Endogenous ligands of cannabinoid receptors have been discovered recently and include some N -acylethanolamines (NAEs; e.g., N- arachidonoylethanolamine) and some 2-acylglycerols (e.g., sn -2-arachidonoylglycerol). Previously, we found these compounds to be active biologically when administered per os in large quantities to mice. In the present work, piglets were fed diets with and without 20:4 n −6 and 22:6 n −3 fatty acid precursors of NAEs, in levels similar to those found in porcine milk, during the first 18 days of life, and corresponding brain NAEs were assessed. In piglets fed diets containing 20:4 n −6 and 22:6 n −3, there were increases in several biologically active NAEs in brain homogenates—20:4 n −6 NAE (4-fold), 20:5 n −3 NAE (5-fold), and 22:5 n −3 and 22:6 n −3 NAE (9- to 10-fold). These results support a mechanism we propose for dietary long-chain polyunsaturated fatty acids influences on brain biochemistry with presumed functional sequelae. This paradigm will enable targeted investigations to determine whether and why specific populations such as infants, elderly, or persons suffering from certain clinical conditions may benefit from dietary long-chain polyunsaturated fatty acids.

Abstract:Recent studies have shown that the pharmacological tolerance observed after prolonged exposure to synthetic or plant-derived cannabinoids in adult rats is accompanied by down-regulation/desensitization of brain cannabinoid receptors. However, no evidence exists on possible changes in the contents of the endogenous ligands of cannabinoid receptors in the brain of cannabinoid-tolerant rats. The present study was designed to elucidate this possibility by measuring, by means of isotope dilution gas chromatography/mass spectrometry, the contents of both anandamide (arachidonoylethanolamide; AEA) and its biosynthetic precursor, N-arachidonoylphosphatidylethanolamine (NArPE), and 2-arachidonoylglycerol (2-AG) in several brain regions of adult male rats treated daily with ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) for a period of 8 days. The areas analyzed included cerebellum, striatum, limbic forebrain, hippocampus, cerebral cortex, and brainstem. The same regions were also analyzed for cannabinoid receptor binding and WIN-55,212-2-stimulated guanylyl-5Ј-O-(␥-[ 35 S]thio)-triphosphate ([ 35 S]GTP␥S) binding to test the development of the well known down-regulation/desensitization phenomenon. Results were as follows: As expected, cannabinoid receptor binding and WIN-55,212-2-stimulated [ 35 S]GTP␥S binding decreased in most of the brain areas of ⌬ 9 -THC-tolerant rats. The only region exhibiting no changes in both parameters was the limbic forebrain. This same region exhibited a marked (almost fourfold) increase in the content of AEA after 8 days of ⌬ 9 -THC treatment. By contrast, the striatum exhibited a decrease in AEA contents, whereas no changes were found in the brainstem, hippocampus, cerebellum, or cerebral cortex. The increase in AEA contents observed in the limbic forebrain was accompanied by a tendency of NArPE levels to decrease, whereas in the striatum, no significant change in NArPE contents was found. The contents of 2-AG were unchanged in brain regions from ⌬ 9 -THCtolerant rats, except for the striatum where they dropped significantly. In summary, the present results show that prolonged activation of cannabinoid receptors leads to decreased endocannabinoid contents and signaling in the striatum and to increased AEA formation in the limbic forebrain. The pathophysiological implications of these findings are discussed in view of the proposed roles of endocannabinoids in the control of motor behavior and emotional states. Key Words: Endocannabinoids-Anandamide-2-Arachidonoylglycerol-Cannabinoid receptor binding-Tolerance-⌬ 9 -Tetrahydrocannabinol.

Stage B patients with a small number of examined nodes may be understaged. Thus, these patients might be considered for adjuvant therapy because of their poorer life expectancy than other stage B patients. For stage C patients, the number of recovered nodes does not seem to affect long-term outcome.

Gastrointestinal stromal tumors are malignancies originating from stromal/mesenchymal tissues, most commonly in the stomach and small intestine, although they can be located everywhere in the gastrointestinal tract. Diagnosis is based on histological and immunohistochemical examination, and these rare tumors are characterized by c-kit (CD117) staining. Complete removal of the tumor is often curative in localized gastrointestinal stromal tumors and is always recommended. Clinically, their behavior is difficult to predict, and mitotic count and tumor size seem to be the most effective prognostic factors. We performed a retrospective analysis of clinical presentation and course, surgical management and pathological features of patients with gastrointestinal stromal tumors treated in our institution from 1995 to 2003. Twenty-two patients were enrolled in the study, and all of them underwent surgery. There were two perioperative deaths, and global morbidity was about 13%. Nineteen patients were followed (mean, 31 months): 4 patients had disease progression/recurrence and died, and one patient experienced a local recurrence and was reoperated with a curative intent; 14 patients were disease free. Our experience shows that histological and immunohistochemical examinations are fundamental for a definitive diagnosis and to assess the risk of aggressive behavior. Moreover, our results confirm that in stromal tumors complete surgical resection remains the mainstay of treatment in localized gastrointestinal stromal tumors, although the recurrence rate is relatively high. It is conceivable that treatment and prognosis of metastatic and non-resectable gastrointestinal stromal tumors, as well as the adjuvant treatment of high-risk, radically excised gastrointestinal stromal tumors will be strongly impacted by the c-kit target therapy.