Mechanistic and therapeutic implications of angiogenesis in endometriosis

Like tumor metastases, endometriotic implants require neovascularization to proliferate and invade into ectopic sites within the host. Endometrial tissue, with its robust stem cell populations and remarkable regenerative capabilities, is a rich source of proangiogenic factors. Among the most potent and extensively studied of these proteins, vascular endothelial growth factor has emerged as a critical vasculogenic regulator in endometriosis. Accordingly, angiogenesis of the nascent endometriotic lesion has become an attractive target for novel medical therapeutics and strategies to inhibit vascular endothelial growth factor action. Vascular endothelial growth factor gene regulation in endometrial and endometriosis cells by nuclear receptors, other transcription factors, and also by infiltrating immune cells is emphasized. New data showing that oxidative and endoplasmic reticulum stress increase vascular endothelial growth factor expression are provided. Finally, we review the clinical implications of angiogenesis in this condition and propose potential antiangiogenic therapies that may become useful in the control or eradication of endometriotic lesions.

BOLD correlates of EEG alpha phase-locking and the fMRI default mode network

Phase locking or synchronization of brain areas is a key concept of information processing in the brain. Synchronous oscillations have been observed and investigated extensively in EEG during the past decades. EEG oscillations occur over a wide frequency range. In EEG, a prominent type of oscillations is alpha-band activity, present typically when a subject is awake, but at rest with closed eyes. The spectral power of alpha rhythms has recently been investigated in simultaneous EEG/fMRI recordings, establishing a wide-range cortico-thalamic network. However, spectral power and synchronization are different measures and little is known about the correlations between BOLD effects and EEG synchronization. Interestingly, the fMRI BOLD signal also displays synchronous oscillations across different brain regions. These oscillations delineate so-called resting state networks (RSNs) that resemble the correlation patterns of simultaneous EEG/fMRI recordings. However, the nature of these BOLD oscillations and their relations to EEG activity is still poorly understood. One hypothesis is that the subunits constituting a specific RSN may be coordinated by different EEG rhythms. In this study we report on evidence for this hypothesis. The BOLD correlates of global EEG synchronization (GFS) in the alpha frequency band are located in brain areas involved in specific RSNs, e.g. the 'default mode network'. Furthermore, our results confirm the hypothesis that specific RSNs are organized by long-range synchronization at least in the alpha frequency band. Finally, we could localize specific areas where the GFS BOLD correlates and the associated RSN overlap. Thus, we claim that not only the spectral dynamics of EEG are important, but also their spatio-temporal organization.

Swimming as a model of task-specific locomotor retraining after spinal cord injury in the rat

BACKGROUND: The authors have shown that rats can be retrained to swim after a moderately severe thoracic spinal cord contusion. They also found that improvements in body position and hindlimb activity occurred rapidly over the first 2 weeks of training, reaching a plateau by week 4. Overground walking was not influenced by swim training, suggesting that swimming may be a task-specific model of locomotor retraining. OBJECTIVE: To provide a quantitative description of hindlimb movements of uninjured adult rats during swimming, and then after injury and retraining. METHODS: The authors used a novel and streamlined kinematic assessment of swimming in which each limb is described in 2 dimensions, as 3 segments and 2 angles. RESULTS: The kinematics of uninjured rats do not change over 4 weeks of daily swimming, suggesting that acclimatization does not involve refinements in hindlimb movement. After spinal cord injury, retraining involved increases in hindlimb excursion and improved limb position, but the velocity of the movements remained slow. CONCLUSION: These data suggest that the activity pattern of swimming is hardwired in the rat spinal cord. After spinal cord injury, repetition is sufficient to bring about significant improvements in the pattern of hindlimb movement but does not improve the forces generated, leaving the animals with persistent deficits. These data support the concept that force (load) and pattern generation (recruitment) are independent and may have to be managed together with respect to postinjury rehabilitation.

About the role of visual field defects in pure alexia

Pure alexia is an acquired reading disorder characterized by a disproportionate prolongation of reading time as a function of word length. Although the vast majority of cases reported in the literature show a right-sided visual defect, little is known about the contribution of this low-level visual impairment to their reading difficulties. The present study was aimed at investigating this issue by comparing eye movement patterns during text reading in six patients with pure alexia with those of six patients with hemianopic dyslexia showing similar right-sided visual field defects. We found that the role of the field defect in the reading difficulties of pure alexics was highly deficit-specific. While the amplitude of rightward saccades during text reading seems largely determined by the restricted visual field, other visuo-motor impairments-particularly the pronounced increases in fixation frequency and viewing time as a function of word length-may have little to do with their visual field defect. In addition, subtracting the lesions of the hemianopic dyslexics from those found in pure alexics revealed the largest group differences in posterior parts of the left fusiform gyrus, occipito-temporal sulcus and inferior temporal gyrus. These regions included the coordinate assigned to the centre of the visual word form area in healthy adults, which provides further evidence for a relation between pure alexia and a damaged visual word form area. Finally, we propose a list of three criteria that may improve the differential diagnosis of pure alexia and allow appropriate therapy recommendations.

