A review of research undertaken to evaluate the biomechanical stability and biotribological behaviour of osteochondral grafts in the knee joint and a brief discussion of areas requiring further improvement in future studies are presented. The review takes into consideration osteochondral autografts, allografts, tissue engineered constructs and synthetic and biological scaffolds. Patients suffering with osteoarthritis of the knee account for just over half (4.71 million) of all individuals living with osteoarthritis in the United Kingdom. The prevalence of knee osteoarthritis and the associated socioeconomic pressures it presents are set to increase in the future; accounting for predicted increases in population obesity, growth and ageing, the incidence of osteoarthritis of the knee in the UK population is estimated to have nearly doubled by 2035  and chronic mechanical overload due to factors such as severe joint misalignments and the removal of meniscal tissue.A wide variety of surgical methods for the treatment of osteochondral defects are currently available ; these r12 Cell-based approaches to the treatment of osteochondral defects, such as ACI and matrix-assisted ACI utilising scaffolds have also demonstrated a number of inherent limitations on clinical follow-up. These limitations include (1) fibrocartilage formation, (2) incomplete defect filling and (3) limited integration with surrounding tissues.13The clinical application of osteochondral grafts in the knee currently involves the implantation of single or multiple (mosaicplasty) autologous or allogeneic grafts. The aim of osteochondral graft implantation is to achieve a congruent articular surface resembling that of the native joint in order to restore the biomechanics and biotribology of the joint. The current clinical use of osteochondral autografts and allografts is limited by a number of factors, including (1) tissue availability, (2) donor site morbidity, (3) disparity in congruency between graft and host tissues and (4) lack of integration between graft and host articular cartilage.14 By engineering an osteochondral construct, constructs may be developed with biological, structural, biomechanical and tribological properties that closely mimic those of natural cartilage and bone, which are essential for long-term performance and durability in the natural knee joint. To date, no tissue engineered osteochondral construct has yet regenerated functional tissues that possess the properties of native cartilage and bone.Tissue engineering of osteochondral constructs has the potential to overcome the limitations of existing therapies and provide surgical solutions with improved long-term outcomes. The design of tissue engineered constructs is often based on a combination of three fundamental elements, namely, scaffolds, cells and bioactive molecules, with the aim of producing functional tissues in vitro or in vivo.A number of approaches have been adopted in the research and development of a potential regenerative solution for osteochondral replacement; these include synthetic and natural scaffolds pre-seeded with cells in vitro or as intelligent scaffolds capable of in vivo regeneration utilising the body’s own endogenous cells. Scaffolds may be monophasic, biphasic, triphasic or multiphasic in structure, consisting of one or more layers or scaffold materials  with difThe predicted future population trends regarding ageing, obesity and osteoarthritis and the limitations in current therapies for the treatment of osteochondral defects indicate a clear requirement for the development of effective early stage interventions to repair or regenerate osteochondral defects in the knee. Regenerative solutions for osteochondral defect repair have the potential to delay or halt further degenerative changes and may ultimately negate the requirement for total joint replacements in the long term. This review aims to present the research undertaken to assess and evaluate the biomechanics and biotribology of osteochondral autografts, allografts, tissue engineered constructs and scaffolds for the repair or regeneration of osteochondral defects in the knee.Two major challenges exist for the successful application of osteochondral grafts and novel regenerative solutions, the first being the restoration of biomechanical and biotribological function in order to establish the correct environment for tissue repair and regeneration, which is the primary focus of this review. The second challenge is the stratification of the population and the development of segmented product interventions designed with appropriate levels of precision, which can be delivered to reliably restore function and performance. This is addressed as a future challenge in the discussion.The aim of osteochondral grafts is to restore the congruent articulating surfaces of the joint, restoring normal joint biomechanics and biotribology (the biphasic load carriage and lubrication). Achieving and maintaining the congruent articular surfaces, along with the integrated support from the underlying bone are paramount to the long-term success of osteochondral graft procedures and the prevention of further progressive degenerative changes in the joint. Graft stability in the initial period following implantation is dependent on the resistance to motion arising from the graft–host interference fit and where present, support from the underlying trabecular bone structure. The graft–host interference fit (press-fit) is a direct product of the material properties and geometries of the graft and the host implantation site. Grafts that protrude above or subside below congruency level following implantation may induce inferior biomechanical and tribological conditions in the joint, potentially resulting in the onset of degenerative changes.19 These studies have evaluated graft stability by measuring the compressive push in forces required to displace grafts a set depth below congruency level with the surrounding host cartilage.Biomechanical studies that have evaluated the effects of graft and defect geometry have shown that the primary stability of osteochondral autografts or allografts in the initial post implantation period is greater when the graft and defect length are equal , grafts with larger diameters resist greater push in forces; similarly, graft stability also increases with increasing graft length with unbottomed grafts. Conversely, shorter bottomed grafts have been shown to provide greater resistance to push in forces than longer bottomed grafts.18The stability of bottomed grafts  is great20 concluded that shorter grafts and those of smaller diameter resisted significantly lower pull out loads; these results are in agreement with those obtained by Kock et al.18 and Kordás et al.19 for unbottomed grafts during push in tests. In vivo tests in both human and animal models have also demonstrated that the lack of basal support in unbottomed grafts is likely to predispose them to a tendency to subside below congruency level.22Investigations that have assessed graft pull out strength have measured the resistance to graft movement due to the graft–host interference forces. The study conducted by Duchow et al.23 showed that the implantation of congruent osteochondral grafts into the femoral condyle resulted in altered stress and strain distributions in the opposing cartilage surface when compared to an intact joint. A discontinuous contact stress profile over the graft–host interface was present when the grafts were inserted congruent to the native cartilage surface. The differences in the contact stress profiles are attributable to the discontinuous cartilage surface and may negatively affect the development of repair tissue in the graft–host boundary space. The finite element simulations also highlighted that there was an abnormal local tensile stress present in the opposing articulating surface of the tibial plateau when grafts were inserted either proud or countersunk to the host cartilage layer; such abnormal stresses may compromise the integrity of the opposing cartilage surface resulting in degenerative changes.Finite element simulations conducted by Wu et al.25 Kock et al. showed that the implantation of osteochondral grafts in a mosaicplasty procedure reduced the contact stress present around the edge of osteochondral defects. Furthermore, the study indicated that similar to untreated osteochondral defects, unbottomed grafts that had subsided below congruency also had increased rim stresses compared to implanted grafts that had remained congruent.22 Gratz et al.26 reported increased axial, lateral and shear strains in cartilage adjacent to defects and slightly elevated shear strains in the opposing cartilage surfaces. Grafts experiencing subsidence, similar to untreated osteochondral defects, are likely to result in altered stress–strain distributions in the surrounding and opposing articular cartilage surfaces. Elevated stress–strain levels and abnormal distributions may place the articulating cartilage surfaces of the knee joint at risk of damage through biomechanical and mechanobiological mechanisms; therefore, it is important that new graft designs have adequate material properties to provide suitable resistance to motion and loading.The effects of osteochondral defects on the contact stress of the surrounding articular cartilage have been studied experimentally. Elevated contact stresses have been shown to occur in the rim of osteochondral defects with peak stresses and increased contact stress gradients also occurring in the cartilage surrounding the defect.28 have demonstrated significant increases in contact pressure when grafts are inserted proud . Follow-up arthroscopies showed that protruding plugs displayed fibrillation at the graft edges and degenerative changes in the opposing tibial surfaces including cartilage softening and fibrillation. Studies evaluating the effects of altered joint biomechanics due to protruding osteochondral grafts indicate a clear relationship between altered contact mechanics and subsequent damage of the articulating cartilage surfaces; this is likely due to resultant changes in the local biotribology of the joint.Nakagawa et al.3033 Fibrocartilage was also shown to have grown above the subchondral bone level in the void between the periphery of the graft and the host tissue. However, fibrocartilage in-growth was inconsistent with some specimens displaying clefts in the repair tissue from the cartilage surface down to the subchondral bone level at the graft–host cartilage interface.3034Several animal studies examining the outcomes of single osteochondral graft transfer and mosaicplasty procedures have indicated integration of the subchondral and underlying trabecular bone with the surrounding host bone at 3–6 months postoperatively.34 The studies by Huang et al.34 and Nosewicz et al.21 indicated that when grafts subside less than 1 mm below congruency, cartilage thickening may occur, compensating for the difference between the surface profiles of the graft and host cartilage. Subsidence of grafts below 1 mm has been shown to induce significant fibrocartilaginous overgrowth; despite this, the surface profiles of the graft and host often still remain incongruent.34 These results correlate with the clinical observations of Nakagawa et al.,29 where all grafts that had subsided greater than 1 mm below congruency displayed fibrocartilage overgrowth. The presence of fibrocartilage on the articulating joint surfaces is undesirable as fibrocartilage is known to be biomechanically and histologically inferior to articular cartilage; this may result in the onset of degenerative changes in the cartilage of the graft and surrounding host tissue.3537Unbottomed grafts, due to a lack of support from underlying bone, rely predominantly on the interference fit to resist subsidence below congruency in the post-operative period until integration with underlying bone occurs. A number of studies performed in ovine models to investigate the effects of osteochondral graft alignment and subsidence have shown that when grafts subside to expose the subchondral host bone of the defect walls, the articular cartilage surface of the graft is susceptible to fibrous tissue overgrowth.38 reviewed studies between 2009 and 2012 that were concerned with the evaluation of osteochondral repair by constructs implanted into animal models. This review indicated that only 15% of the studies reviewed reported mechanical evaluation of explants following in vivo implantation. Lopa and Madry39 in their review of preclinical studies applying biphasic