A centrifugally controlled circuit in the avian retina and its possible role in visual attention switching

The isthmo-optic nucleus (ION) is the main source of efferents to the retina in birds. Isthmo-optic neurons project in topographical order on amacrine cells in the ventral parts of the retina, and a subclass of these known as proprioretinal neurons project onto the dorsal retina. We propose that, through the intermediary of the amacrine target cells, activity in the isthmo-optic pathway excites ganglion cells locally in the ventral retina but inhibits those in dorsal regions. This circuit would thereby mediate centrifugally controlled switches in attention between the dorsal retina, involved in feeding, and the more ventral parts, involved in scanning for predators. This hypothesis accounts for a wide range of disparate data from behavior, comparative anatomy, endocrinology, hodology, and neurophysiolog

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Nuclear translocation of components of the neuronal plasma membrane oxidoreductase after oxidative stress and its effects on induction of apoptosis

Mittels Immunocytochemie untersuchten wir die Rolle der fünf Komponenten des Plasmamembran- Oxidoreduktase (PMO) Komplexes, GAPDH, Hsc70, Enolase γ, Aldolase C und Ulip, während des Oxidativen Stresses und in der Apoptose. Um die Rolle dieser fünf Proteine, welche von unserer Forschungsgruppe isoliert worden waren, zu erforschen, machten wir uns die Konfokal Laser Scanning Microscopie zu nutze. Darüberhinaus wurden Zellen aus dem Zentral-Nervensystem (ZNS), Maus NB41A3 Neuroblastomen, und Nicht-ZNS Zellen, namentlich R6 Fibroblasten und eine Apoptoseresistente Bcl-2 exprimierende Transfektanten (R6Bcl-2), sowohl transient als auch stabil mit GFP- und BFP-Fusions Konstrukten, die entweder GAPDH, Hsc70, Enolase γ, Aldolase C oder Ulip enthalten, transfektiert. Expression von GAPDH, dem wichtigsten Protein des PMO Komplexes, war vorwiegend im Zellkern in NB41A3 und cytoplasmisch in R6 and R6-Bcl-2 Zellen. Induktion von Apoptose und Oxidativem Stress erhöhte den Import von zelleigenem GAPDH in den Kern. In apoptotischen Zellen war die GAPDH-Expression 3 mal höher als in nicht-apoptotischen. Zellen, in denen GAPDH gekoppelt an GFP überexprimiert wurde, waren per se zu 10% apoptotisch und erhöhten den Zellkern-Import von GAPDH-GFP und und die Sensibilität auf durch Staurosporine oder MG132 induzierte Apoptose. Bcl-2 Ueberexpression vermindert den Kern-Import von GAPDH als auch Apoptose in nicht transfektierten, nicht aber in GAPDH-GFP transfektierten Zellen. Kern-Import von zelleigenem Hsc70 oder überexprimiertem Hsc70-GFP wird nur während des Oxidativen Stresses, nicht aber während der Apoptose beobachtet. Ausserdem zeigen Hsc70-GFP überexprimierende Zellen verminderte Anfälligkeit gegenüber Effekten des Oxidativen Stresses, aber nicht gegenüber der Apoptose. Aldolase und überexprimiertes Aldolase-GFP werden vorwiegend in Kernnähe und am Ansatz von Axonen im Cytoplasma exprimiert. Währendem sich die Aldolase-Expression nach Induktion von Oxidativem Stress im Kern erhöhte, wurde sie durch Apoptose weder in Zellen mit noch ohne Aldolase- GFP Ueberexpression beeinflusst. Bei Oxidativem Stress translosziert Ulip vom Cytoplasma in den Kern, währenddem Ulip-GFP auch häufig in intrazellulären Aggregaten zu finden ist. Von den fünf Proteinen des PMO Komplexes, zeigt die cytoplasmische Exxpression von Enolase die geringsten stress-induzierten Veränderungen. Die gleichzeitige Ueberexpression verschiedener dieser PMO Komponenten steigerte den Kern- Import während des Oxidativen Stresses zusätzlich. Wir schliessen aus dieser Studie, dass die Translokation der PMO assozierten Proteine, speziell von GAPDH und Hsc70, eine bedeutende Rolle während der Apoptose und des Oxidativen Stresses spielen. Zudem können die Effekte dieser Proteine bei Ueberexpression scheinbar nicht durch Bcl-2 verhindert werden.The plasma membrane oxidoreductase (PMO) complex may exert important functions in cellular defence mechanism against oxidative stress and in apoptosis. Thus, we aimed to investigate the function of the five proteins GAPDH, Hsc70, enolase γ, aldolase C and Ulip, all of them tightly bound members of a neuronal PMO multi-protein complex, previously isolated and purified from synaptic vesicles and synaptic plasma membranes by our group. Earlier reports have shown an altered subcellular distribution of some these members in both apoptosis and in the cellular response to oxidative stress. We have now extended these