text:
|Home | About | Journals | Submit | Contact Us | Français
The hippocampus is one of the most interesting and studied brain regions because of its involvement in memory functions and its vulnerability in pathological conditions, such as neurodegenerative processes. In the recent years, the increasing availability of Magnetic Resonance Imaging (MRI) scanners that operate at ultra‐high field (UHF), that is, with static magnetic field strength ≥7T, has opened new research perspectives. Compared to conventional high‐field scanners, these systems can provide new contrasts, increased signal‐to‐noise ratio and higher spatial resolution, thus they may improve the visualization of very small structures of the brain, such as the hippocampal subfields. Studying the morphometry of the hippocampus is crucial in neuroimaging research because changes in volume and thickness of hippocampal subregions may be relevant in the early assessment of pathological cognitive decline and Alzheimer's Disease (AD). The present review provides an overview of the manual, semi‐automated and fully automated methods that allow the assessment of hippocampal subfield morphometry at UHF MRI, focusing on the different hippocampal segmentation produced. © 2017 The Authors Hippocampus Published by Wiley Periodicals, Inc.
The hippocampal formation (HF), centerpiece of the medial temporal lobe (MTL), is a complex brain region of enormous interest in research on aging, memory, psychiatric disorders and neurological pathologies such as most notably Alzheimer's disease (AD). The study of volumetry and morphometry of the hippocampus has an important role for neuroimaging, because this region is a focus of structural changes in AD (Laakso et al., 1998; Apostolova et al., 2006), in epilepsy (Cendes et al., 1993; Iglesias et al., 2015), and also in normal aging (Petersen et al., 2000; Frisoni et al., 2008).
The HF is composed of several intricate and packed subregions (see Fig. Fig.1)1) that include the cornu ammonis fields (CA1, CA2, CA3, and CA4), the dentate gyrus (DG) and the subiculum (Duvernoy, 2005). These subregions are known to be involved selectively, non‐uniformly and in complex progression in different psychiatric and neurological disorders (Arnold et al., 1995; Braak and Braak, 1995; Simiæ et al., 1997; De Lanerolle et al., 2003; West et al., 2004; Lucassen et al., 2006; Small et al., 2011), making the information about their structural properties and changes highly desirable to achieve. Unfortunately, each hippocampal subfield measures a very small volume, and the limited spatial resolution obtained by MR systems with magnetic fields lower than 3T does not allow detecting small volumetric differences and subtle changes within these structures.
During the last years, several studies have demonstrated that 7T MR scanners may overcome these limitations. The high‐resolution structural imaging and the excellent image contrast achieved using ultra‐high field (UHF) MR systems allow the accurate depiction of several small brain structures, and the submillimetric resolution imaging achievable at UHF opens new perspectives in clinical research studies (Van Der Kolk et al., 2013; Kraff et al., 2015; van der Zwaag et al., 2016). In addition to the investigation of basal ganglia and brainstem (Cosottini et al., 2014), one of the main research field at 7T is focused on the hippocampus. The high‐resolution imaging is useful in the visualization of hippocampal subfields (Thomas et al., 2008) and in the search for in vivo radiological biomarkers of disease (Parekh et al., 2015). With UHF magnetic resonance imaging (MRI), the quantification of subtle differences in hippocampal strata, such as strata lacunosum‐moleculare and pyramidale of the CA1 (Kerchner et al., 2010), has been proved to be possible. Moreover, the ability of UHF to reveal and visualize noninvasively the endfolial pathway in the HF (Parekh et al., 2015) opens new directions in future studies on hippocampal functions and alterations in neurodegeneration. More than 20 protocols for labelling hippocampal subfields have been already published (de Flores et al., 2015a; Yushkevich et al., 2015a), confirming the increasing interest in the neuroimaging community for in vivo interrogation on the structural and functional disease‐related properties of HF subregions. A number of high‐resolution sequences centered on the MTL have been developed to acquire oblique coronal images, oriented perpendicular to the longitudinal axis of the hippocampus. The submillimetric resolution and the image contrast allow the visualization of internal details of the hippocampus, and the development of anatomical landmarks and geometrical rules to perform manual delineation of HF subfields. Despite subfield segmentation is based on morphological boundaries derived from anatomical atlases, the anatomy of human hippocampus is rather complex and the boundaries between adjacent subfields may be difficult to visualize in vivo. This leads to a certain disagreement in the way HF substructures are identified in the neuroanatomy literature.
The disease‐related modifications in the entire hippocampal morphology have been investigated through MRI, adopting several manual and automated segmentation protocols (de Flores et al., 2015a). Some methods were then quantitatively compared by the EADC‐ADNI work group (Boccardi et al., 2011). Despite the considerable improvements in MRI acquisition techniques and the great number of manual, automated and semi‐automated segmentation protocols developed, a notable between‐study variability still remains, and up to date there are not common set of rules adopted by neuroimaging groups. This heterogeneity regards the number of delineated subfields, which subregions are segmented separately or grouped together, whether the boundary delineation is focused on the hippocampus body only or on its full length, and whether the protocol concerns volumetric or strata thickness issues. An attempt to overcome the lack of consensus protocol on the segmentation of HF subfields was carried out by the Hippocampal Subfields Group (HSG, http://www.hippocampalsubfields.com). This initiative brings together researchers with the aim of characterizing the differences among existing HF subfield segmentation protocols, of identifying why they occur, and of establishing a more unified protocol to segment subfields (Dill et al., 2015).
During the last years, a number of manual and automated protocols have been developed for the segmentation of the entire hippocampus, as extensively reviewed by Konrad et al. (2009) and Dill et al. (2015). Despite the latter includes a brief section on the segmentation techniques for subfields, most of previous effort was actually focused on the segmentation of the entire hippocampal formation. Moreover, the already reviewed methods were developed and tested on data acquired with clinical field strengths, that is up to 3T. MRI data acquired at field strength below 7T have been successfully employed in a number of studies performed on large populations aimed at the identification of reliable biomarkers of pathology based on group analyses, including the noteworthy body of literature related to the ADNI initiative (Weiner et al., 2012). By contrast, UHF MRI, relying on the higher spatial resolution and signal to noise ratio than conventional magnetic fields, is expected to provide more reliable sequences able to give information about the clinical outcome of each single subject. The UHF studies are particularly aiming at the discovery of reliable biomarkers of pathology, requiring extremely high sensitivity and specificity, thus allowing moving MRI toward future personalized medicine. In particular, the presence of new image contrasts, such as susceptibility weighted imaging (SWI) technique, could be really important to identify new measures that can be correlated to AD, as first introduced by Nakada et al. (2008). In the following years, 7T imaging has been proven to be exquisitely sensitive to microscopic iron, and then it could be used to explore iron‐associated neuroinflammatory AD pathology (Zeineh et al., 2015). Additionally, the possibility to derive quantitative susceptibility maps (QSM), reflecting the presence of iron deposits, allows for a direct study of correlations between physical parameters and clinical scores of patients, as demonstrated in a study on Amyotrophic Lateral Sclerosis (Costagli et al., 2016).
The present review has the purpose of providing an overview of the state of the art of HF subfield segmentation methods working at UHF to researchers in the field aiming at exploiting the UHF potential in the assessment of HF subfield involvement in normal aging and pathological conditions. This review can be also intended as a starting point for researchers interested in improving current technical tools for HF subfield measurement or in developing new ones. Different protocols that allow the study of hippocampal subfield volumetry and morphometry using MRI data generated at UHF are presented, including manual, semi‐automated and automated methods. Several high‐resolution sequences targeting the MTL have been set up, allowing for new contrasts, increased signal‐to‐noise ratio and very high spatial resolution. These features drastically improve the capability to visualize HF subregions (Theysohn et al., 2009; Boutet et al., 2014) and to discriminate such submillimetric boundaries and hippocampal cellular strata. Even though UHF MRI may represent an important tool to investigate the early sites of AD pathology, a great deal of effort is required to combine the information obtained from standard imaging techniques, new image weightings and quantitative information achievable at UHF.
An overview of the MRI acquisition characteristics implemented in the different UHF studies targeted on hippocampal subfield segmentation is reported in Table 1. In particular, the field strength, the RF coil specification, the image weighing (T1‐w, T2‐w, T2*‐w), the acquisition sequence parameters (including TR, TE, and flip angle), the image resolution and the total acquisition time are reported.
Several manual methods for both mono‐dimensional and three‐dimensional measures of hippocampal subfields at UHF were developed over time (Tables 2 and 3). The volumetric assessment of hippocampal body substructures was performed in a number of studies (Boutet et al., 2014; Parekh et al., 2015; Santyr et al., 2016). Parekh and colleagues used a balanced steady‐state free precession (bSSFP) sequence for 7T whole brain images with 0.4 × 0.4 × 0.4 mm3 resolution. The final reconstructed and aligned bSSFP volumes were visualized using ITK‐SNAP (www.itksnap.org; Yushkevich et al., 2006) and segmented according to anatomical atlases and prior works (Duvernoy, 2005; Insausti and Amaral, 2008; Yushkevich et al., 2009; Zeineh et al., 2012). They segmented nine subfields: CA1‐4, stratum radiatum and stratum lacunosum‐moleculare (SRLM), alveus, fornix, subiculum and subiculum along with its molecular layer, and a hypointense structure centered in the hilus that resembled the endfolial pathway. Boutet et al. used T2*‐w images with 0.3 × 0.3 × 1.2 mm3 resolution acquired with a GRE sequence to identify hippocampal layers based on their relative amount of neuronal bodies. Manual delineation was done using the object‐based ROI module of the Anatomist software (http://www.brainvisa.info/index.html). Extending the protocol proposed by Henry et al. (2011), they segmented five subregions in the hippocampal body: alveus, SRLM, hilum, stratum pyramidale of CA and stratum pyramidale of the subiculum. They normalized the volume of each subregion to the ipsilateral hippocampal body length, obtaining measures of average cross‐sectional area. The authors demonstrated that hippocampal segmentation at 7T allows the detection of volume loss in specific layers, making it as a promising tool for AD research. Santyr et al. (2016) adapted the 4T subfield delineation protocol proposed by Mueller et al. (2007) and the atlas of Duvernoy (2005) to manually segmented five subfields (subiculum, CA1‐3, and DG+CA4) only in the hippocampal body. The segmentation was made using ITK‐SNAP software on images acquired with a multi gradient echo sequence with 0.5 × 0.5 × 1.5 mm3 resolution, and images were visually inspected for accuracy and edited for additional refinement when necessary. They apply this method in a study on hippocampal subfield volumetry at 7T for the identification of hippocampal sclerosis in temporal lobe epilepsy.
