Experiential contributions to social dominance in a rat model of fragile-X syndrome.

Social withdrawal is one phenotypic feature of the monogenic neurodevelopmental disorder fragile-X. Using a 'knockout' rat model of fragile-X, we examined whether deletion of the Fmr1 gene that causes this condition would affect the ability to form and express a social hierarchy as measured in a tube test. Male fragile-X 'knockout' rats living together could successfully form a social dominance hierarchy, but were significantly subordinate to wild-type animals in mixed group cages. Over 10 days of repeated testing, the fragile-X mutant rats gradually showed greater variance and instability of rank during their tube-test encounters. This affected the outcome of future encounters with stranger animals from other cages, with the initial phenotype of wild-type dominance lost to a more complex picture that reflected, regardless of genotype, the prior experience of winning or losing. Our findings offer a novel insight into the complex dynamics of social interactions between laboratory living groups of fragile-X and wild-type rats. Even though this is a monogenic condition, experience has an impact upon future interactions with other animals. Gene/environment interactions should therefore be considered in the development of therapeutics.

[Willingness of Patients with Obesity to Use New Media in Rehabilitation Aftercare]. / Die Nutzungsbereitschaft von Patienten mit Adipositas gegenüber neuen Medien in der Rehabilitationsnachsorge.

Digital media offer new possibilities in rehabilitation aftercare. This study investigates the rehabilitants' willingness to use new media (sms, internet, social networks) in rehabilitation aftercare and factors that are associated with the willingness to use media-based aftercare. 92 rehabilitants (patients with obesity) filled in a questionnaire on the willingness to use new media in rehabilitation aftercare. In order to identify influencing factors, binary logistic regression models were calculated. 3 quarters of the rehabilitants (76.1%) reported that they would be willing to use new media in rehabilitation aftercare. The binary logistic regression model yielded two factors that were associated with the willingness to use media-based aftercare: the possession of a smartphone and the willingness to receive telephone counseling for aftercare. The majority of the rehabilitants was willing to use new media in rehabilitation aftercare. The reasons for refusal of media-based aftercare need to be examined more closely.

The development and activity-dependent expression of aggrecan in the cat visual cortex.

The Cat-301 monoclonal antibody identifies aggrecan, a chondroitin sulfate proteoglycan in the cat visual cortex and dorsal lateral geniculate nucleus (dLGN). During development, aggrecan expression increases in the dLGN with a time course that matches the decline in plasticity. Moreover, examination of tissue from selectively visually deprived cats shows that expression is activity dependent, suggesting a role for aggrecan in the termination of the sensitive period. Here, we demonstrate for the first time that the onset of aggrecan expression in area 17 also correlates with the decline in experience-dependent plasticity in visual cortex and that this expression is experience dependent. Dark rearing until 15 weeks of age dramatically reduced the density of aggrecan-positive neurons in the extragranular layers, but not in layer IV. This effect was reversible as dark-reared animals that were subsequently exposed to light showed normal numbers of Cat-301-positive cells. The reduction in aggrecan following certain early deprivation regimens is the first biochemical correlate of the functional changes to the γ-aminobutyric acidergic system that have been reported following early deprivation in cats.

Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).

PURPOSE: This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure. METHODS: EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions. RESULTS: Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states. CONCLUSIONS: A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects.

PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex.

During development of the cerebral cortex, the invasion of thalamic axons and subsequent differentiation of cortical neurons are tightly coordinated. Here we provide evidence that glutamate neurotransmission triggers a critical signaling mechanism involving the activation of phospholipase C-beta1 (PLC-beta1) by metabotropic glutamate receptors (mGluRs). Homozygous null mutation of either PLC-beta1 or mGluR5 dramatically disrupts the cytoarchitectural differentiation of 'barrels' in the mouse somatosensory cortex, despite segregation in the pattern of thalamic innervation. Furthermore, group 1 mGluR-stimulated phosphoinositide hydrolysis is dramatically reduced in PLC-beta1-/- mice during barrel development. Our data indicate that PLC-beta1 activation via mGluR5 is critical for the coordinated development of the neocortex, and that presynaptic and postsynaptic components of cortical differentiation can be genetically dissociated.

Cortical plasticity: is it time for a change?

