The prevalence of both urinary and faecal incontinence, and also chronic constipation, increases with ageing and these conditions have a major impact on the quality of life of the elderly. Management of bladder and bowel dysfunction in the elderly is currently far from ideal and also carries a significant financial burden. Understanding how these changes occur is thus a major priority in biogerontology. The functions of the bladder and terminal bowel are regulated by complex neuronal networks. In particular neurons of the spinal cord and peripheral ganglia play a key role in regulating micturition and defaecation reflexes as well as promoting continence. In this review we discuss the evidence for ageing-induced neuronal dysfunction that might predispose to neurogenic forms of incontinence in the elderly. The lower abdomino-pelvic cavity contains organs including the small and large intestines, the bladder and components of the lower urinary tract. Numerous studies have demonstrated that these structures are subject to age-related changes that may lead to an increase in the incidence of bladder/bowel disorders in the elderly. The causes of these changes are likely to be multifactorial including ageing of the effector cells (e.g. smooth muscle) and also the cells that regulate their function . The aim of this review is to discuss the potential neurogenic (e.g. defective neurotransmission) mechanisms resulting in ageing of these different abdomino-pelvic organs with an emphasis on the spinal and peripheral neurons that provide the efferent (motor) innervation of these structures to regulate bladder and bowel function.Ageing of the bladder and lower bowel may result in problems of storage of faecal material and urine (waste), manifest in incontinence  and neurogenic incontinence have been suggested to be equally common in elderly individuals (aged 80+) in residential care with a study showing that in a small sample  of both men and women 52 % of patients developed faecal incontinence secondary to faecal impaction whilst in 48 % the incontinence was neurogenically mediated  but the properties and arrangement of the cells in these organ systems is very different. Here the main focus of this review is on the neuronal control of the bladder, bowel and lower urinary tract structures and a detailed discussion of other cell types is not included.The bladder is a hollow muscular organ connected to the kidneys by the ureters. Urine is excreted from the kidneys, passes through the ureters, and is stored in the bladder before elimination via the urethra during the micturition reflex  are also present in the bladder and urethra  acetylcholine (Ach) and Substance P , which is equivalent to the more diffuse plexus of postganglionic cells supplying the pelvic organs of larger mammals , are present in the detrusor muscle, but there is also a significant innervation of the lamina propria lying next to the urothelium [see above and Birder ]. These A group of sympathetic preganglionic neurons, located within the intermediolateral cell column and dorsal grey commissure of upper thoracolumbar  spinal cord  to the lumbosacral spinal cord . Sensory information is also relayed via the thalamus to other brain regions including the hypothalamus and areas of the forebrain such as the insula and pre-frontal cortex  level have shown structural changes in ageing rat bladder  Elbadawi . The rectum exhibits some differences from, but has the same general structure and organisation as the distal colon, while the ASC has some distinct anatomical features.Like that of the rest of the GI tract, the rectal wall consists of two outer smooth muscle layers , between which a complex network of ganglia, the myenteric plexus, is located. A second network of smaller ganglia, the submucous plexus, is present in the connective tissue that lies between the muscularis externa and the mucosa. These two networks of intrinsic ganglia constitute the enteric nervous system (ENS). The smooth muscle layers are richly supplied with nerve fibres, including intrinsic nerves and the processes of extrinsic fibres , and the structurally similar fibroblast-like cells (FLCs) are present throughout the GI tract, including the terminal bowel. They are present around the myenteric ganglia (ICC-MY), in the muscle layers (ICC-LM and ICC-LM), and in some gut regions, in the submucosa see e.g. Komuro . In the The intestinal mucosa consists of the epithelium, which is composed of diverse epithelial cells  that release gut peptide hormones or serotonin, absorptive enterocytes and mucus-secreting goblet cells) and underlying connective tissue that is richly supplied with nerve fibres, associated glial cells, blood vessels and immune system cells. The intestinal mucosa is thus a highly complex tissue with a range of important roles, including barrier function and defence, as well as absorption of nutrients and also neural and endocrine signalling and appetite regulation. It is also the interface with the microbiota, which are now appreciated to have a major influence on the whole organism.There is evidence that changes in mucosal epithelial cells take place during ageing. For example, some populations of gut hormone-producing EECs have been found to increase in number, while others decrease in old age [reviewed in Saffrey ]. ElucidLike other parts of the digestive tract, the ano-rectum is innervated by intrinsic neurons of the ENS, and by extrinsic sensory and autonomic neurons Furness , 2012. TThe terminal bowel (but not the EAS) receives postganglionic parasympathetic and sympathetic innervation from neurons of the pelvic ganglia. As is the case for the innervation of the bladder, the ganglionic organisation of the peripheral neurons that innervate the terminal bowel varies between species. The preganglionic input to sympathetic neurons is from the lumbar spinal cord; that of the parasympathetic is from the sacral spinal cord see e.g. Keast . The senNormal defaecation depends upon the voluntary relaxation of the EAS and pelvic floor muscles and the involuntary relaxation of the IAS. This involuntary action is the recto-anal inhibitory reflex (RAIR). The RAIR is stimulated when stools pass into the rectum from the sigmoid colon and cause rectal distension. This distension is sensed by mechanoreceptors in the rectal wall, which cause a neurally-mediated relaxation of the IAS muscle. The reflex is an intrinsic one, as it occurs even after spinal cord transection and is absent in patients with Hirschprung’s disease, in which the terminal bowel lacks enteric neurons  receives extrinsic parasympathetic efferent innervation via the vagus nerve  and gut regions  during ageing have not yet been performed;  with work focusing mainly on the innervation of the