The horizontal raphe (HR) as a demarcation line dividing the retina and choroid into separate vascular hemispheres is well established, but its development has never been discussed in the context of new findings of the last decades. Although factors for axon guidance are established  they do not explain HR formation. Early morphological organization, too, fails to establish a HR. The development of the HR is most likely induced by the long posterior ciliary arteries which form a horizontal line prior to retinal organization. The maintenance might then be supported by several biochemical factors. The circulation separate superior and inferior vascular hemispheres communicates across the HR only through their anastomosing capillary beds resulting in watershed zones on either side of the HR. Visual field changes along the HR could clearly be demonstrated in vascular occlusive diseases affecting the optic nerve head, the retina or the choroid. The watershed zone of the HR is ideally protective for central visual acuity in vascular occlusive diseases but can lead to distinct pathological features.  The horizontal raphe (HR) was first described in the early 1800s as a horizontal demarcation line that extends from the macula to the temporal Ora dividing the temporal retinal nerve fiber layer into a superior and inferior half . Polyak Renewed interest in the HR resulted from innovative retinal imaging instruments with advanced software analysis in in vivo retinae. The confocal scanning laser ophthalmoscope and the optical coherence tomography (OCT) instruments using interface reflectance analysis can measure the thickness of the retinal nerve fiber layer surrounding the optic nerve head, and the latter can also measures the nerve fiber layer and retinal ganglion cell layer thickness surrounding the macula. Advanced optics confocal scanning laser ophthalmoscopy (AOSLO) can measure the various retinal layers temporal to the macula. These instruments objectively measure the nerve fiber layer thickness and defects in the nerve fiber layer thickness that exists adjacent to the optic nerve head and at the macula in aging and glaucoma ,9,10,11.Although the concept of a temporal HR is accepted, its length, width, and depth have not been adequately researched. We performed a literature review using the key words: Temporal raphe, horizontal raphe, nerve fiber layer development, and retinal ganglion cell axon by pooling single published data over the last four decades.Understanding the complex developmental anatomy of the retina and choroid in the fetus and childhood allows one to better understand the HR’s origin, composition, and extent along the horizontal meridian, along with the role it plays in the clinical picture of adult occlusive vascular disease involving the optic nerve head, the retina, or the choroid.Although little data exists on nerve fiber layer axon guidance in human fetal tissue, fetal molecular guidance signals are considered similar in most mammals. Numerous studies on mice revealed some key players involved in the different steps of axon growth into the nerve fiber layer, their elongation toward the optic nerve head, and their passage along the retrobulbar optic nerve ,18. The During the sixth to eighth wog, the retinal ganglion cells differentiate first in the future macular region of the optic cup . These rSince neither molecular signals nor definite retinal structures can sufficiently explain the creation of the HR, some local intrinsic factors must be considered. Perhaps the most striking structural influence can be found in the developing choroidal vasculature ,42. The Summarizing the data concerning the origin of the HR, we speculated that the initial cause for HR formation comes from the choroid and is morphologically stabilized due to biochemical factors guiding the developing nerve fibers and blood vessels.The first three years of life result in rapid eye growth that involves the peripheral retina more than the retina at the posterior pole. This phase of nonuniform expansion of the retina, together with the greater fetal retinal ganglion cell apoptosis in the peripheral retina, leads to a decreased density of retinal ganglion cells and their axon bundles in the peripheral nerve fiber layer. At birth, the papillomacular bundle is of even thickness in an arc along the temporal side of the optic nerve head . As the The nerve fiber layer is composed of multiple bundles of retinal ganglion cell axons and increases in thickness as these bundles approach the optic nerve head. The retinal ganglion cell axon bundles surrounding the fovea measure 60–70 μm in diameter and are similar in size to the diameters of the capillary nets perfusing them . In monkThe perfusion of the retinal nerve fiber layer along the HR is complex, as it is derived from different capillary beds in different regions of the retina . GeneralA watershed zone is the border between the territories of distribution of any two end arteries . The HR A 91-year-old female demonstrated progression of her visual field defect from the temporal to the nasal HR at the posterior pole . The optAn 81-year-old female developed a sudden onset of a painless scotoma in front of her left eye. The retinal edema associated with this scotoma resulted from occlusion of a cilioretinal artery arising on her temporal optic nerve head . Her HumUnfortunately, we have only this retinal angiogram image  as a couOn retinal exam, a 57-year-old female bilateral pseudophake was found to have an abnormally appearing optic nerve head in the right eye. A large superior arcuate visual field defect was found abutting the HR . RetinalA 93-year-old male with controlled capsular glaucoma and moderate age-related retinal macular degeneration (dry) in both eyes developed a vein occlusion in his left eye that progressed to inferior hemiretinal vein occlusion . RetinalThe formation of the HR in humans occurs with the growth of the long posterior ciliary arteries along the horizontal meridian during the seventh week of gestation and is summarized in The fetal retinal capillary bed development begins with first the superficial capillary bed in the fourth month of gestation, followed, in order, by the radial peripapillary capillary bed, the deep capillary bed, and the creation of the foveal avascular zone in the ninth month of gestation ,79. All As retinal vascular maturation continues on both sides of the HR, one finds precapillary arterioles perfusing some retinal capillaries that cross the HR and become contralateral precapillary venules. These venules drain into contralateral retinal veins and finally into the contralateral central retinal vein. This filling of central retinal veins by some venous blood from the contralateral retinal vascular hemisphere can be demonstrated in the ischemic side of the branch retinal artery occlusion, and particularly, the marked accumulation of hemorrhages along the inferior nasal and temporal HR in the hemiretinal vein occlusion. At the fovea, there is a paucity of HR hemorrhages due to the adequate venous drainage by the dense retinal capillary bed anastomoses surrounding the avascular zone. Around the age of three, the raphe is composed of different components: A barrier of vertical silo-like structures measuring 50–70 µm in diameter, passing from the external limiting membrane to the internal limiting membrane, containing nerve fiber bundles and neurons from the retinal photoreceptors to the retinal ganglion cells, shrink-wrapped by Mueller’s glial processes ,16,81; aIn early fetal development, molecular signals define a retinal nasal-temporal axis orientation, but no markers have been found that established a retinal superior–inferior axis orientation. This deficiency may play a role in the direction of growth of the long posterior ciliary arteries in the vertical plane and explain the varying angle that the adult HR forms with the anatomical horizontal meridian.Images of retinal and cilioretinal arteries occlusions from emboli are well-documented in the literature. Similar embolic disease or arteriosclerosis affecting the vessels of the optic nerve head or the choriod occur, but these occlusions remain difficult to demonstrate in vivo. In Case 1 and Case 4, we suspected that the visual field defect was caused by occlusion of a posterior ciliary artery. In Case 1, the swollen superior temporal quadrant of the optic nerve head demonstrated the area of ischemic infarct but not the posterior ciliary artery occlusion. The best explanation is that this ischemia was caused by occlusion of one posterior ciliary artery in an eye with four posterior ciliary arteries, according to Hayreh .In Case 4 of suspected posterior ciliary artery occlusion, the triad of intact RNFL analysis, a mainly intact RGC layer, and a marked superior arcuate field defect could only occur with a normal functioning superficial retinal capillary bed. The arcuate visual field defect was the result of apoptosis of photoreceptors not the retinal ganglion cells. This choroidal was probably due to occlusion of one posterior ciliary artery in an eye with three posterior ciliary arteries, where the vertical watershed zone occurred temporal to the optic nerve head . What roThe preservation of central visual acuity is often achieved in occlusive vascular disease of retina and choroid due to the dense retinal anastomosing capillary ring surrounding the foveal avascular zone and due to the drainage of the choroidal submacular capillary bed ,75. This


Purpose: To correlate computed tomographic (CT) appearance of the thymus with results from histologic examination of thymic tissue in myasthenic patients who underwent thymectomy.Materials and methods: A retrospective study, based on case series report, between January 2000 and December 2010 on 247 patients with generalized myasthenia gravis or myasthenic syndrome explored by CT using a specific protocol, in the Radiology and Medical Imaging Department of Fundeni Clinical Institute. All subjects in the study were operated and had a histologic evaluation.Results: CT examinations of these 247 subjects showed remaining thymic mass, remnant of thymic tissue, fatty infiltration of the thymus and tumoral thymus or focal thymic mass. The results of histologic examination showed normal thymus, thymic lymphoid follicular hyperplasia, thymic atrophy, fatty infiltration and thymoma.Conclusion: It was a 100% correlation between CT examinations and intra-operative findings regarding the presents of focal thymic masses in our study. In the diagnostic of focal thymic mass, the only inter-disciplinary correlation is between radiological and macroscopic aspects. CT examination has a limited value in differential diagnosis between thymic lymphoid follicular hyperplasia and thymoma. The thymus is a heterogeneous admixture of lymphoid and epithelial elements located in the superior and anterior portions of the mediastinum. It is an integral part of the immune system.Its shape is partially determined by adjacent structures. Posteriorly, it molds itself against the trachea, the left brachiocephalic vein, the aortic arch and its branches, and the pericardium covering the ascending aorta and the pulmonary trunk. Anteriorly, the sternum and the antero-medial margins of the lungs cover it. It is a bilobed structure, with the left lobe usually extending further inferiorly than the right. The two lobes usually make contact superiorly near the midline and then diverge inferiorly. Each lobe is enclosed in its own thin fibrous capsule; delicate septa divide the thymic lobes into irregular lobules in the younger subjects .The width decreases in older patients, but a large variation exists within each age group. The thymus becomes narrower with increasing age, a wide variation of the thickness exist in different age groups [The density of normal thymus in adults. The mean attenuation value of the thymus was obtained and compared with that of the chest wall muscles. The CT attenuation values decrease with aging. In patients under 25 years of age, the thymus is isodense or with a higher density than the chest wall musculature; between 25 and 49 years the thymus appears with a lower density than that of associated soft tissues because of progressive fatty infiltration; patients over 50 years of age had a thymic density approaching to the fat , diffuse enlargement of the thymus and thymic focal mass.Although CT is useful in differentiating non-invasive from invasive thymomas, it has a limited value in differentiating thymomas from lymphoid follicular hyperplasia. Sometimes, CT may suggest the histologic nature of a thymic lesion.