Classical studies of plasticity in the visual cortex have been interpreted in terms of heterosynaptic competition between inputs. But an alternative type of 'homosynaptic' plasticity can explain many recent observations and has recently received experimental support. Perhaps both types of plasticity are important.

Plasticity: downstream of glutamate.

Glutamate neurotransmission is an essential component of many forms of neuronal plasticity, however, the intracellular mechanisms that mediate plasticity are only beginning to be elucidated. The emerging image of the NMDA receptor complex reminds us that the similarity between mechanisms of plasticity in various model systems is greater than their apparent differences. For example, the cAMP-dependent protein kinase A signalling pathway is crucial for plasticity in a variety of neuronal systems and across a wide variety of species.

Neural activity: sculptor of 'barrels' in the neocortex.

A major portion of the primary somatosensory cortex of rodents is characterized by the discrete and patterned distribution of thalamocortical axons and layer IV granule cells ('barrels'), which correspond to the spatial distribution of whiskers and sinus hairs on the snout. In recent years several mutant mouse models began unveiling the cellular and molecular mechanisms by which these patterns emerge presynaptically and are reflected postsynaptically. Neural activity plays a crucial role in conferring presynaptic patterns to postsynaptic cells via neurotransmitter receptor-mediated intracellular signals. Here we review recent evidence that is finally opening the doors to understanding the cellular and molecular mechanisms of pattern formation in the neocortex.

Photodynamic therapy induces expression of interleukin 6 by activation of AP-1 but not NF-kappa B DNA binding.

Inducibility and regulation of the pleiotropic cytokine interleukin 6 (IL-6) upon photodynamic therapy (PDT) was studied in the epithelial cell line HeLa. Photofrin-mediated photosensitization resulted in a rapid and dose-dependent induction of IL-6 mRNA production. Maximal levels were reached after 4 h and had decreased to baseline levels after 24 h. This photochemical induction of IL-6 transcription was followed by a strong secretion of IL-6 protein. In comparison to stimulation by 12-O-tetradecanoylphorbol-13-acetate, the kinetics of IL-6 mRNA and protein synthesis after PDT were delayed, although the maximal amounts of secreted IL-6 protein were comparable. As compared to UV irradiation, on the other hand, PDT-induced IL-6 protein levels were 2- to 10-fold higher and were detectable 4 h earlier. Several potentially relevant regulatory DNA elements of the IL-6 promoter were analyzed by gel retardation assays for PDT-induced protein binding. Interestingly, increased AP-1 DNA binding was detected only at the distal AP-1-specific motif and not at the proximal site, differing in 1 bp. Binding of c-Fos-containing AP-1 heterodimers to the specific motif was up-regulated 30 min after PDT, reaching maximal activity at 4 h. This PDT-induced AP-1 activation was independent from protein kinase C activity. Photosensitization did not induce increased binding at the well-characterized NF-kappa B element, nor at the multiple cytokine- and second messenger-responsive element of the IL-6 promoter. By analyzing the molecular mechanisms of IL-6 up-regulation upon PDT, we provide evidence for regulatory differences compared to UV light, ionizing irradiation, or stimulation by phorbol ester. Furthermore, this study suggests that the "proinflammatory" cytokine IL-6 might be involved in the inflammatory reaction and subsequent immunological antitumor responses.

The pRb-related protein p130 is a possible effector of transforming growth factor beta 1 induced cell cycle arrest in keratinocytes.

Transforming growth factor beta 1 (TGF-beta 1) is known to inhibit epithelial cell growth by inducing a G1 cell cycle arrest. We have studied the effect of TGF-beta 1 on protein binding to a transcription factor E2F consensus element in extracts from early passage human keratinocytes (HFKs) and a permanent human keratinocyte cell line (HaCaT). Treatment of these cells with TGF-beta 1 resulted in the formation of a DNA binding complex between the pRb-related protein p130 and E2F. Formation of the E2F-p130 complex correlated with inhibition of cell cycle progression in G1 and suppression of the E2F-regulated cdc2 gene. While p130 mRNA and protein levels were not influenced by TGF-beta 1, the activity of cyclin-dependent kinase 2 (Cdk2) towards p130 in vitro was inhibited. The results identify p130 as a downstream target of TGF-beta 1 and a possible mediator of the G1 cell cycle arrest.