High-resolution paleoclimatology of the last millennium: a review of current status and future prospects

This review of late-Holocene palaeoclimatology represents the results from a PAGES/CLIVAR Intersection Panel meeting that took place in June 2006. The review is in three parts: the principal high-resolution proxy disciplines (trees, corals, ice cores and documentary evidence), emphasizing current issues in their use for climate reconstruction; the various approaches that have been adopted to combine multiple climate proxy records to provide estimates of past annual-to-decadal timescale Northern Hemisphere surface temperatures and other climate variables, such as large-scale circulation indices; and the forcing histories used in climate model simulations of the past millennium. We discuss the need to develop a framework through which current and new approaches to interpreting these proxy data may be rigorously assessed using pseudo-proxies derived from climate model runs, where the `answer' is known. The article concludes with a list of recommendations. First, more raw proxy data are required from the diverse disciplines and from more locations, as well as replication, for all proxy sources, of the basic raw measurements to improve absolute dating, and to better distinguish the proxy climate signal from noise. Second, more effort is required to improve the understanding of what individual proxies respond to, supported by more site measurements and process studies. These activities should also be mindful of the correlation structure of instrumental data, indicating which adjacent proxy records ought to be in agreement and which not. Third, large-scale climate reconstructions should be attempted using a wide variety of techniques, emphasizing those for which quantified errors can be estimated at specified timescales. Fourth, a greater use of climate model simulations is needed to guide the choice of reconstruction techniques (the pseudo-proxy concept) and possibly help determine where, given limited resources, future sampling should be concentrated.

Ctp1 and the MRN-complex are required for endonucleolytic Rec12 removal with release of a single class of oligonucleotides in fission yeast

DNA double-strand breaks (DSBs) are formed during meiosis by the action of the topoisomerase-like Spo11/Rec12 protein, which remains covalently bound to the 5' ends of the broken DNA. Spo11/Rec12 removal is required for resection and initiation of strand invasion for DSB repair. It was previously shown that budding yeast Spo11, the homolog of fission yeast Rec12, is removed from DNA by endonucleolytic cleavage. The release of two Spo11 bound oligonucleotide classes, heterogeneous in length, led to the conjecture of asymmetric cleavage. In fission yeast, we found only one class of oligonucleotides bound to Rec12 ranging in length from 17 to 27 nucleotides. Ctp1, Rad50, and the nuclease activity of Rad32, the fission yeast homolog of Mre11, are required for endonucleolytic Rec12 removal. Further, we detected no Rec12 removal in a rad50S mutant. However, strains with additional loss of components localizing to the linear elements, Hop1 or Mek1, showed some Rec12 removal, a restoration depending on Ctp1 and Rad32 nuclease activity. But, deletion of hop1 or mek1 did not suppress the phenotypes of ctp1Delta and the nuclease dead mutant (rad32-D65N). We discuss what consequences for subsequent repair a single class of Rec12-oligonucleotides may have during meiotic recombination in fission yeast in comparison to two classes of Spo11-oligonucleotides in budding yeast. Furthermore, we hypothesize on the participation of Hop1 and Mek1 in Rec12 removal.

Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel

Gastro-intestinal nematodes in ruminants, especially Haemonchus contortus, are a global threat to sheep and cattle farming. The emergence of drug resistance, and even multi-drug resistance to the currently available classes of broad spectrum anthelmintics, further stresses the need for new drugs active against gastro-intestinal nematodes. A novel chemical class of synthetic anthelmintics, the Amino-Acetonitrile Derivatives (AADs), was recently discovered and the drug candidate AAD-1566 (monepantel) was chosen for further development. Studies with Caenorhabditis elegans suggested that the AADs act via nicotinic acetylcholine receptors (nAChR) of the nematode-specific DEG-3 subfamily. Here we identify nAChR genes of the DEG-3 subfamily from H. contortus and investigate their role in AAD sensitivity. Using a novel in vitro selection procedure, mutant H. contortus populations of reduced sensitivity to AAD-1566 were obtained. Sequencing of full-length nAChR coding sequences from AAD-susceptible H. contortus and their AAD-1566-mutant progeny revealed 2 genes to be affected. In the gene monepantel-1 (Hco-mptl-1, formerly named Hc-acr-23H), a panel of mutations was observed exclusively in the AAD-mutant nematodes, including deletions at intron-exon boundaries that result in mis-spliced transcripts and premature stop codons. In the gene Hco-des-2H, the same 135 bp insertion in the 5' UTR created additional, out of frame start codons in 2 independent H. contortus AAD-mutants. Furthermore, the AAD mutants exhibited altered expression levels of the DEG-3 subfamily nAChR genes Hco-mptl-1, Hco-des-2H and Hco-deg-3H as quantified by real-time PCR. These results indicate that Hco-MPTL-1 and other nAChR subunits of the DEG-3 subfamily constitute a target for AAD action against H. contortus and that loss-of-function mutations in the corresponding genes may reduce the sensitivity to AADs.