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In this work, the results of Technology-CAD (TCAD) device-level simulations of non-irradiated and irradiated Low-Gain Avalanche Diode (LGAD) detectors and their validation against experimental data will be presented. Thanks to the intrinsic multiplication of the charge within these silicon sensors, it is possible to improve the signal to noise ratio thus limiting its drastic reduction with fluence, as it happens instead for standard silicon detectors. Therefore, special attention has been devoted to the choice of the avalanche model, which allows the simulation findings to better fit with experimental data. Moreover, a radiation damage model (called “New University of Perugia TCAD model”) has been fully implemented within the simulation environment, to have a predictive insight into the electrical behavior and the charge collection properties of the LGAD detectors, up to the highest particle fluences expected in the future High Energy Physics (HEP) experiments. This numerical model allows to consider the comprehensive bulk and surface damage effects induced by radiation on silicon sensors. By coupling the “New University of Perugia TCAD model” with an analytical model that describes the mechanism of acceptor removal in the multiplication layer, it has been possible to reproduce experimental data with high accuracy, demonstrating the reliability of the simulation framework.

In this contribution, we present an innovative design of the Low-Gain Avalanche Diode (LGAD) gain layer, the p$^+$ implant responsible for the local and controlled signal multiplication. In the standard LGAD design, the gain layer is obtained by implanting $\sim$ 5E16/cm$^3$ atoms of an acceptor material, typically Boron or Gallium, in the region below the n$^{++}$ electrode. In our design, we aim at designing a gain layer resulting from the overlap of a p$^+$ and an n$^+$ implants: the difference between acceptor and donor doping will result in an effective concentration of about 5E16/cm$^3$, similar to standard LGADs. At present, the gain mechanism of LGAD sensors under irradiation is maintained up to a fluence of $\sim$ 1-2E15/cm$^2$, and then it is lost due to the acceptor removal mechanism. The new design will be more resilient to radiation, as both acceptor and donor atoms will undergo removal with irradiation, but their difference will maintain constant. The compensated design will empower the 4D tracking ability typical of the LGAD sensors well above 1E16/cm$^2$., Comment: Keywords: Silicon sensor, LGAD, Compensation, Compensated LGAD, Gain layer, 4D tracking, Radiation hardness

Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats.Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed.A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P.05). Liver fibrosis was reduced in group 2 by 30% (P.05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score.Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.

Background and purpose: Obesity is a risk factor for several inflammation-based diseases including arthritis. We investigated the anti-nociceptive and anti-inflammatory effects of the cannabinoid CB1 receptor antagonist rimonabant in lean and diet-induced obese female rats with arthritis induced by complete Freund's adjuvant (CFA) injected in the right hind-paw. Experimental approach: The effect of oral rimonabant was assessed in rat paws on thermal hyperalgesia, mechanical allodynia, oedema, global arthritis score, nitrite/nitrate levels and ankle widths. Key results: After 7 but not after 14 days, the inflammatory response to CFA was significantly higher in obese than lean rats; however, the nociceptive response (thermal hyperalgesia and mechanical allodynia) was similar. Oral rimonabant (3 or 10 mg kg−1, once a day for 1 week from day 7 after CFA) only reduced the global arthritic score and joint width in obese rats, with no effect on the paw oedema. It also markedly reduced thermal hyperalgesia and mechanical allodynia in both lean and obese rats, with a greater effect in the latter. Conclusion and implications: Rimonabant appears to be a potent inhibitor of sensorial hypersensitivity associated with CFA-induced arthritis in obese rats, in which the inflammatory reaction is more severe than in lean rats. It may thus have therapeutic potential in obesity-associated inflammatory diseases, particularly in the treatment of the pain associated with arthritis. British Journal of Pharmacology (2007) 150, 559–566. doi:10.1038/sj.bjp.0707138

PURPOSE: To report the case of a woman with a diagnosis of grade II (low grade) parosteal osteosarcoma with the occurrence of myocardial metastasis 13 years after resection, and to present a review of the existing literature on the subject. METHODS: Description of the case and review of the literature. CONCLUSION: The review leads to the conclusion that the occurrence of metastasis from parosteal osteosarcoma can occur in up to 38% of the cases, in spite of its relatively low aggressiveness. However, myocardial metastasis of a parosteal osteosarcoma is an event that was not found in the literature.OBJETIVOS: Os autores relatam um caso de uma paciente do sexo feminino, com diagnóstico de osteossarcoma parostal grau II (baixo grau), que evoluiu com a ocorrência de metástase miocárdica 13 anos após a ressecção do tumor e incluem uma revisão da literatura sobre o assunto. MÉTODOS: Descrição do caso e revisão da literatura. CONCLUSÕES: A revisão leva à conclusão que a existência de metástases oriundas do osteossarcoma parosteal pode ocorrer em até 38 % dos casos, a despeito da sua relativa baixa agressividade. No entanto, a metástase miocárdica constitui um evento não relatado na literatura.

