Providing meaningful care for families experiencing stillbirth: a meta-synthesis of qualitative evidence.

OBJECTIVE: The objective of this study was to explore the meaningfulness of non-pharmacological care experienced by families throughout the experience of stillbirth from diagnosis onwards. STUDY DESIGN: A comprehensive systematic review was conducted. Multiple sources were searched for relevant studies including gray literature. Studies were included if they reported the experiences of families with the care they received throughout the experience of stillbirth, from diagnosis onwards. Studies were assessed for methodological quality prior to inclusion. Qualitative findings were extracted from included studies and pooled using a meta-aggregative approach. This paper reports the results of one meta-synthesis from the systematic review. RESULTS: Ten qualitative studies of moderate to high quality informed this meta-synthesis. The meta-aggregative synthesis included 69 findings that informed the development of 10 categories and one final, synthesized finding. Emerging themes that underpinned the meaningfulness of care provided to parents experiencing stillbirth included: information provision, the need for emotional support and appropriate maternity ward environments and systems. CONCLUSION: The results of this meta-synthesis revealed the elements of care that were experienced as meaningful from the perspective of parents who had experienced stillbirth. Exploration of these elements has provided important detail to underpin a growing understanding of how parents experience care and what may help or hinder parents' experience of distress, anxiety and grief throughout the experience of stillbirth.

Gly166 in the NK1 receptor regulates tachykinin selectivity and receptor conformation.

We have studied the pharmacological properties of genetically engineered human NK1 tachykinin receptors in which residues at the extracellular surface of the fourth transmembranal domain were substituted with the corresponding amino acids from the NK2 receptor. We show that substitution of G166C:Y167F in the human NK1 receptor induces high affinity binding of a group of tachykinin ligands, known as 'septides' (i.e. neurokinin A, neurokinin B, [pGlu6,Pro9]-substance P6-11 and substance P-methylester). In contrast, binding of substance P and non-peptide antagonists is unaffected by these mutations. This effect parallels that found on the rat receptor and is therefore species specific. Second, we demonstrate that mutation of Gly166 to Cys alone is both necessary and sufficient to create this pan-reactive tachykinin receptor, whereas replacement of Tyr167 by Phe has no detectable effect on the pharmacological properties of the receptor. Furthermore, analysis of the effect of N-ethylmaleimide and dithiothreitol on binding of radiolabelled substance P documents differences in the mode in which this ligand interacts with wild-type and mutant receptors and supports the existence of a mutational induced change in the conformational status of the NK1 receptor.

A mutation changes ligand selectivity and transmembrane signaling preference of the neurokinin-1 receptor.

We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK1R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK1R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N- or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK1R preference for distinct G protein-mediated signaling pathways. NK1R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells. The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK1R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK1R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor.

Selective enhancement by serum factors of cyclic AMP accumulation in rat microglial cultures.

Using purified microglial cultures obtained from the neonatal rat brain we found that media containing fetal calf serum (as well as human, horse and goat sera) enhanced by about 3-fold the accumulation of cyclic AMP induced by the beta-adrenergic agonist isoproterenol and did not affect in a significant way that induced by the direct adenylyl cyclase stimulator forskolin. The effect of fetal calf serum was (i) dose dependent, and statistically significant also at serum concentrations below 1%; (ii) rapidly lost (half life of about 15 min) when the serum-containing medium was exposed to microglia, astrocytes or neuroblastoma cells; (iii) present also when cyclic AMP accumulation was enhanced by prostaglandin E2 or by cholera toxin; (iv) absent on basal cyclic AMP levels. When media containing fetal calf serum or the other mammalian sera mentioned above were tested on astrocyte cultures, an inhibitory, rather than enhancing activity on cyclic AMP levels was observed, indicating that the facilitatory factor(s) present in serum acts specifically on microglial cells. Moreover, in astrocytes the effect of serum was identical when tested on basal and on isoproterenol or forskolin-stimulated cyclic AMP levels. Thus, the mechanism of cyclic AMP inhibition in astrocytes is unrelated to the mechanism of activation in microglia. Our observations suggest that serum contains factor(s), promptly cleared by different cell types. Such factors may interact with so far unidentified microglial receptors responsible for a facilitation of G protein-mediated activation of adenylyl cyclase. Regulation of the cyclic AMP cascade at this step has not been described previously, and may be important for the modulation of microglial functions controlled by the cyclic nucleotide.