The segmentation of the whole hippocampal formation was made for the first time at UHF by Chupin and colleagues in 2009. They used T2‐w images with in plane resolutions of 0.5 × 0.5 × 1.3 mm3, 0.612 × 0.612 × 1.1 mm3, and 0.612 × 0.612 × 1.2 mm3 to delineate six subparts of the hippocampus: the grey matter of CA1‐3), the stratum moleculare of CA, DG+CA4, the alveus, the fimbria and the subiculum. Successively, Cho et al. (2010) developed a manual method to divide the HF into head, body and tail on 3D T2*‐w images with 0.35 × 0.35 × 0.35 mm3 resolution (Jack et al., 1995; Pantel et al., 2000). The work of Duvernoy was used as a reference for anatomical details (Duvernoy 1998) and the manual tracings were made using two software packages: 3D slicer (http://www.slicer.org) and MRIcro (http://www.sph.sc.edu/comd/rorden/mricro.html). In this study, they compared reliability and sensitivity of the method with those of existing MRI techniques at 1.5T and 3T, clearly demonstrating the superiority of UHF in the boundary detection of the hippocampal head, body and tail. More recently, Wisse et al. performed the HF subregions segmentation along its full length in three works (Wisse et al., 2012, 2014a, 2016a). In the first study, they developed a protocol guided by two atlases (Duvernoy, 2005; Mai et al., 2008) and previous protocols of Knoops et al. (2010) and Goncharova et al. (1990) on T2‐w images with 0.7 × 0.7 × 0.7 mm3 resolution. Using such instruments, they manually outlined CA1‐3, CA4 and DG, subiculum and entorhinal cortex (ERC) and calculated both absolute subfield volumes and volumes normalized to the total intracranial volume [TIV, obtained from the T1‐w 7T sequence, using the tissue segmentation implemented in SPM8 (Ashburner and Friston, 2005)]. Subsequently they extended the segmentation protocol to include the most posterior part of the hippocampal tail (Wisse et al., 2014a), then they compared the volumetric results obtained with this manual protocol with those achieved with a fully automated procedure (Wisse et al., 2016a), as described later in this review. In the second study, analyses of covariance, adjusted for age, sex, and TIV showed that patients with AD had significantly smaller ERC, subiculum, CA1, CA3, and CA4±DG volumes in comparison with controls and MCI patients (Wisse et al., 2014a). Furthermore, the volume of the entire hippocampus has been evaluated as the sum of its subfields in the studies of Cho et al. (2010), Wisse et al. (2012, 2014a) and in Apostolova et al. (2015) (as reported in Tables 2 and 3, where the total hippocampal volume is labelled with "H"). Despite the great effort spent in the segmentation of hippocampal subfields, the comparison of results among different studies and the evaluation of reliability of single layers or whole hippocampal measures are hard. The comparison is mostly limited by the variability of boundary definition between subfields.
One of the first studies to assess the hippocampal body strata thickness in vivo at UHF was carried on by Kerchner et al. (2010). In this study, in addition to the measurement of the whole hippocampal body volume normalized to TIV, the authors developed a method to manually measure the thicknesses of the SRLM (CA1:SRLM) and of the stratum pyramidale of the CA1 (CA1:SP) using a 2D T2*‐w GRE sequence with an in‐plane resolution of 195 μm. On each side of the brain, they made six measurements of the thickness of the stratum at different points along the CA1 subfield, three each on two adjacent slices and then they were averaged. The same method was used for both the measures. In addition, for each stratum they computed the mean thickness from both sides then normalized by dividing for TIV1/3 (Kerchner et al., 2010), showing that such normalization did not influence data interpretation (Kerchner et al., 2012).
Another important application of manual HF subfield segmentation methods is the construction of high‐resolution anatomical atlases using ex vivo data. Ex vivo imaging allows using greater field strength, smaller field of view and longer acquisition time, yielding high‐contrast images with voxels about 100 times smaller in volume than in typical in vivo imaging (Yushkevich et al., 2009). Yushkevich and his group consistently identified four layers in the hippocampus: the stratum oriens and the pyramidal cell layer; the stratum radiatum, stratum lacunosum‐moleculare and the vestigial hippocampal sulcus; the stratum moleculare of the dentate gyrus; and the dentate hilus (CA4). The resulting high‐resolution computational atlas has been considered in other studies as a reference for the segmentation protocols (e.g., Parekh et al., 2015) in addition to the usually used anatomical studies (e.g., Duvernoy, 2005; Amaral and Lavenex, 2007; Insausti and Amaral, 2008). More recently, Iglesias et al. (2015) made precise delineations of 13 HF subregions in 7T ex vivo scans with extraordinary resolution. In addition to the hippocampal subfields, manual tracings for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo images, and they combined this information to obtain a single computational atlas with Bayesian inference. Another work on UHF ex vivo data was carried out by Apostolova et al. (2015). His group performed a manual segmentation of ex vivo temporal lobes scanned at 7T and obtained neuronal counts, β‐amyloid, and tau burden for each hippocampal traced subfield. The hippocampal labels selected for the segmentations of the studies cited above are reported in Tables 2 and 3.
The relevance of the ex‐vivo studies consists in the high precision of the resulting anatomical information and in their applicability, both for the automated segmentation of the hippocampal subregions in structural MRI images and as reliable reference for manual protocols.
Recently, aiming to investigate on hippocampal pathology along the anterior‐posterior extent in patients with temporal lobe epilepsy, Coras et al. 2014 used high‐resolution diffusion tensor imaging and coronal 2D T2‐w images of ex vivo hippocampal specimens. The values of average MRI signal intensity, areas, mean diffusivity, fractional anisotropy and histological measures were evaluated in patients and healthy subjects separately for subfields of CA1, CA2, CA3, and CA4, as identified by pathologist. The group demonstrated that the discrimination among hippocampal subfield pattern based on diffusion data could have diagnostic and prognostic value.
Finally, a recently published study by Wisse et al. (2016b) has presented a manual segmentation of ex vivo images (9.4 T, 0.2 × 0.2 × 0.2 mm3 resolution) to validate hippocampal subfield segmentation technique in vivo. The authors evaluated the ability to match information between in vivo (3T MRI scans) and ex vivo MRI in the same subjects using both rigid and deformable registration. The in vivo and ex vivo scans were registered based on manually outlined outer hippocampal boundaries. The quantitative comparison was based on SRLM thickness measurements in corresponding locations of in vivo and ex vivo scans. The registration achieved was satisfactory, with a median distance of 0.29 mm for the rigid registration, and 0.25 mm for the deformable registration, in both cases below the in vivo voxel size (0.4 × 0.4 mm2 in‐plane). Moreover, comparisons of thickness of the hippocampus and hippocampal subfields between in vivo and ex vivo pairs of images were performed.
Despite the impressive anatomical details depicted with high‐resolution images at UHF, the image analysis has still a great limitation. The majority of hippocampal subfield measurements, in fact, are based on manual method of segmentation. This is a laborious and time‐consuming process (ca. 1 h for scan) that deeply limits the amount of data that can be analyzed. Furthermore, it is affected by intra‐ and inter‐rater variability which sometimes invalidates the subfield boundary delineation and limits the following statistical analysis. Therefore, there is a need for more automation in the segmentation and measurement methods of hippocampal subfield characteristics in order to achieve more reliable and reproducible results. For these reasons, the number of semi‐automated and automated methods for HF subfield characterization is increasing, as reported in the following sections.
We assigned to the category of semi‐automated methods the protocols that require manual intervention involving anatomical knowledge at the beginning, and then proceed without user intervention.
The first semi‐automated method designed to estimate HF subfield measures was published by Kerchner et al. in 2012. In this study, they visually identified hippocampal subfields based on landmarks derived from human atlases (Amaral and Lavenex, 2007; Insausti and Amaral, 2012), and combined a manual measure of DG+CA3 cross‐sectional area and entorhinal cortex (ERC) width. The semi‐automated procedure allowed measuring in vivo the widths of the CA1:SP and of the CA1:SRLM. The SRLM is an extremely thin structure whose width can be assessed only from ultra‐high resolution scans. In fact, they used 7T T2‐w fast spin echo sequence with in‐plane isotropic resolution of 222 μm to optimally view hippocampal cross‐sectional anatomy and to facilitate the quantitative study of strata thickness. In this routine, the user is asked to draw a line through the middle of the region of interest on each slice; then from a fitted spline and a set of orthogonal vectors determined along the spline, the width is measured analyzing the first derivative of the T2 signal intensity. This method was applied for the first time in 2012 and later in 2013 and 2014 to study hippocampal CA1 atrophy in AD (Kerchner and Bernstein 2013; Kerchner et al., 2014). Following the basic ideas of this method, another semi‐automated procedure that estimates the SRLM thickness has been developed and applied to 7T T2*‐w GRE sequence images with in plane resolution of 0.3 × 0.3 mm2 (Retico et al., 2016). Here, a user‐defined line following the shape of the CA1:SRLM is interpolated with a spline, and the SRLM width is calculated from the average intensity curve obtained from many profiles extracted along the vectors normal to the spline.
The approaches briefly explained above lead to extract 1D and 2D measurements from MR images, that is, widths and areas of certain hippocampal subfields, but they do not calculate volumes. During the very last years a semi‐automated volumetric approach has been developed for studying specific human hippocampal subfield functions during associative learning. The approach was based on the use of both high‐resolution 7T fMRI and hippocampal high‐resolution structural scans (HHRs), the latter acquired with a turbo spin echo sequence (Suthana et al., 2015). In this study, the method of computational unfolding was applied to 7T HHRs for segmenting HF in CA 1–3, DG+CA4, subiculum, ERC, perirhinal cortex (PRC) and parahippocampal cortex (PHC). The manual segmentation of the white matter and CSF was mandatory in order to identify 3D grey matter of hippocampal formation and adjacent MTL regions. Using atlases by Insausti and Amaral (2012) and Duvernoy (2005), they automatically assigned the subfield labels to the hippocampal grey matter (computationally unfolded to 2D space using an iterative algorithm). In a second step, they created anatomical 3D regions of interest (ROIs) by projecting the bounded regions from 2D to 3D space, allowing final manual editing if needed. The resulting hippocampal 3D ROIs were used to measure the percent signal changes in blood oxygen level dependent (BOLD) activation in separate subfields of HF.
In the very last years a certain effort to develop and improve fully automated methods for hippocampal subfield segmentation has been spent. Automated methods are based on manually labeled atlases built on high‐resolution images or manually segmented training data inserted by the user. They only require initial configuration and setup but no anatomical initial knowledge is needed on MRI data to perform new segmentations.
Up to date, there are three automated and open‐access methods for HF subfield volumetry: Freesurfer, multiple automatically generated templates (MAGet‐Brain) and automatic segmentation of hippocampus subfields (ASHS) software packages (see Table 4).
