Highly hydrophobic surfaces can have very low surface energy and such low surface energy biological interfaces can be obtained using fluorinated coatings on surfaces. Deposition of biocompatible organic films on solid-state surfaces is attained with techniques like plasma polymerization, biomineralization and chemical vapor deposition. All these require special equipment or harsh chemicals. This paper presents a simple vapor-phase approach to directly coat solid-state surfaces with biocompatible films without any harsh chemical or plasma treatment. Hydrophilic and hydrophobic monomers were used for reaction and deposition of nanolayer films. The monomers were characterized and showed a very consistent coating of 3D micropore structures.The coating showed nano-textured surface morphology which can aid cell growth and provide rich molecular functionalization. The surface properties of the obtained film were regulated by varying monomer concentrations, reaction time and the vacuum pressure in a simple reaction chamber. Films were characterized by contact angle analysis for surface energy and with profilometer to measure the thickness. Fourier Transform Infrared Spectroscopy (FTIR) analysis revealed the chemical composition of the coated films. Variations in the FTIR results with respect to different concentrations of monomers showed the chemical composition of the resulting films.The presented approach of vapor-phase coating of solid-state structures is important and applicable in many areas of bio-nano interface development. The exposure of coatings to the solutions of different pH showed the stability of the coatings in chemical surroundings. The organic nanocoating of films can be used in bio-implants and many medical devices. The interface between biomedical and nanotechnology is an area of intense research. Integration of biomedical micro/nanoelectromechanical systems (BioMEMS/NEMS) and materials offers tremendous potential to tackle medical problems in the areas of diagnostics, therapy, surgical implants and drug delivery . In pastH,1H,2H,2H-Perfluorooctyl-trichlorosilane (PFTS) are non-toxic monomers commonly used to create fluorinated surface [Structural stabilization of the coatings can be achieved from multiple covalent and hydrogen bonds using self organized silane films ,15. Fluo surface ,19. APTM surface -23. APTM surface . PFTS is surface . Fluorin surface .This paper reports a novel vapor-phase approach to coat solid-state substrates with a complex of APTMS and PFTS directly by controlling the vacuum Figure . The varThe morphology and the surface chemistry of the nanocoatings are critical factors which determine the biocompatibility and biostability of the films in biomedical applications. Vapor-phase deposition resulted in smooth continuous films. The thicknesses of coatings were measured with respect to the deposition time as shown in Table The films formed after 60 minute deposition were thick, continuous and porous at nanoscale (sample E). Figure Surface energy was measured with respect to the variations in the relative concentrations of the polymers. An uncoated Si chip was used as control to analyze the difference in the film properties. Table The chemical compositions of the organic films were analysed using FTIR. Nanolayers were made with 3 different ratios of APTMS and PFTS and their chemical composition was studied.The surface state analysis of polymeric surfaces have been reported before using X-ray Photoelectron Spectroscopy . The eleThe stability of the nanocoatings was characterized in de-ionized (DI) water and in solutions of various pH values. The surface showed no change when the coated chips were washed with DI water. There was no difference in the contact angle and the surface energy before and after DI water wash of the layer indicating the stability of the layer. But, when the coated chips were left in the DI water for 24 hrs, there was increase in the surface energy. This could be due to hydrolysis of the film in the DI water. The same process was carried out with pH solutions of 2, 4, 7 and 10. The coatings were analyzed from SEM micrographs after these were left immersed in respective solutions for 15 hrs. It was observed that the nanocoatings were still intact on the chips but the stability varied with the pH solution used. Figure The nanolayers were used to coat 3D structures of micro and nanopores. The data showed that micro- or nano-sized structures can be coated evenly on all the sides using this simple approach. Depending on the coating needed, the concentrations of the monomers can be varied. Figure Nanolayers of biocompatible coatings are the most desired properties for a number of device applications in medicine and engineering. Surface coating of the 3D micro and nano structures are reported using a simple method of vapor-phase vacuum chamber reaction. The coatings show biocompatible, low surface energy fluorinated layers which are ideal for many biomedical applications. The vacuum-based approach helps coating the inner surfaces of the devices and structures without need of any special equipment. This can be helpful in coating medical implants which need to be medicated on all sides of the device. Desired thickness and smoothness of the nanolayers can be acquired with respect to the type of application needed. The characterization showed that the nanolayers are stable at different pH solutions.APTMS (hydrophilic) and PFTS (hydrophobic) were used as received (Sigma Aldrich). Silicon wafers were <100> orientation p-type doped, oxidized in a thermal oxidation furnace. The wafers were diced into small dyes and used as solid substrates to deposit the nanocoatings.The substrate was kept in a vacuum reaction chamber and the two monomers were allowed to react in vapor-phase at a controlled vacuum and reaction time allowing the consecutive nanolayer deposition. Schematic diagram of this set up is shown in figure The thickness of the layer formed was measured with respect to time. The samples were made with different ratios of APTMS and PFTS for 20, 30, 40, 50 and 60 mins of deposition time Table . After t-1 using Nicolet 6700 FTIR spectrophotometer.The films were made with different concentration ratios of APTMS: PFTS  and the chemical composition of each were characterized using Fourier Transform Infrared Spectroscopy (FTIR). The spectrum was recorded in transmission mode on kBr crystals at a resolution of 4 cmThe surface energies of the coatings were calculated from the contact angle measurements of the water droplet on the surface of the coated chip . To checThe 3D micropore structures were coated using these layers. A Si wafer chip with a micropore of size 11.7 μm is shown as an example. The vapor-phase reaction was done using the two monomers. The coating formed a nanolayer on the pore covering all the sides.The authors declare that they have no competing interests.SDV synthesized nanocoatings and carried out the measurements, WA fabricated the micropores, SDV and SMI wrote the manuscript. SMI conceived the design of experiments and supervised all aspects of the work. All authors read and approved the final manuscript.


The dairy cattle breeding industry is a highly globalized business, which needs internationally comparable and reliable breeding values of sires. The international Bull Evaluation Service, Interbull, was established in 1983 to respond to this need. Currently, Interbull performs multiple-trait across country evaluations (MACE) for several traits and breeds in dairy cattle and provides international breeding values to its member countries. Estimating parameters for MACE is challenging since the structure of datasets and conventional use of multiple-trait models easily result in over-parameterized genetic covariance matrices. The number of parameters to be estimated can be reduced by taking into account only the leading principal components of the traits considered. For MACE, this is readily implemented in a random regression model.This article compares two principal component approaches to estimate variance components for MACE using real datasets. The methods tested were a REML approach that directly estimates the genetic principal components (direct PC) and the so-called bottom-up REML approach (bottom-up PC), in which traits are sequentially added to the analysis and the statistically significant genetic principal components are retained. Furthermore, this article evaluates the utility of the bottom-up PC approach to determine the appropriate rank of the (co)variance matrix.Our study demonstrates the usefulness of both approaches and shows that they can be applied to large multi-country models considering all concerned countries simultaneously. These strategies can thus replace the current practice of estimating the covariance components required through a series of analyses involving selected subsets of traits. Our results support the importance of using the appropriate rank in the genetic (co)variance matrix. Using too low a rank resulted in biased parameter estimates, whereas too high a rank did not result in bias, but increased standard errors of the estimates and notably the computing time.In terms of estimation's accuracy, both principal component approaches performed equally well and permitted the use of more parsimonious models through random regression MACE. The advantage of the bottom-up PC approach is that it does not need any previous knowledge on the rank. However, with a predetermined rank, the direct PC approach needs less computing time than the bottom-up PC. Globalization of dairy cattle breeding requires accurate and comparable international breeding values for dairy bulls. The international Bull Evaluation Service, Interbull, has for years performed international genetic evaluations for dairy cattle for several traits, serving the cattle breeders worldwide. Due to different trait definitions and evaluation models in countries participating in the international genetic evaluation of dairy bulls, biological traits like protein yield are treated as different, but genetically correlated traits across countries . TherefoDifferent solutions have been proposed to deal with the problem of over-parameterisation. Madsen et al.  have intThe principal component (PC) approach has also been investigated as a possible solution to deal with the problems of variance component estimation for the international genetic evaluation of dairy bulls. This approach is of special interest because it allows for a dimension reduction. Principal components are independent, linear functions of the original traits. PC are obtained through an eigenvalue decomposition of a covariance or correlation matrix, which yields its eigenvectors and corresponding eigenvalues. Eigenvalues describe the magnitude of the variance that the eigenvectors explain. For highly correlated traits, the first few principal components explain the major part of the variation in the data and those with the smallest contribution on the variance can be excluded without notably altering the accuracy of the estimates, e.g. . Factor The above studies were motivated by an attempt to reduce the number of parameters in the variance component estimation for MACE, but except for the study of Rekaya et al. , they wet countries is applied using the modelClassical MACE  includinyi is a i nvector of national de-regressed breeding values for bull i, b is a vector of t country effects, ui is a vector of t different international breeding values for bull i and i εis a i nvector of residuals. Xi and Zi are incidence matrices and the variance of the bull's breeding values is Var(ui) = G. Differences in residual variances, var(iε), were taken into account by carrying out a weighted analysis. Specifically, this involved fitting residual variances at unity and scaling the other terms in the model (1) with weights, ij w= ij/gjjλjEDC, where jj gis the sire variance of the j'th country, j and ij EDCis the bull's effective daughter contribution in country j . IntereThe effects of the possible problems in the datasets accumulated as the bottom-up PC approach was used, which the protein yield data clearly demonstrated Table . The firr elements of r × r Dr-matrix in the parameter estimation step and therefore, there is no danger of picking up the wrong subset of principal components.Overall, both approaches tested in this study performed very well and estimates of genetic correlations were similar to the Interbull estimates. Both PC approaches were applied to complete datasets unlike those suggested in the earlier studies ,12,9 andThis study shows that both the direct and the bottom-up principal component approaches and the use of models with optimal rank are useful in the variance component estimation for MACE. Furthermore, both approaches can be applied to large datasets and data sub-setting is not needed. Based on the results, we emphasize the importance of the selection of the appropriate rank of the (co)variance matrix to obtain good estimates. The bottom-up PC approach is capable of determining the appropriate rank for highly over-parameterized models and thus leads to a more parsimonous variance structure. However, with a predetermined rank, the direct PC approach needs less computing time than the bottom-up PC. The third approach that is considered for variance component estimation for MACE is the direct factor analytic approach that will be presented in an upcoming paper.The authors declare that they have no competing interests.AMT performed the statistical analyses, modified the bottom-up PC approach and wrote the first draft of the manuscript. EAM developed the bottom-up PC approach and supervised the study. KM developed the direct PC approach, modified WOMBAT for the needs of this study and supervised the study. JJ and WFF provided the datasets. MHL, VD, WFF and JJ also supervised the study. All authors contributed to the writing of the manuscript.