osteochondral scaffolds also reported limited numbers of studies reporting biomechanical analysis of explants to assess osteochondral repair. Where mechanical testing is reported, this tends to be limited to basic indentation, stiffness and stress relaxation tests of the explanted grafts without consideration of the effects of the grafts on the whole joint system.The evaluation of the biomechanics of osteochondral autografts, allografts and tissue engineered constructs is limited in the published literature. Studies designed to assess the in vivo and in vitro development of tissue engineered osteochondral constructs have focused predominantly on morphological and histological scoring and assessment as opposed to mechanical and tribological functionality. Jeon et al.40 The cartilage layer, integrated to the underlying bone, is primarily responsible for the biotribological function of osteochondral grafts in the natural joint environment and the subsequent maintenance or disruption of the biotribology in the surrounding and opposing cartilage surfaces.Osteochondral grafts consist of an articular cartilage component and an underlying supporting bone component that also serves to anchor and constrain the articulating hyaline cartilage interface of the graft and establish the essential thin layer constrained contact mechanics in the articular cartilage layer. Cartilage is a biphasic tissue with a complex zonal structure and composition; the structure and composition of cartilage endow the tissue with exceptional functional properties allowing low friction movement under high load bearing conditions. The complex organisation of collagen type II fibres and hydrophilic proteoglycans in a dense cross-linked network results in the retention of interstitial fluid within the tissue, under the severe loading conditions in the natural knee. Load is initially carried by the fluid phase in cartilage tissue, facilitated through an increase in internal fluid pressure; this results in a very low coefficient of friction.The main aim of osteochondral grafts is to reconstruct the natural articulating surface and biphasic biotribology of the joint and restore low friction articulation, in order to resist degeneration and wear. For osteochondral grafts to be successful, they must possess adequate tribological and mechanical properties to withstand the complex loading environment within the joint. The structure, composition and subsequent material properties of osteochondral grafts (the integrated structure to replace the bone and the cartilage) must first be sufficient in the short term for the graft to support the growth and integration of repair tissue under complex loading in the joint. Second, the biomechanical and biotribological properties of the graft and repair tissues should not compromise the integrity of the surrounding and opposing cartilage surfaces. Osteochondral grafts aim to repair the underlying supporting bone structure and restore a near frictionless articulating surface; therefore, the biotribological performance of these grafts in the natural joint is a key factor in determining their success.4145 The use of these test methods has also been extended to study the tribology of cartilage scaffold biomaterials and tissue engineered cartilage constructs.4651 Pin-on-plate test methods involve the translation and/or rotation of a pin against a larger counterface in the presence of a lubricant. Commonly used counterface materials are natural cartilage–bone plate specimens or materials such as stainless steel and glass. Small-scale in vitro pin-on-plate test methods allow for the control of experimental variables such as normal load, sliding distance and velocity, contact pressure and tissue loading and unloading intervals which dictate the outcomes under investigation such as friction and wear.52 These simple small-scale in vitro tests can be utilised to assess the tribological performance of newly developed biomaterials and engineered tissues at an early stage. The knowledge gained from pin-on-plate test methods may also be used to better understand the tribological behaviour of complex whole joint simulation models that are capable of reproducing the natural physiological conditions experienced in synovial joints such as the knee.52Biotribological evaluation is used to simultaneously study the friction, lubrication and wear of materials under compressive loading and sliding shear stress; the biotribological properties of a graft may provide a better indication of functionality compared to the uniaxial biomechanical properties alone. Pin-on-plate tribological test methods  have commonly been used to study the tribology of cartilage.23 When implanting osteochondral grafts, it is particularly difficult to achieve a perfectly congruent articulating surface; therefore, it is likely that even with grafts inserted to flush level, there may be subsequent increased wear in the joint due to an increased coefficient of friction arising from a discontinuous articulating surface (edge effects).Analysis of osteochondral graft insertion into the knee joint using finite element simulations has indicated that the implantation of grafts results in altered stress and strain distributions in the cartilage surfaces, with discontinuous stress profiles noted in the region of the graft and host tissue interface.53 studied the effects of osteochondral allograft implantation on the coefficient of friction of cartilage in a caprine knee model in vitro. The study highlighted a significant increase in coefficient of friction when no graft was inserted into the defect and when grafts were inserted flush, protruding and recessed in respect to the host cartilage surface  compared to the intact joint. Following osteochondral graft implantation, cartilage damage was only observed on the edge of the graft and defect hole. A lack of integration between the graft and surrounding host cartilage on the articulating surfaces may result in increased friction and wear due to the effects of the tibia moving across the edge between the graft and host tissue. This may induce increased levels of friction and wear at the graft edges, on the host tissue adjacent to the graft and on the opposing articulating surfaces.Bobrowitsch et al.4657 Previous in vitro experiments evaluating the friction and wear response of tissue engineered cartilage in pin-on-plate experimental set-ups have reported a higher equilibrium coefficient of friction compared to native cartilage.4757 Several of these studies have shown a time-dependent frictional response of the tissue engineered cartilage constructs49 similar to that of native cartilage. The presence of a time-dependent frictional response is indicative of the presence of some biphasic behaviour and interstitial fluid pressurisation within the tissue engineered cartilage constructs. To date, however, tissue engineered cartilage constructs have yet to demonstrate the tribological function of natural cartilage.A limited number of studies have investigated the biotribology of tissue engineered cartilage and scaffold materials designed for the regeneration of articular cartilage.56 Whitney et al.46 compared the frictional response of scaffold-free tissue engineered cartilage constructs to bovine cartilage specimens in a pin-on-plate test configuration. The tissue engineered cartilage exhibited a time-dependent frictional response similar to that of native cartilage. The measured frictional force was initially low and then increased over time before appearing to approach equilibrium; however, at later time points, the frictional coefficient of friction of the tissue engineered specimen was seen to decrease. The average reported mean frictional shear stress was not significantly different between the two groups; despite this, all of the tissue engineered cartilage samples clearly showed evidence of surface peeling with 90% of samples delaminating before equilibrium was reached. Delamination of tissue engineered cartilage in the superficial zone has also been reported previously by Plainfosse et al.40 The tissue engineered cartilage constructs studied by Whitney et al.46 were found to have a significantly lower glycosaminoglycan and collagen content compared to native tissues; similarly, the shear and aggregate modulus of the tissue engineered specimens were approximately 60% that of their natural counterparts. Lima et al.49 also reported similarly low levels of collagen in the tissue engineered cartilage samples, therefore limiting the constructs ability for internal fluid pressurisation and the maintenance of a low coefficient of friction. Plainfosse et al.40 reported that levels of matrix components, particularly collagen type II, are commonly lower in tissue engineered cartilage compared to mature natural articular cartilage and may be considered structurally immature; the tissue immaturity is reflected in the low aggregate modulus often obtained during compression testing of such constructs. Investigations by both Plainfosse et al.40 and Whitney et al.46 reported an increasing coefficient of friction with time during testing followed by a notable decrease at later time points. The decrease in coefficient of friction may have arisen from the generation of wear debris and the potential accumulation of wear particles on the counterface plates, acting to reduce the surface roughness and therefore resistance to motion.58Studies have shown that that the composition and structure of engineered tissues and scaffolds for osteochondral repair play a key role in dictating their frictional response and susceptibility to damage during biotribological testing.47 also reported a time-dependent frictional response for cartilage that had been engineered utilising a fibrin scaffold. The equilibrium coefficient of friction reached was higher when compared with native cartilage; however, this was reported to decrease when the engineered cartilage was cultured for longer time periods. Increased culture time was associated with an increase in deposition of surface layer extracellular matrix and an increase in proteoglycan content allowing for improved retention of proteoglycans and interstitial fluid.Morita et al.56 showed that the level of friction of acellular poly(ε-caprolactone) scaffolds under shear was predominantly dependent on surface morphology and fibre orientation, which in turn determined the onset and degree of damage sustained. For acellular scaffolds with aligned fibre orientations, it was shown that alignment of the scaffold fibres in the direction of shear, as is present in native cartilage collagen fibres, was preferential in order to increase the resistance to tension and damage due to shear. The fibre orientation in the cellular scaffolds did not appear to have a significant effect on their friction and wear characteristics due to a masking effect by the deposited extracellular matrix. These tissue engineered scaffolds did not exhibit the time-dependent frictional response typically seen in native cartilage; furthermore, the cellular scaffolds also demonstrated a higher equilibrium coefficient of friction compared to the acellular scaffolds. These factors were attributed to limited culture time, a lack of extracellular matrix deposition and a subsequently limited fluid load support. The reduced load bearing capacity of the tissue was thought to result in the formation of surface damage and wear debris leading to an increase in the surface roughness and coefficient of friction.Acellular and cellular cartilage scaffolds have been shown to display differing levels of resistance to friction and wear during shear testing. Accardi et al.56 indicate that in order to improve the frictional properties, it would be beneficial to more closely replicate the tissue structure and composition of extracellular matrix components such as collagen and proteoglycans; this may subsequently allow for improved biphasic behaviour and a low coefficient of friction.40 The complex fibre structure and orientation in natural cartilage with an orientated surface layer of fibres, which carries tensile stresses, have been shown to be necessary to sustain the hydrostatic stress field and fluid pressurisation in cartilage.Studies investigating the frictional response of tissue engineered cartilage replacements60 These whole joint simulation models can be utilised to study the friction and wear properties of potential osteochondral repair solutions under a variety of dynamic loading profiles simulating those experienced in the natural joint in vivo; furthermore, such models will allow for the effects of