The first method is a part of the FreeSurfer open‐source software package (Fischl, 2012, http://freesurfer.net/) and approaches the segmentation problem from a parametric perspective. This algorithm is based on a statistical atlas of hippocampal anatomy and a generative model of MRI data, where the segmentation of the observed image data is carried out by learning the hippocampal subregions from labelled training data (Van Leemput et al., 2009; Iglesias et al., 2015). The original subfield segmentation method, which was implemented in Freesurfer v5.3 and is described in detail in Van Leemput et al. (2009), is based on a probabilistic in vivo atlas generated from MR images with 0.38 × 0.38 × 0.38 mm3 resolution. Despite the high spatial resolution, it was insufficient to label the molecular layer; moreover, the protocol was designed for the hippocampal body only. This software version for hippocampal subfield segmentation has been widely criticized by other research groups (Pluta et al., 2012; Wisse et al., 2014b; de Flores et al., 2015b) and the same Freesurfer authors (http://www.freesurfer.net/fswiki/HippocampalSubfieldSegmentation; Iglesias et al., 2015). Successively, Iglesias and colleagues improved the segmentation method in 2015 with a new version (now implemented in Freesurfer v6.0 and freely available at https://surfer.nmr.mgh.harvard.edu/fswiki/HippocampalSubfields). They built a new atlas using ex vivo 7T images with spatial resolution (0.13 × 0.13 × 0.13 mm3, on average) and signal‐to‐noise ratio strongly higher than those achievable in vivo. The advantage of the resulting atlas (Iglesias et al., 2015) is its applicability within a generative Bayesian framework to directly segment in vivo MR images with various contrast properties. Freesurfer v6.0 has two main modes of operation depending on the input images. First, the segmentation can work only with standard resolution (~1 mm) T1‐w scan available. Second, if an additional MRI volume (e.g., a T2‐w scan, proton density, or even an additional T1‐w scan) covering the hippocampus is available; it can be used to obtain a more reliable segmentation (mainly if resolution is higher than 1 mm, even if anisotropic). In this case, the only requirement is that the additional scan is coarsely aligned to the 1 mm T1‐w scan. Despite the new FreeSurfer method has been developed by using high resolution 7T ex vivo data, its applicability has been validated only on lower field strengths (T1‐w and T2‐w MRI data up to 3T). Although Iglesias et al. (2015) outline the improvements of the new atlas used in Freesurfer v6.0, a number of limitations are reported. In fact, despite the new atlas is based on ultra‐high resolution MRI, some boundaries cannot be seen in the training data, for example the interfaces between the CA fields along the pyramidal layer of the hippocampus, or the interface between the CA4 and the Granule Cell Layer of the DG (DG:GCL). Another potential limitation is that this atlas was built from manual delineations in elderly subjects only, hence it might include data of hippocampal atrophy potentially limiting its applicability in studies on younger populations (Iglesias et al., 2015). In addition, when the atlas was used to segment standard resolution (1 mm) T1‐w MR scans, the molecular layer was not visible. Because the fitting of the internal structure of the atlas relies on this prior information, volumetric results from individual subfields should be interpreted carefully.
Second, Pipitone et al. in 2014 developed MAGeT‐Brain that acts as a multi‐atlas method for the segmentation of the whole hippocampus and its subfields (CA1, CA2‐3, DG+CA4, SRLM, and subiculum) based on a priori knowledge. This technique requires in input a set of manually segmented images (known as the atlas library) to generate a much larger group of automatically segmented images (known as template library). The segmentations are propagated to a subset of the template library (created by sampling either randomly or representatively from the subject images) via image registration and then the labels are combined into a single one by label fusion. When only a single atlas is used, the multi‐atlas segmentation method degenerates into model‐based segmentation technique: labels are propagated from the atlas to the target, without any label fusion step. Although the authors have demonstrated a reliable reproduction of hippocampal subfield segmentations in standard 1.5–3T T1‐w images, the method has never been validated at higher field strengths.
A third automated method has very recently been applied to 7T MRI data (Wisse et al., 2016a). ASHS consists in a combination of multi‐atlas algorithm (non‐parametric and registration‐based) and machine learning techniques. The first version of the method needed prior knowledge to run, hence it was semi‐automated; moreover, it was designed to be used only on high‐resolution anisotropic T2‐w images and was based on the VACIND atlas (Yushkevich et al., 2010, Pluta et al., 2012). The most recent version is fully automated (i.e., it requires no manual initialization), labels hippocampal subfields over a greater anterior‐posterior extent, and delineates the perirhinal cortex which is further subdivided into Brodmann areas 35 and 36 (Upenn PMC atlas, Yushkevich et al., 2015b). ASHS consists of a training pipeline and a segmentation pipeline. The first procedure generates an atlas package requiring in input a set of manually labeled dedicated T2‐w scans and standard whole‐brain T1‐w images. The ASHS segmentation pipeline allows the automated segmentation of hippocampal subfields on the T2‐w MRI scan of a new subject, using the T1‐w MRI as an additional input. Moreover, it allows both volume and thickness analyses. Compared to semi‐automated methods, a great advantage of this software is the possibility to run a completely automated procedure using one of the freely available atlases developed by the authors of ASHS (https://sites.google.com/site/hipposubfields/). Another point of force is that it can be easily re‐trained on a set of scans acquired with a different MRI sequence and labeled with a different segmentation protocol.
To the best of our knowledge, ASHS is the unique fully automated software for HF subfield volumetry that has been applied to UHF MRI in vivo data. This study was recently made by Wisse et al. (2016a) and used ASHS with the aim of comparing automated segmentations of CA1, CA2, CA3, CA2‐3, DG, subiculum, and ERC with the corresponding manual segmentations. As shown in Table 1, their protocol included 0.7 × 0.7 × 0.7 mm3 3D T2‐w TSE and 1.0 × 1.0 × 1.0 mm3 T1‐w sequences and both the acquisitions were used for the segmentation. In this work, a high and competitive accuracy emerged for most subfield segmentations with respect to the labor‐intensive manual segmentation, and their results indicated that there might be a benefit in using 7T data for the segmentation of hippocampal subfields.
All the protocols described above are targeted to the measurement of either volumes or thicknesses of subtle regions of the hippocampus. Despite the use of UHF MR systems allows the accurate depiction of such small brain substructures, a number of uncertainties emerge from the use a nonstandardized set of sequences and image acquisition protocols (see Table 1), from the application of large variety of segmentation methods (see Tables 2 and 3) to identify and measure the HF subfields.
As reported in the study by Yushkevich et al. (2015a), that quantitatively compared 21 segmentation protocols applied both at 3T and 7T images, significant variability exists among the protocols in terms of what labels are used, where the boundaries between substructures are placed, and what extent of the hippocampal region is labeled. That paper offered strong motivations for protocol harmonization and took an important first step in that direction, such as the activity of the HSG (http://www.hippocampalsubfields.com/whitepaper).
In addition to the variability between segmentation protocols, a relevant aspect that limits clinical usability of these methods is the paucity of implementations of reliability assessment procedures. Indeed, intra‐ and inter‐rater reliability evaluations are carried out only by a few of the studies reported here.
Repeat‐measurement reliability was assessed in the in vivo study of Wisse et al. (2012) using Intraclass Correlation Coefficient (ICC) and Dice Similarity Comparison (DSC). The reliability measures are usually reported in terms of ICC and DSC scores. The guidelines for the interpretation of ICC agreement measures (whose range is [0, 1]) indicate excellent agreement for ICC≥0.75 (Cicchetti, 1994). The DSC index quantifies the degree of overlap of two segmented regions at the voxel level, accounting for the region size. Its values are in the [0,1] range, and values greater than 80% are considered satisfactory levels of concordance. Wisse et al. concluded that a good‐to‐excellent consistency was achieved between two manual segmentations of one rater for all subfields (ICC varying from 0.74 to 0.98). Furthermore, accuracy measured with DSC was >0.82 for all subfields, with the exception of the smaller subfield CA3 (0.68–0.70).
Inter‐rater reliability was performed by Cho et al. (2010) with two manual tracers. They evaluated the ICC and the sensitivity (Pantel et al., 2000), which indicates the likelihood of agreement between two raters. These estimations were performed for the same protocol applied at both 7T and 1.5T MR images. Paired sample t‐test was used to assess the significance of the differences in reliability and sensitivity between 7T and 1.5T MRI. At 7T, the ICC ranged from 0.93 to 0.97 and sensitivity ranged from 0.85 to 0.91. Moreover, their results clearly demonstrated better boundary detection for hippocampal head, body and tail at 7T than at lower field MRI (P≤0.05), suggesting the usefulness of UHF MR imaging in the accurate diagnosis of diseases related to hippocampal atrophy.
Intra‐ and inter‐rater reliability were also assessed in the study of Yushkevich et al. (2009), regarding ex vivo MRI at 9.4T. The repeatability of the segmentation in terms of Dice overlap by one rater ranged from 0.56 to 0.92. Inter‐rater reliability ranged from 0.47 to 0.87 and was significantly lower for CA1 and CA23 and approximately the same for other subfields. The authors attributed the lower reliability for CA23 to differences in the extension of the label. Lastly, Iglesias et al. (2015) used seven tracers to construct their atlas from ex vivo MRI data. Because the annotation of each scan required about 60 h, they did perform neither repeat measurements nor inter‐rater reliability, but one expert tracer served as quality control for each case, refining the segmentations where necessary. However, the applicability of this atlas, which has been released as part of FreeSurfer v6.0, was demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results showed that the atlas and companion segmentation method can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1‐w data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and the classification based on whole hippocampal volume (82% accuracy) (Iglesias et al., 2015).
Regarding semi‐automated methods, Kerchner et al. (2012) found a significant correlation between the output of their protocol and manual measures using statistical Pearson correlation (CA1‐SP: r=0.74, P≤0.001; CA1‐SRLM: r=0.75, P≤0.001).
ASHS is the only automated method already applied to UHF MR images. The reliability analysis made by Wisse et al. (2016a) used both DSC and ICC indices to compare manual segmentation of two independent manual tracers and the automated to the corresponding manually segmented regions. About the manual segmentation assessment, the intra‐rater reliability resulted in DSC ranged between 0.66 and 0.87, and ICC ranged between 0.80 and 0.90; on the other hand, the inter‐rater reliability resulted in DSC ranged between 0.57 and 0.82, whereas ICC was very low for the ERC (0.27) but it reached 0.94 for the CA1. ICC and DSC calculated between manual and automated segmentation for each subfield showed that ASHS allowed high accuracy (ICC>0.74 and DSC>0.75) for larger subfields, including CA1, DG, and subiculum, and low accuracy for ERC and smaller subfields, including CA2 and CA3. More in detail, the mean generalized DSC across all subfields was 0.80±0.03 in the left hemisphere and 0.79±0.03 in the right hemisphere. The anterior and posterior boundaries of the ERC were an important source of disagreement between the manual and automated segmentation. The accuracy increased by restricting the range of ERC segmentation, suggesting that the ERC segmentation is accurate except at its anterior and posterior segments. In light of these results, the authors concluded that automated segmentation of hippocampal subfields and the ERC at 7T MRI was feasible and that the errors of automated segmentation were comparable or lower than the disagreement between two manual raters applying the same segmentation protocol.