BioVid Heat Pain Database (Part A) and experimental validation demonstrates that the proposed uni-modal architecture for the electrodermal activity (EDA) and the deep fusion approaches significantly outperform previous methods reported in the literature, with respective average performances of Leave-One-Subject-Out (LOSO) cross-validation evaluation setting. Moreover, the experimental results clearly show the relevance of the proposed approaches, which also offer more flexibility in the case of transfer learning due to the modular nature of deep neural networks.Standard feature engineering involves manually designing measurable descriptors based on some expert knowledge in the domain of application, followed by the selection of the best performing set of designed features for the subsequent optimisation of an inference model. Several studies have shown that this whole manual process can be efficiently replaced by deep learning approaches which are characterised by the integration of feature engineering, feature selection and inference model optimisation into a single learning process. In the following work, deep learning architectures are designed for the assessment of measurable physiological channels in order to perform an accurate classification of different levels of artificially induced nociceptive pain. In contrast to previous works, which rely on carefully designed sets of hand-crafted features, the current work aims at building competitive pain intensity inference models through autonomous feature learning, based on deep neural networks. The assessment of the designed deep learning architectures is based on the  Conventional machine learning approaches are built upon a set of carefully engineered representations, which consist of measurable parameters extracted from raw data. Based on some expert knowledge in the domain of application, a feature extractor is designed and used to extract relevant information in the form of a feature vector from the preprocessed raw data. This high level representation of the input data is subsequently used to optimise an inference model. Although such approaches have proven to be very effective and can potentially lead to state-of-the-art results (given that the set of extracted descriptors is suitable for the task at hand), the corresponding performance and generalisation capability is limited by the reliance on expert knowledge as well as the inability of the designed model to process raw data directly and to dynamically adapt to related new tasks.Meanwhile, deep learning approaches  automatiA steadily growing amount of work has been exploring the application of deep learning approaches on physiological signals. Martinéz et al.  were ablSenseEmotion Database (SEDB) 29], the e (SEDB) , by usine (SEDB)  were usee (SEDB) , the autBioVid Heat Pain Database [In ,37,38, tDatabase  (BVDB). Database , KächeleDatabase  based onDatabase . The autDatabase , BoostinDatabase  and RandThe current work focuses on the application of deep learning approaches for nociceptive heat-induced pain recognition based on physiological signals ). Several deep learning architectures are proposed for the assessment of measurable physiological parameters in order to perform an end-to-end classification of different levels of artificially induced nociceptive pain. The current work aims at achieving state-of-the-art classification performances based on feature learning , therefore removing the reliance on expert knowledge for the design and optimisation of reliable pain intensity classification models (since most of the previous works on pain intensity classification involving autonomic parameters rely on a carefully designed set of hand-crafted features). The remainder of the work is organised as follows. The proposed deep learning approaches as well as the dataset used for the validation of the approaches are described in BioVid Heat Pain Database [http://www.medoc-web/products/pathway) thermode attached to the participants’ right forearm. Before the data were recorded, a personalised calibration step was undertaken for each participant to determine individual levels for the pain threshold, as well as the tolerance threshold. Therefore, starting at a temperature of 32 °C  since most of the related works were conducted based on this specific database. The database is publicly available and consists of a total of 87 participants. Due to technical issues during the recordings, some of the data specific to three participants are missing [BioVid Heat Pain Database (Part A).The Database  (BVDB) wDuring the experiments, three different physiological signals were recorded, namely electrodermal activity (EDA), electrocardiogram (ECG) and electromyogram (EMG)  in order to achieve state-of-the-art classification performances. Therefore, multi-layer CNNs were designed and fed with the preprocessed physiological signals in order to automatically compute relevant signal representations and at the same time optimise the classification architectures. In the following sections, convolutional layers, pooling layers and fully connected layers. Convolutional layers are characterised by a set of neurons (or kernels), whereby each specific neuron extracts a specific pattern of information from a patch of the layer’s input. Each neuron consists of a set of trainable weights, the size of which is determined by the patch’s size (or kernel size). The output of each neuron is calculated by applying a non-linear activation function  on the weighted sum of the neuron’s input. Each neuron scans the layer’s input sequentially and the aggregation of the resulting local information extracted at each specific patch constitutes a feature map. Thus, the output of a convolutional layer is a set of feature maps generated by the convolution of each neuron across the layer’s input. Pooling layers reduce the spatial resolution of the generated feature maps by merging semantically similar features. Max Pooling is a commonly used pooling approach and consists of computing the maximum value of a defined local patch (the size of the patch related to a specific pooling layer is referred in the current work as “pool size”) of each feature map. Fully connected layers are basically single-layer feed-forward networks that perform the classification or regression task based on the learned deep representations.CNNs ,46 constvanishing or exploding gradients problem, which is caused by the internal covariate shift (constant fluctuations in layers’ input distributions) occurring in deep architectures during the training process. In [Batch Normalisation to address this specific issue. Batch Normalisation consists of automatically learning the optimal scaling and shifting parameters of each layer’s input, so that each layer’s input is dynamically normalised, thus significantly reducing the effects of the internal covariate shift and therefore stabilising the training process. Another common challenge occurring when training CNNs is the overfitting problem caused by the large amount of parameters that have to be consistently and effectively optimised. Applying regularisation techniques can help to significantly reduce this issue. The authors of [dropout approach, which is one of the most commonly used regularisation techniques for deep neural networks. The dropout approach consists of randomly and temporarily removing a set of neurons (or units) from the neural network during each training step, each neuron having a fixed probability Several challenges emerge when it comes to optimising such architectures. One of those challenges is the so-called cess. In , the autthors of  introducExponential Linear Unit (ELU) function [softmax function defined in Equation  are optimised using the cross entropy loss function defined in Equation , and thEquation ). FurtheEquation ,(5)L=∑iEquation ,(6)LossAdam) [Leave-One-Subject-Out (LOSO) cross-validation setting, which means that 87 experiments were conducted. During each experiment, the data specific to a single participant were used to evaluate the performance of the trained deep model and were never seen during the optimisation of this specific deep model. The data specific to each single participant were therefore used once as an unseen test set, and the results depicted in this section consist of averaged performance metrics from a set of 87 performance values.All previously described deep architectures are trained using the Adaptive Moment estimation (Adam)  optimisature see b were emes Keras , Tensorfes Keras  and Scikes Keras . The evaA performance evaluation of the designed architectures in a binary classification task consisting of the discrimination between the baseline temperature The deep architecture based on the EDA modality significantly outperforms all previously reported classification results with an average accuracy of 84.57%.Based on these findings, further classification experiments were conducted, based on each physiological modality and also the best performing fusion architecture (Late Fusion (b)). The performance evaluation of the conducted experiments consisting of several binary classification experiments and a multi-class classification experiment is summarised in EDA significantly outperforms both EMG and ECG in all conducted classification experiments and constitutes the best performing single modality, which is consistent with the results reported in previous works. Both EMG and ECG depict similar classification performances and also perform poorly for almost all classification experiments. The discrimination between the baseline temperature The information stemming from both modalities EMG and ECG harms the optimisation process of the fusion architecture due to its inconsistency. However, it can be seen in true positives(tp) correspond to the number of correct acceptances, false positives(fp) correspond to the number of false acceptances, true negatives(tn) correspond to the number of correct rejections and false negatives(fn) correspond to the number of false rejections. These four values stem from the confusion matrix of an evaluated inference model and are used to define different performance measures. Those used for the current evaluation of the designed classification architectures are defined in Subsequently, the performance of both EDA and late fusion architectures were further evaluated using different performance measures. In the case of binary classification experiments, The performance evaluation of the EDA architecture is depicted in We therefore compared the performance of the EDA and proposed late fusion approach to early works. For the sake of fairness, we considered the related works performed on the exact same dataset, using the exact same evaluation settings . The results depicted in Furthermore, we also compared the proposed late fusion approach with other fusion approaches proposed in early works. The results depicted in thors of  reportedthors of  reportedBioVid Heat Pain Database (Part B). The database was generated using the same exact procedure as Part A. However, it consists of 86 participants and two additional EMG signals (from the corrugator and the zygomaticus muscles) were recorded. In this evaluation, we used the same signals as in Part A , and used the same fusion architecture (Late fusion (b) depicted in Moreover, the designed fusion architecture was tested on the The methods reported in previous works consist of fusion approaches involving all the recorded signals and based on hand-crafted features ,56. AlthBioVid Heat Pain Database (Part A). Furthermore, several deep fusion architectures were also proposed for the aggregation of relevant information stemming from all involved physiological modalities. The proposed architecture specific to EDA significantly outperformed the results presented in previous works in all classification settings. For the classification task This work explored the application of deep neural networks for pain intensity classification based on physiological data including ECG, EMG and EDA. Several CNN architectures, based on 1D and 2D convolutional layers, were designed and assessed based on the end-to-end manner. Therefore, it is believed that the pre-training and fine tuning at different levels of abstraction of the CNN architectures, as well as the combination with recurrent neural networks , could potentially improve the performance of the current system, since such approaches have been successfully applied in other domains of application such as facial expression recognition [Moreover, all designed architectures were trained in an ognition ,60,61. FIn summary, the performed assessment suggests that deep learning approaches are relevant for the inference of pain intensity based on 1D physiological data, and such methods are able to significantly outperform traditional approaches based on hand-crafted features. Domain expert knowledge could be bypassed by enabling the designed deep architecture to learn relevant features from the data. In the future iterations of the current work, approaches consisting of combining both learned and hand-crafted features should be addressed. In addition, the designed architectures should be also assessed by replacing the classification experiments by regression experiments. Additionally, several data transformation approaches applied to the recorded 1D physiological data in order to generate 2D visual representations  should also be investigated in combination with established deep neural network approaches, specifically designed for this type of data representation.