stomach and small intestine, and to a lesser extent, on the colon. Here we briefly summarise the changes that have been reported in these areas, to highlight that this is likely to be an area of importance in the terminal bowel.Analysis of changes in the density of extrinsic parasympathetic nerve fibres in the GI tract during ageing is difficult, because populations of intrinsic enteric neurons express the same markers as extrinsic parasympathetic nerves. A similar problem exists in many species for extrinsic afferent fibres. Studies of change to the extrinsic innervation have therefore involved anterograde tracing , hence these can be used as markers. A reduction in the density of varicosities and glyoxylic acid fluorescence has been described in the rat small intestine, along with swollen axons  to the anal sphincter in the elderly have been described Hall  which inIn preparation).Interstitial cells are now known to play essential roles in the regulation of intestinal muscle contractility and most likely also in the bladder (McCloskey The major pelvic ganglion (MPG) in rodents has been the focus of a number of ageing studies and in the context of this review is important because it contains autonomic postganglionic neurons that project to both the bladder and terminal bowel (colon/rectum)  then studies of age-associated changes to these neurons may be key to understanding neurogenic forms of bladder and bowel dysfunction in the elderly. In a series of studies using quantitative immunocytochemistry a number of significant changes have been noted in terms of the innervation patterns contained within specific spinal nuclei that govern these behaviours. Similar to the relationship described for the MPG (see above), sympathetic preganglionic neurons and their innervation may be more prone to the effects of ageing. Studies have shown that sympathetic preganglionic neurons, projecting to the MPG, are reduced in length and exhibit less branching  of the rat, which contains somatic motoneurons that innervate the external urethral sphincter and ischiocavernosus muscles. Results were again variable with serotonin immunoreactive densities significantly decreased, substance P and tyrosine hydroxylase showing no change and vesicular acetylcholine transporter containing terminals significantly increased . A loss of hind limb motor function has previously been linked to the neurodegenerative loss of serotonin releasing long-descending axons from the medulla to lumbosacral regions of the spinal cord that govern hind limb muscle contraction  that might influence bladder and bowel function in the elderly. Some recent work has employed functional magnetic resonance imaging to look at brain activation during micturition in humans with urge incontinence. These studies have found lower activation in structures including the insula and dorsal anterior cingulate cortex, leading the authors to conclude that with increasing age there are weaker signals in the bladder control network as a whole and that this may be responsible for the development of urge incontinence  occur in some of the populations of neurons that regulate bladder and bowel function. Not all neuronal populations, however, seem to be similarly affected e.g. parasympathetic cells versus sympathetic cells in controlling bladder function. There is also variation in the extent of the changes seen in some populations of enteric neurons. The differences between different populations may in part be due to differences in the inherent properties of distinct groups of neurons. Differences between studies that have quantified neuronal losses have also emerged , and bowel, and the microbiota. The gut microbiota are now appreciated to play a major role in many aspects of the biology of the whole organism, including the gut-brain axis, and recent evidence indicates that changes in the intestinal microbiota occur during ageing (see Saffrey


Ixodes ricinus, and how these may affect the modelling outcomes. We aim to provide a background of rules against which develop reliable models for these parasites. The use of partial sets of occurrences of the tick might produce unreliable associations with climate because the algorithms cannot capture the complete niche to which the tick is associated. Reliability measures of the model cannot detect these inaccuracies, and undesirable estimations of the niche will prevail in the chain of further calculations. The use of inadequate environmental variables (covariates) may lead to inflation of the results of the model through two statistical processes, called autocorrelation and colinearity. The high colinearity existing in climate products derived from interpolation of climate recording stations is demonstrated, and it is explicitly advised the training of climate models with satellite-derived information of climate, of which colinearity of the time series has been removed through a harmonic regression. The high uncertainty if inference on the climate niche is applied into different time slices, like projected climate scenarios is also pointed in the results.There is a growing interest in inferring the associations of health-threatening arthropods to capture the climate niche to which they associate, projecting such inference on a territory. This is intended to predict the range of distribution of the tick and to understand their responses to climate scenarios, using the so-called correlative models. However, some methodological gaps might prevent to obtain an adequate background against which test hypotheses. We explore, describe and illustrate these procedural inaccuracies with examples focused on the tick


Rhinogenic contact point headache (RCPH) is a pain that arises from two opposing mucosal surfaces in the nose. The diagnosis is made by history and physical examination along with nasal endoscopy and imaging. The mainstay of treatment is surgical removal of contact area.To evaluate the effectiveness of non-surgical managements including behavioral and pharmacotherapy in treatment of RCPH.Thirty patients with confirmed diagnosis of RCPH underwent non-surgical management of RCPH using recommendations for absolute contralateral nostril breathing during the pain period, applying warm cushion and medical treatment with non-steroidal analgesics and beta blocker. The results of treatment compared with the results of a group of patients who underwent surgical management.More than eighty six percent of patients experienced a significant relief in the severity of the pain. In contrast to the surgically managed group, the frequency of headaches was not altered.Non-surgical management of RCPH may have a role in patients who do not accept surgery or are not a candidate for surgical management.No conflict of interest.


