Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

Ctp1CtIP and Rad32Mre11 nuclease activity are required for Rec12Spo11 removal, but Rec12Spo11 removal is dispensable for other MRN-dependent meiotic functions

The evolutionarily conserved Mre11/Rad50/Nbs1 (MRN) complex is involved in various aspects of meiosis. Whereas available evidence suggests that the Mre11 nuclease activity might be responsible for Spo11 removal in Saccharomyces cerevisiae, this has not been confirmed experimentally. This study demonstrates for the first time that Mre11 (Schizosaccharomyces pombe Rad32(Mre11)) nuclease activity is required for the removal of Rec12(Spo11). Furthermore, we show that the CtIP homologue Ctp1 is required for Rec12(Spo11) removal, confirming functional conservation between Ctp1(CtIP) and the more distantly related Sae2 protein from Saccharomyces cerevisiae. Finally, we show that the MRN complex is required for meiotic recombination, chromatin remodeling at the ade6-M26 recombination hot spot, and formation of linear elements (which are the equivalent of the synaptonemal complex found in other eukaryotes) but that all of these functions are proficient in a rad50S mutant, which is deficient for Rec12(Spo11) removal. These observations suggest that the conserved role of the MRN complex in these meiotic functions is independent of Rec12(Spo11) removal.

Percutaneous closure of patent foramen ovale in cryptogenic embolism

BACKGROUND The options for secondary prevention of cryptogenic embolism in patients with patent foramen ovale are administration of antithrombotic medications or percutaneous closure of the patent foramen ovale. We investigated whether closure is superior to medical therapy. METHODS We performed a multicenter, superiority trial in 29 centers in Europe, Canada, Brazil, and Australia in which the assessors of end points were unaware of the study-group assignments. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy. The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population. RESULTS The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy group (hazard ratio for closure vs. medical therapy, 0.63; 95% confidence interval [CI], 0.24 to 1.62; P=0.34). Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group (hazard ratio, 0.20; 95% CI, 0.02 to 1.72; P=0.14), and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively (hazard ratio, 0.71; 95% CI, 0.23 to 2.24; P=0.56). CONCLUSIONS Closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT00166257.).

Skin cancer education for general practitioners is recommended

Hautkrebs-Schulung für Hausärzte ist sinnvoll

Dissecting the Interaction between p53 and TRIM24

Dissecting the Interaction of p53 and TRIM24 Aundrietta DeVan Duncan Supervisory Professor, Michelle Barton, Ph.D. p53, the “guardian of the genome”, plays an important role in multiple biological processes including cell cycle, angiogenesis, DNA repair and apoptosis. Because it is mutated in over 50% of cancers, p53 has been widely studied in established cancer cell lines. However, little is known about the function of p53 in a normal cell. We focused on characterizing p53 in normal cells and during differentiation. Our lab recently identified a novel binding partner of p53, Tripartite Motif 24 protein (TRIM24). TRIM24 is a member of the TRIM family of proteins, defined by their conserved RING, B-box, and coiled coil domains. Specifically, TRIM24 is a member of the TIF1 subfamily, which is characterized by PHD and Bromo domains in the C-terminus. Between the Coiled-coil and PHD domain is a linker region, 437 amino acids in length. This linker region houses important functions of TRIM24 including it’s site of interaction with nuclear receptors. TRIM24 is an E3-ubiquitin ligase, recently discovered to negatively regulate p53 by targeting it for degradation. Though it is known that Trim24 and p53 interact, it is not known if the interaction is direct and what effect this interaction has on the function of TRIM24 and p53. My study aims to elucidate the specific interaction domains of p53 and TRIM24. To determine the specific domains of p53 required for interaction with TRIM24, we performed co-immuoprecipitation (Co-IP) with recombinant full-length Flag-tagged TRIM24 protein and various deletion constructs of in vitro translated GST-p53, as well as the reverse. I found that TRIM24 binds both the carboxy terminus and DNA binding domain of p53. Furthermore, my results show that binding is altered when post-translational modifications of p53 are present, suggesting that the interaction between p53 and TRIM24 may be affected by these post-translational modifications. To determine the specific domains of TRIM24 required for p53 interaction, we performed GST pull-downs with in vitro translated, Flag-TRIM24 protein constructs and recombinant GST-p53 protein purified from E. coli. We found that the Linker region is sufficient for interaction of p53 and TRIM24. Taken together, these data indicate that the interaction between p53 and TRIM24 does occur in vitro and that interaction may be influenced by post-translational modifications of the proteins.

Dermatology in the immunosuppressed patient

This anniversary book gives an animated description of the first one hundred years of the Swiss Society of Dermatology and Venereology (SSDV – SGDV). The approximately 60 authors write from the subjective perspective of the contemporary witness and thus create a vibrant picture of their field and the times in which we live. “Spirit and Soul of Swiss Dermatology and Venereology 1913 – 2013” is therefore an ideal companion to the medical history book “Dermatologie und Venerologie in der Schweiz – ein historischer Rückblick” (2002 Editions Alphil, ISBN 2-940235-08-2), published in 2003 by the SSDV – SGDV for its 90th anniversary. The anniversary edition for the centennial is written in English in order to make the history of the SSDV – SGDV accessible to a larger international public. The introductory chapter is written in all four national languages (German, French, Italian, and Romansh) and also translated into English. It is followed by chapters about the university and non-university public dermatology and venereology departments, the memoirs of those presidents still living, and the depiction of the numerous sub-disciplines of dermatology. Further important chapters include a large contribution on the beginnings of dermatological research in Switzerland, a series of pieces on medical education and continuing education, and finally an overview of healthcare politics in Switzerland. Our friends in Germany, Austria, France, Italy and the USA have provided the outside perspective on Swiss dermatology and venereology in their essays. All in all an informative and entertaining overview of a very diverse medical specialty has been created, which combines historical facts with dynamic insights into this topical field and the current political healthcare framework.