(R)-3-(1-[2-(4-benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)- ethyl]-4-phenylpiperidin-4-yl)-1-dimethylurea (SR 144190) is a new non-peptide antagonist of tachykinin NK2 receptors. SR 144190 potently and selectively inhibited neurokinin A binding to NK2 receptors from various species, including humans. In in vitro functional assays, it was a potent, selective and competitive antagonist of NK2 receptors with apparent affinities (pA2 values) between 9.08 and 10.10. In vivo, SR 144190 blocked [Nle10]neurokinin A-(4-10)-induced bronchoconstriction in guinea pigs (ID50 = 21 micrograms kg-1 i.v. and 250 micrograms kg-1 i.d.) and [beta Ala8]neurokinin A-(4-10)-induced urinary bladder contraction in rats (ID50 = 11 micrograms kg-1 i.v. and 190 micrograms kg-1 i.d.). It prevented citric acid-induced cough and airway hyperresponsiveness to acetylcholine in guinea pigs (1 mg kg-1 i.p.) as well as castor oil-induced diarrhoea in rats (0.01-10 micrograms kg-1 s.c. or p.o). Finally, it blocked the turning behaviour induced by intrastriatal injections of [Nle10]neurokinin A-(4-10) in mice (ID50 = 3 micrograms kg-1 i.v. and 16 micrograms kg-1 p.o.).

Traditional approaches for the classification of Small Supernumerary Marker Chromosomes (sSMC), mostly based on FISH techniques, are time-consuming and not always sufficient to fully understand the true complexity of this class of rearrangements. We describe four supernumerary marker chromosomes that, after array-CGH, were interpreted rather differently in respect to the early classification made by conventional cytogenetics and FISH investigations, reporting two types of complex markers which DNA content was overlooked by conventional approaches: 1. the sSMC contains non-contiguous regions of the same chromosome and, 2. the sSMC, initially interpreted as a supernumerary del(15), turns out to be a derivative 15 to which the portion of another chromosome was attached. All are likely derived from partial trisomy rescue events, bringing further demonstration that germline chromosomal imbalances are submitted to intense reshuffling during the embryogenesis, leading to unexpected complexity and changing the present ideas on the composition of supernumerary marker chromosomes. © 2012 Elsevier Masson SAS.

It was demonstrated that potent and selective ligands for the 5-HT4 receptor devoid of 5-HT3 receptor antagonist properties could be designed from the esters of 4-amino-5-chloro-2-methoxybenzoic acid and the conformationally flexible piperidine framework derived from the locked structure of the quinuclidine ring of zacopride. The compounds were evaluated in binding assays with [3H]-GR-113808 and [3H]-BRL-43694 and fonctionally using electrically-evoked contractions in the guinea-pig ileum. Coumpound 7 exhibited nanomolar 5-HT4 receptor agonist activity.

A series of substituted phenylethanolaminotetralins were synthesized as pure stereoisomers and their ability to stimulate atypical β-adrenoceptors selectively was evaluated. The compounds in vitro relative potencies were assessed using the atypical β response of inhibition of rat proximal colon motility and the typical β1 (increase in guinea-pig right atrial frequency) and β2 (guinea-pig tracheal relaxation and rat uterus motility inhibition) responses. Compound 42 (SR 58611A) was found to be the most potent and selective.

A series of substituted phenylethanolaminotetralins were synthesized as pure stereoisomers and their ability to stimulate atypical β-adrenoceptors selectively was evaluated. The compounds in vitro relative potencies were assessed using the atypical β response of inhibition of rat proximal colon motility and the typical β1 (increase in guinea-pig right atrial frequency) and β2 (guinea-pig tracheal relaxation and rat uterus motility inhibition) responses. Compound 42 (SR 58611A) was found to be the most potent and selective.