Shifting the line of sight is naturally accomplished by the movements of both eye and head. We are studying the oclumotor system responsible for planning such head-free gaze-shifts. This includes not only the study of the kinematic mechanisms for coordination of eye and head in three-dimensional space, but also an inquiry into the nature of the internal representations that underlie the observed behavior. The latter is believed to be based on neural representations of sensory signals, coding information is receptors’ frame of reference, being transformed into representations of motor commands, coding information in effectors’ reference frame.At the behavioral level, we propose a kinematic model which gets retinal error and initial eye and head orientations as input and describes an experimentally-inspired sequence of rotations including saccadic eye movement, head movement and vestibule-ocular reflex (VOR). Experimentally observed constraints, Listings’ law for eye and Fick strategy for head , have beAt the representation level, we have used the neural engineering framework (NEF)  to impleThe success of our theoretical study will be evaluated by its success in simulating the known behavior and replicating internal neural signals resembling those recorded by neurophysiologists. The kinematic model has been evaluated based on successfully simulating the known behavior: the accuracy of the gaze shifts and obeying the kinematic constraints for eye and head. The neural network model will be evaluated based on its success in replicating the internal neural signals resembling those recorded by neurophysiologists: the frames of reference and position dependencies of the artificial units.


Status Epilepticus, which have apical dendritic alterations and spine loss, and control animals, which do not have these alterations. This complex arrangement of cells and processes allowed us to study the combined effect of mossy fiber sprouting, altered apical dendritic tree and dendritic spine loss in newborn granule cells on the excitability of the dentate gyrus model. Our simulations suggest that alterations in the apical dendritic tree and dendritic spine loss in newborn granule cells have opposing effects on the excitability of the dentate gyrus after Status Epilepticus. Apical dendritic alterations potentiate the increase of excitability provoked by mossy fiber sprouting while spine loss curtails this increase.Temporal lobe epilepsy strongly affects hippocampal dentate gyrus granule cells morphology. These cells exhibit seizure-induced anatomical alterations including mossy fiber sprouting, changes in the apical and basal dendritic tree and suffer substantial dendritic spine loss. The effect of some of these changes on the hyperexcitability of the dentate gyrus has been widely studied. For example, mossy fiber sprouting increases the excitability of the circuit while dendritic spine loss may have the opposite effect. However, the effect of the interplay of these different morphological alterations on the hyperexcitability of the dentate gyrus is still unknown. Here we adapted an existing computational model of the dentate gyrus by replacing the reduced granule cell models with morphologically detailed models coming from three-dimensional reconstructions of mature cells. The model simulates a network with 10% of the mossy fiber sprouting observed in the pilocarpine (PILO) model of epilepsy. Different fractions of the mature granule cell models were replaced by morphologically reconstructed models of newborn dentate granule cells from animals with PILO-induced  Status Epilepticus (SE) by pilocarpine (PILO). Several days after the injury the new cells show different morphological alterations, for example, in dendritic spines and branching patterns, as well as with the formation of axonal sprouting. The way in which these new cells are integrated into the hippocampus is still unknown with conflicting data in the literature. Here we used computer simulation to test if the activity of the dentate gyrus is affected by the presence of different proportions of new cells after PILO-induced SE. Our results show that the specific morphological alterations present in the granule cells in rats with PILO-induced SE may be responsible for increasing (mossy fiber sprouting) or decreasing (spine loss) the activity in the network. The imbalance between these effects may be manifest as an epileptiform network behavior.Neurogenesis is currently a well known phenomenon in the adult brain, in special in some areas such as the subventricular zone and the dentate gyrus in the hippocampus, in which different endogenous and exogenous factors provoke cell proliferation. In the specific case of the dentate gyrus, granule cells proliferate exhibiting altered morphology after the induction of  Status Epilepticus (SE) induced by kainic acid or pilocarpine Several evidences have shown that prolonged seizures such as those in the animal models of In this scenario, some of the most studied phenomena are the plastic alteration of the circuits of the DG GCs. In fact, DG GCs present a series of morphological and anatomical alterations induced by temporal lobe epilepsy (TLE) Mossy fiber sprouting is the most widely studied of the above