the osteochondral repair solution on the whole joint system to be evaluated. As highlighted by Jeon et al.,38 appropriate mechanical and tribological assessment of explants from in vivo animal test models in addition to purely histological methods should also be carried out in order to provide valuable information for the development of successful osteochondral repair solutions.Biotribological assessment of osteochondral repair solutions in the literature is predominantly limited to small-scale pin-on-plate methodologies and basic whole joint torsion models. In order to progress the development of novel osteochondral repair solutions, such as tissue engineered constructs and their successful delivery to the clinic, effective preclinical evaluation is required in order to assess their efficacy in the short and long terms. The development of in vitro whole joint simulation models capable of reproducing the physiological and anatomical conditions of the natural joint may prove to be an invaluable preclinical testing tool.The restoration of a low friction congruent articulating surface and the stability of osteochondral repair solutions are key factors in avoiding the introduction of abnormal stress and strain distributions in the surrounding and opposing cartilage surfaces. Research has indicated a clear link between protruding grafts and cartilage wear and degeneration; similarly, recessed grafts have been shown to induce similar stress and strain changes in the adjacent and opposing articulating surfaces as untreated osteochondral defects. The subsidence of osteochondral grafts below flush level following implantation has also been shown to induce significant fibrocartilaginous overgrowth of the graft surface.Studies assessing the tribological performance of tissue engineered cartilage constructs have highlighted that the structure and composition of repair tissues play a key role in dictating their frictional response and susceptibility to damage. Although some tissue engineered osteochondral constructs have shown a time-dependent frictional response, they have yet to demonstrate the true biphasic behaviour of native cartilage. There is a clear interdependency between the biomechanical and biotribological properties of osteochondral grafts and their functional performance in the natural joint environment. The biomechanical, biotribological and structural properties of osteochondral grafts ultimately determine their ability to withstand wear and the local biotribology within the joint, therefore preventing or promoting further degenerative changes in the surrounding and opposing articular surfaces.At present, there is a distinct lack of mechanical and tribological assessment of potential osteochondral repair solutions in order to evaluate their functional performance and efficacy in the natural knee joint. In order to efficiently develop successful osteochondral repair solutions, in vitro and in vivo evaluations should not be purely limited to the assessment of gross morphology, structure and composition. Preclinical evaluations should also assess the mechanical and tribological performance, as functionality is key to producing osteochondral constructs capable of withstanding the complex loading environment of the knee joint while supporting the growth of repair tissue.In addition to the standard indentation and compression tests generally used to assess material properties, it would be useful to assess the stability of osteochondral repair solutions in the knee joint using push in and push out tests. These methods allow for an assessment of stability and resistance to motion, and they have previously been utilised in published research studies but have been limited to the testing of osteochondral autografts and allografts. Biotribological evaluation of osteochondral repair solutions can provide a better understanding of functional performance than uniaxial biomechanical testing alone. Small-scale biotribological pin-on-plate tests can provide key information regarding the ability of osteochondral repair solutions to restore a biphasic, low friction articulation with negligible wear. Robust preclinical assessment of osteochondral repair solutions may be achieved through the use of whole joint simulators capable of reproducing the natural physiological and anatomical conditions within the knee joint. Whole joint simulation models should allow for the biotribological assessment of repair solutions under dynamic loading profiles and the evaluation of the resulting friction, lubrication and wear in the wider joint. Future studies evaluating performance should include appropriate control groups and comparisons to existing osteochondral repair therapies; where appropriate, these may include experimental groups such as cartilage defects, osteochondral allografts or autografts, disease models and commercially available osteochondral scaffolds.Robust evaluation of osteochondral repair solutions through both in vitro and in vivo preclinical testing will aid the efficient development of current and future osteochondral repair solutions. A more systematic approach to the assessment of osteochondral repair solutions will allow for easier comparison of functional performance between different regenerative osteochondral repair strategies and to current repair strategies used in the clinic.The predicted future population trends indicate a clear requirement for the development of effective therapies for the repair or regeneration of osteochondral defects in the knee. A wide variety of strategies to produce potential regenerative osteochondral repair solutions is currently been researched; however, to date, there has been limited evaluation of the biomechanical and biotribological properties of potential osteochondral repair solutions and their effects within the natural joint environment. The structure and composition of osteochondral repair solutions have been shown experimentally to have a direct impact on the functional performance; therefore, therapies which more closely mimic the structure and composition of natural cartilage and bone tissue are likely to have improved functional properties. In addition to these improvements, the development of an effective, functional osteochondral repair solution for successful delivery to the clinic requires the implementation of robust in vitro preclinical evaluation strategies simulating the in vivo physiological conditions of the natural joint.


We read with interest the manuscript entitled"Serum and peritoneal fluid levels of vascular endothelialgrowth factor in women with endometriosis"recently published in the International Journalof Fertility and Sterility . The autin vitro is the maincontributor to the level of serum VEGF and maynot reflect the level of circulating VEGF producedby peripheral tissues (such as endometrioticlesions)  . In the lesions) , small dlesions) .Furthermore, when serum is used for themeasurement of VEGF, the methodology ofcollection and processing of samples should bestandardised and declared. In fact, spinning thesamples for different times and with differentforces may influence the levels of VEGF .FurtherGiven these considerations, we believe thatthe authors’ conclusion that "circulating" VEGFis similar in blood of women with and withoutendometriosis is not supported by the presenteddata.


Sound information is encoded as a series of spikes of the auditory nerve fibers (ANFs), and then transmitted to the brainstem auditory nuclei. Features such as timing and level are extracted from ANFs activity and further processed as the interaural time difference (ITD) and the interaural level difference (ILD), respectively. These two interaural difference cues are used for sound source localization by behaving animals. Both cues depend on the head size of animals and are extremely small, requiring specialized neural properties in order to process these cues with precision. Moreover, the sound level and timing cues are not processed independently from one another. Neurons in the nucleus angularis (NA) are specialized for coding sound level information in birds and the ILD is processed in the posterior part of the dorsal lateral lemniscus nucleus (LLDp). Processing of ILD is affected by the phase difference of binaural sound. Temporal features of sound are encoded in the pathway starting in nucleus magnocellularis (NM), and ITD is processed in the nucleus laminaris (NL). In this pathway a variety of specializations are found in synapse morphology, neuronal excitability, distribution of ion channels and receptors along the tonotopic axis, which reduces spike timing fluctuation in the ANFs-NM synapse, and imparts precise and stable ITD processing to the NL. Moreover, the contrast of ITD processing in NL is enhanced over a wide range of sound level through the activity of GABAergic inhibitory systems from both the superior olivary nucleus (SON) and local inhibitory neurons that follow monosynaptic to NM activity. The auditory nervous system is highly sensitive to changes in acoustic signals both in the frequency and the level . IPD modulates the activity of NA neurons in the chick through the acoustic interaction across the interaural canal that connects the middle ear cavities of two sides  neuron but not in low CF neurons. Accordingly the EPSCs recorded in the high-middle CF NM neurons are large and generated in all-or-none manner with a small number of amplitude steps when the intensity of electrical stimulation applied to the ANFs bundle is changed, while the EPSCs recorded in the low CF neurons are small and the size gradually increases depended on the intensity of electrical stimulus , the site of action potential initiation, is extended longer in the axon of low CF NM neurons than the high-middle CF NM neurons. Clustering of a large number of Na+ channels at the AIS would allow sufficient current to generate action potentials even under a certain level of inactivation  channels have a reversal potential around −30 mV, are activated by membrane hyperpolarization, and the voltage-sensitivity is modulated by cyclic nucleotides. Channel gating is shifted in the positive direction when the cytosolic concentration of cyclic nucleotides is high, and the sensitivity to cyclic nucleotide is greater in HCN2 than in HCN1 channel subtype Pape, . In the The fast time course of EPSPs is critical to enhance the coincidence detection; however the sharpness of coincidence detection depends also on the size of EPSPs (Kuba et al., −, GABA was depolarizing in brainstem auditory neurons (Hyson et al., B receptors and mGluRs in NL of embryonic age (E19-E21, Tang et al., B and mGluRs are cooperative and may improve the coincidence detection in NL neurons.Because of the relatively high intracellular concentration of Clin vivo recordings from the barn owl (Pena et al., Firing rates of ITD processing neurons alternates periodically as ITD changes during a tonal stimulation, and the period of the ITD tuning curve was determined by the CF of the neuron (Goldberg and Brown, in vivo, ITD tuning was found dependent both on the sound frequency and the sound pressure level (Nishino et al., By recording single unit activity in NL A receptor (Goldstein et al., We further found a phasic IPSC in the low CF NL neurons in slice preparations, which followed the ipsilateral NM inputs with a short time delay and small timing jitter; thus the phasic IPSC likely follows monosynaptically the ipsilateral NM activity (Yamada et al., Interaural difference cues are small, particularly for animals endowed with small heads. This review has focused on works conducted on the chick, which provide profound insights into the mechanisms that contribute to the accuracy of ITD processing. Further, these studies reveal how ITD tuning is maintained over a wide range of sound pressure level in birds. The morphological specializations complement the roles of ionic channels in the ITD tuning. The distribution of ionic channels and receptors including the inhibitory synapses in the NL is critically arranged to optimize the ITD processing, and in turn, sound source localization. Moreover, timing and level cues of sounds are used cooperatively in both mammals and birds to improve the processing of small interaural difference cues.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