Basic and Clinical Neuroscience published an article by Co-occurence of Pituitary Adenoma with Suprasellar and Olfactory Groove Meningiomas. They claimed it as the first case of co-occurence of these two malignancies. However, to our knowledge, this is not the first case reported in this regard. We reported the same case scenario in a 61-year-old woman referred to our outpatient clinic in 2007. In this commentary, we are going to discuss our reported case and present a brief review over co-occurence of intracranial meningioma with pituitary adenoma.Recently,  We read with interest the case report by However, in a paper published in Pituitary, we reported the first case ever diagnosed of simultaneous occurrence of GH-secreting pituitary adenoma, intracranial meningioma and two intracavernous asymptomatic aneurysms in a 61-year-old woman who was referred to our outpatient clinic reporting severe obesity and appearance of typical acromegalic features 13 years after a right frontal craniotomy for a pituitary tumor . EndocriIn the case by In our case, not cited in the case report by Lim, MRI showed a homogeneously enhancing intrasellar pituitary macroadenoma (12×10 mm) extending superiorly with visual pathways compression and bilateral intracavernous invasion, and simultaneous coexistence of a large intracavernous aneurysm of the right Internal Carotid Artery (ICA) adjacent to the pituitary adenoma. The presence of the right ICA aneurysm was confirmed by MRI angiography with 3D evaluation by Maximum Intensity Projection (MIP) reconstruction. Somatostatin Analog (SSA) treatment normalized GH and IGF-1 levels in a few weeks. Eight months later, the patient underwent a balloon ICA occlusion by endovascular approach with disappearance of the right ICA aneurysm. After one year, a new MRI confirmed the presence of the pituitary adenoma along with the appearance of a right frontal meningioma and a new ICA aneurysm on the left side. The patient preferred an expectation management refusing the surgical option. The last MRI confirmed the presence of three distinct lesions, showing the growth both of meningioma and of the left ICA aneurysm.Coexistence of pituitary lesion and other brain diseases has been frequently reported in literature. Moreover, an elevated co-prevalence of independent primary tumors has been found in patients with benign and malignant pituitary tumors and in their relatives . AssociaIn conclusion, in literature the association of intracranial meningioma with pituitary adenoma is a rarely reported surgical entity, but the simultaneous occurrence of multiple meningiomas and pituitary adenoma is an even more rare clinical event. Our case, described in 2007, represents the first case of an equally rare simultaneous occurrence of pituitary adenoma, intracranial meningioma and two intracavernous aneurysms adjacent to the pituitary adenoma and the first in which MRI allowed preoperative identification. In the presence of concomitant brain morbidities  treatment must be tailored to each patient. For this reason, the adequate knowledge of these coexistences, based on their location, is an essential precondition to plan a correct surgical approach, and to avoid life-threatening complications.


In this opinion article, we intend to elaborate on thyroid mediation of isoflavone effects mainly on the bone of aging males, which appears to have an important role but is still insufficiently analyzed in the existing literature. Namely, the consequences of exposure to endocrine-disrupting chemicals strongly depend on the timing of interaction and life stages of humans and animals, so we intended to highlight the thyroid-related mechanism underlying the beneficial effect of isoflavones on aged male bone.d-glucosides (genistin and daidzin) and only in minor amounts in their free form as aglycones (genistein and daidzein)  . The aglaidzein) . The potaidzein) .Several epidemiological studies and clinical trials have revealed that supplementation with soy isoflavones improves bone health status in early and postmenopausal women . In parain vitro and in vivo studies indicate different mechanisms of their action, whereas the changes of circulating thyroid hormone levels represent the outcome of all these effects. Namely, they inhibit thyroid peroxidase (TPO) activity by acting as competitive substrates for iodination , subcutaneous application of various doses of genistein or daidzein  suppressed thyroid activity, decreased thyroxin (T4) and T3, and elevated thyroid-stimulating hormone (TSH) in serum , 20. Sucin vitro . Howeverin vitro . Endogenin vitro . The trein vitro , which iin vitro .2+ concentrations were observed in comparison with those in orchidectomized controls 2–vitamin D3/calcitonin balance -1 and LAT-2 was confirmed in osteoblasts and osteoclasts at all stages of cell differentiation -equol produced from daidzein by the gut microbiota. Great variations in response to pharmacotherapeutics, including isoflavones, point to a personalized approach. Definition of isoflavone metabolizing phenotypes as a strategy for identification of individuals might benefit from osteoporosis-preventive strategies using isoflavones.The biopotency of aglycones is highly questioned at the moment because of their rapid metabolism, low serum concentration, and bioavailability upon supplementation . HoweverThis opinion article is founded on the fact that soy isoflavones represent effective bioactive compounds that interfere with thyroid cascade and signaling at various points in a sex-and-age-dependent manner. A deeper understanding of the mechanisms involved in thyroid-mediated isoflavone action in the bone is even more important considering the complexity of regulation of bone remodeling, as well as the actuality of the bone disorders in advanced age. Potentially, therapeutic exploitation of biomedical essence presented here may inspire further research and development of isoflavone-based supplementation for men suffering from endocrine disorders and secondary osteoporosis. Basic and clinical research about isoflavone effects in thyrotoxicosis and associated bone pathology could be of particular interest.All authors named have participated in the work in a substantive way. BŠ-J the Opinion concept creator, has written the majority of the article, analyzed the specific topics and interpreted the results of the research group in a broader context of literature. VA also contributed significantly to the writing of the article and provided the comprehensive approach to the scientific issue elaborated in the article. BF has included his focused expertise regarding bone microarchitecture and designed the figure. WS has carefully read and critically revised the manuscript for its scientific merit and intellectual content and has supplemented the literature survey. VM has supervised the work, carefully read the article for its scientific merit and intellectual content as well as supplemented the literature survey.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The most prevalent primary headaches tension-type headache and migraine are frequently associated with neck pain. A wide variety of treatment options is available for people with headache and neck pain. Some of these interventions are recommended in guidelines on headache: self-management strategies, pharmacological and non-pharmacological interventions. Physical treatment is a frequently applied treatment for headache. Although this treatment for headache is predominantly targeted on the cervical spine, the neurophysiological background of this intervention remains unclear. Recent knowledge from neuroscience will enhance clinical reasoning in physical treatment of headache. Therefore, we summarize the neuro- anatomical and—physiological findings on headache and neck pain from experimental research in both animals and humans. Several neurophysiological models  are proposed to understand the co-occurrence of headache and neck pain. This information can be of added value in understanding the use of physical treatment as a treatment option for patients with headache and neck pain. Headache causes substantial pain and disability in people's daily life and delivers a high burden and cost to society that is estimated only in Europe at 173 billion Euro per year , 3. A reδ- and C afferent neurons of the ophthalmic nerve together with first order Aδ- and C nociceptive afferent neurons from predominantly the dorsal root C2. These afferent neurons are directly or indirectly connected via wide dynamic range neurons to second-order neurons  increase in the excitability to electrical stimulation of the greater occipital nerve in C-fiber responses  into the temporal muscle in rats induces ongoing activity of spinal trigeminal neurons with meningeal receptive fields. In the same study local anesthesia of single neck muscles, but not of the musculus temporalis, shows a significant decrease of the provoked central trigeminal activity . This suC fibers , 70. Aff nucleus –76. Near nucleus , 77. Act nucleus . The par nucleus , 80.δ- and C fibers by manual pressure can activate the supraspinal DNIC system that acts specifically on spinal wide-dynamic-range (WDR) neurons and is able to modulate nociception at the TCC  and significantly increased R2 latencies of the nociceptive blink reflex only at the side of an anesthetic unilateral nerve blockade of the greater occipital nerve with prilocaine in healthy persons. These findings not only confirmed previous results related to anatomical and functional convergence of trigeminal and cervical afferent pathways, but also suggested that modulation hereof could be beneficial in treatment of primary headache disorders . In pati the TCC , 86.