ASHS has been partially validated in the recent study by Wisse et al. (2016b), where the SRLM surface inferred from ASHS segmentation performed on in vivo 3T images was compared with that obtained from manual ex vivo segmentation (MR acquisition at 9.4 T, see Table 1 for more details). The distance statistics between ASHS‐derived SRLM and ex vivo SRLM was computed using a deformable in vivo to ex vivo alignment. Median surface distance was within a voxel and only 0.1 mm larger than the median distance between manually traced in vivo and ex vivo SRLM surfaces, confirming that ASHS can accurately pick up this anatomical boundary on the in vivo images.
During last years, the increasing number of patients affected by pathological cognitive deterioration has strengthened the interest of researchers in the investigation on hippocampus. The availability of UHF MRI is changing the target of this research. Differently from past approaches, the possibility to obtain high‐resolution images is increasing knowledge on in vivo radiological anatomy of the hippocampus and mainly of the hippocampal subfields.
In the present review, we provided an overview of the neuroimaging studies performed at UHF MRI with the aim of assessing hippocampal subfield morphology and morphometry. We presented the numerous methods for segmentation and measurement of the hippocampal subregions according to (i) the presence of automatism in the procedure, (ii) the segmented subfields, and (iii) the type of subfield measure. In the latest years, the increasing number of MRI systems that operate at UHF has allowed the quantification of volume and thickness of the inner strata of the hippocampus using images with submillimetric resolution. The features of UHF open new perspectives in the identification of radiological biomarkers for AD at its prodromal clinical stage (i.e., the mild cognitive impairment), and in the improvement of diagnostic accuracy of the disease.
When approaching HF assessment, it is important to remember that pathological cognitive decline is most frequent in the elderly population and it is characterized by a pathological brain atrophy, mainly involving frontotemporal lobes. Nevertheless, a para‐physiological brain atrophy takes place over time also in healthy people, but it is usually diffuse and not confined to frontotemporal regions. Therefore, in order to correctly assess abnormal decline trajectories, the age‐related confounding effects should be accounted for in the analysis, in addition to other confounding variables, such as gender. To account for global effects, the measurements of the whole hippocampus and its subfield are sometimes standardized with respect to an anatomical reference, such as TIV (Wisse et al., 2012), or the ipsilateral hippocampal body length in other cases (Boutet et al., 2014), thus assuming a linear scaling between the sizes of the different structures. Other research groups introduced TIV as covariate in statistical analyses of covariance of hippocampal subfield volumes (Wisse et al., 2014a; Santyr et al., 2016). Despite some researchers normalized the thickness of the CA1 pyramidal cell layer and SRLM to the TIV1/3 (Kerchner et al., 2010), it is not proven that such tiny structures scale linearly with head size. However, the choice of the appropriate anatomical reference quantity and the normalization method are not immediately identifiable.
The main issues limiting the comparison of results among studies are: (i) the absence of guidelines for the choice of target hippocampal subfields; (ii) the lack of standardized technical parameters for acquisition protocols; (iii) the absence of a unique anatomical reference; and (iv) the lack of consistency in the data normalization strategy. The recent work of the Hippocampal Subfield Group (HSG, http://www.hippocampalsubfields.com) aimed to address the second issue, and a white paper for harmonization has been developed (http://www.hippocampalsubfields.com/whitepaper) to define the next steps (for additional details, see Yushkevich et al., 2015a). About the third issue, although Zeineh et al. (2012) developed diffusivity‐based rules for hippocampal subfield manual delineation at 3T, the majority of segmentation protocols refers to anatomical studies. The most applied are the anatomical studies of Duvernoy (1998, 2005), then the works of Insausti and Amaral (2008, 2012), of Mai et al. in 2008, and Amaral and Lavenex in 2007. The interest on high‐resolution anatomical atlases using ex vivo data as a gold standard for hippocampal subfield assessment is increasing. The new automated protocols are based on the ex vivo atlases constructed by Yushkevich et al. (2009, 2015b) and employed in ASHS, and on the segmentations of Iglesias et al. (2015) used in Freesurfer. With respect to the forth issues, a growing body of literature is aiming at finding shared guidelines and reliable methods to correctly account for confounding effects occurring in pathological conditions and also in healthy aging (Edland et al., 2002; Barnes et al., 2010; Voevodskaya et al., 2014).
A very important issue, which is not always fully addressed in research studies, is the assessment of intra‐ and inter‐rater reliability of segmentation algorithms. Intra‐rater reliability of manual segmentation represents the theoretic upper bound for the agreement of automated with manual segmentation (Wisse et al., 2016a). A lack in reliability assessments of a manual protocol limits both its clinical application and a trustworthy comparison for automated methods. In fact, the benchmark for the semi‐automated and automated segmentation methods should be to introduce an error comparable or lower than the disagreement between two manual raters carrying out the same segmentation. Additionally, semi‐automated and automated segmentation methods could be of limited clinical utility if their reliability and measure reproducibility are not demonstrated. Regarding the hippocampal subfield segmentation, the reported ICC and DSC scores are very variable for different segmented subfields, with unsatisfactory values for small regions (Yushkevich et al., 2009; Wisse et al., 2012).
Despite 7T MRI scanners are spreading in human clinical research, there still are some limitations in the direct application of ex vivo achievements to in vivo sequences. First, the acquisition times of ex vivo studies are much longer than those reasonable for clinical protocols, as evidenced in Table 1. Second, ex vivo MRI exams are free from motion artefacts degrading image quality, such as natural vascular pulsatility and additional movement effects. Even so, the development of new hardware and the improvement of acquisition sequences and post‐processing methods are expected to change for the better the image quality of clinical 7T MRI and to render such ex vivo studies a more reliable reference for future clinical studies.
In spite of the notable number of methods developed at UHF MRI, the majority of protocols is based on manual segmentations, which are extremely time consuming and suffer of intra‐ and inter‐rater variability. Only in the very recent years, three automated segmentation packages have become available: MAGet‐Brain, Freesurfer and ASHS. Nevertheless, the first two methods have not been validated on images acquired at 7T and above. Moreover, the Freesurfer software has shown considerable limitations in its first version 5.3, and, despite its latest version 6.0 overcomes many difficulties, a number of limitations still remain. The necessity of a reliability assessment at UHF for the version 6.0 is also evident, since its applicability has been validated only on MRI data acquired at lower field strengths (up to 3T). By contrast, ASHS was applied on 7T data and a reliability comparison with manual segmentations was performed, showing high accuracy for most subfields. ASHS can be run only when a whole brain T1‐w sequence and an oblique coronal T2‐w sequence oriented along the main axis of the hippocampus have been acquired for each subject. In addition, ASHS allows for the definition and use of user‐defined segmentation protocols, thanks to the ASHS training pipeline. Hence, ASHS presents both the advantages of a fully automated implementation using two MR sequences (T1‐w and T2‐w) and the versatility of being adaptable to different segmentation protocols, if labeled training data are available. The latter feature is particularly interesting as it can allow the comparison among different subfield definitions on the same data and with the same segmentation software, trained on different labeled data. It is highly desirable that in the near future similar segmentation tools include the possibility to handle also additional contrasts, for example SWI, or quantitative images, for example QSM, to fully exploit the added value of UHF MRI.
In conclusion, despite the potential key role of UHF MRI in the study of the selective involvement of the hippocampal subfields in healthy aging, neurodegenerative processes and other pathologies affecting the HF is evident, a stronger effort in neuroimaging research is still necessary to address the following issues: (i) the harmonization of a manual segmentation protocol for the subfields, which is fundamental by itself and constitutes also the reference standard for semi‐automated and automated segmentation tools; (ii) the definition of guidelines for standardized global measures to account for during the analysis, for example total HF volume and TIV; (iii) the development of more versatile and reliable tools for automated segmentation; (iv) inter‐ and intra‐rater reliability assessment of segmentation methods. Once these open issues are fully addressed, the reliability and the reproducibility of the studies will be guaranteed and the inter‐study comparison will be easily allowed. An additional final effort required to the neuroimaging research community is to design more versatile segmentation tools able to accommodate and exploit the complementary information available from different MRI acquisition sequences, whose informative content is particularly enhanced at UHF.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
1300 36 33 32
Win a $500 Gift Voucher for Christmas | Great Gifts in the Boomerang Books 2017 Christmas Catalogue
Buy Natural Capitalism by Paul Hawken from Australia's Online Independent Bookstore, Boomerang Books.
Book Details
(June 2017)
(October 2000)
(November 2000)
(September 1999)
» Have you read this book? We'd like to know what you think about it - write a review about Natural Capitalism book by Paul Hawken and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a Boomerang Books Account Holder - it's free to sign up and there are great benefits!)
Write Review
Paul Hawken is an environmentalist, educator and best-selling author of The Ecology of Commerce, The Next Economy and Growing a Business (also a TV series). Amory B Lovins is Co-founder, Chairman, and Chief Scientist of Rocky Mountain Institute and a co-author of Factor Four (Earthscan, 1997). The Centennial Issue of The Wall Street Journal named him among 39 people in the world most likely to change the course of business in the 1990s, and Time in 2009 called him one of the 100 most influential people in the world. L. Hunter Lovins is the President and Founder of Natural Capitalism Solutions. She is a founding professor of sustainable management at Presidio Graduate School, and a consultant to companies around the world. A co-author of Factor Four (Earthscan, 1997) her latest book, Climate Capitalism, will be published in 2011.
Boomerang Books customers who bought Natural Capitalism by Paul Hawken also bought the following titles:
Phone: 1300 36 33 32
(10am-5pm Mon-Fri AEST)
+61 2 9960 7998
© 2003-2017. All Rights Reserved. Eclipse Commerce Pty Ltd - ACN: 122 110 687 - ABN: 49 122 110 687