Merkel cell carcinoma is a rare malignant cutaneous neoplasm that is locally invasive and frequently metastasizes to lymph nodes, liver, lungs, bone and brain. The incidence of Merkel cell carcinoma has increased in the past three decades.A 65-year-old Caucasian man presented with a sudden onset of severe headache and a three-month history of balance disturbance. Magnetic resonance imaging revealed a large meningeal metastasis. The radiologic workup showed retroperitoneal and inguinal lymph node metastases. Biopsy of the inguinal lymph nodes showed metastases of Merkel cell carcinoma. Biopsy from three different suspected skin lesions revealed no Merkel cell carcinoma, and the primary site of Merkel cell carcinoma remained unknown. Leptomeningeal metastases, new axillary lymph node metastases, and intraspinal  metastases were detected within six, seven and eight months, respectively, from the start of symptoms despite treating the intracranial metastasis with gamma knife and the abdominal metastases with surgical dissection and external radiotherapy. This indicates the aggressive nature of the disease.To the best of our knowledge, this is the first report in the literature of an intracranial meningeal metastasis of Merkel cell carcinoma treated with gamma knife and of intraspinal intradural metastases of Merkel cell carcinoma. Despite good initial response to radiotherapy, recurrence and occurrence of new metastases are common in Merkel cell carcinoma. Merkel cell carcinoma (MCC) is a rare malignant neoplasm of the skin that is locally invasive and frequently metastasizes to lymph nodes, liver, lungs, bone and brain . The tumWe report a case of MCC with extensive central nervous system (CNS) metastases with (1) intracranial meningeal, (2) intraspinal epidural and (3) intraspinal intradural metastases. A literature review of the reported cases of the intracranial and the intraspinal spread of MCC was also performed and presented.N-acetylaspartate and choline:creatine ratios  as well as occurrence of lactate and lipid peak in the tumor but not in the surrounding edema. Although the morphologic findings of the supratentorial mass on conventional MRI were consistent with meningioma, the occurrence of the extensive edema and the MR spectroscopy findings were highly suggestive of metastasis, and our final radiologic diagnosis was meningeal metastasis. The patient was admitted to the neurology department, and immediate treatment with cortisone therapy was started. A search for the primary tumor with CT and FDG-PET (fluorodeoxyglucose positron emission tomography) revealed lymph node enlargement and increased FDG uptake in the left inguinal region, iliac, aortocaval and paraaortic regions. Needle biopsy was obtained from the enlarged lymph nodes in the left inguinal region. Removal of three skin lesions in the left lower limb showed no definite primary tumor.A 65-year-old Caucasian man presented with a sudden onset of severe headache and with a three-month history of balance disturbance. Apart from a pathologic finger-nose test result and positive Grasset test result on the left side, no other physical or neurologic abnormalities were found. Computed tomography (CT) showed a large 4 cm, right-sided parietal parasagittal tumor. Magnetic resonance imaging (MRI) showed a large 4 cm, inhomogeneously enhancing mass that exhibited a wide falx attachment and dural tail. The meningeal mass was surrounded by extensive edema of the right parietal lobe Figure . CerebraThe large supratentorial meningeal tumor was treated with gamma knife. MRI control 13 days after treatment with gamma knife showed marked reduction of the volume of the intracranial meningeal tumor Figure . RetropeAbout three months after the retroperitoneal and inguinal lymph node dissection, the patient received 40 Gy of external radiation for the paraaortal and iliac retroperitoneal lymph node metastasis and 50.9 Gy for the metastasis in the left inguinal region. Thereafter, FDG-PET showed total regression of the FDG uptake in the lymph nodes, which previously had shown increased uptake. A planned MRI of the brain about six months after the onset of symptoms showed evidence of cerebellar leptomeningeal enhancement Figures  and 1F, et al. .-17.13-17Our patient with extensive CNS, abdominal and inguinal metastases showed a good initial response to radiation therapy. However, evidence of progressive metastatic spread was demonstrated already six months after the onset of the patient's symptoms. This is the first report in the literature of spinal intradural metastases of MCC, which further contributed to worsening the patient's prognosis because it restrained a debulking and decompressive laminectomy.Written informed consent was obtained from the patient's next of kin for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief.The authors declare that they have no competing interests.KAK conceived the idea of the study. All authors participated in data collection. KAK wrote the manuscript. All authors read and contributed to the editing of the manuscript and gave their approval of the final manuscript.


Objectives. To review the current knowledge of the aetiology of vestibular neuritis including viral infections, vascular occlusion, and immunomediated mechanisms and to discuss the pathogenesis with relevance to pharmacotherapy. Systematic Review Methodology. Relevant publications on the aetiology and treatment of vestibular neuritis from 1909 to 2013 were analysed. Results and Conclusions. Vestibular neuritis is the second most common cause of peripheral vestibular vertigo and is due to a sudden unilateral loss of vestibular function. Vestibular neuronitis is a disorder thought to represent the vestibular-nerve equivalent of sudden sensorineural hearing loss. Histopathological studies of patients who died from unrelated clinical problems have demonstrated degeneration of the superior vestibular nerve. The characteristic signs and symptoms include sudden and prolonged vertigo, the absence of auditory symptoms, and the absence of other neurological symptoms. The aetiology and pathogenesis of the condition remain unknown. Proposed theories of causation include viral infections, vascular occlusion, and immunomediated mechanisms. The management of vestibular neuritis involves symptomatic treatment with antivertiginous drugs, causal treatment with corticosteroids, and physical therapy. Antiviral agents did not improve the outcomes.  Vestibular neuritis (VN) is the second most common cause of peripheral vestibular vertigo  and is a disorder thought to represent the vestibular-nerve equivalent of sudden sensorineural hearing loss.The first case of VN was reported by Ruttin in 1909  and Dix Vestibular neuronitis is caused by a sudden unilateral loss of vestibular function. In the majority of cases, the functions of the organs that are innervated by the superior vestibular nerve  are damaged, but the functions of the organs that are innervated by the inferior vestibular nerve  are spared .Vestibular neuritis has an incidence of approximately 3.5 cases per 100,000 people . The typIn a recent long-term follow-up study of 103 patients with vestibular neuritis, only two patients 1.9%) developed a second case of vestibular neuritis, which occurred 29 to 39 months after the first vestibular neuritis case [% developCases of vestibular neuronitis are typically sporadic , but theThe characteristic signs and symptoms of vestibular neuritis include sudden, severe, and prolonged vertigo measured over several days, the absence of auditory symptoms (deafness or tinnitus), and the absence of other neurological symptoms (particular diplopia or dysarthria).Vestibular neuronitis is a benign condition. The severe initial phase of the disease usually lasts between two and three days, but it may last a week or longer. The course of the entire illness averages six weeks , but it The complete or partial resolution of vestibular symptoms is standard in vestibular neuritis. In a clinical follow-up of 38 patients with vestibular neuritis, Matsuo and Sekitani  demonstrVestibular neuronitis is diagnosed using clinical diagnostic criteria, and there is no specific investigation to confirm the diagnosis. Meniere's disease can almost always be excluded on the basis of the absence of hearing loss. In rare cases, hearing loss can be absent early in the course of Meniere's disease. If the diagnosis is unclear, the character of the vertigo may help to differentiate between the two conditions. The vertigo of Meniere's disease is characteristically episodic and lasts a few hours , while tIn younger adult some condition to consider in the diagnosis is multiple sclerosis. Multiple sclerosis rarely presents as isolated vertigo, and when multiple sclerosis presents with isolated vertigo, it may be impossible to distinguish it from vestibular neuronitis until further evidence of central nervous system involvement emerges. The differential diagnosis is difficult, and the final diagnosis is confirmed by neuroimaging  Figure .It is difficult to identify patients with “pseudoneuritis” secondary to an ischemic stroke in the posterior fossa , especiaThe differential diagnosis of peripheral labyrinthine and vestibular nerve disorders that mimic vestibular neuritis includes several rare conditions.Initial burning pain and blisters that occur with hearing disorders and facial paresis are typical for herpes zoster oticus (Ramsay-Hunt syndrome).Cogan syndrome is a severe autoimmune disease accompanied by interstitial keratitis and audiovestibular symptoms .Vogt-Koyanagi-Harada syndrome is a rare multisystemic disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin .Histopathological studies of patients who died after the onset of symptoms of unrelated clinical problems demonstrated isolated degeneration of the superior vestibular nerve, vestibular neuroepithelium, and vestibular ganglion  with a dIt is a well established axiom of otolaryngology that when the inner ear is involved in disease, cochlear and vestibular elements are compromised, which leads to hearing loss and vertigo. In cases of vestibular neuronitis, vertigo occurs in the absence of hearing loss, the inner ear is not involved, and the lesion lies in the vestibular neurons central to the labyrinth.The absence of brainstem involvement suggests that the lesion is limited to the vestibular nerve. It is helpful to think of vestibular neuronitis as being a mononeuropathy, although this finding has not been confirmed. Whether the disease is caused by direct infection, localised thrombosis, or an autoimmune reaction remains unclear.An infective aetiology of vestibular neuronitis has long been hypothesised  on the bSeveral studies have demonstrated serological evidence of recent viral upper respiratory tract infections, particularly those caused by influenza virus A, influenza virus B, and adenoviruses, as well as infections caused by herpes simplex virus, cytomegalovirus, Epstein-Barr virus, rubella virus, and parainfluenza virus , 31. DesThe histopathology of the vestibular nerve in cases of vestibular neuritis has exhibited atrophy of the vestibular nerve and the vestibular sensory epithelium. These results are similar to the histopathological findings in known viral disorders, such as herpes zoster oticus . Herpes An animal model of vestibular neuritis was developed by inoculating HSV-1 into the auricle of mice . In animThere are many similarities between VN and Bell palsy, and the reactivation of neurotropic viruses, including herpes simplex virus type 1, has been suggested as the cause of both conditions. Herpes simplex virus type 1 DNA is detected by polymerase chain reaction in approximately two-thirds of human vestibular and facial ganglia –37.If HSV-1 is the most likely cause of VN, the virus would reside in a latent state in the vestibular ganglia. The virus could be located in the ganglionic nuclei, as has been reported in other cranial nerves , 39. OthAlthough the most popular theory of the pathogenesis of vestibular neuritis is based on a viral infection, the evidence to support this hypothesis remains circumstantial , 41.Vestibular neuronitis is associated with an inflammatory event in acute episodes. Plasma fibrinogen and C-reactive protein (CRP) levels are increased, while lipoprotein (a) behaves as an acute-phase negative reactant .There is increasing evidence for an inflammatory component that might be the result of a viral infection in the progression and aetiology of this disease , 44. Patα (TNF-α) family, and its ligand (CD40L) play important roles in the progression and genesis of inflammatory processes by the production of several proinflammatory cytokines, such as TNF-α, cellular adhesion molecules, or the expression of tissue factor [The CD40 receptor, which belongs to the tumour necrosis factor-e factor .