δ- and C fibers afferent input. Stimulation of proprioceptive input by active exercises for neck muscles may decrease the excitability of second order neurons at the TCC  neck and trigeminal nerve has to be incorporated in development of physical treatment for headache targeted at the cervical spine, especially the upper cervical region. According to the ‘gate-control' hypothesis, the relative high amount of proprioceptive afferent muscular input of upper cervical segments  to the c the TCC  and actied value . The imped value .In the last decades experimental research in both animals and humans on neuro-anatomy and neuro-physiology has contributed to understand the co-occurrence of headache and neck pain. Based on this information we further present a neuro-physiological background for physical treatment of headache and neck pain. Studies have gain new insights on the neuro-anatomical and neuro-physiological relation between headache and neck pain, but also raise questions if and how this relation can be influenced by physical treatment. Headache , neck pain, and cervical musculoskeletal dysfunctions seem to be related in case-control studies, although the strength, significance and explanation of this relation varies per type of headache.Clinicians have to consider, by sound clinical reasoning, whether cervical musculoskeletal dysfunctions are related to the patient's headache and which neurophysiological mechanisms could be involved. Therefore, we support the recommendation to classify headache according to the ICHD III criteria and to determine cervical musculoskeletal dysfunctions in patients with migraine, tension-type headache and cervicogenic headache . AdditioIt is a great challenge for clinicians and researchers to develop effective treatment strategies for headache targeted on modulation of cervical afferent input in order to decrease the excitability of first- to second order neurons at the level of the TCC. Experimental studies of the neurophysiological effect of physical treatment and randomized clinical trial on this topic are scarce and urgently warranted. Meanwhile, there is no standard recipe for physical treatment on the neck for different types of headache. But clinicians may be encouraged by recent evidence and new insights on headache and neck pain and may use this knowledge in clinical reasoning to provide a tailored and evidence based neuro-physiological approach for patients with headache and neck pain.RC and WD: concept development and writing of the manuscript; Both authors approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Musculoskeletal models enable movement scientists to examine muscle function by computing the mechanical work done by muscles during motor tasks. To estimate muscle work accurately requires a model that is physiologically plausible. Previous models of the human shoulder have coupled scapula movement to humeral movement. While coupled movement produces a stereotypical scapulohumeral rhythm, it cannot model shrugging or independent movement of the scapula and humerus. The artificial coupling of humeral elevation to scapular rotation permits muscles that cross the glenohumeral joint, such as the rotator-cuff muscles and deltoids, to do implausible work to elevate and rotate the scapula. In reality, the motion of the scapula is controlled by thoracoscapular muscles, yet the roles of these muscles in shoulder function remains unclear. To elucidate the roles of the thoracoscapular muscles, we developed a shoulder model with an accurate scapulothoracic joint and includes scapular muscles to drive its motion. We used the model to compute the work done by the thoracoscapular muscles during shrugging and arm elevation. We found that the bulk of the work done in upper-extremity tasks is performed by the largest muscles of the shoulder: trapezius, deltoids, pectoralis major, and serratus-anterior. Trapezius and serratus anterior prove to be important synergists in performing upward-rotation of the scapula. We show that the large thoracoscapular muscles do more work than glenohumeral muscles during arm-elevation tasks. The model, experimental data and simulation results are freely available on SimTK.org to enable anyone to explore our results and to perform further studies in OpenSim 4.0. Abnormal scapular movement is indicative of shoulder dysfunction, such as subacromial impingement, rotator-cuff tears, and other injuries . Bones and corresponding joint locations and muscle attachment locations were scaled linearly based on marker-based distances between the subject and the base (generic) model. Muscle optimal fiber and tendon slack lengths were scaled to preserve their ratio over the muscle path length in the scaled model. The ellipsoid surface of the thorax in the scapulothoracic joint was scaled by optimizing the ellipsoid tilt and radii that minimized marker-tracking errors. The thorax muscle wrapping object was initially scaled according to the thorax scale factors, however this lead to serratus anterior insertions on the anterior scapula to enter the wrapping surface, which results in the wrapping path becoming undefined. The wrapping ellipsoid surface was then hand adjusted by tilting the top of the ellipsoid toward the sternum until the path of the serratus anterior was well-defined for the complete scapula range of motion across all tasks. The greater freedom of the scapula also resulted in some muscles exceeding 150% of the optimal fiber-length and/or being too short (<50%) resulting in their inability to produce active force during the range-of-motion of the anticipated tasks. In these situations, the muscle optimal fiber-length was incrementally increased (by 2%) and tendon slack-length reduced by the same length until muscle forces alone were sufficient to track desired task kinematics. See Computed muscle control (CMC)  and Motion Monitor software  to simultaneously and continuously track four miniaturize sensors (model 800) at a sampling rate of 120 Hz. Three sensors were fixed to the thorax, scapula and humerus, respectively. Prior to continuous collection, a fourth sensor was rigidly affixed to a stylus and used to digitize the locations of bony landmarks with respect to the corresponding sensors, while the subject was in a neutral pose. The thorax sensor was placed on the T1 spinous process; the scapula sensor was placed over the flat surface on the superior acromion. Both sensors were held in place with double-sided adhesive tape wrapped with EnduraSports tape (Endura-Tape). The arm sensor was fixed on a strap that was tightly adjusted around the lateral aspect of the most distal part of the humerus. The ISB shoulder protocol  electrodes were placed on the skin after preparation  over the shoulder task interval  and shortening velocity, where concentric contractions yield positive power. The total positive muscle work during the elevation phase of the tasks was compared to the external work computed as the change in model potential energy due to elevating the arm (and added mass) against gravity. We expected the positive muscle work to be greater than external work due to negative work of lengthening muscles and the acceleration of limb segments relative to the center-of-mass.We generated muscle-driven simulations for all (18) experimental trials. Inverse kinematics accuracy for each trial was within 1 cm RMSE with respect to experimental marker locations and computed within 1.3 × of real-time. The average computation to real-time ratio for all CMC muscle-driven simulations was below 400 compute/real time. Muscle activations from muscle-driven simulations of the shoulder model were compared to the EMG for the same tasks, which yielded an average MAE of 0.06, with the vast majority of measured muscles below 0.1 . The PecThe simulated shoulder shrug demonstrates that the model can elevate and rotate the scapula independent of humerus rotations . SimulatThe MAE values for superior trapezius, deltoids and serratus anterior muscle activations when compared to EMG during shoulder flexion and abduction tasks  where 0.J exceeded the total external work (49.5J) necessary to elevate the arm during abduction with a 2 kg handheld weight.Superior trapezius, serratus anterior, and deltoids showed the greatest muscle activity and did the most positive work during the elevation phase of each task . As expeWe have developed a musculoskeletal shoulder model that reproduces the observed skeletal kinematics and muscle activity during shoulder shrugging and arm-elevation tasks. The model enabled us to compute the work done by upper-extremity muscles that drive the scapula and the glenohumeral joint. Prior to this study, scapulothoracic interaction was modeled either by forces of deformation using finite elements . The model runs natively in OpenSim without third party dependencies. Clinicians, researchers and students can probe the model for muscle and joint reaction forces from the analysis of subject and patient motion capture data as we have demonstrated. The capability of running the model in a purely forward dynamics simulation also makes the model suitable to ask “what if?” questions. For example, in the case that serratus anterior is weakened, can external bracing prevent winging? If so, why might bracing outcomes vary widely  are provided freely from SimTK.org  are freely available, deployable, and modifiable for any research or commercial use without restrictions from SimTK.org at This study was carried out in accordance with the recommendations of the Ethics Committee of the Polytechnic Institute of Setúbal with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the Polytechnic Institute of Setúbal.AS and RM conceived of the shoulder model and study aims. AS supervised and performed data analysis and wrote first draft of the manuscript. MD extensively refined the muscle paths, performed the analyses, and generated the reported results. RM initiated the addition of thoracoscapular muscles and led the data collection effort. SD supported the study, contributed to study aims, and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The cardiac lymphatic system drains excess fluid from the cardiac interstitium. Any impairment or dysfunction of the lymph structures can result in the accumulation of interstitial fluid, and may lead to edema and eventually cardiac dysfunction. Lymph originates directly from the interstitium and carries real-time information about the metabolic state of cells in specific regions of the heart. The detailed anatomy of the epicardial lymphatic system in individuals is broadly unknown. Generally, the epicardial lymphatic system is not taken into consideration during heart surgery. This study investigates the feasibility of detailed mapping and cannulation of the porcine epicardial lymphatic system for use in preservation of explanted hearts and heart failure studies in pigs and humans.The anatomy of the epicardial lymphatic systems of forty pig hearts was studied and documented. Using a 27 G needle, India ink was introduced directly into the epicardial lymphatic vessels in order to visualise them. Based on the anatomical findings thus obtained, two cannulation regions for the left and right principal trunks were identified. These regions were cannulated with a 26 G intravenous Venflon cannula-over-needle, and a Galeo Hydro Guide F014 wire was used to verify that the lumen was patent.The main epicardial lymphatic collectors were found to follow the main coronary arteries. Most of the lymph vessels drained into the left ventricular trunk, which evacuates fluid from the left heart and also partially from the right heart. The right trunk was often found to drain into the left trunk anterior basally. Right heart drainage was highly variable compared to the left. In addition, the overall cannulation success rate of the selected cannulation sites was only 57%.Mapping of the porcine epicardial lymphatic anatomy is feasible. The right ventricular drainage system had a higher degree of variability than the left, and the right cardiac lymph system was found to be partially cleared through the left lymphatic trunk. To improve cannulation success rate, we proposed two sites for cannulation based on these findings and the use of Venflon cannulas (26 G) for cannulation and lymph collection. This method might be helpful for future studies that