Background/aim: Endotoxaemia can complicate hepatic ischaemia–reperfusion (IR) injury. Endocannabinoids appear to modulate the haemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxaemia. Methods: Sprague–Dawley rats pre-treated with Rimonabant 3 or 10 mg/kg or vehicle underwent partial hepatic IR and lipopolysaccharide (LPS) injection at reperfusion. Liver injury was evaluated by serum alanine aminotransferase (ALT) and necrotic-cell count. The inflammatory response was investigated by assessing hepatic neutrophil infiltration, tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin 6 (IL6), and suppressor of cytokine signalling (SOCS) 1 and SOCS3 gene expression by real-time polymerase chain reaction (RT-PCR). Systolic blood pressure and hepatic blood flow were measured as haemodynamic parameters. Finally, lipid peroxidation, glutathione status, and immunoreactive CB1 receptor expression in the liver were also determined. Results: Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism. Rimonabant-treated rats showed significantly higher gene expression of IFNγ, IL6, SOCS1 and SOCS3 in “early” reperfusion, while that of TNFα was reduced. These findings were associated with increased STAT3 phosphorylation. Furthermore, CB1-receptor antagonism significantly improved the oxidative injury and haemodynamic alterations occurring during reperfusion in untreated rats. Finally, CB1-receptor immunoreactivity was upregulated early after reperfusion. Conclusions: This study demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved.

Beta(3)-adrenoceptor agonists protect against experimental gastric ulcers. We investigated the effects of the beta(3)-adrenoceptor agonist SR58611A on 2,4-dinitrobenzene sulphonic acid-induced colitis in rats and analysed the expression of beta(3)-adrenoceptors in the colonic wall. SR58611A was administered orally (1-10 mg kg(-1)) for 7 days, starting the day before induction of colitis. Colitis was assessed by macroscopic and histological scores, tissue myeloperoxidase activity, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) levels. Reverse transcription-polymerase chain reaction and immunohistochemical analysis were used to examine the expression of beta(3)-adrenoceptors. SR58611A significantly reduced the severity of colitis as well as the tissue levels of TNF-alpha, IL-1beta and IL-6. Colitis was associated with a decreased expression of beta(3)-adrenoceptor mRNA in the mucosal/submucosal layer of distal colon and this reduction was not affected by SR58611A. Immunohistochemical analysis revealed beta(3)-adrenoceptors within the muscularis externa, in myenteric neurons and nerve fibres and in the submucosa. beta(3)-Adrenoceptor immunoreactivity was decreased in inflamed tissues compared to controls, particularly in the myenteric plexus; this reduction was counteracted by SR58611A. Amelioration of experimental colitis by the selective beta(3)-adrenoceptor agonist SR58611A suggests that beta(3)-adrenoceptors may represent a therapeutic target in gut inflammation.

Obesity is a risk factor for several inflammation-based diseases including arthritis. We investigated the anti-nociceptive and anti-inflammatory effects of the cannabinoid CB1 receptor antagonist rimonabant in lean and diet-induced obese female rats with arthritis induced by complete Freund's adjuvant (CFA) injected in the right hind-paw.The effect of oral rimonabant was assessed in rat paws on thermal hyperalgesia, mechanical allodynia, oedema, global arthritis score, nitrite/nitrate levels and ankle widths.After 7 but not after 14 days, the inflammatory response to CFA was significantly higher in obese than lean rats; however, the nociceptive response (thermal hyperalgesia and mechanical allodynia) was similar. Oral rimonabant (3 or 10 mg kg-1, once a day for 1 week from day 7 after CFA) only reduced the global arthritic score and joint width in obese rats, with no effect on the paw oedema. It also markedly reduced thermal hyperalgesia and mechanical allodynia in both lean and obese rats, with a greater effect in the latter.Rimonabant appears to be a potent inhibitor of sensorial hypersensitivity associated with CFA-induced arthritis in obese rats, in which the inflammatory reaction is more severe than in lean rats. It may thus have therapeutic potential in obesity-associated inflammatory diseases, particularly in the treatment of the pain associated with arthritis.

Background and aims: Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis). Methods: The neural contractile response to electrical field stimulation of longitudinal muscle strips from the colon of patients undergoing surgery for colonic cancer or diverticulitis was challenged by different receptor agonists and antagonists. Results: Contractions of colonic strips from healthy controls and diverticulitis specimens were abolished by atropine. The β adrenergic agonist (−) isoprenaline and the tachykinin NK 1 receptor antagonist SR140333 had similar potency in reducing the electrical twitch response in controls and diseased tissues, while the cannabinoid receptor agonist (+)WIN 55,212-2 was 100 times more potent in inhibiting contractions in controls (IC50 42 nmol/l) than in diverticulitis strips. SR141716, a selective antagonist of the cannabinoid CB 1 receptor, had no intrinsic activity in control preparations but potentiated the neural twitch in diseased tissues by up to 196% in a concentration dependent manner. SR141716 inhibited (+)WIN 55,212-2 induced relaxation in control strips but had no efficacy on (+)WIN 55,212-2 responses in strips from diverticular disease patients. Colonic levels of the endogenous ligand of cannabinoid and vanilloid TRPV1 receptors anandamide were more than twice those of control tissues (54 v 27 pmol/g tissue). The axonal conduction blocker tetrodotoxin had opposite effects in the two preparations, completely inhibiting the contractions of control strips but potentiating those in diverticular preparations, an effect selectively inhibited by SR140333. Conclusions: Neural control of colon motility is profoundly altered in patients with diverticulitis. Their raised levels of anandamide, apparent desensitisation of the presynaptic neural cannabinoid CB 1 receptor, and the SR141716 induced intrinsic response, suggest that endocannabinoids may be involved in the pathophysiology of complications of colonic diverticular disease.