α is a useful marker to monitor inflammatory processes, and it regulates the adhesion molecule CD38 [TNF-ule CD38  that medule CD38 .Kassner et al.  demonstrFreedman and Loscalzo found a significantly increased percentage of CD40-positive monocytes and macrophages in patients with VN compared to control subjects. An elevated expression of CD40 on monocytes/macrophages is known to cause the formation of platelet-monocyte aggregates, which contributes to thrombotic and inflammatory changes in the vascular system .It is conceivable that these proinflammatory activated monocytes and macrophages might cause microvascular occlusion through the formation of platelet-monocyte aggregates by interactions with the CD40 receptor.Several authors found a significantly positive expression of COX-2 in the B lymphocytes of patients with VN compared to healthy controls, which supports the idea of a proinflammatory state in patients with VN. COX-2 is a generally accepted inflammation marker and can be found in the PBMCs of patients with cardiovascular risk factors such as hyperlipidemia and smoking and in patients with other diseases, such as stroke and Alzheimer's dementia –56.α-positive cells in the B lymphocyte and monocyte subpopulation of patients with VN. TNF-α, a generally accepted inflammation marker, activates leucocytes, enhances the adherence of neutrophils and monocytes to the endothelium, promotes the migration of inflammatory cells into the intercellular matrix, and triggers local production of other proinflammatory cytokines [A proinflammatory activation of PBMCs is demonstrated by the significantly increased percentage of TNF-ytokines .The results support the notion of a proinflammatory state in patients with VN. It can be hypothesised that the proinflammatory activation of PBMCs (and an elevation of CD40 in monocytes and macrophages) leads to reduced microvascular perfusion of the vestibular organ caused by an increase in thrombotic events. This hypothetical mechanism could cause a loss of function of the vestibular organ secondary to reduced perfusion and/or infarction.Vascular occlusion as a cause of vestibular neuritis is not supportable on the basis of the peripheral vestibular histopathology.The characteristic interval that separates the onset of a respiratory tract infection and the onset of vertigo may suggest that the disease is caused by an immune mediated complication of the infection rather than direct viral infection of the nerve.Immune mediated neurological disease is a well-recognised sequela of infectious fevers, and a parallel of localised immune mediated peripheral neuropathy is vaccine-induced brachial neuropathy that occasionally complicates deltoid immunisation.Immunologic mechanisms have been suggested as possible causes for vestibular neuritis following influenza vaccination .The view that vestibular neuronitis is immune mediated is supported by a study in which thymus lymphocytes-subpopulations (T4 T-helper and T8 T-suppressor cells) were found in inner ear diseases  by specific monoclonal antibodies. The T-cell subset ratio (T4/T8) was elevated (less than 3) in approximately 50% of all patients. DR-typing was performed because of the well-known control of the immunoregulation through the class II HLA-DR antigens. There was a relative risk of 5.2 in peripheral vestibular lesion (neuronitis vestibularis). The relative risk of autoimmune diseases is found at this level .Numerous and varied immunological tests have been developed in recent years for researching and diagnosing immunological diseases of the labyrinth. In spite of the different possibilities of immunological testing, Veldmann  is correThis diagnosis involves immunoregulation, in which the T-helper lymphocytes (CD4)/T-suppressor lymphocyte CD8 ratio is determined. Diagnosis also involves a testing method to measure immunogenetics by HLA-DR typing. A simplified, hypothetical scheme for immunoregulation is that macrophages produce interleukin. This production causes the proliferation of CD4 helper cells, which leads to the activation of CD8 suppressor cells by interleukin .B cells, which produce antibodies, are activated by CD4 helper cells and are impeded by CD8 suppressor cells. A pathological CD4/CD8 quotient appears in 57% of cases of Meniere's disease, 48% of cases of neuronitis vestibularis, and 39% cases of Bell's palsy. Sudden hearing loss is demonstrated as a pathological quotient in approximately 50% of patients .There is only an imbalance in the CD4/CD8 quotient in inner ear diseases of unknown cause. This finding favours a causative immunological origin . The priThe decrease of suppressor cells is an essential immunopathological finding. One hypothesis is that when the control of plasma is reduced through the decreased suppressor cells, the so-called “forbidden clones” become active. These “forbidden clones” may subsequently produce autoantibodies against the vestibular nerve. According to recent immunological knowledge, the immunological imbalance described above is most likely consistent with an autoimmune disease .This immunological imbalance has a great similarity to findings in multiple sclerosis, as described by Reinherz et al.  and BachThe approach to VN patients has evolved since the 1980s with the introduction of early mobilisation, vestibular rehabilitation, and a reduced use of sedating vestibular suppressants .The management of vestibular neuritis involves (1) symptomatic treatment with antivertiginous drugs to reduce vertigo, and nausea/vomiting, (2) causal treatment with corticosteroids to improve the recovery of peripheral vestibular function, and (3) physical therapy  to improve central vestibular compensation .It is generally believed that vestibular suppressants should be used only during the acute phase of the disease. This belief is based on the hypothesis that the protracted use of vestibular suppressants may impede central vestibular compensation.The main classes of drugs used during the first 1 to 3 days for symptoms of acute vertigo include antihistamines, anticholinergic agents, antidopaminergic agents, and aminobutyric acid-enhancing (GABAergic) agents . These dThe drugs are effective in most patients with vestibular neuritis, but there have been few controlled studies comparing the efficacy of these drugs . There hDuring the acute phase, severe nausea and decreased gastric motility make the intramuscular or intravenous route for drugs preferable. The response is clearly dose-dependent; therefore, if the initial dose is not effective, higher doses should be tried.Although the exact mechanisms of action of these drugs are unclear, they act at the level of the neurotransmitters involved in the propagation of impulses from the primary to secondary vestibular neurons and in the maintenance of tone in the vestibular nuclei. The drugs also act on the areas of the nervous system that control vomiting, including the central components that are loosely described as the “emetic centre” and the peripheral components in the gastrointestinal tract.All of the medications can be sedating; therefore, they should not be used when patients are engaged in activities that require a high level of alertness. Less sedating drugs, such as oral meclizine and transdermal scopolamine, are useful for milder cases of vertigo.Monotherapy with steroids significantly improves the peripheral vestibular function of patients with vestibular neuritis. Treatment with methylprednisolone alone significantly improved the long-term outcomes of the peripheral vestibular function in patients with vestibular neuritis, while treatment with the antiviral agent  did not improve the outcomes. The combination of these drugs was no more effective than methylprednisolone alone.Methylprednisolone was administered daily as a single morning dose of 100 mg, and the dose was tapered every third day by 20 mg until the patient was receiving only 20 mg/day . ValacycValacyclovir was used because the serum concentrations that result from its use are similar to those resulting from intravenous acyclovir  and becaGianoli et al.  used 50 The bony canal of the superior vestibular nerve is longer and narrower than the bony canal of the inferior vestibular nerve, and the superior vestibular nerve  might beAnother important effect of steroids can also be depression of the immunological system. This finding supports the hypothesis that vestibular neuritis is an autoimmune disease similar to sudden hearing loss and Bell's palsy.Animal experiments have shown that treatment with glucocorticoids accelerates vestibular compensation after unilateral vestibular lesions . An imprRecovery from a peripheral vestibular lesion results from a combination of the restoration of peripheral labyrinthine function   and centPatients usually improve, even if they have a permanent unilateral loss of vestibular function. Clinicians have long felt that vestibular compensation occurs more rapidly and is more complete if the patient begins exercising as soon as possible after the occurrence of a vestibular lesion .The goal of vestibular exercises is to accelerate the process of vestibular compensation and improve the final level of recovery. Vestibular exercises should be started when the acute stage of nausea and vomiting has ended.A gradual program of physical exercise under the supervision of a physiotherapist improves the central vestibular compensation of a peripheral deficit. First, static stabilisation is focused on; then dynamic exercises are performed for balance control and gaze stabilisation during eye-head-body movements. The efficacy of physiotherapy in improving central vestibulospinal compensation in patients with vestibular neuritis has been demonstrated in a prospective, randomised, and controlled clinical study , 78.Vestibular neuronitis is a disease in which vertigo occurs in the absence of hearing loss because the inner ear is not involved, and the lesion lies in the vestibular nerve. Vestibular neuritis is characterised by sudden and prolonged vertigo with the absence of auditory or neurological findings.The most characteristic histopathology of vestibular neuritis in the human temporal bone is degeneration of the superior vestibular nerve and vestibular ganglion with variable involvement of the neuroepithelium of the end organs and a deficiency in the population of the nerve fibres and microscopic findings of myelin degeneration.The vascular hypothesis is supported by the idea of a proinflammatory state and by the sudden onset of the disease. Further studies are needed to elucidate whether the interruption of the inflammatory changes in patients with VN can influence the recovery of the disease and the efficacy of clinical treatment.Therapy with corticosteroids showed better clinical outcomes compared to placebo, while virostatics alone did not improve recovery. These results are in agreement with the hypothesis that VN is not a viral disease but is an autoimmune disease.The most important issues requiring elucidation in the future include the pathogenesis of the disorder. The elucidation of the pathogenesis of vestibular neuritis may be facilitated by the use of molecular biological techniques on human temporal bone material and experimental animal models.Vestibular neuronitis is a sudden unilateral loss of vestibular function and is the vestibular-nerve equivalent of sudden sensorineural hearing loss.In vestibular neuronitis, vertigo occurs in the absence of hearing loss; the inner ear is not involved, and the lesion is in the vestibular nerve. Vestibular neuronitis can be thought of as a mononeuropathy.The aetiology of the disease remains unclear. Vestibular neuronitis could be an autoimmune disease, but other pathological possibilities include viral infections and vascular disorders.The management of vestibular neuritis involves symptomatic treatment with antivertiginous drugs, causal treatment with corticosteroid, and physical therapy.


