In LGG, neuropsychological assessment is encouraged in addition to KPS. vWM evaluation before treatment showed that most patients had a cognitive deficit. Moreover, surgery induced a transient vWM worsening, which nevertheless recovers within 3 months. Specific rehabilitation might help to recover and even to improve the preoperative cognitive status.

The mechanisms that lead to the onset of human parturition are still unknown, although selected critical factors have been identified. To investigate the changes in myometrial gene expression associated with parturition, we used two macroarrays each containing 1176 different complementary human cDNA clones. Methods involving hierarchical clustering and conventional statistical analysis allowed us to generate a profile of genes expression at three stages of late pregnancy: preterm (29 wk amenorrhea); full term, not in labor (38 wk amenorrhea); and full term in labor (39 wk amenorrhea). Only 4% of the genes investigated were differentially expressed between the preterm and term groups (P < 0.05). These genes could be clustered as groups of either down-regulated or up-regulated transcripts. The changes in transcript abundance were particularly marked between the preterm and term stages of gestation, whereas the differences between term not in labor and term in labor were less pronounced. The parturition was characterized by a massive down-regulation of a large panel of developmental, cell adhesion molecule and proliferation-related genes, along with the up-regulation of inflammatory, contraction and apoptosis associated genes. We propose that the mechanisms of parturition consist primarily in the arrest of the processes of myometrial development, a step that might be essential to allow the uterus to recover appropriate contractile function before delivery.

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The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-α, IL-1β, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NFκB, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the glycogen-trophoblastic cells of the placenta. This activation was disrupted by PDE4 inhibition, and inflammation-induced preterm delivery and fetal demise were prevented. PDE4 selective inhibitors may thus represent a novel effective treatment to delay inflammation-induced preterm delivery and to prevent adverse outcomes in infants.

The distributions of the mRNAs for estrogen receptors (ERα and ERβ) and their binding properties in myometria of pregnant and nonpregnant women and in leiomyoma were studied. RT-PCR analysis indicated that the term pregnancy myometria had little ERα mRNA, whereas the amounts of ERβ mRNAs in pregnant or nonpregnant myometria appeared to be similar. Both ERα and ERβ mRNA were greater in certain leiomyoma than in normal nonpregnant myometria. The binding kinetics revealed that two specific binding sites (with high or low affinity) for 17β-estradiol were present in the nonpregnant myometrium. Only the low-affinity binding sites were detectable in late-pregnancy myometria and in leiomyoma, and their capacities were increased two- to threefold ( P < 0.001) in leiomyoma. The pregnancy- and leiomyoma-related changes in myometrial ER status, especially the low concentration of ERα mRNA and the lack of high-affinity ER in pregnant women, plus the increased ERα and ERβ mRNAs and the increased low-affinity ER in some leiomyoma, suggest that the redistribution of ER subtypes is associated with the pathological and/or normal growth of the myometrium.

Stimulation of rat adipocytes with insulin and isoproterenol results in serine phosphorylation and activation of the adipocyte cGMP-inhibited phosphodiesterase (cGI PDE), events believed to be important in the antilipolytic action of insulin (Degerman, E., Smith, C. J., Tornqvist, H., Vasta, V., Manganiello, V. C., and Belfrage, P. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 533-537). Here we demonstrate, by two-dimensional phosphopeptide mapping, that the major phosphopeptide generated by trypsin, or trypsin followed by Asp-N protease digestion of [ Insulin controls cell metabolism and proliferation through several multicomponent diverging pathways, which are only partially understood (1-3). One important and well known metabolic effect is to antagonize hormone-activated lipolysis in adipose tissue, brought about mainly via insulin-mediated activation of a membrane-associated cGMP-inhibited phosphodiesterase (cGI PDE, 1 referred to as the PDE 3 gene family; Ref. 4), which leads to a reduction in cAMP, a decrease in cAMPdependent protein kinase (protein kinase A) activity, and a lowering of the phosphorylation and thereby the activity of the hormone-sensitive lipase, the rate-limiting enzyme in the regulation of lipolysis (5-11).Insulin and cAMP-increasing agents induce serine phosphorylation and activation of cGI PDE in rat adipocytes (12, 13). An insulin-stimulated cGI PDE serine protein kinase activity in rat adipocytes has previously been partially characterized (14,15). In the presence of both isoproterenol and insulin, the phosphorylation/activation of cGI PDE is more than additive (13, 16), suggesting cross-talk between the two signal transduction pathways.To further dissect the components of the antilipolytic signaling pathway controlling the cGI PDE, we used two-dimensional tryptic phosphopeptide mapping and other methods to analyze the site(s) phosphorylated in this enzyme in 32 P-labeled rat adipocytes incubated with insulin, isoproterenol, or both. Since the amount of labeled phosphopeptides that could be obtained from experiments with intact cells was far less than that required for amino acid sequencing, the phosphorylation site(s) was identified by comparison of properties of phosphopeptides from cGI PDE phosphorylated in adipocytes, or from recombinant cGI PDE expressed in NIH 3006 human fibroblasts 2 (rcGI PDE) phosphorylated by protein kinase A, with peptides synthesized on the basis of the deduced sequence of rat adipocyte cGI PDE (17) and phosphorylated by protein kinase A. Peptides chosen for these studies contained consensus sequences for phosphorylation by protein kinase A (18), since preliminary results indicated that the site(s) phosphorylated during incubation of adipocytes with insulin or isoproterenol was located in the same tryptic phosphopeptide.EXPERIMENTAL PROCEDURES

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.

1 In order to compare the b 2 -and b 3 -adrenoceptor (b-AR) desensitisation process in human nearterm myometrium, we examined the influence of a pretreatment of myometrial strips with either a b 2 -or a b 3 -AR agonist (salbutamol or SR 59119A, respectively, both at 10 mM, for 5 and 15 h) on the relaxation and the cyclic adenosine monophosphate (cAMP) production induced by these agonists. 2 To assess some of the mechanisms potentially implicated in the b-AR desensitisation process, we studied the influence of such treatment on the number of b 2 -and b 3 -AR binding sites, the b 2 -and b 3 -AR transcripts expression and the phosphodiesterase 4 (PDE4) activity. 3 Salbutamol, but not SR 59119A, concentration-response curve (CRC) was shifted by a 15 h salbutamol preincubation, with a significant difference in Àlog EC 20 values (6.3170.13 vs 5.5870.24, for control and 15 h salbutamol pretreatment, respectively, Po0.05). Neither salbutamol nor SR 59119A CRCs were modified after a 15 h preincubation with SR 59119A. 4 A 15 h exposure of myometrial strips to salbutamol significantly reduced the salbutamol-induced (0.6070.26 vs 1.5470.24 pmol mg À1 protein, Po0.05), but not the SR 59119A-induced, cAMP production. No decrease in cAMP production was observed after a 15 h SR 59119A exposure. 5 A 15 h salbutamol exposure of myometrial strips significantly reduced the b 2 -but not the b 3 -AR binding site density, whereas no decrease in the number of b 2 -and b 3 -AR binding sites was observed after a 15 h SR 59119A treatment. 6 Neither PDE4 activity nor the b 2 -and b 3 -AR mRNA expression levels were affected by salbutamol or SR 59119A treatments. 7 Our results indicate that b 3 -AR, but not b 2 -AR, are resistant to the agonist-induced desensitisation. In our model, b 2 -AR desensitisation is mediated by a decreased number of b 2 -AR that was not explained by transcriptional regulation of the receptor.