When looking back to nothing goes back to nothing

Previous research showed that the eyes revisit the location in which the stimulus has been encoded when visual or verbal information is retrieved from memory. A recent study showed that this behavior still occurs 1 week after encoding, suggesting that visual, spatial and linguistic information is tightly associated with the oculomotor trace and stored as an integrated memory representation. However, it is yet unclear whether looking behavior simply remains stable between encoding and recall or whether it changes over time in a more fine-tuned manner. Here, we investigate the time course of looking behavior during recall in multiple sessions across 1 week. Participants encoded visual objects presented in one of the four locations on the computer screen. In five sessions during the week after encoding, they performed on a visual memory recall task. During retrieval, participants looked back to the encoding location, but only in the recall sessions within 1 day of encoding. We discuss different explanations for the temporal dynamics of looking behavior during recall, searching for the role of eye movements in memory.

In pediatric lymphoblastic leukemia of B-cell origin, a small population of primitive blast cells is noncycling, suggesting them to be leukemia stem cell candidates

Kinetic investigations in pediatric acute lymphoblastic leukemia (ALL) are based on all blast cells and, therefore, reflect the proliferative characteristics of the predominant immunophenotype of leukemic cells. Nothing is known about proliferation of immunologically defined rare subpopulations of leukemic cells. In this study, mononuclear cells from the bone marrow of 15 children with untreated CD19 B-cell precursor ALL were examined for proliferative features according to the immunophenotype. After exclusion of highly proliferating residual normal hematopoietic cells, ∼ 3% of blast cells were CD19 and showed a low percentage of cells in S-phase assessed by the bromodeoxyuridine labeling index (BrdU-LI): median BrdU-LI, 0.19% [interquartile range (IQR), 0.15-0.40%]. In contrast, a median BrdU-LI of 7.2% (IQR, 5.7-8.8%) was found for the major CD19 blast cell compartment. Staining smears of sorted CD19 cells for CD10 or CD34 revealed a small fraction of CD19CD10 or CD19CD34 blast cells. These cells were almost nonproliferating with a median BrdU-LI of <0.1% (IQR, 0-0.2%). This proliferative behavior is suggestive of a stem/progenitor cell function and, in addition, the low proliferative activity might render them more resistant to an antiproliferation-based chemotherapy. However, xenotransplantation experiments will be necessary to demonstrate a possible stem cell function.

Nursing the fatherland? Hohenzollern statebuilding and the hidden transcript of political resistance in Hanoverian female charity during the Second German Empire

In summer 1866 the Austro-Prussian struggle for supremacy in Germany erupted into open conflict. King Georg V of Hanover sided with other governments loyal to the German Confederation against Prussia, but after initially defeating Prussian forces at Langensalza, he was forced to capitulate. Two days after the battle, on June 29, 1866, the widow of the Hanoverian general Sir Georg Julius von Hartmann told her daughter in no uncertain terms how she felt about the Prussian government and its allies. In her opinion they were nothing more than “robber states” that cloaked their disregard for the Ten Commandments in sanctimonious public displays of piety. “These Protestant Jesuits,” she continued, “offend me more than the Catholic ones. You know that I am German with all my heart and love my Germany, but I cannot consider them genuine Germans anymore because they only want to make Germany Prussian.”

Putative functions of extracellular matrix glycoproteins in secondary palate morphogenesis

Cleft palate is a common birth defect in humans. Elevation and fusion of paired palatal shelves are coordinated by growth and transcription factors, and mutations in these can cause malformations. Among the effector genes for growth factor signaling are extracellular matrix (ECM) glycoproteins. These provide substrates for cell adhesion (e.g., fibronectin, tenascins), but also regulate growth factor availability (e.g., fibrillins). Cleft palate in Bmp7 null mouse embryos is caused by a delay in palatal shelf elevation. In contrast, palatal shelves of Tgf-β3 knockout mice elevate normally, but a cleft develops due to their failure to fuse. However, nothing is known about a possible functional interaction between specific ECM proteins and Tgf-β/Bmp family members in palatogenesis. To start addressing this question, we studied the mRNA and protein distribution of relevant ECM components during secondary palate development, and compared it to growth factor expression in wildtypewild type and mutant mice. We found that fibrillin-2 (but not fibrillin-1) mRNA appeared in the mesenchyme of elevated palatal shelves adjacent to the midline epithelial cells, which were positive for Tgf-β3 mRNA. Moreover, midline epithelial cells started expressing fibronectin upon contact of the two palatal shelves. These findings support the hypothesis that fibrillin-2 and fibronectin are involved in regulating the activity of Tgf-β3 at the fusing midline. In addition, we observed that tenascin-W (but not tenascin-C) was misexpressed in palatal shelves of Bmp7-deficient mouse embryos. In contrast to tenascin-C, tenascin-W secretion was strongly induced by Bmp7 in embryonic cranial fibroblasts in vitro. These results are consistent with a putative function for tenascin-W as a target of Bmp7 signaling during palate elevation. Our results indicate that distinct ECM proteins are important for morphogenesis of the secondary palate, both as downstream effectors and as regulators of Tgf-β/Bmp activity.