Decisions regarding choice and dose of anti-epileptic drug (AED) are driven by considering the potential benefits of reducing seizure frequency against the potential harms of alternative AEDs. Such decisions should be made using the best available evidence, which often requires a quantitative synthesis of data from multiple randomised controlled trials (RCT). However, the systematic review and meta-analysis of harms data is hindered by problems such as inadequate reporting, heterogeneity of harms definitions, and selective reporting bias. Here we will evaluate the quality of reporting of harms data in epilepsy trials, and assess the potential added value of incorporating harms data beyond the clinical indication of epilepsy.To evaluate the quality of reporting of harms data in RCTs of AEDs in patients with epilepsy we have undertaken a systematic review . We searFor the reporting quality review we identified 152 RCTs that met the eligibility criteria. None of the trials satisfied all criteria. The mean number of criteria per trial was 11.3 . No improvement could be detected following publication of the CONSORT statement for harms (difference in means: 0.6 with 95% CI (-0.9 to 1.8) p=0.53). Items that were not frequently reported were; definition of adverse events , use of a validated dictionary , use of a validated instrument , reporting of both number of patients and number of adverse events  and methods for handling of recurrent events . In the summary of harms data, borrowing strength from other indications resulted in a more precise effect estimate, and indicate that there is evidence for some adverse events across the range of indications.Reporting of harms in RCTs of AEDs is poor and has not improved since the publication of the CONSORT guidelines on the reporting of harms. To allow reliable meta-analyses of harms data, improvements to reporting quality are essential. Preliminary results suggest that harms data from AEDs prescribed for headache and neuropathy may be useful to inform the harms profile of AEDs prescribed for epilepsy.


Baurusuchus pachecoi, and no work has attempted to study the internal relationships of the group or diagnose the clade and its members.Baurusuchidae is a group of extinct Crocodyliformes with peculiar, dog-faced skulls, hypertrophied canines, and terrestrial, cursorial limb morphologies. Their importance for crocodyliform evolution and biogeography is widely recognized, and many new taxa have been recently described. In most phylogenetic analyses of Mesoeucrocodylia, the entire clade is represented only by Based on a nearly complete skull and a referred partial skull and lower jaw, we describe a new baurusuchid from the Vale do Rio do Peixe Formation (Bauru Group), Late Cretaceous of Brazil. The taxon is diagnosed by a suite of characters that include: four maxillary teeth, supratemporal fenestra with equally developed medial and anterior rims, four laterally visible quadrate fenestrae, lateral Eustachian foramina larger than medial Eustachian foramen, deep depression on the dorsal surface of pterygoid wing. The new taxon was compared to all other baurusuchids and their internal relationships were examined based on the maximum parsimony analysis of a discrete morphological data matrix.The monophyly of Baurusuchidae is supported by a large number of unique characters implying an equally large morphological gap between the clade and its immediate outgroups. A complex phylogeny of baurusuchids was recovered. The internal branch pattern suggests two main lineages, one with a relatively broad geographical range between Argentina and Brazil (Pissarrachampsinae), which includes the new taxon, and an endemic clade of the Bauru Group in Brazil (Baurusuchinae). Baurusuchus pachecoie. g.:Baurusuchus is certainly a key taxon in crocodyliform phylogeny, but its use as the only baurusuchid in phylogenetic analyses , Faculadade de Filosofia Ciências e Letras de Ribeirão Preto (FFCLRP), Universidade de São Paulo (USP) as LPRP/USP 0018 and LPRP/USP 0019, and come from the municipality of Campina Verde, in the region known as Triângulo Mineiro, Minas Gerais state, Brazil . The matThe new taxon is undoubtedly a baurusuchid, based on its derived dog-like skull and hypertrophied canines. We tested the taxon's phylogenetic position with the first comprehensive analysis of the better known putative bauruschids. Characters in the phylogenetic analysis were compiled from previous studies, and a suite of new characters were added to account for previously unrecognized transformation series. The analysis clarifies the neglected internal relationships of Baurusuchidae and presents a set of new apomorphies for the clade. We also present a set of formal definitions for the group.The fossil material was mechanically prepared using pin vice and pneumatic air scribe. Paraloid B72 dissolved in acetone was used for surface consolidation and as an adhesive.http://zoobank.org/”. The LSID for this publicaftion is: urn:lsid:zoobank.org:pub:023DCB79-D033-4FB0-81C0-28302E440E15.The electronic version of this document does not represent a published work according to the International Code of Zoological Nomenclature (ICZN), and hence the nomenclatural acts contained in the electronic version are not available under that Code from the electronic edition. Therefore, a separate edition of this document was produced by a method that assures numerous identical and durable copies, and those copies were simultaneously obtainable (from the publication date noted on the first page of this article) for the purpose of providing a public and permanent scientific record, in accordance with Article 8.1 of the Code. The separate print-only edition is available on request from PLoS by sending a request to PLoS ONE, 185 Berry Street, Suite 3100, San Francisco, CA 94107, USA along with a check for $10 (to cover printing and postage) payable to “Public Library of Science”. In addition, this published work and the nomenclatural acts it contains have been registered in ZooBank, the proposed online registration system for the ICZN. The ZooBank LSIDs (Life Science Identifiers) can be resolved and the associated information viewed through any standard web browser by appending the LSID to the prefix “No live animals were used in this study.th March, 1942.The permission for fossil collection was obtained from Deparftamento Nacional de Produção Mineral (document: 36/DIFIS) based on ordinance n° 4.146 from 4Benton & Clark 1988 sensu Benton & Clark 1988 Whetstone & Whybrown 1983 Price, 1945 Pissarrachampsa gen. nov.The generic epithet is a combination of the local name for the fossil bearing sandstones, piçarra, and the Greek suffix Χάμψαι (latinized as “champsa”) meaning crocodile.Pissarrachampsa seraurn:lsid:zoobank.org:act:F69BDAD1-38B7-4F89-9591-2C503826C91ESame as for the only known species. Pissarrachampsa seragen. et. sp. nov. .Vale do Rio do Peixe Formation, Bauru Group, Bauru Basin; Late Cretaceous  and lateral lacrimal surfaces, well developed rounded foramen between the palpebrals, quadratojugal and jugal do not form a continuous ventral border , four quadrate fenestrae visible laterally, quadrate lateral depression with anteroposteriorly directed major axis, sigmoidal muscle scar in the medial surface of the quadrate (ridge ‘A’), ectopterygoid almost reaching the posterior margin of the pterygoid wings, a single ventral parachoanal fenestra, and one ventral parachoanal fossa , lateral Eustachian foramina larger than the medial one, and a deep depression on the posterodorsal surface of the pterygoid wings.Pissarrachampsa sera and other baurusuchids, the separation between external and internal supratemporal fenestrae is useful.The anatomical description and soft tissue inferences will follow The following anatomical description is primarily based on the cranium LPRP/USP 0019 , 14, 15.Pissarrachampsa in the category of short snouted Crocodyliformes In dorsal view, LPRP/USP 0019 has a triangular shape. The combined morphologies of LPRP/USP 0018 and 0019 allow the reconstruction of a relatively short snout ,4,6,7. TThe external nares are partially preserved in LPRP/USP 0018. They face anteriorly and were probably completely divided. The antorbital fenestra is completely closed without even a trace of the antorbital fossa. The orbits are subcircular and face anterolaterally. The anterior and posterior portions of the orbits are roofed by thick palpebrals. The external supratemporal fenestra is nearly equal in size to the orbit, and the internal supratemporal fenestra is only about half of the orbit size. The supratemporal fenestrae are longer than wide and triangular in dorsal aspect with a wide posterior margin. The triangular infratemporal fenestra is smaller than the orbit and the external supratemporal fenestra, but larger than the internal supratemporal fenestra. The infratemporal fenestra real orientation is hard to determine given the distortion of the skull. On the right side, the infratemporal fenestra faces laterally, but faces dorsolaterally on the left side. In both sides, it faces slight anteriorly. The suborbital fenestra is large, and its long axis is oriented anteroposteriorly. The choanae are wide and, together with the parachoanal structures, occupy a great part of the posterior palate. The choanae face ventrally and are limited anteriorly and anterolaterally by the palatines and ectopterygoid, and posteriorly by the pterygoid. The choanae are lozenge shaped, with the greatest axis oriented transverse of skull major axis. The anteroposterior axis is divided by a median bony septum formed by the pterygoids. The occipital region is partly damaged in LPRP/USP 0019, but a post-temporal fenestra is not present.Only a small portion of the paired premaxillae is present as a round suture just posterior to the preserved anteroventral limit of LPRP/USP 0019. A nearly complete right premaxilla is preserved in LPRP/USP 0018. The premaxilla bounds the anteroventral, ventral, posterior, and posterodorsal edges of external nares. The nares are surrounded by a broad circumnarial fossa that faces anteriorly on its posterior portion and is not visible in lateral view . A shortA large, laterally facing notch is present at the lateral premaxilla-maxilla suture. This notch curves ventromedially towards the palate and received an enlarged dentary caniniform tooth (d4). The notch is large enough to create a diastema between the premaxillary and maxillary dentition and a constriction in the rostrum in dorsal and lateral profiles. The exact position of the premaxilla-maxilla suture within the notch is not visible. The premaxilla has three teeth with subcircular alveolar cross-sections. The first and second are similar in size, whereas the third is hypertrophied. A deep pit is located between, and slightly distal to, the first two alveoli and probably received the first dentary tooth.Pissarrachampsa suggests its highly reduced tooth formula in the maxilla may be the result of loss of posterior teeth and subsequent closing of the alveolar groove during ontogeny. The lateral wall of the maxilla extends back to the level of palpebral support structures. The tooth rows are slightly arched outwards, and both ends tend to converge to their counterparts in the opposite maxilla. The internal and external alveolar walls are not symmetrical; the latter is more ventrally developed, and the lingual tooth surfaces are further exposed. Posterolaterally, the maxilla contacts the jugal and lacrimal with a