Evaluating positive experiences of very severe dementia patients

We developed a Snoezelen application to promote the wellbeing of people with severe dementia. During a Snoezelen session, patients are provided with positive and pleasurable experiences, through a combination of visual, auditory, olfactory, and haptic stimuli. Because no measure to evaluate appreciation or enjoyment by this target group themselves could be found, a new observation measure was created and compared to existing proxy measures in a visual stimulation study based on the Snoezelen philosophy. This measure contains three domain scales, Attention, Arousal, and Valence; two (Attention and Arousal) were sensitive enough to capture an effect, or at least a trend towards an effect, of stimulus condition. This finding is seen as promising for the further development of these kinds of observational measures for testing designs for and with this target group

Triple faeces test: An effective tool for detection of intestinal parasites in routine clinical practice

Microscopic examination of stool specimens is the cornerstone of detection of intestinal parasites in parasitology laboratories. In Europe, fresh, nonpreserved stool specimens are generally used for examination. Because intestinal parasites are shed intermittently, patients are asked to deliver multiple stool samples for examination. The limitation of this diagnostic approach is that detection of the vegetative stages of protozoa may be missed because of delays in processing and/or low compliance with the request to submit multiple stool samples. To overcome this limitation, a diagnostic test that combines multiple sampling (on 3 consecutive days), a fixative (SAF; sodium acetate acetic acid formalin), a concentration method and an easy-to-use permanent stain (chlorazol black dye) was developed for use in routine clinical practice. The results of the test, called the "Triple Faeces Test" (TFT), were compared with those of the conventional diagnostic method, i.e. ether sedimentation of a single fresh stool specimen. Stool samples from 544 patients were examined. Vials from the TFT-sets were filled by patients precisely according to instructions in 462 of 544 (85%) of the cases. Using the conventional method and the TFT, 106 and 209 patients, respectively, were diagnosed with infection by one or more parasitic species (P <0.005). Pathogenic species were detected by the conventional method and by the TFT in 39 and 94 cases, respectively, and nonpathogenic species were detected in 124 and 288 cases, respectively (P <0.05). Additional costs for the sampling device, laboratory reagents and handling of the TFT were acceptable. The results of this study suggest that the TFT is an effective method for detection of intestinal parasites in stool samples in routine clinical practic

Mecp2 regulates tnfa during zebrafish embryonic development and acute inflammation

Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MECP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2 deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. By contrast, expression of the proinflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in mecp2-null animals during development, representing the earliest developmental phenotype described for MECP2 deficiency to date. Expression of tnfa was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional mecp2. Thus, Mecp2 is required for tnfa expression during zebrafish development and inflammation. Finally, RNA sequencing of mecp2-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes

Atypical E2Fs inhibit tumor angiogenesis

Atypical E2F transcription factors (E2F7 and E2F8) function as key regulators of cell cycle progression and their inactivation leads to spontaneous cancer formation in mice. However, the mechanism of the tumor suppressor functions of E2F7/8 remain obscure. In this study we discovered that atypical E2Fs control tumor angiogenesis, one of the hallmarks of cancer. We genetically inactivated atypical E2Fs in epithelial and mesenchymal neoplasm and analyzed blood vessel formation in three different animal models of cancer. Tumor formation was either induced by application of 7,12-Dimethylbenz(a)anthracene/12-O-Tetradecanoylphorbol-13-acetate or by Myc/Ras overexpression. To our surprise, atypical E2Fs suppressed tumor angiogenesis in all three cancer models, which is in a sharp contrast to previous findings showing that atypical E2Fs promote angiogenesis during fetal development in mice and zebrafish. Real-time imaging in zebrafish displayed that fluorescent-labeled blood vessels showed enhanced intratumoral branching in xenografted E2f7/8-deficient neoplasms compared with E2f7/8-proficient neoplasms. DLL4 expression, a key negative inhibitor of vascular branching, was decreased in E2f7/8-deficient neoplastic cells, indicating that E2F7/8 might inhibit intratumoral vessel branching via induction of DLL4

Hallowell Weekly Register : September 1, 1900

Epithelial cell migration is crucial for the develop- ment and regeneration of epithelial tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the develop- ment of cancer metastasis and tissue fibrosis. Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B- kinase-b and casein kinase-1a and consequently degraded by the proteasome via the SCFbTrCP ubiq- uitin ligase. Failure to degrade RAPGEF2 in epithelial cells results in sustained activity of Rap1 and inhibi- tion of cell migration induced by HGF, a potent metastatic factor. Furthermore, expression of a degradation-resistant RAPGEF2 mutant greatly suppresses dissemination and metastasis of human breast cancer cells. These findings reveal a molecu- lar mechanism regulating migration and invasion of epithelial cells and establish a key direct link be- tween IKKb and cell motility controlled by Rap- integrin signaling

E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1

The E2F family of transcription factors plays an important role in controlling cell-cycle progression. While this is their best-known function, we report here novel functions for the newest members of the E2F family, E2F7 and E2F8 (E2F7/8). We show that simultaneous deletion of E2F7/8 in zebrafish and mice leads to severe vascular defects during embryonic development. Using a panel of transgenic zebrafish with fluorescent-labelled blood vessels, we demonstrate that E2F7/8 are essential for proper formation of blood vessels. Despite their classification as transcriptional repressors, we provide evidence for a molecular mechanism through which E2F7/8 activate the transcription of the vascular endothelial growth factor A (VEGFA), a key factor in guiding angiogenesis. We show that E2F7/8 directly bind and stimulate the VEGFA promoter independent of canonical E2F binding elements. Instead, E2F7/8 form a transcriptional complex with the hypoxia inducible factor 1 (HIF1) to stimulate VEGFA promoter activity. These results uncover an unexpected link between E2F7/8 and the HIF1-VEGFA pathway providing a molecular mechanism by which E2F7/8 control angiogenesis. The EMBO Journal (2012) 31, 3871-3884. doi:10.1038/emboj.2012.231; Published online 17 August 201