International audience; To assess whether pregnancy might influence the functionality and expression of human myometrial beta(2)- and beta(3)-adrenoceptors (beta(2)- and beta(3)-AR), we performed functional, binding, Western blot, and molecular biology experiments in human nonpregnant and near-term pregnant myometrium. Inhibition of spontaneous contractions induced by a beta(3)-AR agonist, SR 59119A, was significantly greater in pregnant, compared with nonpregnant, myometrial strips (E'(max) = 61 +/- 5% vs. 44 +/- 5% for pregnant and nonpregnant myometrium, respectively), whereas salbutamol, a beta(2)-AR agonist, was significantly less efficient in pregnant, compared with nonpregnant, myometrium (E(max) = 29 +/- 4 vs. 54 +/- 8%). Although two populations of binding sites corresponding to beta(2)- and beta(3)-AR were identified in both nonpregnant and pregnant myometrium, we found a clear predominance of the beta(3)-AR subtype. Moreover, beta(3)-AR binding sites were up-regulated 2-fold in myometrium at the end of pregnancy. Both beta(2)- and beta(3)-AR mRNA were expressed in human nonpregnant and pregnant myometrium. Contrary to beta(2)-AR, the expression of the beta(3)-AR transcripts and immunoreactive proteins was increased in pregnant, compared with nonpregnant, myometrium. Such compelling data suggest a predominant role for beta(3)-AR in the regulation of human myometrium contractility, especially at the end of pregnancy, which might have important consequences for the clinical management of preterm labor.

Background & aims. The notion that specific receptors account for the ability of natural and synthetic cannabinoids to alter physiological functions, prompted this study aimed at assessing their functional presence in the human gut. Methods. The effects have been studied of cannabinoids and selective antagonists of their receptors on chemically or electrically evoked contractions in preparations of human intestinal smooth muscle in vitro. Results. Atropine prevented the contractions of longitudinal and circular muscle strips of ileum and colon induced by carbachol or electrical field stimulation; tetrodotoxin abolished only the latter, which suggests they do involve activation of cholinergic neurons. The synthetic cannabinoid (+)WIN 55,212-2 had no effect on carbachol contractions, but in a concentration-dependent fashion prevented those elicited by electrical field stimulation - which were insensitive to the putative endogenous cannabinoid anandamide - more potently in longitudinal than in circular strips. The selective CB, receptor antagonist SR141716, which had no effect in the absence of (+)WIN 55,212-2, competitively antagonised its inhibition of electrical field stimulation contractions, unlike the selective CB2 antagonist SR 14452B. Conclusions. Cannabinoid CB, receptors are functionally present in the human ileum and colon; their pharmacological activation apparently results in inhibition of excitatory cholinergic pathways subserving smooth muscle contraction.

5-Hydroxytryptamine (5-HT)4 receptor agonists stimulate gut motility through cholinergic pathways, although there are data suggesting that noncholinergic (tachykininergic) excitatory pathways may also be involved. Differences may exist between the small bowel and colon. Our aims were: (i) to compare the prokinetic effect exerted by the 5-HT4 receptor agonist ML10302 in the canine small bowel and colon in vivo; and (ii) to investigate the role of tachykininergic pathways in mediating this response. In fasting, conscious dogs, chronically fitted with electrodes and strain-gauge force transducers along the small bowel and colon, intravenous injection of ML10302 (35 microg kg-1) immediately stimulated spike activity and significantly increased propagated myoelectrical events at both intestinal levels. In the small bowel, the effects of ML10302 were unchanged by previous administration of the selective NK1 tachykinin receptor antagonist SR140333, the NK2 tachykinin receptor antagonist SR48968, or the NK3 tachykinin receptor antagonist SR142801. In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events. Atropine (100 microg kg-1 i.v.) suppressed the stimulatory effect of ML10302 at both intestinal levels. In conclusion, the 5-HT4 receptor agonist ML10302 induced significant prokinesia both in the small bowel and colon through activation of cholinergic pathways. Tachykininergic pathways are not involved in the ML10302-induced prokinesia in the small bowel, but they play an important role in mediating the colonic motor response to ML10302.