Eukaryotic translation elongation factor 1A (eEF1A) domain I from S. cerevisiae is required but not sufficient for inter-species complementation

Ethanolamine phosphoglycerol (EPG) is a protein modification attached exclusively to eukaryotic elongation factor 1A (eEF1A). In mammals and plants, EPG is linked to conserved glutamate residues located in eEF1A domains II and III, whereas in the unicellular eukaryote Trypanosoma brucei, only domain III is modified by a single EPG. A biosynthetic precursor of EPG and structural requirements for EPG attachment to T. brucei eEF1A have been reported, but nothing is known about the EPG modifying enzyme(s). By expressing human eEF1A in T. brucei, we now show that EPG attachment to eEF1A is evolutionarily conserved between T. brucei and Homo sapiens. In contrast, S. cerevisiae eEF1A, which has been shown to lack EPG is not modified in T. brucei. Furthermore, we show that eEF1A cannot functionally complement across species when using T. brucei and S. cerevisiae as model organisms. However, functional complementation in yeast can be obtained using eEF1A chimera containing domains II or III from other species. In contrast, yeast domain I is strictly required for functional complementation in S. cerevisiae.

Distribution of RTX toxin genes in strains of [Actinobacillus] rossii and [Pasteurella] mairii

Strains of [Actinobacillus] rossii, [Pasteurella] mairii and [Pasteurella] aerogenes can be isolated from abortion in swine. The RTX toxin Pax has previously been found only in those [P.] aerogenes strains isolated from abortion. Nothing is known about RTX toxins in field isolates of the other two species. To gain insight into the distribution of selected RTX toxin genes and their association with abortion, PCR screening for the pax, apxII and apxIII operons on 21 [A.] rossii and seven [P.] mairii isolates was done. Since species can be phenotypically misidentified, the study was backed up by a phylogenetic analysis of all strains based on 16S rRNA, rpoB and infB genes. The pax gene was detected in all [P.] mairii but not in [A.] rossii strains. No apx genes were found in [P.] mairii but different gene combinations for apx were detected in [A.] rossii strains. Most of these strains were positive for apxIII, either alone or in combination with apxII. Whereas pax was found to be associated to strains from abortion no such indication could be found with apx in [A.] rossii strains. Phylogenetically [A.] rossii strains formed a heterogeneous cluster separated from Actinobacillus sensu stricto. [P.] mairii strains clustered with [P.] aerogenes but forming a separate branch. The fact that [P.] aerogenes, [P.] mairii and [A.] rossii can phylogenetically clearly be identified and might contain distinct RTX toxin genes allows their proper diagnosis and will further help to investigate their role as pathogens.

Opinions on registering trial details: a survey of academic researchers

BACKGROUND: The World Health Organization (WHO) has established a set of items related to study design and administrative information that should build the minimum set of data in a study register. A more comprehensive data set for registration is currently developed by the Ottawa Group. Since nothing is known about the attitudes of academic researchers towards prospective study registration, we surveyed academic researchers about their opinion regarding the registration of study details proposed by the WHO and the Ottawa Group. METHODS: This was a web-based survey of academic researchers currently running an investigator-initiated clinical study which is registered with clinicaltrials.gov. In July 2006 we contacted 1299 principal investigators of clinical studies by e-mail explaining the purpose of the survey and a link to access a 52-item questionnaire based on the proposed minimum data set by the Ottawa Group. Two reminder e-mails were sent each two weeks apart. Association between willingness to disclose study details and study phase was assessed using the chi-squared test for trend. To explore the potential influence of non-response bias we used logistic regression to assess associations between factors associated with non-response and the willingness to register study details. RESULTS: Overall response was low as only 282/1299 (22%) principal investigators participated in the survey. Disclosing study documents, in particular the study protocol and financial agreements, was found to be most problematic with only 31% of respondents willing to disclose these publicly. Consequently, only 34/282 (12%) agreed to disclose all details proposed by the Ottawa Group. Logistic regression indicated no association between characteristics of non-responders and willingness to disclose details. CONCLUSION: Principal investigators of non-industry sponsored studies are reluctant to disclose all data items proposed by the Ottawa Group. Disclosing the study protocol and financial agreements was found to be most problematic. Future discussions on trial registration should not only focus on industry but also on academic researchers.