mentioned alterations using different approaches including animal models Neuronal morphology is an important factor in the determination of the electrophysiological behavior of a cell Status Epilepticus (SE) induced by pilocarpine (PILO) and control animals. The models in the two groups (PILO and control) have the same distributions of ionic channels and the same maximal conductance densities over their dendritic areas measured according to their distance from soma . With this approach we aimed to evaluate the effect of morphological alterations alone on single-cell excitability. We found that GCs with altered morphology are less excitable when stimulated in a simulation of a patch clamp protocol In a previous research In the present work, we extended our single-cell study to a network context (a collection of neurons) to obtain information on the effect on DG hyperexcitability of seizure-induced apical dendritic morphological alterations in GCs in addition to dendritic spine loss. We use a previously described network DG model, which incorporates detailed structural and biophysical information on DG network and cells The model of Santhakumar et al. Thus, the objective of our study was to obtain mechanistic insights on the integrated action of three types of GC seizure-induced morphological alterations, namely mossy fiber sprouting, apical dendritic tree alterations and dendritic spine loss, on DG hyperexcitability.We used a 1∶2000 scaled-down model of the dentate gyrus The network model contains 500 granule cells (GC), 6 basket cells (BC), 15 mossy cells (MC) and 6 hilar perforant-path associated cells (HC), arranged in a ring structure with topographic connections between cells . Each MChttp://senselab.med.yale.edu/ModelDb/ShowModel.asp?model=51781) for the condition with 10% of MFS. The only change we made was to replace the two dendrites model of GC by another with realistic morphology from a sample of 74 normal GCs three-dimensional reconstructions available in neuromorpho.org. The sample consists of neurons reconstructed by the groups of Brenda J. Claiborne Our model of DG was identical to the model by Santhakumar et al. The GC computational models were constructed following the methodology described in Tejada et al. For the location of the synapses it was considered a virtual molecular layer with thickness equal to the average maximum dendritic length observed in the three-dimensional models plus and minus the standard error , we generated two big families of models with different proportions of seizure-induced neurogenesis (from 0 up to 100%) in which the mature GC models were replaced by three-dimensional reconstructions of newborn (30 days old) GCs. In each of these models the mature GCs that were replaced by newborn cells were chosen at random from the entire population of mature GCs in the network. The sample of newborn cells consists of 40 reconstructions of doublecortin-positive DG GCs  have spines implemented explicitly, so we had to represent spine loss in PILO GCs in an indirect way. We chose two ways of doing so here. The default way, present in all spine loss simulations, was done to represent spine loss by a reduction in the probability of connections of the PILO GCs inserted in the model to account for the reduction in dendritic synaptic sites. Three values of probability reduction were considered: 25%, 50% and 75%. The second way, considered together with the reduction in connection probability in some of our simulations, was done to introduce corrections in the membrane resistivity and capacitance of the PILO GC models to account for the reduction in membrane area To implement the change in the probability of connections of the newborn PILO GCs with spine loss, when the network was built a newborn PILO GC had a reduction of 25%, 50% or 75% of receiving a connection from other cell types in the network. However, a change in the probability of connections can affect the convergence and divergence parameters of the network. Because of this, we simulated two possible scenarios in which spine loss is associated (co-exists) with MFS and dendritic alterations. In the first scenario, which we called spine loss 1 (SL1), we maintained the divergence and convergence parameters of the network by compensating the loss of connections by connecting the cells that would be connected with the newborn GCs that lost spines to other mature cells. In the other scenario (SL2), we did not create new connections with mature cells to compensate for the smaller amount of connections with newborn GCs with spine loss.http://www.neuron.yale.edu) to ran the simulations, with a time-step of 0.1 ms and custom-made Matlab  scripts for data analysis and graphs.Our first study was done to compare the intrinsic excitability of the mature and newborn GC models from control (YOUNG) and PILO samples. We compared with the mature GC models only the newborn GC models which have dendrites that reach the outer molecular layer and, consequently, can receive perforant path stimulation (6 YOUNG and 2 PILO GC models). The excitability was assessed via two protocols. The first was used to estimate the minimum depolarizing current pulse of 500 ms duration applied at a proximal dendrite required to evoke a single