As is apparent from reading the first line of nearly any research or review article on speech, the task of perceiving speech sounds is complex and the ease with which humans acquire, produce and perceive these sounds is remarkable. Despite the growing appreciation for the complexity of the perception of music, speech perception remains the most amazing and poorly understood auditory  accomplishments of humans. Over the years, there has been considerable debate on whether this achievement is the result of general perceptual/cognitive mechanisms or “special” processes dedicated to the mapping of speech acoustics to linguistic representations  from non-auditory sources can affect phonetic perception. The famed McGurk effect  call into question the strict dichotomy of speech and general auditory processing .There are many examples of sound perception being influenced by non-auditory information. Detection of low-intensity sounds is enhanced when paired with a task-irrelevant light stimulus  isolated from the full act of communication is unnatural even when bringing to bear information from other sense modalities. The small and context-specific sensorimotor and multisensory effects we can uncover in this artificial task (Hickok et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The recent outbreak of Ebola Virus Disease (EVD) in West Africa has ravaged many lives. Effective containment of this outbreak relies on prompt and effective coordination and communication across various interventions; early detection and response being critical to successful control. The use of information and communications technology (ICT) in active surveillance has proved to be effective but its use in Ebola outbreak response has been limited. Due to the need for timeliness in reporting and communication for early discovery of new EVD cases and promptness in response; it became imperative to empower the response team members with technologies and solutions which would enable smooth and rapid data flow. The Open Data Kit and Form Hub technology were used in combination with the Dashboard technology and ArcGIS mapping for follow up of contacts, identification of cases, case investigation and management and also for strategic planning during the response. A remarkable improvement was recorded in the reporting of daily follow-up of contacts after the deployment of the integrated real time technology. The turnaround time between identification of symptomatic contacts and evacuation to the isolation facility and also for receipt of laboratory results was reduced and informed decisions could be taken by all concerned. Accountability in contact tracing was ensured by the use of a GPS enabled device. The use of innovative technologies in the response of the EVD outbreak in Nigeria contributed significantly to the prompt control of the outbreak and containment of the disease by providing a valuable platform for early warning and guiding early actions. The recent outbreak of Ebola Virus Disease (EVD) in West Africa has been declared by the World Health Organization (WHO) as the world's deadliest international health emergency in the modern time. It has bSlow pace of manual entry of large volume of data from multiple sources using the Epi-Info database of viral hemorrhagic fevers developed by the US Centers for Disease Control on a single computer system, resulting in backlog of data.Delay in receiving reports from the Contact Tracers when they identified onset of symptoms in contacts and or new contacts, causing delay in evacuation of new suspects and registration of new contacts.High turn-around time for receipt of laboratory results leading to delays in confirmation of status of suspect cases on admission for prompt actions by the case management team.The peculiar traffic situation in Lagos and Port Harcourt which led to a delay in collation of reports from different team members.Delayed communication across response teams causing delays in taking immediate follow up actions and strategic decisions.In the recent times, IT has penetrated the domain of public health in many countries and the potential for harnessing information technology for surveillance is evident . The useDue to the need for timeliness in reporting and communication for early discovery of new EVD cases and promptness in response; it became imperative to empower the response team members with technologies and solutions which would enable smooth and rapid data flow. The Strategy group of the Ebola Emergency Operations Committee had a discussion with the IT team and took a decision on deploying IT methods to overcome some of these challenges. Previous experience gained in using the ODK by members of the IT team during Polio surveys and enumeration of hard to reach areas in the country served as a leverage in deploying these techniques. Both ODK and Formhub are open-source and free which need just smartphones and cloud servers to digitalize data collection. This required the setting up of a real time system to ensure that the process is automated from data capture to data retrieval. The EEOC already had a server, funds from the EEOC bought the smartphones and tablets needed, the IT team had the knowledge and expertise and the technology was open source and free. This paper describes the innovative use of public health informatics tools to improve response to an Ebola virus disease outbreak in Nigeria.www.opendatakit.org) and Form Hub Technology (www.formhub.org). Supporting technologies were the Dashboard technology and ArcGIS mapping. The contact listing form, contact follow up form, laboratory investigation request form and case investigation forms were created using the extensible markup language (xml) and eHealth Ebola Sense android app developed for 21 day follow up .Two android base applications were the major technologies used—The Open Data Kit (ODK) (These forms were adapted from the WHO guidelines for Ebola Virus Disease Outbreak Response. The forms were uploaded on the Form Hub server and downloaded to android devices (smartphones or tablets) using the ODK collect application . SmartphThe initial contact listing was done using the paper forms but subsequently as new contacts were identified, the listing was done using both the paper and the ODK forms. Each day as contacts were being monitored for symptoms of EVD, the temperature reading and presence or absence of clinical signs or symptoms of EVD were recorded using the smartphones as well as the GPS coordinates of the place of visit. Once the information was entered in the ODK form on the phone, the finalized form was sent automatically to the Form Hub server that housed information on all contacts in a database.http://www.thesitewizard.com/general/set-cron-job.shtml) which generates a red highlight on the contact’s information on the dashboard  Large touch screen or QWERTY Keys.High speed InternetGood Mobile data plans.eHealth Sense mobile applicationODK Collect SoftwareViewing device such as television for viewing real time data and maps1Open Data Kit (ODK) Collect Application. The ODK Collect application was used in creating respective data collection forms (interfaces) which enable users enter data or edit saved data on their phones/tablets. The entered data are then submitted on finalization. The geo-coordinates were automatically embedded in the data during submission.Seven set of forms were created for the ODK collect. These were the New Contact Form, Contact Follow-Up Form, Laboratory Request/Result Form, Case Investigation Form, Social Mobilization Form, Point of Entry Screening Form and Health Facility Survey Form.2The Form Hub Technology. The hub technology forms were built based on the hard paper forms being used to collect data from the field. When new cases are identified, the details are entered into a new case form on the mobile phone by the contact tracer which is sent directly to the form hub server “3Dashboard Technology. The Dashboard comprises of a segmented output, which focuses on providing evidence-based information to support management in taking prompt decisions. An internet-capable television is used to display the status of contacts followed-up daily, the interviewers and their performance in terms of proportion of contacts followed up “4ArcGIS Mapping. Locations of identified contacts and cases were mapped using the coordinates recorded on the ODK forms and integrated to show the distribution and clustering of contacts and cases within the cities using ArcGIS software. This informed areas to be targeted for social mobilization, sensitization and awareness creation by the social mobilization teams.Improvement was recorded in the reporting of daily follow-up of contacts after the deployment of the integrated real time technology. The electronic data collection and alert system reduced the turnaround time between identification of symptomatic contacts and evacuation to the isolation facility from between 3 to 6 hours to an hour. This aided prompt evacuation of symptomatic contacts to reduce or stop further transmission of the virus in the community.Also, the turnaround time for laboratory results was considerably reduced. This aided the immediate discharge of suspected cases with negative laboratory results from the suspect ward as well as prompt movement of suspected cases with positive laboratory results to the confirmed ward and commencement of supportive treatment.In addition, the Incident Manager and strategy group had timely and complete information required to make informed decisions on all issues. Deployment of the integrated technology also provided other benefits such as simultaneous multiple data entry by different persons into a single database, thereby eliminating the dependency on a single data entry clerk. It introduced accountability in contact tracing exercise thereby ensuring that all contacts were seen physically in their homes because of the use of a GPS enabled device. It also facilitated daily collation of reports from different team members for daily evening review meetings and daily situation report.The deployment of the technology was not without some challenges and these were the initial costs of setting up the required technology , the need for trained personnel  many had participated in polio surveys, some had used the ODK before and most knew how to use smartphones and tablets) and the need to have highly effective internet connections to run the applications. Also the integration of Epi-info VHF with form hub technology to align same data structure across the system posed some challenges.The use of innovative technologies in the response of the EVD outbreak in Nigeria contributed significantly to the prompt control of the outbreak and containment of the disease by guiding the prompt evacuation of symptomatic contacts from the community to the isolation facility thereby reducing contact with others and reducing the risk of transmission of the virus.


Discordant course of the disease in monozygotic (MZ) twins is known to be characteristic for familial amyloidotic polyneuropathy (FAP). Existing cases of FAP in MZ twins refer to amyloidosis due to mutant transthyretin (TTR) Val30Met gene. We present a case of a pair of MZ twins associated with a substitution of tyrosine to cysteine at position 114 in the TTR gene in a Russian kindered. Until now FAP due to mutant TTR Cys 114 has only been described in one Japanese and in one Dutch family. Though in none of them MZ twins were present.Complete laboratory and instrumental investigation of both of the Russian MZ twins was performed. Detailed life history was evaluated in each of the brothers and compared with other known cases of FAP in MZ twins.One of the twins had a prominent clinical picture of FAP and visceral amyloidosis, starting around the age of 45 years. In the mean time the other brother was still clinically healthy at the age of 50. DNA confirmed identical mutation of TTR gene in both brothers. Amyloid depositions were found to be similar in the intestines, but not in other locations. Both patients lived in same district and had similar educational background. Though the patient with a prominent clinical picture of FAP experienced vaccination agravated by side effects as well as appendicitis agravated by severe peritonitis in his twenties.Charactristic feature of FAP in known pairs of MZ twins is the discordance in the disease course with a prominent manifestation in one of the twins, and delayed disease onset and/or only slight presentation in the other. Genetical and non-genetical factors, or their combination, were supposed to be contributing. Non-genetical mechanisms of the phenotypic variability of FAP could consist of influences on the mutant gene expression during twinning process or along the life. In Russian pair of MZ twins different life-course events could determine clinical presentation of the disease.