subset: commoncrawl


text:
What Can You Benefit When You Find the Best Source of Baby Cribs?
If you are planning a baby shower, you might be very excited about it, knowing that it will be a joyful time of celebration with your friends. These women, then, might be planning to have a gift registry, as this will help them obtain the essentials that are needed when the baby is born. One who is making such a list, then, should not forget to think of baby cribs, as a baby crib can certainly make her life much easier when the child finally arrives. This is because a baby crib is something which is essential, something which is indeed very beneficial to own, as a woman is sure to find out when the baby is born.
The first thing that women will be able to gain through baby cribs is the benefit of being able to ensure that their babies will be safer as they sleep. You might know that your child, as he or she grows older, will learn how to move around, and if you put him or her on a regular bed, a fall can be the result of such moving. If you want to make sure that your baby is safe even while sleeping, then, you should definitely put him or her in a crib, as a crib is designed to eliminate the danger of a harmful fall.
Another thing that women will be able to gain when they use a baby crib is the benefit of being able to use a good one for a long time to come. The reason why this is so is because the best baby cribs are certainly made to last, meaning that they will not easily be damaged or be prone to wear and tear. If you plan to have more babies, then, you can be sure that a crib that is made out of good materials will not need to be replaced, and that you can use the crib for all of them.
Last but not least, women will be able to benefit through high-quality baby cribs because through them, they can be sure that their babies will enjoy comfort. One can be sure that a good baby crib will come with a mattress which is both firm and comfortable at the same time, a mattress which is good for the health of the baby as well as for his or her comfort.
One who decides to use a good baby crib for his or her child, then, can be sure that through this crib, a lot of truly wonderful benefits and advantages can be gained altogether.
More reading: my response


text:
That never ending light that guides you if you lose your sparks. Ammi Garritsen in a fashion story by Marco Giuliano, styled by Anca Macavei.
Vad ska du bli
Take charge and revolt against the norm of our twisted society. Take charge of what you will become. Leah in a punk fashion story photographed by Oscar Lindqvist and styled by Kazami Ohsawa.
Poisoned Fish
Out of the depths, rot and blind as a strange creature which has never seen the Sun. A story by Vivienne Moon.
Dernier matin de cet été
Flowers of the equinox and all the colors of a flaming morning in the last day of Summer. Photographed in Russian wasteland by Bogdan Shirokov.
Seeking quite, lonely and dark spaces in the city. Karolina photographed by Tugberk Acar and styled by Melike Barut.
Lou wanders darkling in the silent depths of Paris, photographed by Paul Franco and styled by Alie Suvélor.
No real feelings
Almost blind and downhearted we stray among each other. Only feelings can keep us alive. A story by Marco Giuliano, styled by Anca Macavei.
Purity Fixation
From an underground arcade, to the rooftops, to a love hotel. A story by Cape-Town based photographer Duran Levinson, shot on film in Hong Kong.
She's got the spirit losing the feeling and now you know. A haunting story starring Kristina photographed on film by Olesya Asanova.
Are we there? Can You see Me? We are watching while you are fading in the Daylight. A fashion story starring Gaia shot as-she-is by Paul Franco.
Micol Ragni / Human beings from a distant galaxy
After the Ultraviolet FW'16 presentation in Paris, we met with Micol Ragni, the designer behind unconventional London based label, who gave us a glimpse of her own unique way of approaching fashion, where a party on a distant galaxy is the perfect stage for her new collection.
Heavy Liquid
A curated insight on Nicolas Gavino's body of work. Powerfully raw images in which he blends erotic imagery and deadly human-scapes under an exquisite and ironic extravaganza.