action potential (rheobase current). The second was used to measure the number of spikes evoked by one depolarizing synaptic-like pulse applied at intervals of 100 ms during 1000 ms at a single distal dendrite (to simulate synapses at the outer molecular layer). The results are shown in The simulations of the DG mature cells networks showed that the insertion of GCs with realistic morphology did not modify the expected response of the DG network model. Our simulations are consistent with the original model of Santhakumatar et al. To perform our studies on the effect of the introduction of newborn GCs on the mature DG network, we chose the mature network with 10% of MFS. This case was chosen because this level of sprouting was almost sufficient to produce activity that spread to the entire network , so we cThe addition of spine loss to the PILO GC models dramatically reduced the increase of activity produced by the newborn cells in the case with MFS . In the To quantify the effect of the introduction of newborn GCs on the activity of the network for the case with 10% of MFS we generated the graphs shown in The curves in Incidentally, it is interesting to mention that for proportions of inserted newborn GCs (both YOUNG and PILO) around and above 50% the overall frequency of the network with 10% of MFS became higher than the overall frequency of the mature network with 50% of MFS (data not shown).Corroborating what was observed in In the cases with spine loss in which the convergence and divergence factors of the network were maintained (MPSL1 and MPSL1c), The reduction in the overall frequency of the network due to spine loss was much stronger in the cases in which the convergence and divergence factors of network were not maintained (MPSL2 and MPSL2c). In these cases, the overall frequency of the network always remained at or below 50% of the overall frequency of the networks without spine loss. Moreover, in the cases with spine loss and altered divergence and convergence factors of the mature cells the growth of the overall frequency of the network with the proportion of inserted newborn GCs was much slower than in the cases with either no spine loss or spine loss with unaltered divergence and convergence factors of the mature cells. This indicates a strong limiting effect of spine loss over the network excitability in situations in which the rearrangement of connections do not preserve the original convergence and divergence factors of the mature cells that remain in the network.The effect of altering the probability of connections of newborn PILO GCs with spine loss can be seen in The substitution of the simplified GC models by morphologically realistic GC models into the DG model originally proposed by Santhakumar et al. Another change in comparison with the original model of Santhakumar et al. per se is not able to provoke significant changes in the network behavior despite these cells being smaller and therefore more excitable  were maintained. This reduction is consistent with the idea that spine loss acts to maintain homeostasis Besides the reduction in the number of connections, spine loss also reduces the membrane surface area of a cell with consequent changes in the membrane resistivity and capacitance Our computational modeling study has shown that the different neuronal morphological alterations and seizure-induced neurogenesis considered here act much more in combination than as specific features of epileptogenic network activity. On the one hand, there are alterations that increase the number of recurrent connections, such as MFS, having as outcome an increase in the activity of the circuit. On the other hand, alterations such as spine loss can reduce the number of connections and consequently decrease the activity of the network. Along with the above, the DG is constantly exposed to the generation of new cells, which are usually shorter, much more branched Our simulation suggests that the changes in the morphology of GCs provoke diverse effects in the network activity. Some of these changes could be responsible for the increased activity observed in TLE but other could be acting in the opposite direction, decreasing the excitability of the circuit. The balance between these two drives may depend on other factors that were not included in our model, in special, ion channel alterations which may provoke more complex interactions between all of the factors present in an altered circuit.In relation to the adaptation made in the original model of Santhakumar et al. Future studies will obviously add new features to the current modeling, in order to approximate it even more to the complexity and emergent properties of the actual DG and its associated plastic substrates, for example: presence of synapses on basal dendrites In conclusion, our findings strongly suggest that the combined presence of morphological features such as MFS, altered apical dendritic tree and spine loss, in a computational model of the DG network, can explain better the inherent complexity of the circuits associated to temporal lobe epileptogenicity. The current network perspective reliably mimics dysfunctional characteristics not necessarily present when simplified or isolated parameters are considered.