To illustrate the anatomy of renal vasculature and its variants on cross-sectional imaging.To highlight the benefits of obtaining images in both arterial and venous phase in staging and follow-up of renal cancer.It is common practice to perform dual phase computed tomography (CT) in preliminary staging and subsequent follow-up of renal cancer patients in some institutions across the United Kingdom. We provide the best examples from our institution (2010-2013) with illustrations and the clinical relevance for the conditions stated below.We discuss the normal anatomy and variants of the renal artery including early division of artery, accessory artery and double renal artery. In addition, usual and uncommon sites  of hypervascular metastasis in primary renal cancer patients will be illustrated.We will highlight the normal anatomy and variants of the renal vein  and associated tumour infiltration in unexpected veins  and solid organ metastasis.The renal vasculature is frequently visualised on imaging but often overlooked. This exhibit will provide radiology trainee’s an insight into the anatomical variants and its relevance in management of primary renal cancer. It reminds them of the common and uncommon metastasise and tumour infiltration seen in renal cancer, thus affecting the outcome.


N = 38 healthy participants scanned with the time-of-flight (TOF) magnetic resonance technique, and normalized with procedures analogous to those commonly used in functional neuroimaging studies. Spatial colocalization of brain parenchyma and vessels is shown to affect specific structures such as the anteromedial face of the temporal lobe, the cortex surrounding the Sylvian fissure (Sy), the anterior cingular cortex, and the ventral striatum. The vascular frequency maps presented here provide objective information about the vascularization of the brain, and may assist in the interpretation of data in studies where vessels are a potential confound.While widely distributed, the vascular supply of the brain is particularly prominent in certain anatomical structures because of the high vessel density or their large size. A digital atlas of middle to large vessels in Montreal Neurological Institute (MNI) coordinates is here presented, obtained from a sample of  Digital brain atlases are an increasingly important instrument in neuroimaging research, as they provide a spatial framework for the selection, interpretation, and generalization of complex experimental data  studies, heart pulsation is known to affect the signal near large arterial vessels , which results from the anastomosis of the two cerebral arteries. These vessels were localized consistently in TOF images, with voxels assigned to the vascular structure reaching frequency values of over 80% in correspondence to these vessels. Another important artery giving rise to high localization frequencies was the anterior cerebral artery and its prolongation, the pericallosal artery (PC) Figure . MNI cooThe anterior cerebral and PC arteries are commonly present as a pair of left and right vessels, running side by side deep in the medial longitudinal fissure . This partial overlap may arise from individual differences in the size and shape of these limbic structures, which displace the vessels running close to their surface  was particularly conspicuous in the ventral striatum . The whole space separating the insular cortex from the frontal, parietal, and temporal operculi was characterized by fairly high vascular frequency Figure . The corThe dense web of vascular structures running along the medial wall is displayed in Figure Also the isocortex surrounding the anterior cingulus was bordered by a dense, poorly structured vascular web Figure , top rowWhile the anteroventral part of the brain is characterized by the presence of large arteries, the main vascular structures in the posterior part of the brain are sinuses in the dura mater and tentorial tissue. The sagittal and transversal sinuses were by far the most prominent collectors of venous blood, followed by the straight sinus  and qualitative. The quantitative differences staked out regions where the presence of large vessels was prominent. The qualitative differences were due to different relationships between vessel course and anatomical structures, which may be ordered along a range according to the extent of intermingling.At one extreme of this range, large vessels were located in separate spaces well outside brain parenchyma, but individual variation in their course brought about a partial overlap between vessels and registered brain structures. This kind of overlap was exemplified by the relationship between the amygdala and the terminal part of the internal carotis and the CM. Even if among the least variable of all anatomical structures, the amygdala has a size that varies by a factor of two across healthy individuals .The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


It's difficult to talk about nurse's autonomy in ventilation assistance, because is a medical prescription. However in accordance with the Code of ethics, the professional profile and law 42/99, nurses have decision and operative autonomy in nursing care, which is achieved through specific autonomous and complementary interventions of intellectual, technical-scientific, managerial, relational and educational nature -3. The tMonitoring peripheral oxygen saturation is more suitable method in the ventilated preterm (<27 weeks) because transcutaneous oxygenation monitoring is not of routine use for lack of an adequate correlation with the blood gas and for highly sensitive skin.Many studies suggest the prevention of lung damage and retinopathy of preterm concerning a prolonged hyperoxia by setting alarm limits in the event of administration of an oxygen concentration higher than 21%. Numerous clinical conditions, including the need for mechanical ventilation, can affect and change the brain oxygenation. The near-infrared ray spectrophotometry (NIRS) is a technique that allows non-invasive monitoring of oxygenation and cerebral hemodynamics. It provides a single quantitative parameter rSO2  as an index of tissue oxygenation .Compared to the intubated newborn there is not a unique method and standardized anchorage of the endotracheal tube. The quality of the attachment can vary greatly depending on the choice of the tape and according to the method of taping adopted.No recommendation exists in the literature about the method of taping: the most widely used systems include the use of one or two strips cut to Y or H. The adhesive tape, indisputably considered the system capable of guaranteeing the best results in terms of sealing, when applied with a taping system and encoded together with a hydrocolloid protective largely reduces the risk of injury-8.The aspiration of the airways in infants should be based on careful clinical assessment and not on a routine basis. It recommended to avoid suctioning the nose but use saline drops instead, then suction the oropharynx .Care posture is crucial because it promotes the stabilization of the neonatal functions and prevents bad posture .It is recommended the use of ventilation systems with manual pressure control and delivered volumes in order to safeguard the delicate lung tissue.


However, little information has been put forth on the correlations between coma and cerebral imaging methods. The purpose of the article is to compile the available information derived from various imaging methods and placing it in a context of clinical knowledge of coma and related states. The definition of coma and the cerebral structures responsible for consciousness are described; the mechanisms of cerebral lesions leading to impaired consciousness and coma are explained. Cerebral imaging methods provide a large array of information on the structural changes of brain tissue in the various diseases leading to coma. Circumscript lesions produce space-occupying masses that displace the brain, ultimately leading to various types of herniation. Generalized disease of the brain usually leads to diffuse brain swelling which also can cause herniation. Epileptic states, however, rarely are detectable by imaging methods and mandate EEG examinations. Another important aspect of imaging in coma is the increasing use of functional imaging methods, which can detect the function of loss of function in various areas of the brain and render information on the extent and severity of brain damage as well as on the prognosis of disease. The MRI methods of  Coma is one of the most common clinical signs in critical care medicine and is observed in all areas of critical care. Unfortunately, little interest seems to be directed towards this ubiquitous clinical sign, and few intensivists take the time to closely observe and document phenomena of impaired consciousness and come in their patients. Usually, only global scores of impaired consciousness are documented. This is somewhat astonishing considering the fact that the functional impairment of brain function in any disease course probably has the greatest impact on the long-term outcome of the individual patient.The rapid development of cerebral imaging methods in medicine in general and intensive care medicine in particular has vastly improved our understanding of cerebral lesions and their development in the disease course. On the other hand, only little attention has been directed toward the information on consciousness and come that can be derived from imaging methods.While cerebral imaging is able to detect and assess the localization and size of space-occupying lesions, it can render only little information on the functional impairment of the brain. These functional deficits are usually better studied by neurophysiological methods, such as EEG and evoked potentials. These methods are far better suited to make statements as to the functional disturbance and its prognosis.The authors have attempted to compile an overview of the contribution of brain imaging methods to the knowledge of the phenomenon “coma”. This collection of data can only shed a spotlight on various areas of scientific investigation and cannot provide an exhaustive lexical database on brain imaging and coma. Keeping these limitations in mind, the collection may increase the interest in the contribution of cerebral imaging methods in the assessment of coma.Coma is defined as a severe disturbance of consciousness, which precludes awakening, and the directed movement of extremities. The comatose person demonstrates closed eyes and shows no purposeful reaction to noxious stimuli. The quantitative reduction of wakefulness, or better of arousal function, is the main feature of this condition. Many other qualitative disturbances of consciousness may occur before the manifestation of the state of coma. If both phenomena appear together in a fluctuating or alternating manner, the diagnosis of an organic psychosis of the delirium type should be considered. The broad spectrum of etiologies overlaps and is not specific for either qualitative or quantitative disturbances.In older age, typical etiological factors include metabolic disturbances such as hypoglycemia or hyperglycemia, electrolyte imbalance as well as single and multiple organ failure including hepatic or renal failure and finally focal and global cerebral perfusion deficits especially in stroke or anoxia following resuscitation . Whenever this system is functionally impaired bilaterally, one must anticipate disturbances of consciousness ultimately attaining the degree of coma. The ARAS connects the thalamic and subthalamic nuclei with the reticular intermediary grey substance of the spinal cord. Here, the etiology and exact localization of the functional neuronal disturbance in the ARAS are not especially important: reversible metabolic CNS disease in the context of metabolic derangement is just as well possible as structural lesions along the thalamic loop structures.However, infratentorial