text:
After years of renting boats with Tierra Verde Boat Rental my family and I were extremely disappointed:
The boat was old and terribly maintained...it could barely be used for waterskiing. For about an hour the boat did not work and when we called using the VHF radio we did not get a response. We later found out it is out of service! VHF is not a luxury, it is a requirement. It was probably the worst boat we have ever rented anywhere. The water toys are in so-so shape as well.
The price for gas was a rip-off. The gas meter in the boat didn't even work, so they charged me whatever they wanted.
And most of all, the lady who attended us was rude, sarcastic and unhelpful.
My overall experience was very bad and I will never rent again form them. I recommend to go elsewhere.
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.


text:
Need help? Check out our Support site, then
Back to WordPress.com Forums
- Member Since
- November 7, 2012 (5 years)
- Website
- http://hagarlevy.wordpress.com
User Activity
Recent Replies
- What is wrong with this website... ? User last replied: 5 years ago. Most recent reply: 5 years ago
Threads Started
No more topics posted.


text:
Comments on the Article
"Greek Civil War"
By LEONIDAS SAMOUILIDIS,M.D.
Greek-Amercan Review
This paper is prompted by the very informative (in general and brief terms) article on Greek Civil War by Androniki Janus. However there are certain areas that can be approached from a different interpretative angle; there are other points of misinformation. These I would like to stress in my article.The so-called facts of a historical event are always open to nterpretations that follow basic and even diametrical points of view.
For the sake of completeness I would like to bring forth my opposing views. One thing should be clear is that as far as the communist experience, I am in total agreement with Miss Janus. The Communist party in Greece (KKE) started in 1918 as a socialist party and added the word "Communist" in 1920 when its first representatives joined The Commintern for a meeting.
I would like now to describe some of the events that predated the formation of the August 4th regime (or dictatorship of loannis Metaxas).
In the 14 years (1922-1936) of the Republican Regime, Greece was deteriorating progressively, in spite of the stated accomplishments. It was disturbed by at least 14 different strikes, rebellions, and uprisings. Most of the strikes were promoted by the Communist party. The last big uprising took place March 1, 1935, was repressed, and most of the insurgents were imprisoned for life, but later they may have gotten amnesty. One would wonder what all these centrists and leftists, after having gotten rid of the monarchy in 1922 were trying to accomplish all these years. After a favorable plebiscite in November 1935, the King (George II) returned to Greece. A new government was formed under Constantine Demertzis, a university professor with vice president loannis Metaxas (January 26,1936). In the mean-time the communists were practicing strong propaganda, with threatening proportions. Disillusioned by rotten politics some republicans were encouraging them, hoping that they would find some encouraging improvement there. April 13, 1936 prime minister Demertzis died and Metaxas took his place. Parliamentary rules continued to fail; the country was going to chaos; communist induced strikes were increasing with more violence. July 31,1936 "Rizospastis" the official communist newspaper wrote a threatening article to the effect that laborers were preparing a bloody strike for the 5th of August, which would continue as long as victory in throwing out the govemment, would be accomplished. Late of August 4th Metaxas decided to react swiftly and effectively. He called for a meeting of the ministers, informed King George II and declared martial law (or a dictatorship). The King consented wholeheartedly, but one cannot say that he was disliked for that or disliked at all. As a matter of fact both plebiscites involving the same King (George II) one of 1935 and the other of 1946 showed that the majority of the Greek people were in favor ofthe King.
Metaxas to perform this feat just used two evzones placed in a crucial spot at the gates of Ypourgion Exotericon and logical surveillance from the police.This event was applauded immediately by the entire Greek population except the communists, whose leaders were arrested and imprisoned. The event indicated the end of depraved parliamentarism and a new era for Greece. Later in the regime, republican leaders who seemed to like disturbances wrote several times to the king complaining about different political issues. Metaxas, in turn, went to the King and asked him if he was dissatisfied with the administration and if he said "yes," he was willing to resign and let somebody else (for example Themistoclis Sofoulis, the main instigator) to lead the country. For obvious reasons, the control of the government against these politicians became more rigid.
Thus, it is inaccurate to say that Metaxas and his regime was unpopular in Greece. It is as accurate to say that the August 4th regime was fashioned after the Nazis. Only the superficial manifestations (uniform of EON and salute were similar). The basic differences of a deeper nature were: Metaxas did not create a regime based on any particular party like the Nazi or Fascist. Did not have any form of indoctrination to make brainwashing an essential part of the Nazi philosophy. Metaxas only wanted to start creating a well functioning and disciplined country (given that no gevernmental function was adequately functioning.) He set as a goal for this 10 years (in my opinion that was too little). The emphasis in the military is explained by the fact that as early as 1935 the clouds of a new war were appearing in the horizon (violations of the Versailles treaty by Germany-Italy invades Ethiopia-Seizure of the Rheinland by Germany-Spanish civil war). Furthermore all the neighboring countries were rearming. Thus Metaxas quite wisely put the emphasis on building the military, the result of which was the astounding epic of the Albanian front and the resistance to German attack. Whoever understood the emphasis on the military as being an aggressive move a la Nazi has grossly misunderstood goals of the Metaxas regime. Needless to say that the Greek army was at shambles at that time.
We come now to the events of the second world war and the occupation. Metaxas died January 29,1941 where-as the German attack started April 6, 1941. Thus there is a lapse of the months before Tsolakoglou became the puppet prime minister and the King with government under Emmanuel Tsouderos left Greece to continue the struggle from abroad.
The resistance (sporadic at first) started sometime in June when EAM (backed by hidden communists at the time) appeared with writings of the wall. EAM's military branch, ELAS was formed April 10, 1942. There was no mention of communism at that time. People viewed them as the liberators who were going to fight the armies of occupation. ELAS hidden goals were: 1) To liberate the country. 2) To punish the traitors of 4th August (meaning the King and few of the old ministers. 1) To reinstate the popular liberties.
Later we learned that this meant "to institute a communist regime after the war." That became a major goal of the EAM/ELAS particularly after 1943 when the turn of the war became in favor of the allies. There was only a tri-party membership in each group.The military, the politician (or instructor) and the kapetanios.The latter one was the most powerful of the three. This structure, nevertheless caused major rifts in the KKE internal affairs/as the differences between the kapetanios and politician became more focused. By May 1943 when ELAS was at the peak of its strength, was composed by Kapetanios: Aris Velouhiotis (real name Athanasios Klaras who was not a military man but had been a student of agriculture to end up as a teacher in Larissa.) He ended up being a bloody sadist. Politician: Andreas Tzimas (or Samariniotis) official member of the KKE; and Military leader: Stefanos Sarafis (military man who participated in the uprising of 1935, imprisoned and left free with the opening of the jails in Athens in 1941.)
Beginning of June 1942 another resistance group was formed, the EDES under Napoleon Zervas (another member of the 1935 uprising). He was elected by a group of EDES leaders in Athens (Stylianos Gonatas) after and against Nicolas Plastiras' advice who was then in Paris closely watched by the Germans. Plastiras secretly summoned another EDESite Komninos Pyromaglou, urging him to start a guerrilla organization in Greece. This is what Pyromaglou did, after travelling through German occupied Europe to reach Greece from Nice (France).
There were other smaller groups that developed such as the EKKA under Dimitrios Psaros, some other small royalist groups that eventually were absorbed or destroyed by ELAS. By the end of the occupation ELAS had conquered most of Greece except EDES in Epirus, the Tsaous Anton (Antonios Fosteridis) in Thrace and East Macedonia, some independent guerilla groups in Crete and the areas already dominated by the Security Battalions (Tagmata Asfalias) mostly in Peloponnese.
In statistics brought by Chris Wood-house (British liaison officer for the andartes,) about 80% of ELAS leaders were communists against 20% of enlisted men.
By the end of October 1944, a Soviet envoy colonel Grigori Popov arrived at th ELAS headquarters and that gave a boost to the ELAS sites that they were going to receive the long awaited support of their "Motherland" the Soviet Union. However the opposite occurred and Popov kept silence for some time. Another important event occurred on October 9, 1944, a few days before the Germans left Athens. Winston Churchill had a secret meeting with Josef Stalin in Moscow whereby the fate of the Balkans was determined in a conference where the famous "Blue pencil" was used. This resolved that Greece would be left at 90% under the British influence, which in turn meant that the Soviet Union would stay out of Greece. Thus Popov's mission was never cleared.
As the civil war progressed and Churchill was getting flack from everybody about fighting an allied nation, he was almost ready to abandon the struggle, but the cautious King George II in a touchy letter to him written about December 12, 1944 stated that it would be an injustice for Great Britain to abandon Greece, now when Greece was the only country fighting the Axis 4 years ago and protected the British troops and interests. That letter had an effect on the prime minister. It is not clear how the civil war started in December 4, 1944 in Athens, nevertheless it looked by the facts that the event was unavoidable. At first the ELAS forces gained control of most of Athens with the exception of Scholi Evelpidon, Regiment of Gen-darmes at Makryianni, and an area around the Theseum which was a strong-hold of the right wing organization X lead by George Grivas (the future leader of the EOKA in Cyprus). On December 13, 1944 arrived in Athens from Paris General Nicolas Plastiras who was soon to be nominated as the next prime minister of Greece.
To conclude I would like to say that it seems that Miss Janus has been following what are the generally accepted as facts in this period of time. However I think it is important for people to know some obscure, and yet equally important facts which I have outlined here.
Nikos Antonakeas: Favlokratia (Corruption)
Stefanos Sarafis: O ELAS
Komninos Pyromaglou: Ethniki Antistasis (National Resistance).
Ioannis Metaxas: Imerologion (Diary)
Winston Churchill: World War Two
Chris Woodhouse: Apple of discord
HCS readers may wish to view other articles and releases in our permanent, extensive archives at the URL http://www.helleniccomserve.com/contents.html.
2000 © Hellenic Communication Service, L.L.C. All Rights Reserved.


