Dying at life׳s beginning: Experiences of parents and health professionals in Switzerland when an 'in utero ' diagnosis incompatible with life is made.

OBJECTIVE: The disclosure of a diagnosis during pregnancy of a fetal malformation, which is incompatible with life, normally comes completely unexpectedly to the parents. Although a body of international literature has considered the topic, most of it comes from the United States and little has been generated from Europe. This study aims to illuminate the contemporary treatment associated with such diagnoses, regardless of whether parents decide to terminate or continue the pregnancy. DESIGN: a qualitative design was used with data collected by semi-structured interviews and subjected to a thematic analysis. SETTING: the research was conducted in the German speaking areas of Switzerland with data collected from participants in places of their choice. PARTICIPANTS: 61 interviews were conducted with 32 parents and 29 health professionals. FINDINGS: the theme of 'temporality' identified four main time points from the professionals: diagnosis, decision, birth/death, and afterwards. However, in contrast to these, six major themes in this study, primarily generated from parents and extended from receiving the diagnosis until the interview, were identified: shock, choices and dilemmas, taking responsibility, still being pregnant, forming a relationship with the baby, letting go. Although there was concurrence on many aspects of care at the point of contact, parents expressed major issues as gaps between the points of contact. CONCLUSIONS: care varied regionally but was as sensitive as possible, attempting to give parents the space to accept their loss but fulfil legal requirements. A gap exists between diagnosis and decision with parents feeling pressured to make decisions regarding continuing or terminating their pregnancies although health professionals' testimonies indicated otherwise. A major gap manifested following the decision with no palliative care packages offered. During the birth/death of the baby, care was sensitive but another gap manifested following discharge from hospital.

Heterogeneity of glycinergic and gabaergic interneurons in the granule cell layer of mouse cerebellum.

Interneurons of the cerebellum granule cell layer (GCL) form distinct populations. Golgi cells extend dendrites in the molecular layer (ML) and innervate granule cells. In contrast, Lugaro cells have dendrites confined to the GCL but innervate interneurons in the ML, and globular cells have both their dendrites and axons in the ML. The latter cells were described recently and remain poorly characterized. Although several neurochemical markers have been associated selectively with GCL interneurons, it is unclear how they relate to their morphological classification and neurochemical phenotype (glycinergic and/or gamma-aminobutyric acid [GABA]ergic). Here, we performed a detailed characterization of GCL interneurons in mice expressing enhanced green fluorescent protein (GFP) in glycinergic and GABAergic neurons, respectively. By using immunofluorescence for metabotropic glutamate receptor 2 (mGluR2) and neurogranin as markers, we demonstrate the existence of five non-overlapping subsets of Golgi cells: about 65% are glycinergic/GABAergic and co-express both markers. Two small subsets (5-10%) also contain both neurotransmitters but express only mGluR2; they are distinguished by cell body size and location in the GCL. The fourth subset (15%) is GABAergic only and expresses neurogranin. The fifth subset (5%) is glycinergic only and lacks both markers. Thus, the heterogeneity of Golgi cells suggests that they belong to specific functional circuits and are differentially regulated by mGluRs and Ca(2+)-calmodulin-dependent signaling pathways. In contrast to Golgi cells, Lugaro and globular cells are glycinergic/GABAergic and lack mGluR2 and neurogranin. They each represent at least 15% of GCL interneurons and extensively innervate stellate and basket cells, but not Purkinje cells, emphasizing their contribution to inhibitory control of ML interneurons.

Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of gamma-aminobutyric acid type A receptor alpha1 subunit knockout mice.

