Opposing actions of prostaglandins and oxytocin determine the onset of murine labor

Prostaglandins (PGs) have been recently proven essential for parturition in mice. To dissect the contributions of the two cyclooxygenase (COX) isoforms to the synthesis of PGs during pregnancy, we have characterized the parturition phenotype of COX-1-deficient mice. We find that mice with targeted disruption of the COX-1 gene have delayed parturition resulting in neonatal death. Results of matings of COX-1-deficient females with COX-1 intact males, and blastocyst transfer of COX-1-deficient or -intact embryos into wild-type foster mothers, proved necessity and sufficiency of maternal COX-1 for the normal onset of labor. COX-1 expression is induced in gravid murine uterus and by in situ hybridization; this induction is localized to the decidua. Measurement of uterine PGs further confirmed that COX-1 accounted for the majority of PGF2alpha production. To evaluate the interaction of PGs with oxytocin during murine labor, we generated mice deficient in both oxytocin and COX-1. Surprisingly, the combined oxytocin and COX-1-deficient mice initiated labor at the normal time. COX-1-deficient mice demonstrated impaired luteolysis, as evidenced by elevated serum progesterone concentration and ovarian histology late in gestation, and delayed induction of uterine oxytocin receptors. In contrast, simultaneous oxytocin and COX-1 deficiency restored the normal onset of labor by allowing luteolysis in the absence of elevated PGF2alpha production. These findings demonstrate that COX-1 is essential for normal labor in the mouse, with a critical function being to overcome the luteotrophic action of oxytocin in late gestation.     

The haemodynamic effects of ketanserin versus dihydralazine in severe early-onset hypertension in pregnancy

OBJECTIVE: To compare the haemodynamic efficacy of ketanserin (a selective serotonin2-receptor blocker) with dihydralazine in the management of severe early-onset hypertension in pregnancy. DESIGN: Subgroup analysis within a randomised prospective multicentre trial to compare haemodynamic effects as measured by pulmonary artery catherization. SETTING: Departments of Obstetrics and Gynaecology and Intensive Care Medicine, Free University Hospital, Amsterdam and Sophia Hospital, Zwolle. PARTICIPANTS: Thirty-one women with a diastolic blood pressure > 110 mmHg and a gestational age between 26 and 32 weeks. RESULTS: The antihypertensive efficacy of both drugs was comparable. Dihydralazine significantly increased cardiac output (P < 0.01), while ketanserin induced only minor changes in cardiac output. Systemic vascular resistance decreased in both groups, but the decrease was significantly more pronounced with dihydralazine compared with ketanserin. Ketanserin induced a significant but not clinically relevant increase in heart rate (P < 001, while dihydralazine caused marked tachycardia (P < 0.005). Left ventricular stroke work index was reduced to similar values in both groups. CONCLUSIONS: The antihypertensive profile of ketanserin is characterised by an early and gradual reduction of blood pressure in combination with a moderate decrease in systemic vascular resistance and no significant change in cardiac output. Dihydralazine causes market tachycardia resulting in a considerable increase in cardiac output.     

Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression

OBJECTIVE: To evaluate the effect of early 'aggressive' drug treatment on radiographic progression in patients with recent-onset rheumatoid arthritis (RA), compared to conventional stepwise increasing intensity of treatment. DESIGN: Prospective follow-up study with an experimental group and a historical control group both divided into a high-risk subgroup and a low-risk subgroup, based on prognostic factors. The effect of the 'aggressive' and the conventional treatment strategy was compared between both high-risk groups; the low-risk groups, both treated according to the conventional treatment strategy, were used to ensure internal consistency between the experimental and the historical groups. PATIENTS: A total of 228 consecutive patients with recent-onset RA (complaints < 1 yr at study entry). METHODS: The 'aggressive' drug treatment consisted of institution of relatively fast-acting disease-modifying anti-rheumatic drugs (DMARDs) (sulphasalazine, methotrexate) immediately after diagnosis, and rapid adjustment of dosage and/or drug in the case of insufficient response as measured by a change in C-reactive protein (CRP) level. Radiographic damage was assessed according to a modified version of Sharp's method and cumulative disease activity expressed as CRP-area under the curve (CRP-AUC). The occurrence of side-effects was also evaluated. RESULTS: After 2 yr of follow-up, comparison of the two high-risk subgroups showed the radiographic progression in the 'aggressively' treated subgroup to be significantly lower than that in the control group [Sharp score: median (range) 26 (0-100) vs 35 (1-188); P = 0.03]. Cumulative CRP values were also significantly lower than in the control high-risk subgroup [CRP-AUC: median (range) 1963 (212-8515) vs 3025 (46-15 632) mg.week/1; P = 0.002). This was achieved without an increase in the occurrence of side-effects. There was no difference between the two low-risk subgroups with regard to entry characteristics, CRP-AUC values or radiological progression, indicating comparability between the two groups. CONCLUSION: Early 'aggressive' drug treatment, using sulphasalazine and/or methotrexate, aimed at reduction of the CRP level, significantly reduces the (rate of) radiographic progression in RA.     

Triterpenoids from Acaena pinnatifida R. et P

Eight urs-12-ene triterpenoids, beta-sitosterol, (+)-catechin, and apigenin 7-O-glucoside were isolated from the leaves of Acaena pinnatifida R. et P. The triterpenoids were characterized as pomolic acid, pomolic acid-3-acetate, tormentic acid, 2-epi-tormentic acid, euscaphic acid, tormentic acid glucoside, niga-ichigoside F1, and niga-ichigoside F2.