short posterior projection wedged between those bones, which does not reach the orbital margin. Numerous foramina dot the palatal shelf of the maxilla just lingual to the tooth row. A deep occlusal pit for the reception of a large dentary tooth is situated immediately lingual to the alveolus of m3 and m4. An additional occlusal pit occurs on the left maxilla, medially displaced at the level of teeth 3–4 as well as small aligned deformations in palatal surface indicating a complete overbite.The anteroposteriorly short and dorsoventrally deep maxillae are oriented nearly vertically, comprise most of the sidewalls of the snout, and have nearly no participation in the dorsal surface of the skull. Only four teeth are housed in the maxilla. The first alveolus is relatively small and faces anteroventrally. The second alveolus has the largest anteroposterior length, with an anteroposterior length greater than the other three alveoli and opens ventrally. The third and fourth alveolus are intermediate in size and open posteroventrally. In lateral aspect, the alveolar margin is ventrally arched reaching the greatest depth at the second maxillary tooth. The short tooth row does not extent far, ending posteriorly at the level of the arched maxillary alveolar margin and well anterior to the orbits. A reduced groove with a rugose surface extends posteriorly from the tooth row. This structure may represent a remnant of the alveolar groove. An elongate groove to house the posterior teeth is common in many eusuchians. The presence of this restricted and toothless groove in Medially, the palatal shelves of the maxillae meet to form an extensive secondary bony palate. A deep longitudinal groove is present over most of the palatal shelf midline suture. This is most pronounced throughout the mid-length where three well defined foramina are also visible. The groove partially obscures the sutural contact between maxillae. Posteriorly, the groove graduates into the flat posterior maxillary palatal surface. A pair of foramina is present on the maxillary portion of the palate near the maxilla-palatine contact and appears to represent posterior extensions of the foramina of the midline groove. The palatal maxilla-palatine suture extends transversely from the midline to the medial borders of the suborbital fenestrae. Each maxilla posseses a lateral palatal ramus which extends posteriorly and abuts the ectopterygoid at the level of the midpoint of the suborbital fenestra, causing the maxilla to border not only the anterior portion of suborbital fenestra, but also its anterolateral half.The jugal is long and transversely narrow. Its anterior  process expands greatly from the midlength until the contact with the maxilla and lacrimal. The orbital margin of the jugal posseses a low border that extends slightly lateral to the anterior margin of the postorbital bar. This configuration makes the anterior margin of this bar slightly inset from the outer orbital surface of the jugal. In addition, the postorbital bar does not have the sculptured pattern present in surrounding surfaces. The lateral surface of this process has a long ridge that spans the entire length of the infraorbital process at approximately midheight . The ridAn anterior suture for the nasal is preserved on the right premaxilla of LPRP/USP 0018. The suture indicates that the nasal would have entered the posterior midline of the external nares and likely formed at least a posterior division of the nares. The posteriormost portions of the nasals are preserved in LPRP/USP 0019. The bones are thin, anteroposteriorly elongated elements and participate only in the dorsal portion of the skull. They are fused to each other along most of their extension and have a wide dorsal surface. At the level of the anterior orbital margin, the nasals are dorsally concave, forming a low surface with regard to the remaining portion of the skull roof. The preserved portions indicate a tendency for the lateral margins of the concavity to smoothly converge anteriorly. Sutures between the nasal, prefrontal, and frontal are obscured by heavy sculpting, but there is certainly no nasal-frontal contact posteriorly, at least externally. The posterolateral corner of the nasal concavity forms the upper portion of the stepped prefrontals, which bounds the large anterior palpebral facet.The rhomboidal prefrontals form the anteromedial margin and part of the anterior wall of the orbit. They have a large dorsal exposure, forming different surfaces on the medial and lateral halves that are separated by a step. The medial triangular surface is anteroposteriorly elongated and strongly ornamented with ridges and furrows. At the midlength of this portion, the major medial extension of the prefrontal contacts its counterpart and prevents contact between the frontal and nasal. The prefrontal contacts the frontal along a large, oblique suture. The lateral surface of the prefrontal is smaller and less ornamented. It has a broad articulation with the anterior palpebral bone. The right palpebral is missing, revealing the dorsal surface of the lateral portion of the prefrontal. This region is deeply excavated to form a broad articular facet that receives the anterior palpebral. The lateral margin of the prefrontal contacts the lacrimal along a nearly linear longitudinal suture. The prefrontal contributes to a nearly vertical orbital anterior wall. The prefrontal extends ventrally as a thin sheet of bone that forms the prefrontal pillar . The preThe lacrimal has two different surfaces on the skull. The dorsal portion is accessible on the right side contacting the prefrontal support for the palpebral via a linear, but jagged suture. This surface is almost unornamented and ventrally roofs the lateral surface of the lacrimal. The lateral surface of the lacrimal makes up much of the anterior margin and wall of the orbit. The ventral portion of the bone is firmly sutured to the dorsal region of the infraorbital process of jugal. This contact has a curved profile, which is continuous to the contact with the maxilla. The lacrimal, together with the curvature of the internal surface of prefrontal, also forms the lateral portion of orbital anterior wall. At the inflexion point between its dorsal and the lateral surfaces, the lacrimal is pierced by the foramen for the nasolacrimal duct.sensuThe fused frontals have a complex outline. The anterior margins converge anteriorly, the lateral edge is concave about the orbital margin, and the posterior margin is convex, with the midregion bowing posteriorly. The anterior third is markedly ornamented and bears a smooth, midline depression . The other apertures are rounded and smaller, with the two ventral ones about 5 mm in diameter and the anterodorsal one about 9 mm in diameter. The orientation of the apertures is also variable. The ventral aperture faces posterodorsally, the anterodorsal aperture opens posteroventrally, and the two ventral apertures face more posteriorly. Ventromedially, the quadrate extends along the anteroventral edge of the paroccipital process to contact the basioccipital, basisphenoid, and pterygoid. The midlength portion of the contact between quadrate and basioccipital forms a low crest that is continuous to another crest extending from the medial margin of the medial quadrate condyle. This crest is similar to crest ‘D’ of Two palpebral bones are preserved in the left side of LPRP/USP 0019. They are thick elements with strongly ornamented dorsal surfaces. The anterior bone is hooked-shaped and articulates onto the prefrontal and lacrimal lateral projections, fitting on the step between those structures and the skull roof. Its posteromedial portion also fits in a small facet anterior on the orbital margin of the frontal. The anterior palpebral is dorsally convex, following the dorsal curvature of the skull at this level. Its posterolateral extension contacts the posterior palpebral about the level of the mid length of orbit. The posterior palpebral is small, well ornamented, and has a dorsally convex transverse profile. It has a subquadrate outline, articulates into a postorbital facet for this bone and contacts the anterior palpebral by means of a short spur of its anterolateral corner.The palatine palatal shelves of LPRP/USP 0019 are tightly sutured into a stout element that forms nearly the entire posterior half of the secondary bony palate along most of its length . The palThe fused pterygoids have three distinct regions: a compact body attached to the anteroventral and lateral portions of the neurocranium, a pair of posteroventrally projecting flanges (pterygoid wings), and a broad, transversely concave and posteroventrally inclined sheet of bone bearing the choanal groove and parachoanal structures . A small cranio-quadrate passage occurs ventral to the paroccipital process and medial to the triple contact between the squamosal, quadrate, and paroccipital process. This passage lies in the dorsal portion of a well marked medial depressed area of the occipital plane. The passage is partially covered by sediment, but extends medially into a cranio-quadrate canal running along the otoccipital-quadrate contact. The posterior surface of the distal end of the paroccipital process closes the ventral portion of the auditory meatus and bears distinct striations along its distal margin. These are possibly related to insertions of the musculus longissimus capitis superficialis and musculus iliocostalis capitis The basioccipital forms most of the peg-like occipital condyle, the external surface of which is not well preserved. Yet, it is clear that the basioccipital forms only the medial portion of the floor of the foramen magnum and cranial cavity. The basioccipital's posterior surface is slightly inclined and faces posteroventrally. The posteroventrally curved condylar neck is ornamented with tiny shallow pits and strongly deflected from the posteroventral surface of the basioccipital. The posteroventral surface of that bone slopes anteroventrally, forming an angle of approximately 30° relative to the skull roof plane. A short, median crest occurs from the base of the condylar neck to the opening of the median Eustachian tube (foramen intertympanicum), which is situated within a deep depression on the suture between the basioccipital and basisphenoid. The openings of the lateral Eustachian canals are lateral and slightly posterior to the median opening. The lateral openings are much larger than the medial foramen and have elongate, elliptical outlines . These oThe basisphenoid and parasphenoid appear to be indistinguishably fused. The basisphenoid is largely exposed in ventral aspect and is inclined anteroventrally, following the slope of the basioccipital. The basisphenoid is bounded by the pterygoids anteriorly and basioccipital posteriorly, and the element's lateral projections contact the pterygoid ramus of the quadrate. The ventral surface of the basisphenoid has two short, but well defined, crests oriented parasagittally on the lateral margins of the median Eustachian tube . These cBoth partial mandibular rami of LPRP/USP 0018 are preserved and comprise much of the dentaries and the anterior part of the splenials . The numPissarrachampsa sera has a reduced number of teeth, with only three in each premaxilla and four in each maxilla. The complete dentary tooth row is not preserved, but we estimate that it had more than 8 teeth. The premaxillary and anterior dentary teeth posses round cross-sections and are slightly posteriorly