text:
Posted at February 3rd, 2016, hiero petula about Luminous Bedroom Overhead Lighting Enlightening the Fanciful Bedroom Nuance. The option of bedroom overhead lighting is popular because in modern interior world, practicality in simplicity is adored. Most contemporary style uses these lighting fixtures as the lighting solution in the bedroom. After you determine wha...Read More
Posted at February 24th, 2016, calantha merrick about Swanky Teak Dining Room Furniture Designed for Luxurious Interior. If you want to feel luxurious atmosphere in your dining room, involving teak dining room furniture set will be an effective way to realize it. It is such a simple method to upgrade one of rooms inside your house. And generally, it doesn't...Read More
Posted at January 31st, 2016, hiero petula about Smart Bathroom Cabinets Orange County Ideas You Must Try. Are you currently looking for awesome bathroom cabinets Orange County designs? Or do you plan to optimize your bathroom storage units? If you are and you do, then you have come here at the right time. Today, we will take you to explore some...Read More
Posted at January 27th, 2016, calantha merrick about Recommended Space Saving Bathroom Sinks Options. What can be a better match than space saving bathroom sinks to complement your small bathroom interior? When you are working on remodeling a small bathroom, you will be exposed by many different bathroom sink and cabinet designs worth to co...Read More
Posted at January 24th, 2016, calantha merrick about Ultimate Tips to Remodels for Small Bathrooms. As you may have noticed, there are many ideas and inspirations of remodels for small bathrooms you can find and explore. Well, dealing with a small space is indeed challenging and you surely want to maximize the result—to make the room fe...Read More
Posted at February 3rd, 2016, hiero petula about Surprising Camouflage Bedroom Sets for Covering Cabin Furniture in Sophisticated Style. It's not true if you say that camouflage bedroom sets are just for boys. Camo bedroom theme is mostly for boys but adult bedroom even master bedroom can have it, too. The camouflage bedding is inspired from military scene; therefore camou...Read More
Posted at February 17th, 2016, hiero petula about Eye-Catchy Nautical Kitchen Lighting Options Worth to Consider. It goes without saying that nautical kitchen lighting can bring the visually more attractive look into your kitchen interior. The remarkable nautical design style can evoke the feeling of a day at the beach under beautiful sunny day with cl...Read More
Posted at February 15th, 2016, hiero petula about How to Update and Refinish Oak Kitchen Cabinets. You can refinish oak kitchen cabinets yourself to update your kitchen interior and appearance. We have some great tips to help you doing the work we plan to share today. As you may have noticed, your oak kitchen cabinets are sturdy. They ca...Read More
Most Popular
Pick Categories
Recent Post
Monthly Archives


text:
GREAT STAFF and the rooms are amazing, at the higher end of the price scale and classed as luxury I would say. It's not a place I would stay at all the time but enjoyed when I did, they need to make it a little cheaper or put some deals on once and a while. I would stay again though.
- Official Description (provided by the hotel):
- Hotel Indigo Newcastle is just a two-minute walk from Central Station, and a ten-minute walk to Newcastle United Football Club. This upscale venue features an iconic Marco Pierre White Steakhouse, delivering to our guests a refreshing and welcoming experience.Hotel Indigo is a boutique concept by InterContinental Hotels Group (IHG), offering guests the luxury and individuality you would come to expect of a 4-star hotel. The design of the venue has been heavily influenced by its location within the historic Grainger Town area and will feature bold geometric forms, classical proportions and repeating patterns to mimic the architecture and rows of columns that can be seen around the local neighbourhood. Today, the Grainger town area is a hot-spot for cutting edge architecture and just a short stroll away from the city's art galleries, restaurants, shops, bars and business district. Hotel Indigo Newcastle has a car park at the rear with charges at £12 per night. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Agoda, Booking.com, IHG, Orbitz, Expedia, Hotels.com, Travelocity, Cancelon, Hotwire, HotelQuickly and TripOnline SA so you can book your Hotel Indigo Newcastle reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.


text:
- Security Network Engineer
Reports to:
- LINX Network Operations Manager
Based in:
- The position will be based in the LINX London office, but occasional travel to the LINX Peterborough office will be required along with some international travel
- Work with security office to develop and implement security policies, standards and procedures
- Implement, configure and maintain security platforms including Cisco and Juniper firewalls
- Implement, configure and maintain IDS/IPS platforms
- Implement and maintain DDoS mitigation tools
- Lead and deliver successful projects following Agile processes
- Development and implementation of technology and infrastructure upgrades for the improvement and growth of the exchange
- Plan and implement software and hardware upgrades, usually focusing on improvements to the network, implementation of new technologies, investigations, testing, enhancements etc.
- Configure and maintain network automation platforms
- Ongoing day-to-day Network maintenance
- Expectation to install and test sizable network devices
- Perform and manage significant network maintenance work, some of which could run throughout any period of the day
- 24x7 on call rota
- Third point of escalation for support issues. provide back-up to 2nd line network engineers and 1st line NOC engineers, covering absence and helping with workload and administration
- Awareness of and working to budgets
- Any other duties required for the overall technical and organisational operation of LINX
Prerequisite Skills:
- Minimum 4/5 years experience in network/ISP environment
- Advanced complex problem solving skills
- Debugging/analytical skills
- Good oral and written communication skills
- Eye for detail, self-starting and independent, but able to work within predefined areas of responsibility
- Good project management skills
- Thorough understanding of Security protocols
- Thorough understanding and experience of Ethernet/Layer 2 switched Networks
- Thorough understanding and experience of Juniper routers, firewalls and JUNOS
- Experience of Cisco firewalls and IDS platforms
- Knowledge of vulnerability assessment and penetration testing
- Thorough knowledge of IP routing protocols
- Thorough understanding and experience of MPLS/VPLS/EVPN technologies
- Knowledge of LINUX/UNIX system administration skills
- Working understanding of scripting language (Python, PHP, Perl)
- Experience with automation/configuration management systems
- Must be able to pass LAIT 3 within a reasonable period
Please note:
- This post will be included in an on-call rota
- You are required to be able to access the Docklands area within one hour
- You will be required to be security screened to BS7858:1996 standard and CRB checked (this will start at your induction)
- You are required to have the right to live and work in the UK
Closing date for applications:
11th December 2017 (unless the position is filled sooner)Back to vacancy listing