The aim of this study was to evaluate the in vitro effects of phosphodiesterase 4 inhibitors (PDE4I) and their combination with salbutamol (beta 2-adrenoceptor agonist) on spontaneous contractions and to investigate by in vitro and biochemical studies and analysis of mRNA expression the presence of beta 3-adrenoceptor in human near-term myometrium. Rolipram, RP 73401 and Ro 20-1724 (PDE4I) inhibited spontaneous myometrial contractions (Emax approximately 100 per cent; pD2 approximately 6.80 for the two first and 6.31 for Ro 20-1724). Rolipram 10(-8) M potentiated the response to salbutamol (Emax = 88 per cent vs. 40 per cent and pD2 = 6.93 and 6.36 with or without rolipram respectively). SR 59119A, a beta 3-adrenoceptor agonist, was more efficient than salbutamol in inhibiting the contractions (Emax 52 per cent and 27 per cent respectively, p0.05) but they both induced a significant increase of cAMP production. In both functional and biochemical studies, SR 59119A was only antagonized by the beta 3-adrenoceptor antagonist SR 59230A. The beta 3-AR mRNA was positively expressed in myometrium preparations in a reverse transcription polymerase chain assay. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta 2-adrenoceptor agonists and beta 3-adrenoceptor agonists might have potential interest as tocolytic agents.

BACKGROUND AND AIMS—The subtype and species related heterogeneity of β adrenoceptors prompted a functional reappraisal of these molecular targets of motility inhibition in the human colon. METHODS—Relaxation of muscle strips was measured in vitro. RESULTS—The following agonists had decreasing relaxing potency (effective concentration range 10−8-10−4 mol/l): (−)isoprenaline (non-selective), terbutaline (β2 selective), CGP 12177 (β3 selective, also β1, β2 antagonist), and SR 58611A (β3 selective). Isoprenaline and terbutaline were more potent on circular than taenia strips; CGP 12177 and SR 58611A weakly and partially relaxed taenia but had little effect on circular strips. The potency of isoprenaline on circular strips was greatly reduced by the β1 selective antagonist CGP 20712 (10−7 mol/l), and less so by ICI 118551 (10−7 mol/l, β2 selective). CGP 20712 and ICI 118551 together (both 3×10-6 mol/l) had no effect on taenia relaxation by SR 58611A and rendered isoprenaline and terbutaline virtually inactive on circular strips, although not on taenia, which was relaxed at higher than control concentrations and maximally by isoprenaline. Propranolol, a β1, β2 non-selective antagonist, at high concentrations (10-5 mol/l) prevented taenia relaxation by CGP 12177 and SR 58611A; its quantitative antagonism of isoprenaline (in common with that of CGP 12177 used as an antagonist) was competitive in circular strips but not on taenia. CONCLUSIONS—β1, β2, and β3 adrenoceptors are functionally detectable in the human colon; agonist stimulation of any one type relaxed taenia but only isoprenaline was fully effective at the β3 subtype. Keywords: β adrenoceptor subtypes; human colon; smooth muscle; taenia coli

The possible existence of a beta(3)-adrenoceptor (beta(3)-AR) in human near-term myometrium was investigated by in vitro functional and biochemical studies and analysis of mRNA expression. SR 59119A and SR 59104A and CGP 12177 (two selective agonists and a partial agonist, respectively, of the beta(3)-AR), salbutamol and terbutaline (beta(2)-AR agonists) each produced a concentration-dependent relaxation of the myometrial spontaneous contractions. There were no differences in pD(2) values for the relaxing potencies of terbutaline, salbutamol, CGP 12177 and SR 59119A. The rank order for their relaxing efficacies was SR 59119ASR 59104Aterbutaline approximately salbutamol approximately CGP 12177 (E(max)=52+/-7%, 42+/-12% and approximately 30% respectively). Propranolol, a beta(1)- and beta(2)-AR antagonist, and ICI 118551, a beta(2)-AR antagonist (both at 0.1 microM), did not affect the SR 59119A-induced relaxation whereas SR 59230A, a selective beta(3)-AR antagonist (1 microM), significantly reduced the maximal relaxing effect of SR 59119A. SR 59119A and salbutamol induced a significant increase in cyclic AMP levels that was antagonized by SR 59230A but not by propranolol for SR 59119A, and by propranolol but not by SR 59230A for salbutamol. The beta(3)-AR mRNA was positively expressed in myometrium preparations in a reverse transcription polymerase chain assay. The results presented provide the first evidence for the existence of the beta(3)-AR subtype in human near-term myometrium and suggest that the effects of SR 59119A might be mediated through an increase in cyclic AMP level.