focus on biochemical sample analysis and decompression.Real-time biochemical assessment and decompression of lymph may contribute to the understanding of heart failure and eventually result in preventive measures. First its relevance should be established by additional research in both arrested and working porcine hearts. Imaging and mapping of the epicardial lymphatics may enable sampling and drainage and contribute to the prevention or treatment of heart failure. We envision that this approach may be considered in patients with a high risk of postoperative left and right heart failure during open-heart surgery. Despite its role in controlling cardiac fluid hemostasis and maintaining normal cardiac function, the cardiac lymphatic sys-tem (CLS) has been less studied than coronary vasculature. This lack of interest is probably due to the small size and complex network of lymph vessels. The CLS maintains cellular hemostasis by removing superabundant interstitial fluid from the cardiac cells. Thus, metabolic changes in cardiac muscle can be expected to be detected earlier in lymph than in venous blood. Consequently, analysis of the lymph could be used to identify early cellular metabolic changes.Lymphatic obstructions sustained during surgery could result in interstitial fluid accumulation, which decreases the compli-ance capacity of the heart and leads to an increase in diffusion distance for nutrients and waste products. An increase in the amount of interstitial fluid results in cardiac edema followed by ischemia and a loss of cardiac function in the affected areas of the heart –3. DepreAnalysis of lymph from cannulated vessels has demonstrated that metabolic changes in particular areas of the heart are dependent on the site from which the lymph is taken . Hence, This study aims to illustrate and map the porcine epicardial lymphatic network in detail which will lead to a better under-standing of the network and its variations and potential applica-tions of this knowledge.Forty hearts were obtained from Dutch Landrace hybrid pigs of about 110 kg weight that had been slaughtered for human consumption. All slaughterhouse and laboratory protocols were compliant with EC regulations 1069/2009 regarding diagnosis and research of slaughterhouse animal material, administered by the Dutch Government  and accepted by the related legal authorities of animal welfare (Food and Consumer Product Safety Authority).India ink solution  was used for lymphatic visualization. The solution was injected directly into the epicardial lymphatic vessels with a 27 G needle.Intravenous Venflon cannulas (26 G) with a cannula-over-needle design were used to cannulate the left and right principal trunks. A Galeo Hydro Guide wire  was used to verify that the lumen was open. After the trunks were cannulated, India ink was injected apically. A cannulation was assumed to be successful when the apically injected ink entered the cannula.The inferoposterior cardiac lymphatic networks showed fewer anatomical variations. In all hearts, the CXT was ob-served to follow the circumflex artery and drained large areas of the left and right inferoposterior ventricle  and pulmonary reconstruction   in whichLymphatic vessels often overlapped the coronary arteries  and consLymphazurin could be used to verify the different techniques for lymphatic cannulation described in the literature . During the present study, a cannulation technique was developed by using Venflon cannulas with a cannula-over-needle design. This technique was reliable due to cannula flexibility. The can-nulas were introduced basally between the arteries and the atria as these locations were frequently the paths followed by the left and right principal trunks and could therefore be used for lym-phatic sampling and analysis. Due to the small structure of the epicardial lymphatics, cannulation is expected to be best con-ducted in arrested hearts, but cannulation in beating hearts is possible in experienced hands.Given the similarity between the lymphatic systems of porcine and human hearts, the study described here enables the studying of preservation techniques and heart failure modalities in the ex vivo working model known as PhysioHeart . The plaIt proved feasible to illustrate the porcine epicardial lym-phatic anatomy in detail resulting in a map that enables iden-tification of sites for drainage of lymph. The variability of the right system remains a challenge for identifying an appropriate drainage site. However, the left lymphatic trunk also facilitates partial evacuation of the right cardiac lymph. The proposed can-nulation technique offers an acceptable cannulation success rate to obtain cardiac lymph for analysis of metabolic changes.Epicardial lymphatic imaging and mapping may enable sam-pling and drainage which will potentially contribute to the pre-vention and treatment of heart failure. However, additional re-search in beating heart pig models is indicated to further estimate its relevance. Real-time sampling for biochemical assessment and lymph decompression may contribute to prevent or mitigate imminent heart failure during open-heart surgery.The authors have nothing to disclose.


A 21-year-old African-American male presented to the emergency room with a sudden diffuse onset abdominal pain of one day duration. CT findings revealed mild telescoping of loops of small bowel and mesenteric fat in the left mid abdomen with no apparent masses. The patient underwent an exploratory laparoscopy revealing intussusception of the mid jejunum. As a fair amount of distention compromised safe navigation of the bowel, laparoscopic resection was not warranted at this time. Open approach allowed for segmental resection of the affected segment of the small bowel. This was followed by primary anastomosis. Pathological findings revealed focal reactive lymphoid hyperplasia with marked congestion in the lamina propria of the jejunum. The patient had an unremarkable postoperative period and recovered with no further complications. Intussusception is a potentially life-threatening condition involving intermittent crampy abdominal pain, occurrence of mucoid hematochezia, and threatened ischemia of the small intestine. Intussusceptions originate from telescoping of a segment of the gastrointestinal tracts into an adjacent section of the bowel . The cliA 21-year-old African-American male presented to our emergency department complaining of sudden onset of diffuse abdominal pain. His history was significant for recurrent episodes of gonococcal urethritis and no other ailments. He described this pain as diffuse and constant pressure that started suddenly that morning and had progressed throughout the day. Patient was hemodynamically stable with leukocytosis at 11,200 and a positive urinalysis. Computed Tomography (CT) revealed mild telescoping of loops of the small bowel and mesenteric fat in the left mid abdomen . No obviPersistent abdominal pain after 24 hours of observation prompted diagnostic laparoscopy revealing intussusception of the mid jejunum. This prompted open exploration, segmental resection, and primary anastomosis of the jejunum. Pathology reported marked congestion and focal reactive lymphoid hyperplasia in the lamina propria of the invaginated bowel. The patient was discharged home postop day 2 with an unremarkable follow-up. CT findings revealed mild telescoping of loops of small bowel and mesenteric fat in the left mid abdomen. Uncertain by these radiographic findings, exploratory laparoscopy was initiated, profoundly confirming inflammation and telescoping of the jejunum .A patient presenting with diffuse and vague abdominal pain may have a small bowel obstruction, appendicitis, perforated viscus, inflammatory bowel disease, or other causes of peritoneal inflammation . NoninflDue to the lack of previous surgical history, suspicion for intraperitoneal adhesions was low. A small bowel obstruction of unknown cause ranked amongst the top of our differentials. CT was important in investigating the etiology of the continuous abdominal pain to avoid missing catastrophic sequelae. Laparoscopy and ultimately an open laparotomy were deemed imminent in defining our root cause. With no knowledge of abdominal adhesion or history of hernias, our scope of differentials has to exceed more than just a small bowel obstruction.Contrast air enema reduction was bypassed due to indication for surgical resection as our patient was of adult age and at risk for malignancies and recurrence . This apFollowing the segmental resection and primary anastomosis of the proximal bowel, our patient had no significant postoperative complications and was discharged on day 2 after the procedure. The patient had an unremarkable follow-up.We present a rare case of jejunal intussusception causing bowel obstruction and ischemia in an adult patient. Acute presentation of this disease is usually limited to infants of less than 1 year of age and affiliated with such complaints as red mucinous stools . Yet, weCases of intussusception in the adult population are often easily diagnosed via CT imaging and confined to typical etiologies such as adenomatous polyps, lipomas, Peutz-Jeghers syndrome, neurofibromas, and other benign and malignant tumorous diseases .Ultrasound imaging has proven useful in such cases in the past. Yet sensitivity in this modality is limited to the experience of the technicians and radiologists involved . Cases iPathology from our case revealed lymphoid hyperplasia as the etiology in our lead point. Laparoscopy revealed a significant yet viable portion of the invaginated jejunum approximately 4 feet from the ligament of Treitz. Reduction and further inspection of the involved bowel confirmed indication for segmental resection over en bloc resection. With no concerns of bowel ischemia at this time, we were able to proceed with a simple resection and anastomosis. Current modalities of practice support intraoperative decision towards definitive surgical treatment, depending on such variables as viability and risk of a short gut .Lymphoid hyperplasia though common in the pediatric population, can also lead to acute abdominal pathology in the adult population. Though no presence of malignant disease was found in our patient, such etiologies as lymphoma would also be relevant to such a case . Though We suggest intussusception as a worthy differential for adult patients presenting with obstructive symptoms of unknown origin and nonresolving abdominal pain. These cases should prompt aggressive surgical intervention as other methods can delay necessary diagnostic and therapeutic resolution.Intussusception as a worthy differential for adult patients presenting with obstructive symptoms of unknown originLymphoid hyperplasia, though common in the pediatric population, can also lead to acute abdominal pathology in the adult populationExploratory laparotomy and resection are best indicated to understand the underlying causes of adult intussusceptionThe following are the learning points:


