The mechanism of cell proliferation by a combination of thyroid-stimulating hormone (TSH) and insulin-like growth factor-I (IGF-I) was studied in rat thyroid (FRTL-5) cells. IGF-I stimulated an -3.5-fold increase in the rate of Ca2" influx sustained for at least 6 h in TSH-pretreated cells but not in quiescent cells. The significant cell proliferation was observed when TSH-primed cells were incubated with IGF-I for 24 h but not for 12 h. IGF-I stimulated the rate of Ca2" influx in a dose-dependent manner that was similar to that for induction of DNA synthesis. Both Ca2" influx and DNA synthesis observed in response to IGF-I in TSH-primed cells were inhibited by cobalt. In addition, the stimulations of Ca2" influx and DNA synthesis by IGF-I were dependent on extracellular Ca2+ in TSH-pretreated cells. When TSH-primed cells were pretreated with pertussis toxin, both IGF-I-induced Ca2+ influx and DNA synthesis were abolished. However, pertussis toxin did not block the priming action of TSH or forskolin. When calcium entry was induced by Bay K8644, it stimulated cell growth in TSH-primed cells but not in quiescent cells. Moreover, cobalt and lanthanum inhibited DNA synthesis even when added several hours after the addition of Bay K8644 but not when added 24 h after the growth factor in TSH-primed cells. These findings suggest that at least two important mechanisms may work in response to IGF-I only in the TSH-primed

Squirrel monkeys were trained to emit one response after IV administration of l-nicotine (0.4 or 0.2 mumol/kg) and a different response after IV administration of saline. After stable discriminative performances were established, subjects were tested with cumulative doses of l-nicotine (0.02-2.2 mumol/kg), d-nicotine (0.02-19.7 mumol/kg), l-nornicotine (0.2-12.0 mumol/kg), l-cotinine (56.8-567.5 mumol/kg), and dl-anabasine (0.6-19.7 mumol/kg). All of the drugs produced dose-related increases in the percentage of drug-appropriate responses emitted, from predominantly saline-appropriate responses after low doses, to predominantly drug-appropriate responses at the highest doses studied. Relative potency comparisons indicated that l-nicotine was 28 times more potent than d-nicotine, 29 times more potent than l-nornicotine, and approximately 2000 times more potent than l-cotinine. Each of the drugs also produced decreases in rates of responding, with potency order similar to that obtained for the discriminative effects. The effects of l-cotinine may be attributed to trace amounts of l-nicotine, which existed within the l-cotinine. The effects of dl-anabasine were lethal in one subject and were consequently not studied in the other subjects.

Understanding of cannabinoid (CB) actions has been remarkably advanced during the last decade, due mainly to the identification of the G-protein-coupled cannabinoid receptors, namely, CB1 receptors that are predominantly found in the brain and CB2 receptors that are exclusively found in peripheral tissues. Endogenous ligands for these receptors have also been identified. Research to date suggests that the analgesic effect of cannabinoids and the enhancement of opioid analgesia by cannabinoids are both CB1 receptor-mediated via the activation of opioid receptors. The involvement of the CB1 receptor in mediating reinforcing and physical dependence-producing effects of opioids has also been suggested, with the former being considered the result of interaction with the dopaminergic neurotransmission in the midbrain dopamine system. However, the discriminative stimulus effects of cannabinoids have been reported to be highly specific in that the effects were not substituted by other classes of compounds including opioidergic and dopaminergic agents nor were they antagonized by antagonists of various neurotransmission systems, suggesting that the discriminative stimulus effects only involve the cannabinoid system. Thus the cannabinoid actions appear to be classifiable into at least two kinds: 1) those mediated directly through cannabinoid receptors and 2) those mediated indirectly through other systems such as opioidergic systems. Detailed research into these actions may help to elucidate not only the mechanisms of action of exogenous cannabinoids but also the role of endogenous cannabinoids, especially in the brain reward system.

Abstract.A fifty-year-old woman was admitted to our hospital because of generalized edema, progressive symptoms of fatigue and weakness of ten years' duration.After an uneventful third delivery, 24 years before admission, she could not lactate and developed oligomenorrhea and then amenorrhea. Laboratory evaluation revealed panhypopituitarism and pituitary cell antibodies were positive. Both CT scans and MR images showed empty sella. This case is postpartum hypopituitarism without a preceding history of excessive bleeding and may be autoimmune hypophysitis.

SummaryEicosapentaenoic acid (EPA) has been widely accepted to have antiatherosclerotic effects. The aim of this study was to investigate the antiplatelet effect of EPA combined with acetylsalicylic acid (ASA) following stent implantation. Eighteen patients who had undergone coronary stent implantation at least 8 months previously were included. All patients were given EPA ethyl ester (EPA-E) 1.8 g/day in addition to ASA 100 mg/day for 12 weeks. After the treatment, the plasma EPA/arachidonic acid (AA) ratio increased signifi cantly from 0.40 ± 0.2 to 1.08 ± 0.39 (P < 0.001). There were no changes in the maximum platelet aggregation (MPA) induced by adenosine diphosphate (5 and 20 µmol/L), AA (0.3 and 0.5 mg/mL), or collagen (2 and 4 µg/mL). Furthermore, no signifi cant differences were observed in the expression of PAC-1 and CD62P on the platelet surface membranes or in the soluble P-selectin concentration. With further analysis, a signifi cant negative correlation was found between collagen (2 µg/mL)-induced MPA and plasma EPA/AA ratio (r = -0.507, P = 0.032). The patients were then divided into 2 groups according to the median EPA/AA ratio value of 0.92. In the high EPA/AA ratio group (n = 10), collagen-induced MPA was signifi cantly suppressed after EPA-E administration (45.3 ± 15.9 versus 39.0 ± 16.3, P = 0.033). In contrast, there were no signifi cant changes in platelet aggregation (56.0 ± 9.8 versus 57.1 ± 11.4, P = 0.745) in the low EPA/AA ratio group (n = 8). EPA treatment had a potential to suppress collagen-induced platelet aggregation in patients with a high plasma EPA/AA ratio. (Int Heart J 2014; 55: 228-233) Key words: Omega-3 polyunsaturated fatty acids, Coronary artery disease C oronary revascularization with drug-eluting stents (DES) has become a widespread technique for treating coronary artery disease (CAD). The guidelines recommend that patients with DES should receive dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and thienopyridine for at least 1 year in order to prevent stent thrombosis.1,2) When the risk of stent thrombosis decreases in the chronic phase following DES implantation, secondary prevention becomes a primary target of patient care. In fact, in the chronic phase, the risks of CAD or cerebrovascular disease are much higher than that of stent thrombosis.3,4) Therefore, lifelong treatment with ASA is also recommended for the secondary prevention of atherothrombotic events following DAPT termination. 1,2)Eicosapentaenoic acid (EPA) has been widely accepted to have antiatherosclerotic effects. 5,6) In relation to secondary prevention, the use of eicosapentaenoic acid ethyl ester (EPA-E) in combination with statins successfully reduced the recurrence of cardiovascular events in the Japan EPA lipid intervention study (JELIS). 7) In particular, in patients who underwent coronary artery intervention, the JELIS sub-study showed that the incidence of major coronary events was significantly reduced by 41% in the EPA treatment group. 8) EPA is known to improve vascula...