In five fasting, conscious dogs, we compared the prokinetic action of two selective 5-hydroxytryptamine-4 (5-HT4) receptor agonists with low affinity for 5-HT3 receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-methoxybenzoate) in the duodenum and jejunum, using cisapride as a reference compound. Heart rate and rate-corrected QT (QTc) also were monitored to assess whether or not the cardiac effects of cisapride are shared by other 5-HT4 receptor agonists. Both ML10302 and SR59768 dose-dependently stimulated spike activity in the duodenum with similar potencies (dose range, 3-300 nmol/kg i.v.; ED50 values: 24 and 23 nmol/kg i.v., respectively), mimicking the effect of cisapride (30-3000 nmol/kg i.v.). The maximal effect was achieved with the dose of 100 nmol/kg i.v. for both compounds. Similar findings were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate, selective 5-HT4 receptor antagonist), at doses having no effect per se, antagonized intestinal prokinesia by maximal doses of ML10302 and SR59768. Neither ML10302 nor SR59768 had any effect on heart rate or QTc at any of the doses tested, whereas cisapride, at the highest dose (3000 nmol/kg), induced tachycardia and lengthened the QTC (p.01). In conclusion, ML10302 and SR59768 share with cisapride a similar prokinetic action in the canine duodenum and jejunum in vivo. This effect is mediated by pathways involving activation of 5-HT4 and muscarinic receptors. Unlike cisapride, which induces tachycardia and prolongs the QTc by a mechanism probably unrelated to 5-HT4 receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.

We investigated the effect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical field stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or co-incubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentration-dependently inhibited twitch responses (IC50 73 nM), but had no additive effect with atropine or TTX. The cannabinoid CB1 receptor antagonist SR 141716 (pA2 8.2), but not the CB2 receptor antagonist, SR 144528, competitively antagonized twitch inhibition by (+)WIN-55212-2. Atropine but not (+)WIN-55212-2 or TTX prevented carbachol-induced tonic contraction. These results provide functional evidence of the existence of prejunctional cannabinoid CB1-receptors in the human ileum longitudinal smooth muscle. Agonist activation of these receptors prevents responses to electrical field stimulation, presumably by inhibiting acetylcholine release. SR 141716 is a potent and competitive antagonist of cannabinoid CB1 receptors naturally expressed in the human gut.

1. Human in vitro preparations of transverse or distal colonic circular smooth muscle were potently and dose-dependently contracted by neurokinin A (EC50, 4.9 nM), the tachykinin NK2-receptor selective agonist [beta-Ala8]neurokinin A (4-10) ([beta-Ala8]NKA (4-10)) (EC50, 5.0 nM), neurokinin B (EC50, 5.3 nM) and substance P (EC50, 160 nM), but not by the tachykinin NK1-receptor selective agonist [Sar9Met(O2)11] substance P, or the NK3-receptor selective agonists, senktide and [MePhe7] neurokinin B. No regional differences between transverse and distal colon were observed in response to [beta-Ala8]NKA (4-10). 2. Atropine (1 microM) and tetrodotoxin (1 microM) did not significantly inhibit responses to [beta-Ala8]NKA (4-10), neurokinin A, substance P or neurokinin B. 3. The newly developed non-peptide antagonists for tachykinin NK2-receptors SR 48968, SR 144190 and its N-demethyl (SR 144743) and N,N-demethyl (SR 144782) metabolites, were used to challenge agonist responses, as appropriate. SR 144190 and the metabolites all potently and competitively antagonized the response to [beta-Ala8]NKA (4-10), with similar potency (Schild plot pA2 values 9.4, 9.4 and 9.3, slope = 1). SR 48968 antagonism was not competitive: the Schild plot slope was biphasic with a high (X intercept approximately 9.3) and a low (X intercept 8.4, slope 1.6) affinity site. Co-incubation of SR 48968 (10, 100 nM) and SR 144782 (10 nM) produced additive effects; in this experimental condition, SR 48968 apparent affinity (pKB) was 8.2. In addition, SR 144782 (0.1 microM) antagonized responses to neurokinin A, substance P and neurokinin B, with pKB consistent with its affinity for tachykinin NK2-receptors. The potent and selective NK1 and NK3-receptor antagonists, SR 140333 and SR 142801 (both 0.1 microM), failed to inhibit contractions induced by SP or NKB. 4. In conclusion, the in vitro mechanical responses of circular smooth muscle preparations from human colon are strongly consistent with the presence of non-neuronal tachykinin NK2-receptors, but not tachykinin NK1- or NK3-receptors. Our findings with SR 48968 suggest the existence of two tachykinin NK2-receptor subtypes, that it seems to distinguish, unlike SR 144190 and its metabolites. However, the precise nature of SR 48968 allotopic antagonism remains to be elucidated, since allosteric effects at the tachykinin NK2-receptor might well account for the complexity of the observed interaction.