High resolution ultrasonography (US) has been used for diagnosis and evaluation of entrapment peripheral neuropathy. Ulnar neuropathy at the elbow (UNE) is the second most common focal entrapment neuropathy. The ulnar nerve tends to move to the anteromedial side and sometimes subluxates or dislocates over the medial epicondyle as the elbow is flexed. Dislocation of the ulnar nerve during elbow flexion may contribute to friction injury. We aimed to investigate the effects which the dislocation of ulnar nerve at the elbow could have on the electrophysiologic pathology of UNE.We retrospectively reviewed 71 arms of UNE. The demographic data, electrodiagnosis findings and US findings of ulnar nerve were analyzed. We classified the electrodiagnosis findings of UNE into three pathologic types; demyelinating, sensory axonal loss, and mixed sensorimotor axonal loss. The arms were grouped into non-dislocation, partial dislocation, and complete dislocation groups according to the findings of nerve dislocation in US examination. We compared the electrodiagnosis findings, ulnar nerve cross sectional areas in US and electrodiagnosis pathology types among the groups.A total of 18 (25.3%) arms showed partial dislocation, and 15 (21.1%) arms showed complete dislocation of ulnar nerve in US. In the comparison of electrodiagnosis findings, the partial and complete dislocation groups showed significantly slower conduction velocities and lower amplitudes than non-dislocation group in motor conduction study. In the sensory conduction study, the conduction velocity was significantly slower in partial dislocation group and the amplitude was significantly lower in complete dislocation group than non-dislocation group. In the comparison of US findings, patients in partial and complete dislocation groups showed significantly larger cross sectional areas of the ulnar nerve. The comparison of electrodiagnosis pathologic types among the groups revealed that there were significantly larger proportions of the axonal loss  in partial and complete dislocation groups than non-dislocation group.The ulnar nerve dislocation could influence on the more severe damage of the ulnar nerve in patients with UNE. It might be important to evaluate the dislocation of the ulnar nerve using US in diagnosing ulnar neuropathy for predicting the prognosis and determining the treatment direction of UNE. High resolution ultrasonography (US) has been used for diagnosis and evaluation of entrapment peripheral neuropathy , 2006b. Ulnar neuropathy at the elbow (UNE) is the second most common focal entrapment neuropathy after carpal tunnel syndrome . During The ulnar nerve dislocation could be observed even in healthy individuals . In prevThis was a retrospective observational study conducted on the consecutive patients who underwent electrophysiologic study and US for diagnosis of UNE between January 2013 and December 2015. The inclusion criteria were as follows: (1) typical clinical signs and symptoms indicating ulnar nerve lesion , (2) definite electrodiagnosis findings of UNE. We excluded the patients who met the following criteria: (1) traumatic ulnar nerve lesion, (2) ulnar nerve entrapment in other sites such as wrist, (3) perviously operated UNE, (4) polyneuropathy, (5) C8-T1 cervical radiculopathy, (6) lower trunk brachial plexopathy. We had enrolled twenty arms of 11 subjects who had never experienced symptoms or clinical signs of ulnar neuropathy, as control group. This study was approved by the Institutional Review Board of the Korea University Guro Hospital (2017GR0806). The informed consent from participants was waived by Institutional Review Board.The electrodiagnosis of UNE included the motor and sensory nerve conduction studies (NCS) of ulnar and dorsal ulnar cutaneous nerves and the needle electromyography of abductor digiti minimi (ADM), first dorsal interossei, and flexor carpi ulnaris muscles. The compound motor action potentials (CMAP) were recorded from the ADM muscle. The ulnar nerve short-segmental study was performed in across-the-elbow segment . The elbow was extended in wrist stimulation, and flexed 90° in across-the-elbow segmental study. The recording sites of antidromic sensory conduction studies were the fifth finger and the fourth web space of hand in the ulnar and the dorsal ulnar cutaneous nerve stimulations, respectively.Diagnosis of UNE was made according to diagnostic criteria proposed by the American Association of Electrodiagnostic Medicine (AAEM) .Absolute motor nerve conduction velocity from above elbow (AE) to below elbow (BE) of less than 50 m/s.An AE-to-BE segment greater than 10 m/s slower than the BE-to-wrist segment.A decrease in CMAP negative peak amplitude from BE to AE greater than 20%.A significant change in CMAP configuration at the AE site compared to the BE site.We classified the electrodiagnosis findings of UNE into three pathologic types . The demFor ultrasound examinations, a HD15 ultrasound device  with a 5–12 MHz linear array transducer was used. The examinations were performed by a physician who had more than 10 years of experiences in musculoskeletal US. During the examination, the patients were placed in supine position. The transducer was placed at the medial epicondyle level and cross‐sectional images of the ulnar nerve and the cubital tunnel were taken. In transverse plane, the nerve was traced from the inlet to the outlet of cubital tunnel. The nerve cross-sectional areas (CSAs) were measured at the maximum swelling point. The examiner carefully placed the probe perpendicular to the nerve to obtain the most accurate CSA. The CSA was measured using automatic manual “tracing” just inside the hyperechogenic line that surrounds the nerve perineurium. In each US examination, the examiner measured CSA three times and the mean value was recorded to minimize error.For the evaluation of ulnar nerve dislocation, the elbow was imaged dynamically from full extension to full flexion. An effort was made to minimize transducer pressure on the nerve to minimize its effect on nerve movement. We classified the findings of ulnar nerve dislocation into three categories; non-dislocation, partial dislocation and complete dislocation . The part-test for the quantitative variables , and the chi-square analysis for the nominal variables . We conducted the logistic regression analysis to investigate which factors affected the development of axonal loss of UNE. All p-values were two-sided, and a p-value of < 0.05 was considered to reflect statistical significance. After Bonferroni correction, p < 0.017 (0.05/3) was considered to denote statistical significance. The statistical analyses were conducted using the Statistical Package for the Social Sciences version 22.0  software package for Windows.The analysis of variance was performed to compare the quantitative variables (body mass index (BMI), disease duration and age) of demographic data and the results of electrodiagnosis and ulnar nerve CSAs among the groups according to the ulnar nerve dislocation. Tucky’s test was used for the post hoc analysis. In the analysis of nominal variables (gender and site) of demographic data and the pathology types of neuropathy among the groups, we performed the chi-square analysis. Bonferroni correction was conducted for the intergroup multiple comparisons. In the comparisons between the control group and patients with UNE, we used the independent We enrolled 71 arms (65 patients) of UNE in this study. A total of 38 (53.5%) arms were classified into non-dislocation group, 18 (25.4%) arms were partial dislocation group, and 15 (21.1%) arms were complete dislocation group. The demographic data of the arms are revealed in The comparisons of motor NCS results among the groups are revealed in The results of sensory NCS were significantly different among the groups, as presented in p = 0.000). The intergroup comparisons after Bonferroni correction revealed that there were significantly larger numbers of sensory axonal loss and mixed sensorimotor axonal loss of UNE in the patients with ulnar nerve dislocation than non-dislocation group. However, there was no significant difference between the partial and complete dislocation groups.In p = 0.000). All the other factors were not statistically significant.The results of logistic regression analysis to investigate the factors contributing to the axonal type  UNE are shown in We have investigated the relation between the ulnar nerve dislocation and the pathophysiology of UNE. In this study, more axonal loss of ulnar nerve was observed in patients with dislocation or subluxation of the ulnar nerve at elbow flexion. Not only in the ultrasonographic findings but also the electrophysiologic findings, the ulnar nerve dislocation could influence on the more severe damage of the ulnar nerve in patients with UNE. These results suggest that the dislocation of ulnar nerve at the elbow is related with the pathophysiology of UNE.The ulnar nerve dislocation had been investigated in many previous studies. The ulnar nerve dislocation had been observed in 16.2% out of two thousand elbows according to a study of As the development of US enables the dynamic examination, several studies in which the nerve dislocation was investigated using US have been published. The difference in the incidence rates of ulnar nerve dislocation between the healthy subjects and patients with UNE has not been established yet . Previou2) and US findings could reflect the type and severity of UNE. In our study, the similar findings were observed in comparison of the ulnar nerve CSA between the axonal group  and demyelinating group (n = 40). The analysis using an independent t-test showed that the CSA of axonal group was significantly larger than demyelinating group .There have been some studies that investigated the US findings according to the severity of UNE. In the study of In present study, the pathologic type of UNE was significantly different according to the ulnar nerve dislocation. We had classified the severity of UNE as three levels; demyelinating, sensory axonal, and sensorimotor axonal. Difference between sensory and sensorimotor axonal loss is most probably due to absent collateral reinnervation on the sensory side. There were a significantly larger number of patients with more severe type of UNE in more severe ulnar nerve dislocation group. In the comparison of electrophysiologic findings according to the ulnar nerve dislocation, the patients in partial or complete dislocation group revealed significantly worse findings in multiple electrodiagnostic parameters than non-dislocation group. Not only CMAP and SNAP amplitudes, but also there were significant differences of sensory nerve conduction velocities between the complete dislocation and non-dislocation groups. Because the axonal losses occur more predominantly in large size fibers, the sensory conduction velocity decrements in complete dislocation group may be explained by the axonal losses of large and fast nerve fibers. The ulnar nerve CSAs were also significantly larger in ulnar