space-occupying lesions with consecutive brain stem compression cause disturbances of consciousness through secondary functional disturbances within the ARAS . Even very small lesions, strategically placed bilaterally in the ARAS, can produce coma, e.g. in cases of small bilateral infarctions in the thalamo-mesencephalic border region or in the thalamic nuclei Figure . As a ruUnilateral hemispheric lesions do not produce coma as long as they do not compromise the midline structures or lead to a secondary impairment of the brainstem structures. Both features can be caused by progressive focal cerebral edema and spreading of a lesion to the contralateral side Figure . This prSecondary brain lesions are caused by displacement of brain tissue: The space- occupying lesions lead to lateral displacement  and downward directed herniation toward the brainstem , and the immediately life-threatening lower herniation of the cerebellar tonsils which often occurs in the preterminal phase of disease. The latter compromises the lower brain stem nuclei, which are essential for the regulation of respiratory function and blood pressure regulation.Another important event immediately preceding death in coma is the development of venous congestive swelling and hemorrhages (Duret’s hemorrhages) due to impairment of drainage though swelling of the brainstem tissue. The degree of displacement of the midline  has been correlated in vivo with the depth of coma.In the detection of primary cerebral lesions, the terms of focal and lateralizing signs have been introduced. Usually, ipsilateral pupillary enlargement occurs in uncal herniation, due to the compression of the ipsilateral oculomotor nerve. The rare appearance of contralateral mydriasis is explained by the fact that some space occupying lesions develop less downward, but rather predominantly lateral displacement, resulting in a tipping of the neuraxis. Instead of an obstruction of the ipsilateral parts of the perimesencephalic cisterns, the contralateral fluid compartments are compressed which can be followed in imaging tests. Thus, “false localizing signs” such as a dilated contralateral pupil or spastic signs ipsilateral to the primary cerebral lesion can be well explained and corroborated by neuroradiological findings. In neuropathological terms, this corresponds to the pressure of the brainstem on the tentorium (Kernohan’s notch), and clinically, this is probably closely correlated to the appearance of extensor spasms and posturing.The initial assessment of the clinical presentation is dominated by the neurological and general clinical examination. Aside from determining the vital signs , the presence of neck stiffness and focal neurological deficits must be recorded. The Tables Psychogenic disturbances of consciousness are usually dissociative in nature and only rarely factitious disease. They can mimic any coma-like situation and often also present with focal neurological signs such as speech arrest or sensory-motor hemisyndromes. The verification of the psychogenic nature of these signs is very difficult to achieve, and often evolves over time, after all neurophysiological tests have failed to detect any functional disturbance. Imaging tests invariably demonstrate normal findings or may detect older premorbid conditions that are irrelevant to the presented condition of disturbed consciousness. These patients often demonstrate marked fluctuations of the neurological findings, especially dependent on the attention of the examiner, and often one finds a psychiatric history or a special emotional burden. Reactivation of a traumatic experience in the context of a posttraumatic stress disorder (PTSD) is a common cause for these dissociative states.Even if neurological focal signs are completely absent, multilocular cerebral lesions remain a possible differential diagnosis and must be sought using imaging methods  Figure .Figure 3Furthermore, disorders of consciousness are frequently seen as secondary epileptic complications such as generalized epileptic seizures after stroke. The recovery phase is usually associated with recovery from impaired consciousness during the next few hours, however, in elderly and multimorbid patients, protracted recovery can occur over several days . As far as danger to life is concerned, the generalized and persistent epileptic functional disturbances are most important. These functional disturbances are accompanied by neuronal necrosis and later by life-threatening brain swelling in combination with cerebral lactacidosis, which cannot be measured by clinical methods. Even regularly reoccurring singular epileptic seizures can produce relevant temporal lobe lesions , which are occasionally detectable by imaging methods Duncan .Although the metabolic exhaustion can be detected in the form of tissue diffusion abnormalities (cytotoxic edema) in severe cases, imaging methods at present usually do not provide relevant information for the diagnosis of epileptic functional disturbances  or the minimally conscious state (MCS), functional imaging methods have provided a host of new insights into these syndromes.18 F-2-Fluoro-2-deoxy-D-glucose (FDG), as well as SPECT (single photon emission tomography) has been used for these purposes. The methods provide information on regional and global function of the brain. In coma and related conditions, they usually show severe global decrease of brain activity.Imaging methods have been used for over 20 years to detect the extent of cerebral damage in severe diseases of the brain. The method of Positron-Emission-Tomography (PET), most frequently using the tracer On examination of patients in PVS using FDG PET, which measures the cerebral glucose metabolism, the global cerebral glucose metabolism was reduced by approximately 50%  has been implemented to overcome this dilemma. The goal was to measure a change in brain activity in response to stimuli even if a motor response of the patient was not possible. FMRI is a method to examine activated brain areas with high spatial resolution. The method is used for a number of different motor, sensory, and neuropsychological functions. The activation of a certain brain area, which is activated during a specific task, leads to a change in blood oxygenation. This, on the other hand, leads to a change in the magnetic properties of the hemoglobin molecules, which can be detected by MRI. The signal, which is dependent on the oxygen level of the blood, is called the BOLD (blood oxygen level dependent) signal. In this context, the examination is based on the observation that pure thought (imagination) of motor functions leads to activation of certain cerebral areas. The increased oxygen consumption leads to a change of the BOLD signal, which is detected by MRI.The regions activated by thought tasks could be compared between healthy subjects and patients suffering from PVS or MCS. Owen et al. . The most important methods are native x-ray diagnostics, angiography, computed tomography (CT), and magnetic resonance imaging (MRI).The Ethics Committee of the University of Magdeburg approved the anonymous evaluation of data of comatose patients after head injury for scientific purposes without consent of the patients or their legal guardians (decision 131 of 1997).The indications and relevance of these four examination methods will be discussed in the order of their historical development.Today, the skull x-ray only plays a historical role in the treatment of TBI patients. In patients with impaired consciousness and a skull fracture, the probability of an intracranial hemorrhage amounts to 1 in 4 .To date, the CT scan is the method of choice in TBI and cases of unconsciousness since it can detect density changes between brain tissue and acute hemorrhages with high resolution  implicate that imaging methods can be utilized to define criteria for treatment success or treatment failure which can be detected in an early stage  and can be used for confirmation and documentation of clinical findings. The findings and their technical implementation are focused on better understanding of brain reactions to the primary disease process and its dynamics during treatment.One of the goals of imaging methods is to give a basic view for the detection of loss of function, the documentation of irreversible loss of function as well as the irrefutable documentation of the time point of the total and irreversible loss of brain function which is needed in the determination of brain death to document the cause of death and to reliably assess the absence of therapeutic options.Examinations pertaining to morphological finding of the spinal cord in the phase of spinalisation, i.e. after declaration of brain death have not been published so far. Neuropathological findings in brain death have been referred by Wijdicks and Pfeifer  whereas the 2 phase CT demonstrates the loss of perfusion of the MCA and the perfusion loss of the large cerebral veins  seems to increase the specificity of prognostication up to 97% , which is performed using this diagnosis. There is a new discussion on the problem of decision making on the treatment in patients suffering from a terminal coma or imminent brain death. Criteria of the FOUR score include a catastrophic brain lesion, which has to be documented by adequate imaging techniques, e.g., multimodal MRT imaging (Nichol et al. The compiled data of imaging methods in the context of coma is provided to give an overview of the current knowledge concerning the contribution of brain imaging methods in coma and related states. The focus of the article is not to provide an exhaustive review of all of the various facets of brain imaging in single disease entities, but rather to give information on the approaches to the differentiation of comatose states by imaging methods. Therefore, no attempt was made to describe the vast information gathered in specific disease entities such as stroke or brain tumors, much less in traumatic brain injury. The approach to the clinical sign “coma” is a clinically relevant task, which requires several different approaches. The first and most important approach is the clinical examination, which can differentiate between supratentorial, infratentorial and diffuse brain damage. With this information, it becomes possible to narrow down the differential diagnosis to certain etiologies and brain regions in which the primary cause of disease should be sought. The contribution of imaging methods to this differential diagnostic approach is compiled. The next step is the assessment of disease prognosis. This question can again be based on the clinical findings, and imaging methods can used in certain areas to enhance the clinically assessed prognostic data. Here, certain neurophysiological methods render the most relevant prognostic statements. Imaging methods are especially valuable in the prognostic assessment of PVS and MCS, an area where neurophysiological methods provide little information. The proper selection of examination methods for diagnostic and prognostic purposes in coma and related states requires broad knowledge of the strengths and weaknesses of the various methods. Since the various examination methods are performed by a number of different medical subspecialties, the neurologist caring for comatose patients is in need of knowledge as to what examinations to have performed and for which purpose. As in many circumstances in critical care medicine, the unreflected application of a host of possible diagnostic tests does lead to a better understanding of the disease process per se. The correct selection of technical examinations, depending on the nature of the clinical problem on hand, renders highly sensitive and reliable information in many specific clinical situations. This is especially true in the diagnosis of the terminal phase of comatose patients where multimodal MRI methods may increase the prognostic accuracy earlier in the clinical course.