A complex between E2F and the pRb-related protein p130 is specifically targeted by the simian virus 40 large T antigen during cell transformation.

The p130 protein is a recently cloned member of the retinoblastoma protein family. We show here that transformation of NIH3T3-L1 fibroblasts (L1 cells) by the simian virus 40 large T antigen (LTAg) depends on the disruption of DNA binding complexes between transcription factor E2F and p130. LTAg binds to the pocket region of p130 in vivo and disrupts the E2F-p130 complexes. E2F-p130 complexes are present only in quiescent L1 cells and disappear at the G1/S phase boundary concomitantly to induction of DNA synthesis and expression of the E2F-regulated cdc2 gene. p130 is a substrate of cyclin-dependent kinase 2 (Cdk2) in vitro and associates with a Cdk in vivo which is activated upon serum stimulation in late G1. Overexpression of p130 inhibits cdc2 promoter activity and entry of quiescent L1 cells into S phase. The results demonstrate that p130 is negative regulator of cell cycle progression which is specifically targeted by LTAg during cell transformation.

Ultraviolet B irradiation-induced G2 cell cycle arrest in human keratinocytes by inhibitory phosphorylation of the cdc2 cell cycle kinase.

In response to genotoxic stress, cell cycle progression can be arrested at certain checkpoints which serve to maintain genomic integrity. We have investigated the mechanism of ultraviolet B (UVB) irradiation-induced cell cycle arrest in normal human keratinocytes and in the HaCaT keratinocyte cell line which carries mutant p53 tumour suppressor protein. While only normal keratinocytes showed a delay in G1 following sublethal UVB irradiation both cell types exhibited prolonged G2 arrest attributable to rapid inhibition of cyclin B-associated cdc2 kinase activity. This inhibition coincided with increased tyrosine phosphorylation of cdc2 and was reversed by the cdc25C phosphatase in vitro. The data indicate that UVB-induced G2 arrest in mammalian cells is mediated by inhibitory tyrosine phosphorylation of cdc2 and acts as a defense mechanism against DNA damage irrespective of the cells' p53 status.

Phototesting in lupus erythematosus.

Ultraviolet (UV) irradiation is a major factor in the pathogenesis of certain variants of cutaneous lupus erythematosus. Photosensitivity constitutes one of the criteria of the American Rheumatism Association for the diagnosis of systemic lupus erythematosus, which further emphasizes its importance. The pathomechanism of UV-induced lupus erythematosus remains unknown. The characterization of photosensitive subacute cutaneous lupus erythematosus (SCLE) by Gilliam and Sontheimer has led to a new approach. Through the development of standardized test methods it has became possible to reproduce cutaneous lesions in the UV-A and UV-B spectrum. These standardized test methods allow a better definition of photosensitivity than clinical history does. Recent clinical data show that besides SCLE another variant, lupus erythematosus tumidus, also reveals pronounced photosensitivity. In this review article phototest procedures, phototest results, and clinical correlations in different subgroups are discussed.

Circulating T- and B-cell abnormalities in cutaneous lupus erythematosus.

Seven patients with subacute cutaneous lupus erythematosus (SCLE), 11 patients with discoid lupus erythematosus (DLE), and 17 age-, sex-, and race-matched controls were examined for the number of circulating peripheral blood T and B cells, immunoglobulin (Ig) synthesizing cells, and Ig secreting cells. A significant alteration in T-cell subsets was detected only in SCLE patients who manifested a decreased number of OKT8 cells. Circulating B cells were significantly increased only in the SCLE patients. The percentage of Ig synthesizing and secreting cells was significantly increased in both the DLE and the SCLE groups. The somewhat unexpected increase in Ig synthesizing and secreting cells in the DLE patients could not be accounted for by antimalarial treatment or the concurrence of the HLA-DR3 phenotype. There was, however, a weak but significant correlation between the degree of B-cell activation in the DLE patients and the number of American Rheumatism Association criteria for the classification of systemic lupus erythematosus (SLE) possessed by these patients. These data demonstrate that abnormalities in B-cell function similar to those seen in SLE can also be found in a group of lupus erythematosus patients whose clinical disease expression is limited predominantly to the skin.