text:
Double Front Door
Detail of Simple Double Front Door Mahogany Entry Inside Decorating
Double Front Door tips and photos has Published at May 30, 2017, 02:46 AM. Post name is Contemporary Double Front Door Entry Throughout Design Inspiration in category Decorating with resolution image up to 1440x900 pixel. The post has received a 5 star rating from users and visitors. If you interest of this image, you can press the button "download hd" on the bottom of the post Double Front Door and save image in your computer.
In this post of there is a tag that is derived from the title Contemporary Double Front Door Entry Throughout Design Inspiration, tagged of : double front door, and with an assortment of other tags that are in one category, such as : contemporary double front door entry doors photo 20 in inspiration, interesting double front door of furniture inspiring home element for porch decoration with mahogany glass and inspiration, simple double front door mahogany entry inside decorating, beautiful double front door entry doors photo 20 and inspiration, double front door full size of furniture inspiring home element intended design ideas, Thank you for visiting and happy day.
45 Gallery About Double Front Door
Brilliant Double Front Door Full Size Of Furniture Inspiring Home Element For Front Porch Decoration With Mahogany Glass Arch Intended Ideas
Modren Double Front Door Black Wood Panel Masonite Exterior Entry Doors Design Collections With High Rectangle Shaped Double Side Front Door And
Unique Double Front Door Exterior Double Rustic Entrance Door With Solid Dark Varnished Finishing Design Front Throughout Inspiration
Delighful Double Front Door Dark Brown Color Wooden Front Door With Glass Also Bronze Metal Handles And Orange Double To Idea
Simple Double Front Door Custom Craftsman Style Double Entry Door With Transom This Is Almost What Intended Design
Exellent Double Front Door Double Front Doors For Homes Traditional Exterior With Rustic Door D Picture
Interesting Double Front Door Could Be Single Or Double Craftsman Style Front Door Wood White Throughout Decorating
Fine Double Front Door Exterior Double Doors Doorwoodgrain Fibergllass Solid Front Door With On Decor
Exellent Double Front Door Double Entry Doors Ideas On Pinterest Front And Wood Door C Intended Ideas
Delighful Double Front Door Front Doors For Homes Exterior Photo Gallery Homestead The Affordable Door I Inside
Delighful Double Front Door Wood Doors Exterior Doorsmahogany Doorsentry Canton Double Front Door I To Inspiration
Plain Double Front Door Doors With Only Primary Leaf Plastpro Model Drm 60 Size Front Door With Picture


text:
Candy labels
DIY printable Thanksgiving candy wrappers turn ordinary mini candy bars into something extra fun! Surprise your dinner guests this Thanksgiving
FREE Printable Chevron Labels from Sonya DeHart Design! Chevron theme next year?
19 different messages you can put on candy wrappers to give to friends - Free…
Seminary New Testament Doctrinal Mastery Scripture Passage Candy Label Puns for LDS Youth Bible
So and Sew Productions: Halloween Apothecary Labels
Honeydukes Printable Candy Labels Harry potter party printable candy labels by printedinstinct
tags for dessert table
Free Valentine Candy Labels Walton, will you be my sugar daddy!
Seminary Book of Mormon Doctrinal Mastery Scripture Passage Candy Label Puns for LDS Youth
Check the way to make a special photo charms, and add it into your Pandora bracelets. Rainbow Seeds Free Printable - A simple St. Patrick's Day gift idea via
Sugar fun printable candy labels – A Subtle Revelry
Last week I covered the Harry Potter party invite and "Hoo'ing." This week you will get to see the Honeydukes candy shop! Every candy store needs a sign, so I designed a banner and some candy jar labels to go … Continue reading →
INSTANT DOWNLOAD, Trolls Cotton Candy Label, Treat Bag Toppers, Trolls Hair, Trolls Theme, Trolls Party, Trolls Favor labels, Birthday Party
Vintage Christmas Candy Label 2 Inch Tag by chocolaterabbit
Free Harry Potter Candy Label Printables - perfect for any Harry Potter or Halloween Party! 12 Candy Printable Labels in total!
Printable Christian Halloween Candy Labels | Jesus Love is Sweeter John 3: 16


text:
Recovery Manager for SharePoint Premier Edition
Migration Manager for Sharepoint
Server Administrator for SharePoint
Migration Suite for SharePoint
Migrator for SharePoint Online
We are using QuickApps for SharePoint 6.3 in SP 2013. I created a SharePoint list for our Marketing group to keep track of marketing events. This list contains 87 columns and approx. 2000 rows, and our users want to export ALL of these columns to Excel on a weekly basis, so I created an qExcelviewer web part page and added all of these 87 columns; as the list grows, we noticed significant delay when opening this qExcelviewer web part page. Sometimes it even displays "Unable to read file" error message - screenshot attached.
Could you please advise how to improve the page load performance issue? Any suggestions will be greatly appreciated.
Thank you!
Laurinda M. Chi
Hi Laurinda,
So you have submitted a support case, right?
I will reply you in the support case.
Thank you, looking forward to getting a feasible solution shortly.


text:
I need a list of B2B leads containing first or last name of business owner
Budget $150-450 AUD
Hi There,
I need a list o B2B leads in various industries including, automotive, dentists, chiropractor, accountants, aged care, residential care...
They must be within 50KM of Sydney CBD. I need the mailing address and the business owners firstname and/OR surname.
Please contact me to discuss.
11 freelancers are bidding on average $295 for this job
Hi Dave,I am Joshua.I would like to do this project as per your requirements. I have excellent Web Research & Data Entry Skills.I have 8 [url removed, login to view]'re a professional team. We've done many similar [url removed, login to view] that W More
Sir, I am well versed in this kind of jobs and can do your project as per requirement. Refer my online work portfolio at [url removed, login to view] **** I have all the resources ready to do your project as per More
Dear Sir/Madam, I am familiar with this kind of work because I did several such type of projects in past for so many of clients. I have just made a small sample, please contact me so that I can show you sample. More
Hello, Experienced data collection experts for your service. Details of the projects worked are given below, please check. We have a team of data collection experts who can be assigned to this project and can deliver More
Hi, I'm creating a sample list for example of your project. Please refer to PM for details... Thanks. Best Regards Ferdous
We are having good experience in relevant works, we charge $50 for 1000 Records and can provide you data in thousands with quality in time
Dear Sir, quality and expert researcher here to search a targeted group of people, images, email addresses, database or anything that you are needed you may hire me in full confidence.
Hi, I am ready to provide you quality leads around Sydney. I promise quality service with quick job submission time. I am ready to start the project immediately now and we are also ready to present a sample befo More
Ready to work with you.I can assure you of my timeliness, quality and experience. I can start work immediately.


text:
Barney Dehoney
8781 Columbia Hwy Greensburg, Kentucky 42743(270) 932-7371
Print | Save | Directions
AboutBarney Dehoney is located at the address 8781 Columbia Hwy in Greensburg, Kentucky 42743. They can be contacted via phone at (270) 932-7371 for pricing, hours and directions.
Barney Dehoney has an annual sales volume of 501K - 999,999. .
For maps and directions to Barney Dehoney view the map to the right. For reviews of Barney Dehoney see below.
Phone: (270) 932-7371
Employee Size: 1 To 4
Exact Employee Count: 3
Exact Sales Volume: 100000
Location Type: Single Location
Sales Volume: 501K - 999,999
People Also Viewed
James Allen Kelly
3026 Fry Ridge Rd Greensburg, Kentucky 42743
Barry Russell
4193 Poplar Grove Schl Rd Greensburg, Kentucky 42743
Kenneth Darnell
650 Ralph Vaughn Rd Greensburg, Kentucky 42743
You must Sign in to post reviews.
0 Reviews


text:
Back in the 1998 when Indian market was introduced with Honda City in the premium mid-size car segment it had no competition.This proved to be a beneficial move for the company and it went on to capture the segment and became a default option for the people.Since then , more than 6.5 lakhs units of Honda City car , has already been sold in India.
But the scenario began to change in the year 2014 when in the same segment Maruti Suzuki launched its premium sedan Ciaz.The move was successful and this Maruti's car surpassed the Honda City in-terms of sales.Currently , there is a tough competition between Honda City and Maruti Suzuki Ciaz as far as monthly sales are concerned.
After the launch of new Honda City on Feb 14 , 2017 the company wanted to make it clear that it is not competing with Ciaz and that the new Honda City is again a different car marked by the fact that it has a higher price than Ciaz.
Let us find out what actually is different in these cars.
Looking at the above figures it is a clear indication that Maruti Suzuki Ciaz beats Honda City in terms of Dimensions.
As far engine power comparison is concerned Honda City is a winner over Ciaz for both diesel and petrol engine variants.Also in terms of performance Honda City 2017 outperforms Ciaz due to its superior engine.
In terms of better fuel efficiency Maruti Suzuki Ciaz performs way better than Honda City.The mileage (in kilometer per liter) of Ciaz is better than City because it uses smaller engine which consumes lesser fuel.
Going by the above price comparison , while the cheapest Honda City can be bought for Rs 8.5 lakhs while For Ciaz its 7.97 lakhs.The most expensive Ciaz price is 10.76 lakhs while for Honda City it is 12.86 lakhs.
View all posts by: Team RT
Taming the beast ! - Find Hummer SUV owners in India !
Suzuki To Launch 150 CC Cruiser Bike Next Month To Compete With Bajaj Avenger
Audi A7 Sport back clocks 0-100 kmph in just 5.3-second
Updated Honda Gold Wing to be 1st bike with Apple CarPlay and Reverse Gear
Tata Nexon Review-Powerful Engine and Good Looking Car
Ex Showroom price vs on Road price - What makes so much difference !
Tata Nexon Vs Maruti Suzuki Vitara Brezza compares-Who has an edge ?
Review Talks ! © 2017 All rights reserved