Targeted deletion of the alpha1 subunit gene results in a profound loss of gamma-aminobutyric acid type A (GABA(A)) receptors in adult mouse brain but has only moderate behavioral consequences. Mutant mice exhibit several adaptations in GABA(A) receptor subunit expression, as measured by Western blotting. By using immunohistochemistry, we investigated here whether these adaptations serve to replace the missing alpha1 subunit or represent compensatory changes in neurons that normally express these subunits. We focused on cerebellum and thalamus and distinguished postsynaptic GABA(A) receptor clusters by their colocalization with gephyrin. In the molecular layer of the cerebellum, alpha1 subunit clusters colocalized with gephyrin disappeared from Purkinje cell dendrites of mutant mice, whereas alpha3 subunit/gephyrin clusters, presumably located on dendrites of Golgi interneurons, increased sevenfold, suggesting profound network reorganization in the absence of the alpha1 subunit. In thalamus, a prominent increase in alpha3 and alpha4 subunit immunoreactivity was evident, but without change in regional distribution. In the ventrobasal complex, which contains primarily postsynaptic alpha1- and extrasynaptic alpha4-GABA(A) receptors, the loss of alpha1 subunit was accompanied by disruption of gamma2 subunit and gephyrin clustering, in spite of the increased alpha4 subunit expression. However, in the reticular nucleus, which lacks alpha1-GABA(A) receptors in wild-type mice, postsynaptic alpha3/gamma2/gephyrin clusters were unaffected. These results demonstrate that adaptive responses in the brain of alpha1(0/0) mice involve reorganization of GABAergic circuits and not merely replacement of the missing alpha1 subunit by another receptor subtype. In addition, clustering of gephyrin at synaptic sites in cerebellum and thalamus appears to be dependent on expression of a GABA(A) receptor subtype localized postsynaptically.

Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus.

Major aspects of temporal lobe epilepsy (TLE) can be reproduced in mice following a unilateral injection of kainic acid into the dorsal hippocampus. This treatment induces a non-convulsive status epilepticus and acute lesion of CA1, CA3c and hilar neurons, followed by a latent phase with ongoing ipsilateral neuronal degeneration. Spontaneous focal seizures mark the onset of the chronic phase. In striking contrast, the ventral hippocampus and the contralateral side remain structurally unaffected and seizure-free. In this study, functional and neurochemical alterations of the contralateral side were studied to find candidate mechanisms underlying the lack of a mirror focus in this model of TLE. A quantitative analysis of simultaneous, bilateral EEG recordings revealed a significant decrease of theta oscillations ipsilaterally during the latent phase and bilaterally during the chronic phase. Furthermore, the synchronization of bilateral activity, which is very high in control, was strongly reduced already during the latent phase and the decrease was independent of recurrent seizures. Immunohistochemical analysis performed in the contralateral hippocampus of kainate-treated mice revealed reduced calbindin-labeling of CA1 pyramidal cells; down-regulation of CCK-8 and up-regulation of NPY-labeling in mossy fibers; and a redistribution of galanin immunoreactivity. These changes collectively might limit neuronal excitability in CA1 and dentate gyrus, as well as glutamate release from mossy fiber terminals. Although these functional and neurochemical alterations might not be causally related, they likely reflect long-ranging network alterations underlying the independent evolution of the two hippocampal formations during the development of an epileptic focus in this model of TLE.

Independent maturation of the GABA(B) receptor subunits GABA(B1) and GABA(B2) during postnatal development in rodent brain.

GABA(B) receptors mediate slow inhibitory GABAergic neurotransmission. They are encoded by two distinct subunits, GABA(B1) (GBR1) and GABA(B2) (GBR2), with two major isoforms of GBR1, GBR1a and GBR1b, arising from differential promoter usage. Heterodimerization of GBR1 and GBR2 is essential for GABA(B) receptor function, as shown in recombinant expression systems and in GBR1(-/-) mice. GABA(B) receptors are highly expressed during ontogeny, prior to synaptogenesis, but their developmental function remains elusive. Here we investigated the postnatal development of GABA(B) receptors in rodent brain, focusing on potential differences in the spatial and temporal expression pattern of GBR1 and GBR2. Immunohistochemistry with subunit-specific antibodies revealed a widespread staining for GBR1a and GBR2 in neonatal rodent brain. During the first 2 weeks, these two subunits exhibited largely overlapping regional distribution, but with profound distinctions in cellular and subcellular localization. The adult-like pattern was established during the third week, with a prominent up-regulation of GBR1b, extensively codistributed with GBR2. Several unexpected features were noted at early stages, notably, a selective GBR2 staining of axonal tracts, such as the corticothalamic projection, and a prominent GBR1 expression in astrocytes. The specificity of the antibody labeling was verified in GBR1- and GBR2-knockout mice. In addition, the analysis of these mutants revealed a partial preservation of GBR2 staining in GBR1(-/-) mice and vice versa. Altogether, the results suggest a functional role for GBR1 and GBR2 proteins in immature brain in addition to their contribution to dimeric GABA(B) receptor complexes.