1. We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonists. SR 140333 and SR 48968, respectively. 2. SR 48968 (0.02 to 20 micrograms kg-1, s.c. or p.o.), and the opioid receptor agonist loperamide (1-10 mg kg-1, p.o.), dose-dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 micrograms kg-1, s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 micrograms kg-1, p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3. The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 micrograms kg-1, s.c.) had no effect other than reducing faecal mass at the highest dose tested. 4. SR 48968 (20 micrograms kg-1, p.o.) but not loperamide (10 mg kg-1, p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5. In castor oil-treated rats, naloxone (2 mg kg-1, s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg-1, p.o.) but not of SR 48968 (20 micrograms kg-1, p.o.): a similar result was obtained on faecal mass and water content. 6. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7. In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8. Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from the constipating action of opioids.

The authors present a review of the changes occurred in the treatment of high grade bone sarcomas in the last 20 years. It was discussed the multidisciplinary approach for the local and systemic control of these tumors particularly the neoadjuvant chemotherapy that leads to an increase in the overall survival not only for the osteosarcoma but also for the Ewing sarcoma. They showed the possibilities for limb reconstruction after wide resection of the lesion that includes non conventional endoprosthesis and allografts.

The authors study 24 patients with the histologic diagnosis of osteoblastoma treated from 1953 to 1996, with a mean follow-up of 33.4 months. Two were considered as a malignant osteoblastoma. Twenty-two cases were operated, and in 2 of these was performed only a selective embolization to pelvic and spine localization. It was discussed clinical and radiographic aspects and the response to treatment. It was obtained 20 good and 4 poor results.

Castrol-oil induced diarrhea in rats was potently prevented by compounds SR 140333 and SR 48968, the first a tachykinin NK1- and the second a NK2-receptor antagonist. SR 48968 was more effective and also reduced fecal water content.

Early substantial evidence of the low susceptibility to beta-adrenoceptor antagonists of non alpha-adrenergic responses reducing gut motility and tone was reluctantly accepted as indicating a third beta-receptor subtype different from the beta 1 and beta 2. This applied likewise to lipolysis until new selective "lipolytic" beta-agonists poorly effective at established beta-receptors were introduced. Shortly afterwards these "lipolytic" as well as certain newer and even more selective beta-adrenoceptor agonists were shown to be potent inhibitors of intestinal motility. The latter are the "gut-specific" phenylethanolaminotetralins whose availability as pure isomers attested to the stringent stereochemical requirements for selectivity at non-beta 1, non-beta 2 beta-adrenoceptors. Acceptance of the functionally based concept of a beta 3-adrenoceptor was boosted on structural grounds by molecular biology studies. Sequence analysis indicated the existence in humans and rodents of genes coding for a third subtype of beta-receptor that, when expressed in transfected heterologous cells, had a pharmacological profile distinct from the previously established subtypes. Finally, aryloxypropanolaminotetralins have been prepared as the first selective antagonists of beta 3-adrenoceptors, thus providing unambiguous conclusive evidence of the distinctive functional features of those abundant in the rat colon. The therapeutic potential in gastroenterology of the newer compounds targetable on the beta 3-adrenoceptor is suggested by their potent intestinal action in vivo in animal models without any of the cardiovascular or other unwanted effects of conventional beta-adrenoceptor agonists and antagonists, and by the clinically confirmed importance of beta-adrenergic control of motor function throughout the alimentary canal. However, open questions include the incidence of species-related differences in beta 3-adrenoceptors, and as yet there are no data on gastrointestinal functions in humans under the influence of drugs designed to act selectively at these receptors.

The authors studied, in the period 1990-1993, 31 patients with benign non aggressive bone lesions, surgically treated with intralesional resection followed by the introduction of hydroxyapatite. Their follow-up was two years and one month. The authors discussed the surgical indications, the operative technique employed, and the post-operative results which were considered to be good in 29 of the patients studied. Occurred complications in three patients: local infections in two and sterile fistula in one. It is concluded that the use of hydroxyapatite is a good option as substitute of the autologous bone graft.

The authors report on 18 cases of chondromyxoid fibroma seen at the Institute of Orthopedics and Traumatology, University of São Paulo, from 1953 to 1990. A survey of the literature on chondromyxoid fibromas was conducted and radiographic analysis of all cases is presented, with a mean follow-up of 64 months. The surgical treatment employed in each case is discussed, with emphasis on the use of cement as an adjuvant. This procedure was used in 10 patients, who have been free of recurrence up to the present time.