Specific induction of metallothionein in hairless mouse skin by zinc and dexamethasone.

The stimulation of metallothionein (MT) synthesis in mouse skin after i.p. treatments with various doses of dexamethasone or zinc was demonstrated. Specific MT mRNA induction was determined by Northern analysis. Zinc was a more efficient inducer than dexamethasone. The maximal MT accumulation occurs after i.p. injections of 50-100 mg dexamethasone/kg body weight. The possible role of MT in the skin is briefly discussed.

Transcriptional activation of endogenous retroviral sequences in human epidermal keratinocytes by UVB irradiation.

Ultraviolet radiation is a pathogenic factor in various diseases, e. g., autoimmune disorders such as lupus erythematosus. On the other hand, endogenous retroviruses are discussed as etiologic agents in lupus erythematosus. Therefore, we investigated the influence of ultraviolet irradiation on expression of human endogenous retroviral sequences and human endogenous retroviral sequence promoter-driven transcription of cellular genes using human epidermal keratinocytes as a model system. First, conserved sequences of endogenous retroviral pol genes were amplified from cellular mRNA by reverse transcriptase polymerase chain reaction with degenerate oligonucleotide primers. Polymerase chain reaction products were hybridized in a reverse dot blot hybridization assay to a representative number of distinct cloned human endogenous retroviral pol fragments. Using this method, we could show that irradiation with 30 mJ per cm2 ultraviolet B activates transcription of various endogenous retroviral pol sequences in primary epidermal keratinocytes as well as in a spontaneously immortalized keratinocyte cell line (HaCaT). Interestingly, some of these sequences were found to be closely related to pol sequences of human endogenous retroviral sequences which have been shown to be expressed in autoimmune patients. Analysis of human endogenous retroviral pol expression in vivo using skin biopsies of lupus erythematosus patients revealed similar activation patterns. In a second approach, ultraviolet B- induced chimeric transcripts were isolated which are initiated by human endogenous retroviral promoters and proceed into cellular sequences using a newly established modified differential display polymerase chain reaction technique. The activation of human endogenous retroviral sequence transcription by ultraviolet B may contribute to the pathogenesis of lupus erythematosus, where inappropriate antigenic presentation of ultraviolet B-induced viral and cellular proteins could stimulate autoantibody production.

Effects of early periods of monocular deprivation and reverse lid suture on the development of Cat-301 immunoreactivity in the dorsal lateral geniculate nucleus (dLGN) of the cat.

During certain sensitive periods early in postnatal life, the anatomical and physiological development of the central visual pathways of cats and monkeys can be affected by the nature of an animal's early visual experience. In the last few years, studies have been started on some of the molecular and biochemical events that underlie the many functional changes induced by early selected visual deprivation in the visual cortex of kittens. In this respect, the monoclonal antibody Cat-301 provides a potentially powerful tool, because it recognizes in the cat dorsal lateral geniculate nucleus (dLGN) a proteoglycan associated with the surface of a particular class of cells, namely Y cells. In the dLGN, the Cat-301 proteoglycan appears late in postnatal development, and it expression has been shown to be experience dependent in both the dLGN and visual cortex (M. Sur, D. Frost, and S. Hockfield, 1988, J. Neurosci. 8:874-882; A. Guimaraes, S. Zaremba, and S. Hockfield, 1990, J. Neurosci. 10:3014-3024). We have explored further the experience-dependent nature of Cat-301 expression in the dLGN with a view to establishing a biochemical correlate of the many functional changes induced by early monocular deprivation and its reversal in the kitten visual system. In addition to demonstrating differences in Cat-301 expression between deprived and nondeprived laminae of the dLGNs of kittens monocularly deprived to only 4 or 5 weeks of age, the magnitude of the laminar difference was found to increase as the period of deprivation was extended. Moreover, monocularly deprived kittens that subsequently received long periods of reverse lid suture exhibited a reversal of the pattern of immunoreactivity, so that the greatest immunoreactivity occurred in laminae innervated by the initially deprived eye. However, possibly the most surprising and important finding was the extremely low levels of immunoreactivity observed in both A laminae of monocularly deprived animals that had received relatively short periods of reverse lid suture. These data suggest that Y cell development can be drastically altered depending on the time of initiation of the period of reverse lid suture and its duration.