studies using confocal laser scanning microscopy in the hope of uncovering clues to the elusive role of these five proteins by immunocytochemistry. Furthermore, CNS-derived cells, the mouse neuroblastoma NB41A3, and non-CNS derived cells, R6 fibroblast and an apoptosis-resistant Bcl-2 expressing transfectant (R6Bcl-2), were transiently and stably transfected with GFP- and BFP-fusion constructs containing either GAPDH, Hsc70, enolase γ, aldolase C or Ulip. Expression of endogenous GAPDH, the major protein associated with the PMO complex, was predominantly nuclear in NB41A3 cells and cytoplasmic in R6 and R6-Bcl-2 cells. Induction of apoptosis and oxidative stress by H2O2 or FeCN enhanced the nuclear translocation of endogenous GAPDH in all cell types. In apoptotic cells, GAPDH expression was 3 times higher as compared to non-apoptotic cells. Consistent with a role of GAPDH in apoptosis, cells transfected by a vector coding for a GAPDH-GFP hybrid increased nuclear import of GAPDH-GFP and conferred a higher sensitivity to induction of apoptosis caused by exposure to staurosporine or MG132. Per se 10% of cells overexpressing GAPDHGFP are apoptotic. Bcl-2 overexpression prevents nuclear translocation of GAPDH and apoptosis in untransfected cells, but not in transfected cells overexpressing GAPDH-GFP fusion protein. Hsc70 is localised in the cytoplasm of neuroblastomas and fibroblasts. Partial translocation of endogenous Hsc70 into the nucleus is induced by oxidative stress, but not by apoptosis. The predominantly cytoplasmic localisation of overexpressed Hsc70-GFP in unstressed cells and its subsequent translocation into the nucleus after oxidative stress is similar to what is observed with endogenous Hsc70. Overexpression of Hsc70 makes cells more resistant to oxidative stress. However, in cells exposed to MG132 or staurosporine, no nuclear translocation of Hsc70-GFP is observed and no indications of a protective function of Hsc70 against apoptosis are found. Aldolase and overexpressed aldolase-GFP, which are present both in a soluble and in a cytoskeleton bound form, are expressed predominantly in the cytoplasm of unstressed cells. The expression is highest at the perinuclear area and in the somal area at the bases of axons. Induction of oxidative stress leads to enhanced nuclear expression of endogenous aldolase in NB41A3 cells. The cellular response to apoptosis induced by MG132 or staurosporine is not influenced by overexpression of aldolase-GFP, suggesting that aldolase C does not have a crucial function during apoptosis. Translocation of endogenous Ulip from the cytoplasm to the nucleus in response to oxidative stress is observed in NB41A3 and in R6 cells. In transfected cells overexpressed Ulip-GFP is also imported into the nucleus during oxidative stress, but it is still expressed predominantly in the cytoplasm and often concentrated in Ulip-GFP-positive speckles. 5 Enolase shows the least oxidative stress-induced changes among the five proteins of the PMO complex. The typical cytoplasmic expression of enolase is not significantly altered, except for a slight rise in nuclear enolase-GFP in transfected NB41A3 cells. Finally we were able to show that many combinations between two of the five PMO proteins in double-transfection experiments, enhance differential translocation into the nucleus or into speckles in response to oxidative stress. From this study we conclude, that the translocation of these PMO associated proteins, especially of GAPDH and Hsc70, may be an important event in apoptosis and oxidative stress. Our results also indicate that the effect of these proteins, when they are overexpressed, cannot be counteracted by Bcl-2

Dual role of the NF-kappaB transcription factor in the death of immature neurons

Using the INTERMED, a system for classifying case complexity, the authors evaluated patients admitted to a general internal medicine ward on length of stay (LOS), number of medicines prescribed during the hospital stay, and whether they had received specialist medical consults. Using the patients' INTERMED scores, the authors divided the patients into three clusters of patients: standard (n=41), chronic (n=26), and complex (n=18). A comparison of the three clusters indicated that patients who had scored within the complex cluster were at risk of requiring complex care and an increased LOS. The findings suggest that the INTERMED detects complex patients at admission and may, therefore, be used for early integral case management. Key Words: Case Complexity ; Health Care Utilization