The normal development of an organ depends on the coordinated regulation of multiple cell activities. Focusing on tubulogenesis, we review the role of specialised cells or groups of cells that are selected from within tissue primordia and differentiate at the outgrowing tips or leading edge of developing tubules. Tip or leading cells develop distinctive patterns of gene expression that enable them to act both as sensors and transmitters of intercellular signalling. This enables them to explore the environment, respond to both tissue intrinsic signals and extrinsic cues from surrounding tissues and to regulate the behaviour of their neighbours, including the setting of cell fate, patterning cell division, inducing polarity and promoting cell movement and cell rearrangements by neighbour exchange. Tip cells are also able to transmit mechanical tension to promote tissue remodelling and, by interacting with the extracellular matrix, they can dictate migratory pathways and organ shape. Where separate tubular structures fuse to form networks, as in the airways of insects or the vascular system of vertebrates, specialised fusion tip cells act to interconnect disparate elements of the developing network. Finally, we consider their importance in the maturation of mature physiological function and in the development of disease. Failure to regulate any one of these in time and space has disastrous effects and all need to occur in coordination with the others to produce the final patterned and fully functional structure. While many aspects of developmental control result from reciprocal signalling involving all or the majority of constituent cells, a special class of distinctively placed cells at the tips of tubes or the leading front of migrating cell groups have been found in a wide variety of systems to regulate the activity of their neighbours at key stages of organ development. In this review we discuss the selection and distinctive characteristics of these so-called tip cells and chart their activities and, where known, the mechanisms by which they exert their influence.Dictyostelium) to the most complex  and in tubular systems  as well as in groups of migrating cells   signalling (VEGFR2/3) and low levels of inhibitory VEGFR1 signalling lead to enhanced expression of the Notch ligand, Dll4, enabling these cells to outcompete their neighbours for the tip cell fate  signalling in trachea and of Wingless and JAK/STAT in Malpighian tubules (Breathless (FGF receptor) clones in developing dorsal tracheal branches indicates that cells receiving higher levels of FGF signalling than their neighbours always acquire tip cell fate but that the final outcome is determined by Notch-mediated competitive interactions. However, Araujo and Casanova vs. trailing cell fate. Once specified, tip cells exhibit altered patterns of gene expression, changes in cell shape and in the activity of the cytoskeleton  and extrinsic factors . Ectopic expression of either β-catenin or Ceh-22 is sufficient for both daughters to develop as DTCs In contrast to these mechanisms for tip cell selection, all of which involve competition between cells that receive different levels of signalling, the specification of the distal tip cells (DTCs) in the nematode ependent D. The goThus in each case tip cell fate results from intrinsic and/or inductive factors that confer tip cell potential and, in most cases, refinement of that potential through competitive interactions.3Tip cells regulate tubulogenesis through both tissue-intrinsic and tissue-extrinsic mechanisms, which must be tightly coordinated to generate a physiologically competent organ of appropriate size and shape. In some cases, tip cells play important mitogenic roles, regulating organ growth in a tissue-intrinsic manner, as seen in the nematode gonad and insect renal system  and CED-10 (Rac1 GTPase) acts in the DTC to control cell shape changes during cell migration Cells at the leading edge of the growing tubes play important steering functions to guide the developing organ appropriately through the body cavity. In the Tip cells also play important guidance functions in mammalian systems such as sprouting angiogenesis. Here, pioneering tip cells are found at the outgrowing front of newly sprouting endothelial branches B. These Drosophila salivary gland, cells at the leading front of the primordium guide gland migration along several tissues to establish their final position within the body cavity  is expressed locally in patches of epidermal and mesodermal cells around the tracheal sacs via the FGFr2b receptor, which is required for budding. Cells in the lung bud tips upregulate target genes including sprouty2, bmp2 & 4 and sonic hedgehog that act to further refine FGF signalling and FGF10 expression Although distinctive ‘tip cells’ have not been identified in developing mammalian lung and kidney, groups of cells at the tips of outgrowing branches show specific patterns of gene expression and distinctive behaviours. Branching morphogenesis is induced at the tips of primary lung buds and ureteric buds by local reciprocal interactions with surrounding mesenchyme. In the lung, FGF10 is expressed dynamically in mesenchyme surrounding the primary epithelial buds The developing ureteric bud (UB) of the vertebrate kidney arises from the Wolffian duct, and undergoes a complex pattern of growth, branching and remodelling to form the urinary collecting duct system 3.4A major step during tubulogenesis is the dramatic elongation of the primordial buds into the long tubes of the mature tissue. In the insect tracheal and renal systems, the process of tube extension involves cell rearrangements in the plane of the epithelium, in the absence of cell proliferation. Strikingly these cell intercalation events are triggered by cells at the tips of the developing tubes.Drosophila tracheal system extend dynamic filopodia and lamellipodia in response to FGF signalling, activated by local sources of the ligand Bnl. This tip cell activity leads to the directed migration of the tracheal branch towards the FGF source  that anchor the heart. They contact these muscles at abdominal segment boundaries, moving progressively forwards as cell intercalation lengthens the tubule. Tip cells make a final