Summary The new putative beta-adrenergic agonists SR 58306A, 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride and SR 58339A, 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorphenyl) ethanol hydrochloride, were studied in vitro in comparison with reference compounds. SR 58306A and SR 58339A, unlike isoprenaline and the beta 2 selective adrenergic agonists salbutamol and ritodrine, potently inhibited rat colon spontaneous contractions (EC 50 5.9 and 1.1×10 −7 M) without increasing guinea-pig atrium frequency or relaxing guinea-pig trachea. The non-selective beta-adrenergic antagonists alprenolol, pindolol and propranolol competitively antagonized the action of SR 58306A on the colon, which was not prevented by either of the selective antagonists atenolol (beta 1 ) and ICI 118551 (beta 2 ). In the same preparation only alprenolol competitively antagonized isoprenaline; antagonism by either pindolol or propranolol was not competitive. These results suggest that in the rat colon isoprenaline interacts with different beta-receptor subclasses, whereas our new gut-specific compounds such as SR 58306A inhibit colonic motility by selectively stimulating atypical beta-adrenoceptors.

We have investigated the ability of the new putative beta-adrenergic agonists phenylethanolaminotetralines (PEAT) to inhibit intestinal motility in relation to their cardiovascular effects, in ethylurethaneanesthetized rats. The representative PEAT SR 58375A, SR 58572A and SR 58539B and the reference beta-adrenergic agonists isoproterenol, salbutamol and ritodrine caused dose-related inhibition of proximal colon spontaneous motility: ED50(μg/kg, i.v.) 210, 92 and 19; 5.6, 176 and 201, as listed. This inhibition was prevented by the beta-adrenergic antagonist alprenolol, but not by desipramine (which prevented the inhibition of colonic motility by tyramine and enhanced that by norepinephrine). The minimal effective doses (MED) of isoproterenol, salbutamol and ritodrine raising heart rate and/or lowering blood pressure (by 10 to 20%), was substantially lower (about 1 10 to 1 150 ) than their ED50 for inhibition of colonic motility. The MED raising heart rate of the three PEAT, on the other hand, was about twice (SR 58375A and SR 58572A) to five (SR 58539B) times their ED50 for inhibition of colonic motility. None of the PEAT lowered blood pressure up to the top tested dose. Therefore the PEAT may prove preferable to the currently best tolerated beta-adrenoceptor agonists, because they appear less liable to induce cardiovascular side effects. This supports the prospective therapeutic interest of PEAT for intestinal hypermotility disorders.

The mortalities of mice, rats and guinea-pigs given a single lethal dose of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) were substantially reduced by feeding them with chows containing 2.5 or 5% activated charcoal, which presumably enhances elimination of the toxic agent from the organism. Chows with 0.25 or 0.5% cholic acid and dehydrocholic acid added had a similar protective action on mice intoxicated with TCDD. Since no treatment is currently available for this type of poisoning, charcoal—whose safe clinical use is well established—is worth considering in view of its potential benefit to humans acutely exposed to TCDD.

The early stages of N-2-fluorenylacetamide [(2-FAA) CAS: 59-96-3]-induced liver carcinogenesis in inbred F344 male and female rats and the effect of gonadectomy on liver carcinogen biotransformation capability and hepatocarcinogenesis were studied. Feeding of 2-FAA induced more altered hepatocellular foci characterized by exclusion of cellular iron and gamma-glutamyl-transferase activity in male rats than in female rats. At 6-22 weeks after cessation of carcinogen exposure, only males developed liver neoplastic nodules. Liver cytochrome P450, aryl hydrocarbon hydroxylase, and uridine-5'-diphosphateglucuronosyltransferase activity toward p-nitrophenol, but not phenolphthalein, were greater in males than in females. Gonadectomy of males reduced the activities that were greater than in females, whereas none was significantly altered by gonadectomy of females. Gonadectomy of male rats prior to 2-FAA feeding suppressed the induction of both altered foci and neoplastic nodules, whereas in female rats gonadectomy prior to 2-FAA feeding enhanced the induction of foci. Gonadectomy of males after administration of 2-FAA slightly enhanced the persistence of foci at 6 and 12 weeks after removal of carcinogen, but it did not affect their persistence by 22 weeks post carcinogen or the incidence of neoplastic nodules. However, only the males that were gonadectomized after receiving 2-FAA developed hepatocellular carcinomas at 22 weeks. Gonadectomy of females after receiving 2-FAA did not affect the persistence of foci, and no liver neoplasms developed. Thus gonadectomy of male rats, which reduced liver carcinogen metabolism, when done before carcinogen feeding had the greatest effect on hepatocarcinogenesis.