Procedures for examining whether treatment effects on an outcome are mediated and/or moderated have been well developed and are routinely applied. The mediation question focuses on the intervening mechanism that produces the treatment effect. The moderation question focuses on factors that affect the magnitude of the treatment effect. It is important to note that these two processes may be combined in informative ways, such that moderation is mediated or mediation is moderated. Although some prior literature has discussed these possibilities, their exact definitions and analytic procedures have not been completely articulated. The purpose of this article is to define precisely both mediated moderation and moderated mediation and provide analytic strategies for assessing each.

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Long-term potentiation (LTP), a cellular model of learning and memory, requires calcium-dependent protein kinases. Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA-Rs), which mediate rapid excitatory synaptic transmission. This AMPA-R phosphorylation appeared to be catalyzed by Ca2+- and calmodulin-dependent protein kinase II (CaM-KII): (i) it correlated with the activation and autophosphorylation of CaM-KII, (ii) it was blocked by the CaM-KII inhibitor KN-62, and (iii) its phosphorus-32 peptide map was the same as that of GluR1 coexpressed with activated CaM-KII in HEK-293 cells. This covalent modulation of AMPA-Rs in LTP provides a postsynaptic molecular mechanism for synaptic plasticity.

Structural remodelling of synapses and formation of new synaptic contacts has been postulated as a possible mechanism underlying the late phase of long-term potentiation (LTP), a form of plasticity which is involved in learning and memory. Here we use electron microscopy to analyse the morphology of synapses activated by high-frequency stimulation and identified by accumulated calcium in dendritic spines. LTP induction resulted in a sequence of morphological changes consisting of a transient remodelling of the postsynaptic membrane followed by a marked increase in the proportion of axon terminals contacting two or more dendritic spines. Three-dimensional reconstruction revealed that these spines arose from the same dendrite. As pharmacological blockade of LTP prevented these morphological changes, we conclude that LTP is associated with the formation of new, mature and probably functional synapses contacting the same presynaptic terminal and thereby duplicating activated synapses.

Denninger MH, de Prost D, for the PPH Study Group. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. 2007; 5: 266-73. Summary. Background: Postpartum hemorrhage (PPH) is a major source of maternal morbidity. Objectives: This study's objective was to determine whether changes in hemostasis markers during the course of PPH are predictive of its severity. Patients and methods: We enrolled 128 women with PPH requiring uterotonic prostaglandin E2 (sulprostone) infusion. Two groups were defined (severe and non-severe PPH) according to the outcome during the first 24 hours. According to our criteria, 50 of the 128 women had severe PPH. Serial coagulation tests were performed at enrollment (H0), and 1, 2, 4 and 24 hours thereafter. Results: At H0, and through H4, women with severe PPH had significantly lower fibrinogen, factor V, antithrombin activity, protein C antigen, prolonged prothrombin time, and higher D-dimer and TAT complexes than women with non-severe PPH. In multivariate analysis, from H0 to H4, fibrinogen was the only marker associated with the occurence of severe PPH. At H0, the risk for severe PPH was 2.63-fold higher for each 1 gL )1 decrease of fibrinogen. The negative predictive value of a fibrinogen concentration >4 gL )1 was 79% and the positive predictive value of a concentration £2 gL )1 was 100%. Conclusion: These findings indicate that a simple fibrinogen measurement can anticipate the risk of severe bleeding in PPH. J Thromb Haemost

Hippocampal organotypic slice cultures maintained 10-20 days in vitro express a high level of the polysialylated embryonic form of neural cell adhesion molecule (NCAM) (PSA-NCAM). Treatment of the cultures with endoneuraminidase-N selectively removed polysialic acid (PSA) from NCAM and completely prevented induction of long-term potentiation (LTP) and long-term depression (LTD) without affecting cellular or synaptic parameters. Similarly, slices prepared from transgenic mice lacking the NCAM gene exhibited a decaying LTP. No inhibition of N-methyl-D-aspartic acid receptor-dependent synaptic responses was detected. Washout of the enzyme resulted in reexpression of PSA immunoreactivity which correlated with a complete recovery of LTP and LTD. This reexpression was blocked by TTX and low calcium and enhanced by bicuculline. Taken together, these results indicate that neuronal activity regulates the expression of PSA-NCAM at the synapse and that this expression is required for the induction of synaptic plasticity.

The biochemical composition of the postsynaptic membrane and the structure of dendritic spines may be rapidly modulated by synaptic activity. Here we review these findings, discuss their implications for long-term potentiation (LTP) and long-term depression (LTD) and propose a model of sequentially occurring expression mechanisms.

Conservative treatment for placenta accreta can help women avoid hysterectomy and involves a low rate of severe maternal morbidity in centers with adequate equipment and resources.