target, always the alary muscle at segment A3/4 boundary, and this contact persists into the adult fly. As the tubules elongate they encounter guidance cues provided by TGF-β  to the collecting duct (close to the site of urine outflow). Looping of both the nephron and its vascular supply creates a counter-current system that maximises the efficiency of ion and fluid homeostasis. Both the site of connection to the ureter and the tubule tip, the renal corpuscle, are established early in organ development so that tubule extension occurs between these fixed points 3.6In the development of both the insect tracheal system and vertebrate vasculature, sets of discontinuous tubular elements must be connected to generate a fully functional tubular network.Drosophila tracheal system, fusion cells are specified at the distal ends of the tracheal branches and act to interconnect independent or distant tracheal tubes , they act to explore the environment, responding to guidance cues to contact a series of target cells (thereby stabilising tubule architecture during morphogenesis) and they finally make a permanent specific contact, which maintains the shape and positioning of the mature tubule in the body cavity The activity of tip cells in the development of The distinctive characteristics of tip cells that enable them to regulate such a range of cell activities during tubulogenesis derives from their ability to act as sensors as well as regulators. They respond to signals, for example in responding to high levels of signalling as they promote branching in tracheal/vascular systems or in the recognition of specific cues for tissue guidance or for attachment to target tissues. However equally important is their ability to send signals , to transmit mechanical stress (in tubule extension) and to modify the environment through the secretion of specific factors or by directed uptake and transcytosis of specific cargoes (such as MMPs or polarised endocytosis and transport to clear the overlying basement membrane).This range of tip cell activity clearly depends on changes in their patterns of gene expression and deployment of the resulting gene products. While both mitogenesis and tissue polarity result from the release of EGF from the renal tip cell lineage, tubule architecture is regulated by distinctive, stage-specific filopodial activity, clearing of overlying basement membrane components, cell recognition of targets and the expression of tightly controlled levels of adhesion molecules. While it is likely that transcription of many tip cell specific genes is downstream of the AS-C, which acts to specify tip cells The versatility of renal tubule tip cells depends not only on these changes in tip cell activity but also on alterations in the responding cells. It is striking that the tip cell signal, EGF, controls mitosis during embryonic stages 11–12 and that the same signal regulates the planar polarised activity of Myosin II in the same, now post-mitotic, responding cells from stages 13–16 4The tip cells of many organs, including the insect tracheal system and the mammalian vasculature, remain active post-embryonically and modulate tissue structure in response to changes in organismal physiology or environmental conditions. This is particularly important during periods of hypoxia, where tip cells promote the growth of new tubular branches to adapt to local oxygen availability Acheta domestica are anchored to the body wall to ensure the hundreds of tubules are well dispersed throughout the haemocoel There is currently no evidence that the insect renal system is extensively remodelled post-embryonically. However, renal tip cells remain attached to their muscle and neuronal target tissues throughout larval and adult life 5Tip cells play pivotal roles in multiple ways during normal tubule development as well as in their physiological responsiveness. We have reviewed the defects that arise when their normal activities are compromised; for example without tip cells fly renal tubules contain half the normal number of cells and the short, stumpy tubules fail to elongate or take up their normal positions in the body cavity. As a result, the clearance of toxins from the haemolymph as well as ionic and water balance are severely compromised


Oxygen starvation is observed in a variety of pathological states and serves as one of the urgent problems in medicine. A decrease in oxygen supply to tissues is accompanied by the inhibition of metabolic processes (primarily of energy metabolism), which impairs functional activity of the brain. The main source of energy for brain is adenosine triphosphate (ATP). It was shown that the components of adenylate pool can be used as early predictors of hypoxia. Aim of the study: the aim of our study was analysis of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) experimental concentrations and integral coefficient K= in intact animals brain tissue and in disturbances of the oxygen regime by methods of mathematical analysis, as well as detection of some regularity in the character of their changes under the impact of hypoxia for the assessment and prediction of direction of production and utilization energy in metabolic pathways. Methodology: in this study empirical dependencies and criteria of statistical significance of mathematical modeling of quantitative relation between specified brain nucleotide stock indicators for the assessment and prognostication of brain energy state in extreme conditions were used. Results and area of their application: The use of empirical dependencies methods allowed to create multiregression models, subtly enough to unite experimental indicators ATP and AMP in hypobaric hypoxia and ischemia with different-term exposure. Obtained models can be used for prognostication of ATP and AMP concentrations in disturbances of the oxygen regime in a short or over a long period of time, as well as to receive information of indicator K= changing depending on brain hypoxia. Conclusion: functional dependencies are presented in this study to analyze shape, closeness and stability of relations between adenine nucleotides characterizing coupling of production and utilization energy processes, and also to predict the direction of these processes under hypoxic condition.