nerve partial and complete dislocation groups than non-dislocation group. These findings may indicate that the ulnar nerve dislocation could effect on the severity or pathologic type of UNE. There are still many controversies against the association between the development of UNE and the incidence of ulnar nerve dislocation. However, at least, the results of this study suggest that the dislocation of ulnar nerve in patients with UNE could related with the aggravation of electrodiagnostic findings. It could be thought that the repetitive friction and shear stress additional to the compression due to hypermobility of ulnar nerve would induce deterioration of neuropathy.On the contrary to our study findings, Recently, two studies had been published arguing against the role of ulnar nerve dislocation in UNE. Leis et al., had reported that UNE occurs less frequently and is less severe on the side of complete ulnar nerve dislocation. They concluded that complete dislocation may even have a protective effect on the ulnar nerve . The othIn previous studies, UNE under the humeroulnar aponeurosis were mainly axonal and more severe , 2016b, There are several limitations in this study. First, this study was conducted in a retrospective design. We have reviewed the data of consecutive patients by a single examiner, nonetheless there is a possibility of selection bias. In addition, because of the retrospective design, we could not examine more precise localization of ulnar neuropathy. Second, while the US examination was performed by a single examiner, the electrodiagnostic tests were performed by multiple examiners. In spite that the electrodiagnosis has relatively low risk of examiner dependency, the reliability could be lower than the study by a single examiner. Third, the severity of specific clinical symptoms cannot be analyzed due to limitation of recorded information. If further prospective studies could be planned, the clinical data of specific symptoms, such as parestheisa and weakness, should be included in a study design and analysis. Lastly, the patients included in study were small in number. We have included 71 patients. Compared to previous studies, these numbers are relatively small. Further large-sized studies are needed.Despite the retrospective study, demographic data such as age, disease duration, sex, and BMI of the patients included in this study did not differ between groups according to ulnar nerve dislocation. Therefore, the findings of this study are meaningful in understanding the impact of ulnar nerve dislocation on electrophysiologic pathology of ulnar neuropathy. In particular, the results of logistic regression analysis indicate that the dislocation of ulnar nerve could be an important factor contributing to axonal loss in UNE. The ulnar nerve dislocation could influence on the more severe damage of the ulnar nerve in patients with UNE. Considering these findings, it might be important to evaluate the dislocation of the ulnar nerve using US in diagnosing ulnar neuropathy for predicting the prognosis and determining the treatment direction of UNE.10.7717/peerj.6972/supp-1Supplemental Information 1Click here for additional data file.


Understanding the mode of action of membrane contact sites (MCSs) across eukaryotic organisms at the near-atomic level to infer function at the cellular and tissue levels is a challenge scientists are currently facing. These peculiar systems dedicated to inter-organellar communication are perfect examples of cellular processes where the interplay between lipids and proteins is critical. In this mini review, we underline the link between membrane lipid environment, the recruitment of proteins at specialized membrane domains and the function of MCSs. More precisely, we want to give insights on the crucial role of lipids in defining the specificity of plant endoplasmic reticulum (ER)-plasma membrane (PM) MCSs and we further propose approaches to study them at multiple scales. Our goal is not so much to go into detailed description of MCSs, as there are numerous focused reviews on the subject, but rather try to pinpoint the critical elements defining those structures and give an original point of view by considering the subject from a near-atomic angle with a focus on lipids. We review current knowledge as to how lipids can define MCS territories, play a role in the recruitment and function of the MCS-associated proteins and in turn, how the lipid environment can be modified by proteins. More geynthesis . MCSs’ cynthesis . Many reynthesis . There iynthesis . The exaynthesis . In turnynthesis . In suchWe chose here to give a global view and additional thoughts on the role of lipids at plant MCSs, mainly at endoplasmic reticulum (ER)-plasma membrane (PM) MCSs (EPCSs). In this review, we will first describe the different ways lipids can define specific regions and regulate protein complexes through the formation of lipid domains, the regulation of membrane curvature and membrane electrostatics. Secondly, we will look at the importance of lipid exchange at MCSs. Thirdly, we will open a discussion about the particularity of plasmodesmata MCSs and their potential implications in organelle crosstalk, cell-to-cell communication and trafficking regulation. Finally, we list a number of multidisciplinary approaches that could be used to provide a complete view of these structures at (near) atomic and molecular levels.MCSs have specific molecular compositions in both lipids and proteins, which define nano- and microdomains within the organelle. These subdomains are very important for the cellular polarization of signaling events via the formation of protein complexes, notably receptor complexes that are as such spatially and temporally regulated, driving acute signaling pathways . The molThere are two main elements playing a role in membrane fluidity and lipid domain formation and conservation. A very general feature is the liquid-liquid phase separation, caused by the tendency of sterols to associate with saturated lipids or proteins and form sterol-enriched ordered domains (liquid ordered Lo versus liquid disordered Ld domains) and of unsaturated lipids to tune the phase separation stability . More prPopulus trichocarpa shows an increase in the length of the transmembrane domains of plasmodesmata-associated proteins in comparison with membrane-associated proteins  and the Oxysterol Binding Protein (OSBP), which is very important for the control of trans-Golgi lipid composition, hence PM lipid composition  is the major anionic lipid that drives the electrostatic identity of the PM inner leaflet  but a moNegatively charged lipids are also critical elements of EPCSs, acting as co-factors for membrane tethering through direct interaction with tether proteins. Few examples are tricalbins (Tcb1-3) and Ist2 proteins in yeast , extendeLocal lipid modifications, pH and gradients/local concentrations of ions must also be taken into account in the regulation of the membrane electrostatic signature and thus the ability of anionic lipid-protein interactions. We know that MCSs are places of calcium exchange and anionic lipid concentration . It is iAt MCS, we observe an alternative transport to vesicular trafficking: a direct shuttle/exchange of lipids between membranes. This exchange seems to be a way to guarantee robust mechanism of lipid transfer and regulation between compartments as it results in organellar lipid modifications and plays a major role in cellular events such insulin response  and neurtrans-Golgi network with sterols. This counter-flow process results in sterol enrichment at the trans-Golgi network and PI4P pool maintenance at the ER P2 from the ER  associate with vesicle-associated membrane protein-associated proteins (VAPs) at ER MCSs to specifically exchange sterols, PS and PIP molecules . Osh4 ust the ER . Interesns-Golgi . This trm the ER . OverallPlasmodesmata are plant-specific channels crossing cell walls and enabling cell-to-cell communication . They arPlasmodesmata are also singular amongst MCSs as they present a unique structural organization and membrane biophysical properties. Inside the pore, both the ER and the PM present extreme curvature, both positive and negative. So instead of two “flat” membrane segments tethered together, plasmodesmata MCS features two membrane tubes nested into each other and sitting at cell interfaces . The extremely confined space between the ER and the PM (2–3 nm) is also not usual for MCSs and tight connection between the PM and cell wall components might lead us to someday talk about WALL-PM-ER MCSs.A global view of protein population at plasmodesmata is starting to emerge  and few in silico, biophysical-based tools and electron microscopy for understanding MCSs at atomic/macromolecular-levels. Many options are possible but a number of approaches are especially interesting in the context of protein/lipid interaction, hence MCSs  requires bridging across scales from atomic (or near-atomic) to cellular and tissue levels, to get a comprehensive picture of MCSs. While cellular and tissue-level events can be tackled by classical cell biology  and genetic tools, their limits in terms of resolution encourage the use of MCSs see . For exaMCSs see . Currents -mediated membrane fusion, involved for example in the highly regulated release of neurotransmitters at the synapse in animals , proves There is still a lot to be done in the understanding of plant EPCS function and the molecular mechanisms involved in their dynamics and regulation. Important questions concern the function and role of membrane compartmentalization , the molecular mechanisms associated with the tethering machinery at MCSs  and the roles of the lipid environment in the definition of MCSs . However, increasing technical resources have helped to grasp pieces of the puzzle that we are only now starting to assemble. The complexity arising from the incredible diversity in lipids and proteins and, over all, the complex relationships that interconnect them are not making the task easy to accomplish. The biophysical properties of the membrane derived from the intrinsic nature of a plethora of lipids species and their mutual interactions, is impacting on the recruitment and function of proteins, which in turn are fine tuning their lipid environment. The effects of this cycle are expected to get even more intertwined inside very confined environments, such as MCSs, and the entanglement is such that every molecule and every interaction is part of the dance, driving short or long-term consequences on MCS function.JP did the writing, figure, and table. FI and LL did the corrections and advised on the manuscript content. EB supervised the writing and did the corrections and comments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Diet is a major determinant of bacterial community structure in termite guts, but evidence of its importance in the closely related cockroaches is conflicting. Here, we investigated the ecological drivers of the bacterial gut microbiota in cockroaches that feed on lignocellulosic leaf litter.Ergaula capucina, Pycnoscelus surinamensis, and Byrsotria rothi were similar to those reported for both wood-feeding and omnivorous cockroaches. All gut compartments were anoxic at the center and showed a slightly acidic to neutral pH and variable but slightly reducing conditions. Hydrogen accumulated only in the crop of B. rothi. High-throughput amplicon sequencing of bacterial 16S rRNA genes documented that community structure in individual gut compartments correlated strongly with the respective microenvironmental conditions. A comparison of the hindgut microbiota of cockroaches and termites from different feeding groups revealed that the vast majority of the core taxa in cockroaches with a lignocellulosic diet were present also in omnivorous cockroaches but absent in wood-feeding higher termites.The physicochemical conditions determined with microsensors in the guts of Our results indicate that diet is not the primary driver of bacterial community structure in the gut of wood- and litter-feeding cockroaches. The high similarity to the gut microbiota of omnivorous cockroaches suggests that the dietary components that are actually digested do not differ fundamentally between feeding groups. Fibrobacteres and Spirochaetes . Table