Ischemia-induced up-regulation of heme oxygenase-1 protects from apoptotic cell death and tissue necrosis

BACKGROUND: Tissues are endowed with protective mechanisms to counteract chronic ischemia. Previous studies have demonstrated that endogenous heme oxygenase (HO)-1 may protect parenchymal tissue from inflammation- and reoxygenation-induced injury. Nothing is known, however, on whether endogenous HO-1 also plays a role in chronic ischemia to protect from development of tissue necrosis. The aim of this study is, therefore, to evaluate in vivo whether endogenous HO-1 exerts protection on chronically ischemic musculocutaneous tissue, and whether this protection is mediated by an attenuation of the microcirculatory dysfunction. MATERIALS AND METHODS: In C57BL/6-mice, a chronically ischemic flap was elevated and fixed into a dorsal skinfold chamber. In a second group, tin-protoporphyrin-IX was administrated to competitively block the action of HO-1. Animals without flap elevation served as controls. With the use of intravital fluorescence microscopy, microcirculation, apoptotic cell death, and tissue necrosis were analyzed over a 10-day observation period. The time course of HO-1 expression was determined by Western blotting. RESULTS: Chronic ischemia induced an increase of HO-1 expression, particularly at day 1 and 3. This was associated with arteriolar dilation and hyperperfusion, which was capable of maintaining an adequate capillary perfusion density in the critically perfused central part of the flap, demarcating the distal necrosis. Inhibition of endogenous HO-1 by tin-protoporphyrin-IX completely abrogated arteriolar dilation (44.6 +/- 6.2 microm versus untreated flaps: 71.3 +/- 7.3 microm; P < 0.05) and hyperperfusion (3.13 +/- 1.29 nL/s versus 8.55 +/- 3.56 nL/s; P < 0.05). This resulted in a dramatic decrease of functional capillary density (16 +/- 16 cm/cm(2)versus 84 +/- 31 cm/cm(2); P < 0.05) and a significant increase of apoptotic cell death (585 +/- 51 cells/mm(2)versus 365 +/- 53 cells/mm(2); P < 0.05), and tissue necrosis (73% +/- 5% versus 51% +/- 5%; P < 0.001). CONCLUSION: Thus, our results suggest that chronic ischemia-induced endogenous HO-1 protects ischemically endangered tissue, probably by the vasodilatory action of the HO-1-associated carbon monoxide.

Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

OBJECTIVES We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs). BACKGROUND The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an "all-or-nothing" response but may modify number and duration of AF episodes. METHODS In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up. RESULTS In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 +/- 37% before ablation, 26 +/- 41% directly after ablation, and 10 +/- 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions. CONCLUSIONS The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.

Internationale Kontrolle lokaler Verwaltung in einer Konfliktregion. Das Experiment „Freie Stadt Danzig“ (1920-1939)

The Free City of Danzig was founded by the Allies after World War One to settle the conflict between Poles and Germans as to which territory the town belonged. The League of Nations was designated to be the guarantor of its status. British and American experts and policy advisors saw it as an experiment on the way to new forms of statehood, by means of which nationalism as the founding principle of territorial entities could be overcome. However, the „Free City“ status was rejected by both the city’s inhabitants and German and Polish government agencies, with the result that the League and its local representative, the High Commissioner, were constantly confronted with difficulties in the interpretation of the international treaties and conventions relating to Danzig. In addition, hardly anyone in Danzig, Germany or Poland was interested in the economic and financial situation of the Free City, but were more interested in winning political battles than in the well-being of the city and its inhabitants. As a result, the situation in Danzig became more and more hopeless. The city became increasingly dependent on (illegal) German subsidies, while the High Commissioners generally cared more about their own prestige and that of their home countries than about the interests of the League of Nations. But as no political means of modifying the city’s status had been provided for, nothing changed formally in Danzig until Germany started the Second World War and annexed the city in September 1939. In retrospect, the international control of local government could not contribute to a long-term solution for Danzig. It merely postponed its violent solution for twenty years.