The Dissociation of Location and Object Working Memory using fMRI and MEG

Visual working memory (VWM) involves maintaining and processing visual information, often for the purpose of making immediate decisions. Neuroimaging experiments of VWM provide evidence in support of a neural system mainly involving a fronto-parietal neuronal network, but the role of specific brain areas is less clear. A proposal that has recently generated considerable debate suggests that a dissociation of object and location VWM occurs within the prefrontal cortex, in dorsal and ventral regions, respectively. However, re-examination of the relevant literature presents a more robust distribution suggestive of a general caudal-rostral dissociation from occipital and parietal structures, caudally, to prefrontal regions, rostrally, corresponding to location and object memory, respectively. The purpose of the present study was to identify a dissociation of location and object VWM across two imaging methods (magnetoencephalography, MEG, and functional magnetic imaging, fMRI). These two techniques provide complimentary results due the high temporal resolution of MEG and the high spatial resolution of fMRI. The use of identical location and object change detection tasks was employed across techniques and reported for the first time. Moreover, this study is the first to use matched stimulus displays across location and object VWM conditions. The results from these two imaging methods provided convergent evidence of a location and object VWM dissociation favoring a general caudal-rostral rather than the more common prefrontal dorsal-ventral view. Moreover, neural activity across techniques was correlated with behavioral performance for the first time and provided convergent results. This novel approach of combining imaging tools to study memory resulted in robust evidence suggesting a novel interpretation of location and object memory. Accordingly, this study presents a novel context within which to explore the neural substrates of WM across imaging techniques and populations.

Parenting Pioneers and Parenting Teams: Strengthening Extended Family Ties in Family Support

Starting with the premise that extended family members often have great influence on family functioning, this article describes social work practice techniques for helping families utilize resources available in the extended family network. Two key concepts are presented: "parenting pioneers," who, while attempting newly learned parenting skills, may struggle with resistance from extended family members; and "parenting teams," in which the focal family is giving to or receiving from extended family members substantial family support. The article presents these practice techniques in the context of family support services, which are characterized as voluntary, preventive, developmental, and based in the concept of empowerment and the ecological perspective.

Family Preservation Journal, 1997, Volume 2, Issue 1. (Entire issue)

Entire issue (large pdf file) Articles include: What's Working in Family-Based Services?--or, What's Left to Believe in During a Time of Such Doubt? Roger Friedman The Family Preservation Philosophy and Therapy With Lesbian Clients. Pamela de Santa Parenting Pioneers and Parenting Teams: Strengthening Extended Family Ties in Family Support Programs. Susan Whitelaw Downs Conceptual Bases of the Planning Process in Family Preservation/Family Support State Plans. June Lloyd

Neural correlate of spatial presence in an arousing and noninteractive virtual reality: an EEG and psychophysiology study

Using electroencephalography (EEG), psychophysiology, and psychometric measures, this is the first study which investigated the neurophysiological underpinnings of spatial presence. Spatial presence is considered a sense of being physically situated within a spatial environment portrayed by a medium (e.g., television, virtual reality). Twelve healthy children and 11 healthy adolescents were watching different virtual roller coaster scenarios. During a control session, the roller coaster cab drove through a horizontal roundabout track. The following realistic roller coaster rides consisted of spectacular ups, downs, and loops. Low-resolution brain electromagnetic tomography (LORETA) and event-related desynchronization (ERD) were used to analyze the EEG data. As expected, we found that, compared to the control condition, experiencing a virtual roller coaster ride evoked in both groups strong SP experiences, increased electrodermal reactions, and activations in parietal brain areas known to be involved in spatial navigation. In addition, brain areas that receive homeostatic afferents from somatic and visceral sensations of the body were strongly activated. Most interesting, children (as compared to adolescents) reported higher spatial presence experiences and demonstrated a different frontal activation pattern. While adolescents showed increased activation in prefrontal areas known to be involved in the control of executive functions, children demonstrated a decreased activity in these brain regions. Interestingly, recent neuroanatomical and neurophysiological studies have shown that the frontal brain continues to develop to adult status well into adolescence. Thus, the result of our study implies that the increased spatial presence experience in children may result from the not fully developed control functions of the frontal cortex.

Localized Epidermal Cysts as a Radiation Recall Phenomenon in a Melanoma Patient Treated with Radiotherapy and the BRAF Inhibitor Vemurafenib

BRAF inhibitors are broadly used for metastatic melanoma with BRAF mutations. Their use results in various cutaneous side effects, such as the development of keratoacanthomas and squamous cell carcinomas. We report a patient with metastatic melanoma treated with vemurafenib who developed dozens of histologically confirmed epidermal cysts within 2 months after initiation of vemurafenib administration. The cystic lesions were observed only in the localized area where a large exophytic melanoma tumor mass had been previously irradiated. Localized epidermal cysts may constitute an unusual radiation recall reaction in patients treated with BRAF inhibitors.