curved, lacking well-defined carinae. The maxillary and posterior dentary tooth crowns, on the other side, point backwards, and are strongly laterally compressed, with distinct, finely serrated mesial and distal cutting edges  and are formed by true denticles juxtaposed one another. In this sense, Pissarrachampsa sera is obviously related to Baurusuchidae. The group has long been diagnosed in precladistic and cladistic studies by the presence of a laterally compressed rostrum, absence of antorbital fenestrae, notch in rostrum for the reception of dentary caniniform tooth, approximation of prefrontals, well developed palatine bar, ectopterygoids forming the choanal border, quadratojugal extending dorsally as broad sheet contacting most of postorbital portion of postorbital bar, vertical quadrate, reduced number of teeth, hypertrophied maxillary tooth and ziphodont dentition Pissarrachampsa, but within clade relationships have never been discussed. Although baurusuchids are easily distinguished from the other Mesozoic crocodyliforms, the clade posseses a relatively high degree of ingroup morphological variation that is often overlooked. We present a detailed diagnosis for each putative South American baurusuchid in Cynodontosuchus is the smallest baurusuchid (but see following sections) with a preserved rostrum of less than 100 mm. In contrast, Stratiotosuchus has a skull length of approximately 470 mm. The relative proportions between different skull regions also vary. A most obvious example is the variation of rostral length. In Pissarrachampsa, the rostrum, measured from the anterior edge of the orbit to the tip of the premaxilla is estimated to be only 42% of the total skull length and falls into the “short rostrum category” of Stratiotosuchus and Baurusuchus salgadoensis are nearly 65% of the skull length and classified as “normal”, close to “long” rostra. The robustness of the skull bones also varies, even though this trait is hard to quantify. Pissarrachampsa, Wargosuchus, Baurusuchus pachecoi, and Cynodontosuchus have more lightly built skulls compared to Stratiotosuchus and Baurusuchus salgadoensis, which have more massive skulls.One of the most notable variations within the group is size. Stratiotosuchus open in a more anterodorsal direction, with the dorsal roofing bones of the nares slightly retracted posteriorly.Orientation of the external nares, orbits, choanae, and distal quadrates also vary slightly within the group. This variation is not marked enough to warrant discrete character state coding, but may be useful in future analyses. The external nares of most baurusuchids open directly anteriorly. Those of Stratiotosuchus, Baurusuchus salgadoensis, and B. albertoi have an enlarged otic recess and the descending flange of the squamosal does not cover much the otic aperture. In contrast, this flange partially hides the otic recess and the otic aperture in Pissarrachampsa and Baurusuchus pachecoi. The lateral depression on the quadrate varies from the anteroposteriorly broad depression in Pissarrachampsa, which expands onto the quadratojugal-jugal suture, to the dorsoventrally expanded but anteroposteriorly restricted depression in Stratiotosuchus, to the subcircular depression in other baurusuchids. The anterior support for palpebrals varies from the laterally stepped articulation with the prefrontal in Pissarrachampsa, Wargosuchus and Stratiotosuchus to an abbreviated step in Baurusuchus pachecoi and Baurusuchus salgadoensis.The otic region is highly variable among baurusuchids. Pissarrachampsa sera within Baurusuchidae was examined with a maximum parsimony analysis of discrete morphological characters. The analysis was based on a new dataset constructed to address the morphological variation observed in Baurusuchidae. The taxon sampling scheme was conceived to incorporate a broad diversity of Baurusuchidae, with the ingroup composed of seven putative South American baurusuchids scored at the specific level . Notosuchus terrestris, Mariliasuchus amarali, and Armadillosuchus arrudai were used as outgroups. The data sources for each taxon are given in Bergisuchus dietrichbergiIberosuchus macrodonEremosuchus elkoholicusPabwehshi pakistanensisPehuenchesuchus enderiBergisuchus dietrichbergi (Hessisches Landesmuseum -Me 7003) and Iberosuchus macrodon (Museu Geológico- 5679), as well as descriptive accounts of these taxa Bergisuchus and five premaxillary teeth in Iberosuchus. Those characters are not present in any of the more complete undoubted South American baurusuchids. In the same way, the firsthand analysis of the holotype of Pehuenchesuchus enderi , along with its descriptive accounts Eremosuchus elkoholicus (25) revealed the presence of sixteen alveoli in the dentary of Pehuenchesuchus and twelve in Eremosuchus, which is not congruent with the ten alveoli found in the dentary of the more complete undoubtful baurusuchids. Pabwehshi pakistanensis was excluded because it has a sagittal torus on its maxillary palatal shelves The phylogenetic relationship of Although many early and current analyses have recovered a close relationship between Baurusuchidae and Sebecidae, this is based on only six discrete characters: i.e., a deep rostrum, a well developed notch in premaxilla-maxilla suture, lateral surface of the dentary with longitudinal groove, a hypertrophied dentary tooth, ziphodont dentition, and a sigmoidal tooth row in dorsal view Notosuchus terrestrisMariliasuchus amaraliArmadillosuchus arrudaiThe outgroup was constructed based on the notosuchian affinity of Baurusuchidae Characters were selected focusing on the internal relationship of Baurusuchidae. Thirty-five new characters were added to a set of characters that previous mesoeucrocodylian phylogenetic analyses have recovered as synapomorphies of different clades see . AutapomMariliasuchus amarali as the sister group of Armadillosuchus arrudai plus a monophyletic Baurusuchidae. Cynodontosuchus rothi is the most basal taxon within Baurusuchidae, sister to a dichotomy leading to a clade composed of Stratiotosuchus and all Baurusuchus species and a clade composed of Pissarrachampsa and Wargosuchus. Within Baurusuchus, B. albertoi is the sister taxon to a clade composed of B. pachecoi and B. salgadoensis.The maximum parsimony analysis yielded a single tree  with 80 Small to medium-sized mesoeucrocodylians with premaxillae-maxillae suture internalized in a notch for the reception of lower caniniform; alveolar margin of maxilla in lateral view arched anterior to enlarged caniniform tooth; anterior extension of palatines not reaching the level of the anterior margin of suborbital fenestrae; presence of the posteroventral depressions in the mandibular symphysis; orientation of terminus of mandibular symphysis anterodorsal, at approximately 45 degrees to jaw line; teeth with serrated mesial and distal carinae.Baurusuchus pachecoi Price 1945 Baurusuchidae was established as a family name on the basis of Cynodontosuchus rothi Woodward 1896 Pissarrachampsa seran. gen. n. sp., Stratiotosuchus maxhechti Campos, Suarez, Riff & Kellner 2001 Baurusuchus pachecoi Price 1945 Notosuchus terrestris Woodward 1896 Mariliasuchus amarali Carvalho & Bertini 1999 Armadillosuchus arrudai Marinho & Carvalho 2009 Araripesuchus gomesi Price 1959 Sebecus icaeorhinus Simpson 1937 Bretesuchus bonapartei Gasparini, Fernandez & Powell 1993 Peirosaurus tormini Price 1955 Crocodylus niloticus Laurent 1768 The least inclusive clade containing Baurusuchus and Stratiotosuchus as internal specifiers, and no external specifier was postulated.The primary goal of this work is to examine baurusuchid ingroup relationships and determine a clear defifnition for Baurusuchidae see . The onlCynodontosuchus is historically important for Baurusuchidae because it was the first described member of the group Baurusuchus in early and current literature Cynodontosuchus as an internal specifier in a phylogenetic definition of Baurusuchidae. Yet, if Cynodontosuchus turns out to be a juvenile specimen, or if its phylogenetic position within Baurusuchidae changes in future analyses, the defined clade remains stable (see below). We also included several other taxa as internal specifiers to better sample the morphological variation of the group. External specifiers were selected to avoid misapplication of the name in unlikely event that future alternative topologies recover those taxa as a paraphyletic assemblage.Same as Baurusuchidae.Baurusuchus pachecoi Price 1945. We choose to respect this earlier name and revise its definition to reflect its original intention to demarcate the highly divergent morphology of the clade.The name was proposed Baurusuchus pachecoi Price 1945 Baurusuchus pachecoi Price 1945 Notosuchus terrestris Woodward 1896 Mariliasuchus amarali Carvalho & Bertini 1999 Armadillosuchus arrudai Marinho & Carvalho 2009 Araripesuchus gomesi Price 1959 Sebecus icaeorhinus Simpson 1937 Bretesuchus bonapartei Gasparini, Fernandez & Powell 1993 Peirosaurus tormini Price 1955 Crocodylus niloticus Laurent 1768 We propose Baurusuchia as a stem-based name to encompass Baurusuchidae, based on the large morphological gap between this clade and the outgroup (see below). In the present analysis, Baurusuchia is topologically identical to Baurusuchidae. Although these two taxa share the same diagnosis, our goal for this taxonomic decision is to minimize future, unnecessary taxonomic changes by providing a stable taxonomic framework for baurusuchian systematics.Medium sized baurusuchids with posterior portion of dorsal surface of the nasal bearing a rugose broad depression; approximation of prefrontals along their medial edges anteriorly; presence of a midline longitudinal depression on anterior portion of frontal.Pissarrachampsa seran. gen. n. sp., the most complete member of the clade.Named on the basis of Pissarrachampsa seran. gen. n. sp and all Crocodyliformes that share a more recent common ancestor with Pissarrachampsa seran. gen. n. sp than with Stratiotosuchus maxhechti Campos, Suarez, Riff & Kellner 2001 Baurusuchus pachecoi Price 1945 Notosuchus terrestris Woodward 1896 Mariliasuchus amarali Carvalho & Bertini 1999 Armadillosuchus arrudai Marinho & Carvalho 2009 Araripesuchus gomesi Price 1959 Sebecus icaeorhinus Simpson 1937 Bretesuchus bonapartei Gasparini, Fernandez & Powell 1993 Peirosaurus tormini Price 1955 Crocodylus niloticus Laurent 1768 The basal dichotomy of Baurusuchidae is well supported. Pissarrachampsinae is defined here as a stem-based clade to encompass its morphological unity as recovered in the present analysis.Medium sized baurusuchids with the medial contact for the prefrontals occurring along most of their dorsal medial edge; frontals broad, about twice the width of nasals; quadratojugal dorsal extension ending ventrally, or at the same level, of the dorsal tip of laterotemporal fenestra; quadrate fenestrae internalized in otic notch; muscle scar in the medial surface of quadrate  and delayed (DELTRAN) transformation The proposed phylogenetic hypothesis is used here as a template to describe the evolutionary history of the unique morphology of Baurusuchidae, addressing the synapomorphies of the group and its internal clades. In the present dataset, alternative reconstructions of characters optimizations are more often caused by missing entries , and only three cases are caused by a combination of missing entries and conflicting scoring for different taxa . The use of ACCTRAN is these cases would imply the presence of