octreotate. A cure rate of 75% was achieved after a single administration of 277.5 MBq. In rats bearing larger (≥1 cm2) tumors, 40% and 50% cure rates were achieved in the groups that received 1 or 2 277.5 MBq injections of [177Lu‐DOTA0,Tyr3]octreotate, respectively. After therapy with [177Lu‐DOTA0,Tyr3]octreotide in rats bearing small tumors, these data were 40% cure after 1 injection with 277.5 MBq and 60% cure after 2 repeated injections. In conclusion, [177Lu‐DOTA0,Tyr3]octreotate has demonstrated excellent results in radionuclide therapy studies in rats, especially in animals bearing smaller tumors. This candidate molecule shows great promise for radionuclide therapy in patients with sst2‐expressing tumors. © 2001 Wiley‐Liss, Inc.

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Europe's traditional cultural landscapes have undergone significant land-use and land-cover changes in the past 50 yr. Land-cover inventories facilitate the quantification of the conversion from one land-cover unit to another. However, they often fail to detect fine-grained modifications that occur within one land-cover category. This study aims to detect such land-cover modification at two farms within dehesas, a traditional agroforestry system in Spain. The focus is on the dynamics of holm oak (Quercus ilex) stands as the key landscape element of dehesas. Aerial photography and satellite imagery were used to measure tree expansion and regression between 1956 and 1984, and between 1984 and 2003. With < 0.01-0.03% of the tree cover recruited per year, current recruitment seems too low by a factor of 10 to 50 to maintain existing stand densities. Recruitment rates between 1956 and 2003 were slightly higher, but loss rates were dramatically higher on privately owned land compared to common property. Although higher grazing pressure on common property may have inhibited recruitment, the complexity of land tenure can act as a barrier to forest clearing. The synopsis of high loss rates from 1956 to 1984, low loss rates from 1984 to 2003, and low recruitment rates over both periods indicates that deliberate oak cutting has stopped, but that the problem of regeneration failure still remains unresolved. The analysis of oak expansion and regression as a precursor of land conversion can provide a powerful tool for subtle structural changes and can be used as an early warning system before conversion becomes visible.

Effects of stimulation of intramural nerves in the circular smooth muscle layer of the porcine colon (Sus scrofa domestica) were studied using the sucrose-gap technique. Electrical field stimulation of the preparation, superfused with Krebs solution at 21 degrees C, induced a transient hyperpolarization of the smooth muscle cell membrane. This hyperpolarization was an inhibitory junction potential (IJP). The responses obtained from circular muscle originating from either the centripetal or centrifugal gyri of the ascending colon did not differ significantly. The IJP was characterized as being mediated by intramural, nonadrenergic, noncholinergic (NANC) nerves. The amplitude and latency of the IJP changed linearly with temperature (15-25 degrees C: +1 mV and -0.1 s per degree Celsius, respectively) reflecting a temperature-dependent synchronization of transmitter release. The membrane resistance decreased during the IJP. The IJP amplitude decreased or increased during conditioning hyperpolarizations or depolarizations, respectively, and reversed at membrane potentials about 30 mV more negative than the resting membrane potential. Potassium conductance blocking agents, barium (1 mM), tetraethylammonium chloride (TEA, 20 mM), 4-aminopyridine (4-AP, 5 mM), apamin (1 microM), and aminacrine (10(-4) M) added to the superfusion medium increased the membrane resistance. Only barium, TEA, and apamin depolarized the smooth muscle cell membrane. The IJP amplitude decreased in the presence of aminacrine and apamin to 75 and 35%, respectively, suggesting that apamin-sensitive Ca2+-activated K+ channels are involved in this response. ATP, adenosine, and related adenine nucleotides in concentrations up to 10(-3) M did not mimic the IJP. Superfusion with ATP for 15 min revealed a gradually increasing attenuation by up to 20% of the IJP. This might suggest that the release of neurotransmitter from intramural NANC nerves is modulated presynaptically via purinoceptors. Exogenously applied vasoactive intestinal polypeptide (VIP) in concentrations of 10(-9) to 10(-4) M did not affect the preparation. Also at elevated temperatures (up to 35 degrees C), VIP (10(-7) to 10(-4) M) did not cause measurable effects. It is concluded that the inhibitory mediator of the intramural NANC nerves present in the circular muscle layers of the porcine colon is neither a purine nor VIP.

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The nature of the beta-adrenoceptor population(s) mediating the relaxation of guinea pig and human airway smooth muscle was investigated. On the basis of a preferential blockade by beta 1- and beta 2-selective antagonists of the relaxation induced by beta 1- and beta 2-selective agonists, guinea pig tracheal strip relaxation was found to be mediated both by beta 1- and beta 2-adrenoceptors, the relative participation of which depending on the relative affinities of the agonist towards these two receptors. With highly selective antagonists the noradrenaline (NA)-induced relaxation could be split up biphasically into a beta 1- and a beta 2-component. In contrast, no such differential blockade was observed with the guinea pig lung parenchyma strip relaxation which is mediated by a homogenous beta 2-adrenoceptor population. On comparison of the tracheal, the spirally cut main bronchus- and intrapulmonary airway smooth muscle strips it could be shown that both the sensitivity of NA for neuronal uptake and the apparent affinity of the relaxation by NA decreased in the direction of the lung periphery. Using the same techniques it was ascertained that the relaxation of human tracheal smooth muscle (autopsy, obtained within 6 hours after death), main bronchus and intrapulmonary smooth muscle (operation) are mediated by homogenous beta 2-adrenoceptor populations. In addition, neuronal and extraneuronal uptake sites were not operative in these preparations, whether obtained from operation or from autopsy.

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The Kd-values of some histamine H2-active compounds, obtained from radio-ligand-binding studies on a homogenate of the guinea-pig cerebral cortex with 3H-tiotidine as the labelled H2-ligand, were compared with the pA2/pD2-value of these compounds on the guinea-pig right atrium and guinea-pig isolated gastric fundus. A good correlation was found between the pKd of the H2-antagonists and their pA2 on the guinea-pig right atrium. A much poorer correlation however was obtained between the pKd of the agonists on the cerebral cortex and their pD2-values on the guinea-pig right atrium and the gastric fundus. This poor correlation between true affinity and H2-activity of the agonists might be explained by spare receptors as a much better correlation was obtained between pKd and pD2 of partial agonists.