While historically acetylcholine (ACh) holds a central place in the discovery of chemical transmission in the nervous system, progress in our knowledge of the mechanistic underpinnings of cholinergic transmission in the central nervous system (CNS) has lagged behind its sister transmitters. For example, unlike what we know about glutamatergic transmission, neither the prevalence of fast cholinergic transmission or postsynaptic specializations at cholinergic synapses, is well understood. Every level of inquiry into the cholinergic system reveals a bewildering complexity in signaling and transduction mechanisms. Receptor localizations within and among neurons, along with transmitter source and access to receptors, provide for a system that is capable of neuromodulation at multiple time scales that allow for short- and long-term regulation of circuit output in the brain. The compilation of reviews and primary papers in this research topic provides a sampling of findings at different levels of integration that highlight both the current status of our understanding of CNS cholinergic mechanisms as well as reveals the gaps in our knowledge that need to be filled.How ACh mediates signaling in the brain is still an unresolved issue at the level of synaptic physiology. Cholinergic innervation in the brain arises from two main loci- the basal forebrain and the pendunculo-pontine area of the hindbrain. In both instances a relatively small cluster of neurons send diffuse projections into various target areas. The diffuse nature of the projections, as well as the non-planar relationship between the cholinergic neurons and their targets precludes traditional slice electrophysiology approaches to examining signaling. Recent advances in optogenetic techniques offer a potential solution to this problem and some of the advances made thus far are reviewed in this research topic  but send dense projections throughout the area. Recent findings that are summarized here  and the metabotropic muscarinic acetylcholine receptors (mAChRs), their expression in multiple neuronal types within a region, and varying locations within a neuron  all orchestrate a complex symphony of neuromodulation. A review of receptor localization and function within hippocampal CA 1 interneurons (McQuiston, These local control mechanisms can regulate circuit outputs in various regions of the brain, potentially mediating the attention and learning-specific behaviors ascribed to ACh-driven modulation. In the olfactory system, nAChR activation can filter odor signals such that weak inputs are eliminated while strong ones are allowed through, thus providing a mechanism for altering the gain function of a circuit (D'souza and Vijayaraghavan, Cholinergic receptors are a potential gold mine as targets for therapies and pharmaceutical companies have not been diffident about exploring various receptor ligands as potential therapies. Emerging studies implicate cholinergic receptors in various addictive mechanisms: the direct interaction between cocaine and nAChRs reported in this research topic (Acevedo-Rodriguez et al., This is prime time for the development of clinical therapies that target the cholinergic system for a host of brain disorders. At the same time, as the collection of studies in this research topic illustrates, much remains to be understood regarding the physiology of cholinergic transmission and modulation. There is a risk of pharmacological advances outpacing our knowledge of cholinergic signaling mechanisms in the brain. History tells us that such a disconnect between therapeutic advances and our knowledge of physiology can often lead to unintended complications from novel therapies, a classic example being the aggressive marketing of heroin as a cough remedy at the turn of the twentieth century. There needs to be significant investment in examining the basic biology of cholinergic modulation of brain circuits in order to develop more rational and safe therapeutic targets that the cholinergic system offers.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.


This article presents authors’ methods of digital reconstruction using composite tissue transfer. The authors present their approach to achieve the goal of restoring full cosmetic appearance of the reconstructed toes while preserving the function and cosmetic appearance of the donor foot. The reconstructive procedures for each degree of digit defect are discussed in detail, and pitfalls and technical tips are given. The article is a summary of the authors’ experience in reconstruction of 646 digits since 1998 and the challenges we faced in the complex microsurgical reconstruction necessary in pursuing the goal of restoring the cosmetic appearance of reconstructed digits and donor feet.1. We present our methods of digital reconstruction using composite tissue transfer.2. Our major aims of surgery are to improve the cosmetic appearance of reconstructed hands and donor feet.3. We describe a number of methods using modified or novel designs for composite tissue transfer from the foot to improve cosmetic appearance of the reconstructed digits and to improve both the cosmetic appearance and function of donor feet.4. The article provides technical details of the methods we used to move closer to an ideal reconstruction of digits and minimizing donor foot morbidity.


Background. Descriptive evaluation of nerve variations plays a pivotal role in the usefulness of clinical or surgical practice, as an anatomical variation often sets a risk of nerve palsy syndrome. Ulnar nerve (UN) is one amongst the major nerves involved in neuropathy. In the present anatomical study, variations related to ulnar nerve have been identified and its potential clinical implications discussed. Materials and Method. We examined 50 upper limb dissected specimens for possible ulnar nerve variations. Careful observation for any aberrant formation and/or communication in relation to UN has been carried out. Results. Four out of 50 limbs (8%) presented with variations related to ulnar nerve. Amongst them, in two cases abnormal communication with neighboring nerve was identified and variation in the formation of UN was noted in remaining two limbs. Conclusion. An unusual relation of UN with its neighboring nerves, thus muscles, and its aberrant formation might jeopardize the normal sensori-motor behavior. Knowledge about anatomical variations of the UN is therefore important for the clinicians in understanding the severity of ulnar nerve neuropathy related complications. Ulnar nerve (UN) is the major branch of the medial cord of brachial plexus, given off in the axilla. It consists of fibers of ventral rami of C8 and T1 spinal nerves. But it often receives additional contribution of C7 fibers through median nerve via its lateral root [An anomalous pattern could be appreciated in the division of trunks and formation of the cords of brachial plexus. However, no such aberrations usually could be noticed in the subsequent arrangement of their terminal branches . AnomaloUN variations are consistently located in the origin or course of the distal branches. But, in the available literature describing these variations, it has been noted that much variations in communications between neighboring nerves do exist either in the forearm (most commonly) or in the hand. The present anatomical study aims to identify the variations related to ulnar nerve and to discuss the potential importance of such variations in clinical practice.The present study was conducted in the Department of Anatomy, Melaka Manipal Medical College , Manipal, India. It involved examination of 50 upper limbs of formalin embalmed human cadavers aged between 45 and 60 years. Of the 50 upper limbs 24 were right sided and 26 were left sided. The axillary region of all the limbs was exposed carefully after clearing the entire fascia and to look for the anatomy of ulnar nerve formation from medial cord of brachial plexus. The dissection was further continued towards the anterior compartment of the arm in order to probe any communications of ulnar nerve with neighboring peripheral nerves at high humeral level. Meticulous observation of variant forms and/or abnormal communication if any was made. In the case of persistence of variant communication between neighboring peripheral nerves, the length of the communicating channel has been measured and documented. Relevant photographs of representative specimens were taken and produced herewith.We observed a total of 4 ulnar nerve variations out of 50 upper limbs. It accounted for 8% of incidence cases. All four variations of ulnar nerve were observed in right upper limbs. Aberrant formation of the ulnar nerve with a remarkable contribution from the lateral cord of brachial plexus  was seenIn the remaining two cases, ulnar nerve had abnormal communications with the neighboring nerves, radial nerve , and medIn case of the communication from medial cutaneous nerve of forearm, the nerve gave off a communicating branch on its medial aspect . The comAn effective brachial plexus blockade can be achieved, given that there is possession of thorough knowledge of all possible anatomical variations that can be appreciated in the form of either abnormal origin of its branches or the variant communication between its branches in addition to normal anatomy.Several studies have reported communications between terminal branches of brachial plexus in the forearm as well as in hand. Different terminology has been allotted to the existence of communication between median and ulnar nerve based on the location of their existence as Riche- Cannieu anastomosis in the palm, Martin-Gruber anastomosis and Marinacci communication in the forearm, and Berrettini anastomosis manifested by the communication between digital branches in the palm. Descriptive features of these communications have been discussed by Dogan et al. . HoweverVariant formation of the UN is not common since there are few reports about it existence. Sachdeva and Singla reported a rare origin of UN from median nerve . In theiIn the present study, we came across with the rare aberrant formation of UN by the remarkable contribution from lateral cord in two of 50 upper limbs. Variations in the origin, course, and distribution of nerves are prone to iatrogenic injuries and entrapment neuropathies . TherefoUnusual communications between the branches of brachial plexus are often seen in medial and lateral cords . AberranVery rarely might a communication be observed between ulnar nerve and medial cutaneous nerve of forearm. Medial cutaneous nerve of forearm is found to communicate with medial cutaneous nerve of arm  and radiDiverse opinions of ontogeny of these communications have been put forward by researchers. Probably the simplest cause can be attributed to altered coordination between the mesenchyme responsible for limb muscle and its spinal nerve component which might have led to the formation of aberrant communicating branches .Investigations of peripheral neuropathies are based upon patterns of functional deficits and diagnostic testing. Therefore, an anatomical variation can often lead to confounding patterns of physical and diagnostic findings. According to Ajayi et al., anatomical variant communication between branches of the brachial plexus could obscure the management of complex regional pain syndrome .Ulnar neuropathies are the most frequent causes of nerve injuries as reported by Kroll et al. and they account for a majority with a prevalence of 33%, which is followed by 23% of incidence cases by brachial plexus injuries . AnatomiTherefore, knowledge on the variant pattern of peripheral nerves is imperative not only for the surgeons, but also for the radiologists during image technology and MRI interpretations and for the anesthesiologists before administering anesthetic agents thus in diagnostic approaches . Damage Awareness of an anatomical variation of UN both in its formation and in abnormal communication at the high humeral level is essential because of the frequency of surgeries performed in these regions for various reasons as well as in diagnostic approaches of management of ulnar neuropathy. Knowledge about anatomical variations of the peripheral nerves is therefore important for the clinicians in understanding the severity of neuropathy related complications.