characters that are in fact not preserved in various taxa. Therefore, for the following discussion we adopted DELTRAN as the optimization procedure. This is a more conservative approach for the case at hand, and assigns the synapomorphies to the clades that in fact show the derived states.Sebecus, Bretesuchus, and Iberosuchus, and are considered as ambiguous synapomorphies of Sebecosuchia, when this clade is recovered in the analyses  is confirmed in the present analysis as a baurusuchid synapomorphy, as in previous works Baurusuchidae is diagnosed by seven synapomorphies , including those recovered unambiguously, as well by the optimization process. The presence of the premaxillae-maxillae suture internalized in a notch for the reception of lower caniniform (character 1.1), the alveolar margin of maxilla in lateral view arched anterior to enlarged caniniform tooth (character 22.2), and the teeth with serrated mesial and distal carinae (character 55.2) are character-states with multiple origins within Crocodyliformes. The same conditions are found in “protosuchian”, Peirosauridae, Mahajangasuchidae, Eusuchia, and other taxa. The premaxilla-maxillary notch and the serrated carinae are important characters in the context of the monophyly/paraphyly of Sebecosuchia . These characters are not scored for Cynodontosuchus, but are evidence for the huge morphological changes basal to, or within basal Baurusuchidae. These are a combination of characters previously recognized in the literature as synapomorphies at different levels of mesoeucrocodylian phylogeny, plus a great number of characters proposed here. Among them, the median approximation of prefrontal and the lateral depression of quadrate are tested here under maximum parsimony, turning to be phylogenetically relevant as previously proposed Mariliasuchus and Armadillosuchus), as well other forms not included in the present analysis . The second character is unique to the clade. The combination of these two features, plus the infraorbital portion of the jugal being twice as large as the infratemporal portion, exacerbates the condition for Baurusuchinae and leaded to the oversimplification of the character in previous analyses.A recovered clade grouping the baurusuchids above tosuchus  shows thPissarrachampsa sera is positioned as sister clade to Wargosuchus australis, forming Pissarrachampsinae. This association is based on three synapomorphies: posterior portion of dorsal surface of the nasal bearing a rugose broad depression (character 4.1), prefrontal medial margins anteriorly convergent (character 5.1), and presence of a midline longitudinal depression on anterior portion of frontal (character 10.1). Among these characters, only the presence of the broad depressed area on the posterior portion of the nasal was not considered as an autapomorphy of Wargosuchus in its original description WargosuchusPissarrachampsa (character 20), contrasted to the plesiomorphic condition in Wargosuchus. Considering the fragmentary nature of Wargosuchus, the number of synapomorphies and differences are enough to respectively accept them forming a monophyletic group, but representing different genera.sensuNotosuchus and Mariliasuchus ; frontals broader, about twice the width of nasals (character 8.1); quadratojugal dorsal extension ending ventrally, or at the same level, of the dorsal tip of laterotemporal fenestra (character 32.0); quadrate fenestrae internalized in otic notch (character 34.1); muscle scar in the medial surface of quadrate  and two delayed synapomorphies: major surface of pterygoid wing latero-ventrally oriented (character 48) and musculus pterygoideous posterior insertion in a marked depression on the surangular-angular lateral surface (character 61). Baurusuchus pachecoi shares with B. salgadoensis the ectopterygoid-jugal suture ridge continuous with the ventral ridge of the infratemporal portion of jugal (character 45) and three delayed synapomorphies: cylindrical dorsal portion of palatine constricted posteriorly (character 41 state 2), premaxillae bearing four teeth (character 56), and last premaxillary tooth not hypertrophied (character 58). The new interpretation of the jugal antorbital triangular depression  for the Vale do Rio do Peixe Formation in Minas Gerais State.Text S1Revised diagnosis of baurusuchid species of the ingroup included in the analyses. The specimens circumscribed in each proposed diagnosis are listed. The references for the unique characters previously proposed are given Cynodontosuchus rothiBaurusuchus pachecoiStratiotosuchus maxhechtiBaurusuchus salgadoensisBaurusuchus albertoiStratiotosuchus maxhechti was described by (DOC)Click here for additional data file.Text S2OTUS used in Parsimony Analysis. Specimens studied firsthand are listed. Descriptive accounts taken for the scoring of the OTUS are following Notosuchus terrestrisMariliasuchus amaraliArmadillosuchus arrudaeBaurusuchus pachecoiStratiotosuchus maxhechtiBaurusuchus salgadoensisWargosuchus australisBaurusuchus albertoi(DOC)Click here for additional data file.Text S3List of characters used in phylogenetic analysis. The 66 characters used in the phylogenetic analyses are described . The character–taxon matrix is presented in (DOC)Click here for additional data file.Text S4Character-State Matrix.(DOC)Click here for additional data file.Text S5Synapomorphy List.(DOC)Click here for additional data file.


Goal-directed fluid therapy (GDFT) has been shown to reduce complications and hospital length of stay following major surgery. However, there has been no assessment regarding its use in clinical practice.An electronic survey was administered to randomly selected anaesthetists from the United Kingdom  and the United States of America , and 500 anaesthetists from Australia/New Zealand (AUS/NZ). Preferences, clinical use and attitudes towards GDFT were investigated. Results were collated to examine regional differences.The response rates from the UK (n = 708) and AUS/NZ (n = 180) were 35%, and 36% respectively. The response rate from the USA was very low . GDFT use was significantly more common in the UK than in AUS/NZ (p < 0.01). The Oesophageal Doppler Monitor was the most preferred instrument in the UK  with no clear preferences in other regions. GDFT was most commonly utilised in major abdominal surgery and for patients with significant comorbidities. The commonest reasons stated for not using GDFT were either lack of availability of monitoring tools (AUS/NZ: 57 (70%); UK: 94 (64%)) or a lack of experience with instruments (AUS/NZ: 43 (53%); UK: 51 (35%)). A subset of respondents (AUS/NZ: 22(27%); UK: 45 (30%)) felt GDFT provided no perceived benefit. Enthusiasm towards the use of GDFT in the absence of existing barriers was high.Several hypotheses were generated regarding important differences in the use of GDFT between anaesthetists from the UK and AUS/NZ. There is significant interest in utilising GDFT in clinical practice and existing barriers should be addressed. Over the last decade, there has been a renewed emphasis on research investigating perioperative fluid therapy,2. This GDFT therapy primarily involves the administration of intravenous fluids to optimise pre-defined, patient-specific clinical proxies of tissue perfusion. The indA number of randomised trials and subsequent meta-analyses in various surgical settings have shown that GDFT confers clinical benefits such as decreased postoperative morbidity and decreased hospital length of stay as compared to traditional, liberal fluid therapy-14. ThisHowever, some authors have expressed reservations regarding the proposed benefits of GDFT for all patients. The criticisms include a paucity of trials within an optimised perioperative care environment and no comparison to intraoperative fluid restriction, which is also recognised as beneficial in a similar cohort of patients,14,21,22For those in favour of GDFT, the translation of evidence into practice can be a significant hurdle,26. ClinEthical approval was obtained from the Northern X Regional Ethics Committee NTX/10/EXP/147). An electronic survey was created using a commercially available internet-based service. The sur0/EXP/147The demographic characteristics of respondents and the response rates are presented in Table The use of GDFT is shown in Figure The situations when GDFT is utilised and preferred tools to conduct GDFT are shown in Tables The respondents from the USA indicated a preference towards GDFT in abdominal surgery  with similar barriers to GDFT as described in other regions such as lack of availability of tools , lack of experience  and nil perceived advantage . The most favoured pressor in the USA was phenylephrine , followed by ephedrine .This survey of 1067 anaesthetists from the UK, AUS/NZ and the USA reveals important differences in practice with regards to intraoperative fluid therapy and GDFT specifically. The response rates were moderate or low, especially in the USA, and it is likely that the present data represents views of a self-selected group among the anaesthetists who were randomly invited to participate. Such selection could be based on strong positive or negative views on GDFT. Nevertheless, certain observations can be made and hypotheses generated regarding the interest in and barriers to GDFT in the UK and AUS/NZ. The poor response rate from the USA limits the validity of any statements regarding practice in this region except to speculate that there is comparatively lesser interest in this topic.The use of GDFT seems to be significantly less prevalent in AUS/NZ compared to the UK amongst respondents in this survey. The majority of the respondents were involved in major abdominal surgery and orthopaedic surgery and used GDFT in patients with significant comorbidities. The ODM is the most commonly utilised instrument in the UK with significant variation in preferences in other regions. The most significant barriers to conducting GDFT were either a lack of availability of monitoring tools or a lack of experience with instruments. Even though a proportion of respondents from all regions remain unconvinced of the benefits of GDFT, there was significant enthusiasm overall towards trialling GDFT if barriers were to be removed.The use of GDFT was most common in the UK which may have been made possible by governmental endorsement and funding of the ODM specifically with demonstrated cost-effectiveness,16. NatiMoreover, a significant portion of the evidence supporting GDFT originates from the UK,11,29. TThe barriers identified to the use of GDFT appear eminently solvable especially if the observed benefits from trials are replicated in clinical practice. Many ofA proportion of people from all the regions surveyed remain sceptical regarding the proposed benefits of GDFT. To an extent, this is justified as important questions remain unanswered, such as efficacy in settings where fluid restriction has been shown to be beneficial-23. NoneWhilst the use of intraoperative crystalloids was largely homogeneous between the regions, there were interesting differences in practice between the three regions with regards to colloid use. There are considerable differences between individual classes of colloids as well as between the individual colloid products themselves,36. SuccThere are important limitations to this study which need to be considered alongside the results. The survey was designed on the basis of questions of clinical importance but was not developed with a focus group nor with redundant