The effects of sulfation of yeast glucans was optimized using response surface methodology. The degree of sulfation was evaluated from 0.11 to 0.75 using ion-chromatography. The structural characteristics of SYG (sulfation of yeast glucans) with a DS = 0.75 were determined using high-performance liquid chromatography/gel-permeation chromatography and finally by Fourier transform infrared spectrometry. The SYG had lower viscosity and greater solubility than the native yeast glucans, suggesting that the conformation of the SYG had significantly changed. The results also showed that SYG had a significantly greater antioxidant activity in vivo compared to native yeast glucans. Pleurotus ostreatus) increased SOD and CAT activity in rat erythrocytes . I. I29]. Ip < 0.05) compared to the untreated mice. This decrease showed that the immune system activity had been injured with irradiation and the ConA induced lymphocyte transformation was inhibited. Although the spleen cell proliferation ability treatment with YG or SYG did not reach that of the untreated. With the administration of YG or SYG, the spleen cell proliferation ability improved compared with the irradiated mice. Moreover, the irradiated mice treated with SYG had the same effect on the spleen cell proliferation ability compared with the YG treatment.Lymphocyte immune response is an important function of cellular components, which can be a direct reflection of the conversion capacity of immune cells . The effDuan and Li previously measured lipid oxidative damage as shown by serum lipoperoxide (LPO) levels and superoxide dismutase (SOD) activity . Malondip < 0.05) of antioxidant enzyme activity (CAT) was observed in the spleen with the irradiated mice compared to the untreated mice. Compared with the irradiated mice, the mice treatment with YG and SYG did not significantly reduce the level of MDA, particularly in the YG group. But the administration of SYG increased the activity of both the CAT and the SOD enzymatic antioxidants in the spleen compared with those from the irradiated mice. Moreover, the mice treated with SYG increased the activity of the enzymes CAT and the SOD in the spleen better those mice treatment with YG.The effect of the YG and the SYG on the SOD, CAT, and levels of MDA activities in the mice spleen is shown in The purpose of this study was to study the possibility of obtaining new or robust pharmacological agents with possible therapeutic use using chemical modifications. The research supports the hypothesis that sulfated yeast glucans have significant therapeutic potential. Using RSM simplified the optimization of the temperature, time, and the solvent-solid ratio. Sulfating can improve the water solubility of previously relatively insoluble polysaccharide fractions. The SYG was shown to be better at preventing radiation-induced oxidative damage compared to the untreated YG. Previous research from this laboratory also showed that the immune-enhancing efficacy of sulfated polysaccharides were much better than those of non-modified polysaccharides . Other b


According to the WHO, approximately 254 million patients are chronic carriers of hepatitis B virus (HBV) and the fatalities are in the range of 0.5 to 1 million patients per year [Chronic hepatitis B (CHB) is one of the diseases where therapeutic vaccination has been tested with enthusiasm and hope, due to the limitations and low effectiveness  of curreTherapeutic vaccination can be conceptualized as the immunization strategy aimed at activating or modifying the immune system in order to cure, control or limit the progression of a specific pathological condition, using an active and specific stimulation of the immune system. This therapeutic approach has been attempted in the fields of chronic infectious diseases, cancer, autoimmunity, allergy and the treatment of addiction to several drugs.The working hypothesis of therapeutic vaccination in the field of CHB is based on the understanding of the immunological profile of patients with natural- or treatment-induced serological and virological responses, in contrast to the profile induced in those unable to control HBV replication and the related liver damage. Mimicking this immune profile, several vaccine candidates were developed and tested. Even after the exciting Phase I/II results, several companies have stopped studies with their candidates since they failed to fulfill specific clinical end points in subsequent trials. A closer look into these clinical results is required.Actions have been taken to improve therapeutic vaccines: inclusion of new antigens; the use of different routes of administration; changes in the vaccination schedule; the inclusion of potent adjuvants; the optimization of the antigen dose, etc. One of the reasons of their failure may be the fact that most of these clinical trials were conducted in patients under a deep and long-standing viral suppression .The rationale of therapeutic vaccination when administered under viral suppression, is based on the observation that a decrease in viral load often precedes the detection of anti-HBV-specific T-cell responses, both in patients resolving natural infections and in those achieving HBeAg seroconversion during the chronic infection. Thus, a reduction in HBV load by antiviral treatment with nucleot(s)ide analogs (NUC) may increase the responsiveness of HBV-specific T cells, which are hyporesponsive in cases of persistent HBV infection . HoweverIncreased HBV-specific T-cell responses are detectable during the first few months of lamivudine treatment ; howeverThere are some theoretical disadvantages related to immunizing patients under long-term antiviral treatment. Vaccine-induced T cells should exert their function in the liver. However, the anti-inflammatory liver environment is reinforced, as reflected by the reduction in alanine amino transferase (ALT) levels in most patients few weeks after the start of antiviral treatment . In lineThe suppression of viral replication in patients under NUC therapy leads to a reduction in the number of hepatocytes presenting viral antigens, such as cytoplasmic HBcAg. It has been demonstrated that the control of the replication can be predicted by the low intracellular expression of HBcAg . Taken tHeberNasvac, a therapeutic vaccine used as a monotherapy, was compared with pegylated interferon (PegIFN) in an efficacy Phase III clinical trial . This prThe sanitary registration granted to HeberNasvac in its country of origin (Cuba) as well as the first international activities with this product in Japan  and otheThere is still a long road ahead in the optimization of this product. In fact, the first clinical evaluation of HeberNasvac combined with NUC failed to demonstrate the expected efficacy according to the trial design ,26. TherMajor associations for the study of the liver support antiviral treatment discontinuation under strict monitoring in noncirrhotic HBeAg-negative patients, with long-time virological suppression and low fibrosis. The recommendations of treatment discontinuation in HBeAg-negative patients was preceded by a strong meta-analysis that detected the increase of the anti-HBV immune response after NUC cessation, as a consequence of viral rebound. ALT increases, in patients with low levels of fibrosis and under strict assessment, are considered benign in nature and reflect an immune activation that leads to HBsAg elimination in 20–40% of the patients in the 3-year follow-up period. On the other hand, patients continuing treatment with NUCs evidenced no reduction in their serum HBsAg levels .The European Association for the Study of the Liver (EASL) has established rules for restarting therapy based on the absence of response, or on a clear and sustained re-emergence of the ALT and HBV DNA. Transient and moderate ALT increases after viral rebound are considered physiologically normal. This is later naturally controlled by the immune system. After a solid meta-analysis , EASL guThe currently used clinical trial methodology should be adjusted to implement the novel guidelines proposed in patients discontinuing antiviral treatment. Such modifications favor the incorporation of patients currently under NUC treatment and wishing to stop antiviral treatment after several years. A potential increase in serological responses is likely to occur in such conditions . Hence, A rational design of vaccination in the setting of NUC interruption may also contribute to find a solution for patients needing antiviral treatment cessation due to economic or medical reasons. In this group, ALT exacerbation post-treatment cessation is frequent. In fact, irregular medication with NUCs is one of the major causes of decompensation and acute on chronic liver failure . Thus, tAn approach already under study proposes the use of NUC for a longer period of time after therapeutic vaccination. This approach is intended to favor HBsAg seroconversion without losing the virological, serological and biochemical gain from NUC therapy. In the specific case of HBeAg-negative patients under NUC, HBsAg remains as the only serological variable. The accomplishment of this concept represents a new strategy; in short, more time is given to the immune system to work under virological suppression . The resIn summary, therapeutic vaccination has the potential to modify immune reactivation after treatment cessation. Alternatively, the use of NUC for a longer period of time after therapeutic vaccination should favor HBsAg seroconversion without losing the virological, serological and biochemical gain from NUC therapy. Then, the future of therapeutic vaccination in CHB remains alive and strong, both as a monotherapy and in the setting of rationally combined treatments.