Healthcare in India comes mostly as an out of the pocket payment as health insurance is virtually absent for majority of the population. Determination of the typical hospital cost and length of stay (LOS) are of decisive importance for patients, healthcare providers, and payers who need to make evidence based rational decisions about patient care and the allocation of resources.A cross sectional pilot study was performed and the data for LOS and hospital cost was collected from the medicine ICU and the accounts section for 38 patients with resistant bacterial infections who were admitted to Intensive care unit. The data was analyzed for average LOS and hospital cost for infections. The data was analyzed using univariate analysis.Almost 29% of the patients with resistant infections were between 18-40 years of age. The mean cost of hospitalization was found to be INR76082.79 and only 34% of the patients were having any insurance coverage. The median length of stay in the hospital ICU was 8.5 days. 37% of the patients were on ventilator during the hospitalization and 25% of the total patients died.Resistant bacterial infections may lead to a high LOS in the ICU furthermore adding to the economic burden of the patient, healthcare provider and the payer. These results can be used to study the treatment alternatives in case of resistant infections and making them cost effective at the same time stressing upon the need of health insurance among the population.


Spontaneous ruptures of the quadriceps tendon are infrequent injuries, it is seen primarily in patients with predisposing diseases such as gout, rheumatoid arthritis and chronic renal failure. A 32-year-old man had a history of end stage renal disease and received regular hemodialysis treatment for more than 5 years. He was admitted in our service for total functional impotence of the right lower limb with knee pain after a common fall two months ago. The radiogram showed a ‘'patella baja” with suprapatellar calcifications. The ultrasound and MRI showed an aspect of rupture of the quadriceps tendon in its proximal end with retraction of 3 cm. Quadriceps tendon repair was performed with a lengthening plasty, and the result was satisfactory after a serial rehabilitation program. The diagnosis of quadriceps tendon ruptures needs more attention in patients with predisposing diseases. They should not be unknown because the treatment of neglected lesions is more difficult. We insist on the early surgical repair associated with early rehabilitation that can guarantee recovery of good active extension. Ruptures of the extensor mechanism of the knee joint are defined by the existence of a solution of continuity on the chain bone muscle tendon which provides the extension of the leg on the thighs: patellar tendon, quadriceps tendon and muscle, anterior tibial tuberosity and patella. Spontaneous ruptures of the quadriceps tendon are infrequent injuries; it is seen primarily in patients with predisposing disease such as gout, rheumatoid arthritis and chronic renal failure.Several factors probably combine to weaken the tendon, including a loss of local vascular supply, repeated microtrauma and osteodystrophy secondary to hyperparathyroidism Through one case of spontaneous rupture of the quadriceps tendon occurred in a patient with chronic renal failure we stressed the difficulty of therapeutic management in this patient and the benefit of early rehabilitation.Our patient, a 32 year old man, employee, without any sport practice, had a chronic renal failure, with hemodialysis dependence for 5 years, was admitted in our service for total functional impotence of the right lower limb with knee pain after a common fall two months ago.Clinical examination revealed an inability to walk, a loss of active extension of the knee joint and palpable tendinous suprapatellar defect . RadiogrMRI confirmed the diagnosis of rupture of the quadriceps tendons and eliminates injuries of the cruciate ligament, the menisci, collateral ligaments and patellar tendon . SurgicaPost-operatively, the knee was immobilized with a removable knee splint for a period of six weeks. A week after, the patient was then put on program of rehabilitation based primarily on isometric contractions of the quadriceps and passive mobilization of the knee One month later, an active mobilization was initiated. The recovery of walking was allowed after 6 weeks with protection of external support (crutches). The patient was clinically evaluated each week for a month and every month.After three years of patient follow-up, the results were graded good, based on the range of motion of the knee, the strength of the quadriceps muscle and the ability of the patient to walk with one crutch. The joint assessment found a patella mobile with active extension and flexion.Quadriceps tendon ruptures are uncommon injuries. They most often occur on road accident in the population under 40 years . The spoChronic renal failure can cause several complications related to the process of dialysis as amyloidosis  in which there is abnormal production of beta 2 microglobulin. This molecule normally metabolized by the kidney is accumulated in chronic hemodialysis patients with rates above 30 to 40 times normal, it tends to accumulate in specific structures such as bone and tendon reducing its elasticity and predisposes to ruptures after minimal efforts [Besides amyloidosis, secondary hyperparathyroidism in chronic renal failure leads to dystrophic calcification and resorption of subperiostal bone causing fragility of the bone tendon junction –7. This The injury mechanism is essentially indirect muscle contraction during an extension movement of the thigh on the leg or during a forced flexion above 45° where the balance of forces between the quadriceps tendon and patellar tendon is reversed The diagnosis of tendon rupture is easy in the acute phase with the existence of a suprapatellar depression and pain on palpation a patella in the low position relative to the opposite side and inability of active extension of the knee.In the neglected forms clinical diagnosis is more difficult, the defect may not be evident because of scar-tissue formation, and the signs are present at lower levels which give more importance to the complementary examinations.The lateral view radiograph of the knee shows a patella baja and suprapatellar calcifications Ultrasonography of the soft tissues shows in case of total rupture, a complete interruption of tendon fibers separated by a hypoechogenous track (hematoma), but it remains operator-dependent examination .In case of partial rupture it reveals a partial rupture of the tendon in the transverse plane or dissection of the fibers in the longitudinal plane.Finally MRI shows high signal on T2 signing hemorrhage or edema. She finds its indications in the neglected forms if the clinical examination and ultrasonography cannot conclude. The treatment of a complete rupture of the quadriceps tendon is surgical but it is not always easy. The techniques are quite diverse because of the variety of lesions encountered, recent or old, and evolution of the conception of surgical techniques.According to various authors, the repair of the neglected forms after the sixth week remains difficult because of the tendinous retraction requiring a lengthening plasty. In these cases it is recommended to use Scuderi repair and Codivilla V/Y plasty  and whenThe postoperative immobilization pedal for about 6 weeks, time of healing, is recommended this immobilisation must be made with 15° on flexion to avoid the creation or perpetuation of a patella baja.Rehabilitation is conducted by early passive mobilization of the knee on the first day after surgery, taking into consideration the stability and solidity of surgical repair. This work will be replaced by an active rehabilitation witch it is essentially based on the stretch of the quadriceps, the gradual increase in quadriceps muscle strength and the change in execution speed of movement with the aim of this work is to reinforce the tendon.The spontaneous quadriceps tendon ruptures are uncommon. They should not be unknown because the treatment of a neglected lesion is more difficult. The large number of plasties described in the literature shows the absence of codification of this surgery. We insist on the early surgical repair associated with early rehabilitation that can guarantee recovery of good active extension.


Iatrogenic injury during the posterior approach to the humerus during operative fixation is not an uncommon occurrence. A comprehensive understanding of the normal anatomy and its variants is of paramount importance in order to avoid such injury. Typically, the inferior lateral cutaneous branch of the radial nerve originates towards the distal end of the humerus at the inferior portion of the spiral groove. Here, we report an important variant of this nerve, which originated significantly more proximal than expected, further emphasizing the importance of identification, dissection and protection of the radial nerve and its major branches. Understanding normal anatomy and being aware of potential variants is of paramount importance during the operative fixation of fractures. Especially when regarding the radial nerve, injury can occur despite a comprehensive understanding and meticulous dissection . While tPatient is a 27 year-old right hand dominant female who presented initially following an assault where a car door was closed on her right arm. She was evaluated and treated at a local emergency department with a coaptation splint. She had sustained a closed injury and remained neurovascularly intact. Initial management consisted of conversion over to a fracture brace and close follow-up. However, six weeks from injury, the patient endorsed continued pain. Examination revealed tenderness and movement through the fracture site; radiographs revealed unacceptable angulation and minimal callus formation Figure . With peThe patient was brought to the operating room and placed in the lateral decubitus position. Stress fluoroscopy exhibited gross motion at the fracture site Figure . Via theIatrogenic nerve injuries are among the devastating complications in the treatment of humerus fractures. Recent studies showed the rate of iatrogenic nerve injury in operatively treated supracondylar humerus fractures is 3% to 4% . The iatThe inferior lateral cutaneous nerve of the arm is the branch of radial nerve that provides sensory and vasomotor innervations to the lower, lateral aspect of the arm. Understanding the variants of sensory nerve not only helps in the identification of radial nerve, but also reduces the chance of iatrogenic injury. In this case, the inferior lateral cutaneous nerve of the arm branched off at the level high above the spiral groove with a long arm branching down laterally into the subcutaneous tissue and skin. Hannouche et al, in a cadaveric study, noted the same takeoff origin of the inferior lateral cutaneous branch in all 18 specimens, which was at the inferior end of the spiral groove . In our Despite a seemingly reliable anatomic understanding the radial nerve and its branches, we report here an important variant of the inferior lateral cutaneous branch of the radial nerve. Typically, its origin is in the distal third of the humerus at the inferior end of the spiral groove, however, we report an abnormally high branching variant well above even the proximal extent of the spiral groove. We recommend using the confluence of the triceps lateral head, long head and aponeurosis  to identInformed consent was obtained prior to the completion of this manuscript.