questions to validate its methodology. Moreover, since the survey aimed towards an overview of GDFT, specifics could not be elucidated regarding any one aspect (e.g. specific barriers). Any barriers identified were the opinion of the respondent and may not be reflective of the institution or the region in its entirety. The number of individuals to be surveyed was limited by the respective professional associations. The colleges facilitated selection of individuals with no author input allowed regarding this. The only selection criterion was to prevent administration of the survey to individuals who had previously replied to other college-led surveys to minimise responder fatigue. In the context of a low-moderate response rate, it cannot be assumed with certainty that it is representative of the anaesthetic community in its entirety.There are important differences in fluid administration and the use of GDFT between anaesthetists from the UK and AUS/NZ. The identified barriers can potentially be overcome and though some clinicians remain unconvinced, there is significant interest in utilising GDFT in clinical practice. Future directions from this work can include selective implementation of GDFT or further clinical studies.http://webstarts.com/aerascourse) and have received sponsorship from Pharmaco NZ for this event. Pharmaco NZ has no input into the course content or delivery.The authors are currently running a randomised trial exploring Oesophageal Doppler-guided fluid therapy in colonic resections within an enhanced recovery after surgery protocol. (NCT00911391). The Oesophageal Doppler machine for this trial has been lent by Pharmaco New Zealand. All probes have been bought at regular cost and Pharmaco New Zealand has had no input into the design or conduct of the trial and will not have any influence on publication. The authors of this manuscript run an annual course on the principles of optimised perioperative care (SS- designed the survey, analysed the data, wrote the manuscript. AK- analysed the data, edited the manuscript. MS- edited the survey, revised the manuscript. MT- conceived the idea for the project, revised the manuscript. AH- conceived the idea for the project, designed the survey, assisted in data analysis and revised the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/13/5/prepub


The genome sequencing projects completed in recent years revealed that the number of protein-coding genes does not change appreciably with increasing complexity of the organisms, and it is now generally accepted that this divergence is largely due to variation at the regulatory level. Mechanisms such as alternative splicing, alternative promoters and antisense transcription allow to both obtain a high number of transcripts from a relatively small number of genes and to fine tune isoforms expression in a cell-specific or developmentally-restricted manner. It is likely that the extensive use of such mechanisms plays a pivotal role in development, adult function and ageing of complex tissues like brain.The aim of this study was to characterize transcription start sites (TSSs) in different areas of human aged brain and correlate expression with methylation and structural genomic variation. Since its ability to profile TSSs at high resolution and at a genome wide level, we used Cap Analysis of Gene Expression (CAGE) combined with high-throughput sequencing (deep-CAGE) to collect exact TSSs and their expression levels. We present here our findings on alternative promoters and antisense transcription. Post-mortem tissue from 5 different brain regions was collected from 5 human donors and used to prepare 25 libraries.On average 2 million CAGE tags for each sample were sequenced. Mapping, expression normalization and clustering of the tags were carried out using automated pipelines. Core promoters were defined by merging tags within 300 base pairs of each other on the same strand. We found 22023 promoters, 50% of which mapped to either the promoter region or the 5' UTR of RefSeq transcripts. Ca. 32% of the genes expressed use alternative promoters. Ca. 15% of the promoters found were either part of a bi-directionally transcribed pair or antisense to an annotated RefSeq gene. A promoter was considered preferentially expressed (PEP) in one of the regions if at least 50% of its expression was derived from that region. Around 30% of the alternative promoters were PEP in one of the regions. In 8% of the bi-directional pairs identified, at least one of the members was PEP while 35% of the antisense promoters was.This study confirms deep-CAGE as a suitable approach to characterize mechanisms involved in the regulation of gene expression, such as alternative promoter usage and antisense transcription, even in the challenging context given by the use of post-mortem tissue from aged human brain.


Footwear with a curved sole profile remains popular and there is evidence of its effects on gait and posture ,2. ExistLower limb kinematic and GRF data was collected from twenty subjects during walking in four footwear conditions: flat control shoe, weighted flat control shoe, the new prototype rollover shoe and a MBT shoe. The static sole radii of all footwear was calculated for all and distinct parts of the sole, and correlated with radii of the gait rollover shapes as described by Hansen et al ,4.The radii of the foot–shoe roll-over shapes were significantly changed in response to different shoe conditions (p<0.001), but leg and thigh radii were not. The MBT shoes demonstrated a low positive correlation between the radius of foot-shoe roll-over shape and the static sole radii (whole sole)  and the radii of the heel area of the sole . The new prototype shoes showed no statistically significant correlations.The results of this study indicate that the static curve of the sole is not the main factor influencing gait. It appears that the extent to which the curved sole deforms dynamically during gait (i.e. shoe bending stiffness) influences the strength of the relationship between sole curvature and changes in gait.


Intracellular mechanisms directly or indirectly, influence the electrical activity of neurons in different time scales. These subcellular processes play a crucial role in generating transient dynamics and may shape firing patterns of individual cells and circuit activity in the nervous system -3. Slow We have addressed this question using conductance based models including a description of calcium dynamics. In order to explore their mutual interaction, we evaluated the strength of the causal relationships between the calcium concentration and the membrane potential with Granger Causality (GC). GC is an efficient way to investigate cause-effect relationships between time series, and is currently the state of the art method for this kind of analysis in neural data. For this study we applied Kernel Granger Causality (KGC), a recently proposed approach which allows a straightforward extension to the nonlinear case . The cauThe causal relationship between voltage and calcium was analyzed for different activity modes in the models, i.e., regular spiking, regular bursting, irregular spiking and irregular bursting. The results show several evolving asymmetries between the causality in the voltage -> calcium direction and the other way around. These asymmetries can be related to the different temporal structure of the spiking and spiking-bursting regimes.Carcinus maenas. Figure This study contributes to a better interpretation of the calcium->voltage and voltage->calcium analysis of experimental recordings. In particular, we compare the results of these simulations with the causality analysis performed in simultaneous recordings of membrane potential activity and calcium imaging in CPG neurons from the crab


The Competing Interests Statement contains information that is no longer accurate. The Competing Interests Statement should read: "Mohammed Kashani-Sabet owns stock in Melanoma Diagnostics, Inc., and James R. Miller III has ownership interest in MDMS, LLC. A patent application was filed regarding the patient-centered methodology described here. On the basis of prior work, patent applications were filed regarding the diagnostic and prognostic impact of the some of the markers described here, and were licensed to Myriad Genetics. This does not alter the authors' adherence to all of the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors."


The task of signaling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs), a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs) to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to dopamine (DA) neurons, the VTA also contains approximately 30%  SignaliSchultz, . As a coSchultz, . In thisSchultz, . The rewSchultz, . This peγ-aminobutyric acid (GABA) neurons, and the role of these inhibitory neurons in the mesolimbic system is less well understood. Within the VTA, there are two general populations of GABA neurons: interneurons, which provide local inhibition of DA neurons and projection neurons, which provide long-range inhibition of multiple brain areas including the NAc . It is now evident that these inhibitory circuits critically regulate DA neuron function and reward-related learning. VTA GABA neurons bi-directionally modulate activity of local DA neurons, which underlies reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons  and an unconditioned stimulus (reward or aversive air puff), while the firing rate was not changed during the delivery of the reward or punishment. The authors speculated that this ramping up of GABAergic firing may modulate DA activity during reward expectation and may help compute the reward prediction error  of the NAc  on neuronal activity and plasticity are mediated by α1-containing GABAA receptors. In the α1(H101R) point mutant mouse line, which carries a single nucleotide mutation that disrupts binding of BDZs to the GABAAR binding site  increases the activity of DA neurons and is behaviorally rewarding. The contribution of long-range GABA projection neurons to mesolimbic system function, and the interaction of GPNs with DA projection neurons at the level of their projection areas have also begun to be investigated. For example, despite the established role of the NAc in the maintenance of reward-related behavior (From Introduction), optical inhibition of GPN afferents in the NAc had no effect on reward consumption  glutamatergic and GABAergic projections preferentially innervate putative GABA neurons in the VTA (Jennings et al., DA modulation is important for function of reward, aversion and reward related learning. While much work has been devoted to studying the function of DA neurons and their role in encoding salient information of rewarding or aversive in nature, the role of VTA GABA neurons has been less well characterized. However, as we have discussed, it is now understood that GABA neurons regulate the activity of both VTA DA neurons and target neurons in VTA projection areas. This intimate, bi-directional modulation of DA neurons not only contributes to reward prediction error and DA plasticity, but also encodes the valence state of rewarding and aversive stimuli and also helps orchestrate behavioral responses to salient stimuli. Further characterization of inhibitory circuit function within and beyond the VTA will be necessary to fully understand the function of the mesolimbic system under normal and pathological conditions.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.