Drosophila before going on to discuss our recent findings on the coordinated development of muscles and tendon-like structures in Drosophila leg. By altering apodeme formation  during the early steps of leg development, we affect the spatial localization of subsequent myoblasts. These findings provide the first evidence of the developmental impact of early interactions between muscle and tendon-like precursors, and confirm the appendicular Drosophila muscle system as a valuable model for studying these processes.The formation of the musculoskeletal system is a remarkable example of tissue assembly. In both vertebrates and invertebrates, precise connectivity between muscles and skeleton (or exoskeleton) via tendons or equivalent structures is fundamental for movement and stability of the body. The molecular and cellular processes underpinning muscle formation are well-established and significant advances have been made in understanding tendon development. However, the mechanisms contributing to proper connection between these two tissues have received less attention. Observations of coordinated development of tendons and muscles suggest these tissues may interact during the different steps in their development. There is growing evidence that, depending on animal model and muscle type, these interactions can take place from progenitor induction to the final step of the formation of the musculoskeletal system. Here, we briefly review and compare the mechanisms behind muscle and tendon interaction throughout the development of vertebrates and  In vertebrates, the progenitors of axial tendons arise from a dorsal subdomain of the sclerotome, called syndetome, that is immediately adjacent to the myotome from which myogenic cells originate skeleton in order to transmit the force generated by fiber contraction.Much as in vertebrates, Drosophila studies  cells that are singled out from a cluster of exoskeleton cells called the apodeme  and large Indirect Flight Muscles (IFM)] and the leg muscles  are specified as early as the third larval instar (L3) near these tendon-like precursors , an ortholog of Lbx1, which is a key regulator of appendicular myogenesis in vertebrates  genes are required for proper patterning of leg muscles and that different levels of Lbe protein contribute to myoblast diversity within the leg   were built and visualized using Imaris™ Software  than after SrDN expression in tendon-like precursors , the Association Française contre les Myopathies (AFM), the Fondation pour la Recherche Medicale (FRM) and the national grant IDE-CELL-SPE from the Agence Nationale de la Recherche (ANR).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.


Understanding the growth pattern in Marfan syndrome (MFS) is useful for predicting adult height and for planning the timing of growth reduction therapy. We have reviewed the growth parameters of patients with MFS in Korea and generated the Korean MFS-specific growth curve for understanding the growth pattern in MFS.Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. The standardized growth curves were constructed for weight and height according to gender. Comparisons between MFS patients and the general population were performed using a one-sample T-test.Korean MFS patients had similar height and weight compared with the general population at birth. However, linear growth curve of Korean MFS after two years of age showed that the 50th percentile of MFS is above the 97th percentile of normal in both genders. Regarding body mass, although the mean body weight of MFS patients was larger than that of the general population in males and females, the gap of the mean weight curve was small. In the Korean MFS growth curve, the growth pattern and final adult height were nearly analogous to those of the United States (US).Korean MFS-specific growth charts showed that an excessive growth pattern began in the early infant period, which was prominent in terms of linear growth compared to body mass. There were no ethnic differences in the growth pattern compared with Western MFS patients.


Peristaltic transport of copper-water nanofluid in an inclined channel is reported in the presence of mixed convection. Both velocity and thermal slip conditions are considered. Mathematical modelling has been carried out using the long wavelength and low Reynolds number approximations. Resulting coupled system of equations is solved numerically. Quantities of interest are analyzed through graphs. Numerical values of heat transfer rate at the wall for different parameters are obtained and examined. Results showed that addition of copper nanoparticles reduces the pressure gradient, axial velocity at the center of channel, trapping and temperature. Velocity slip parameter has a decreasing effect on the velocity near the center of channel. Temperature of nanofluid increases with increase in the Grashoff number and channel inclination angle. It is further concluded that the heat transfer rate at the wall increases considerably in the presence of copper nanoparticles. Mixed convective flows have received numerous attention from the researchers the world over due to their wide industrial and engineering applications. Convection is seen in the ocean currents, sea-wind formation, rising of plume of hot air from fire, formation of micro-structures during the cooling of molten metals, solar ponds and in fluid flows around heat dissipation fins. Convection in channels plays a vital role in heat exchangers, removal of nuclear waste and in modern cooling/heating systems. “Nanofluids” refer to heat transfer liquids with enhanced heat transfer capability. Such materials are obtained by suspending nanoparticles in traditional heat transfer liquids e.g. water, ethylene glycol and engine oil. A number of experimental studies elaborate that the convective heat transfer in nanofluids is considerably higher than that of the base fluids. Enhanced heat transfer in nanofluids has enabled there use in several electrical and engineering applications. This gives rise to a new branch of mechanics named nanofluid mechanics. The wide utility of nanofluids is the reason for growing interest in nanofluid mechanics by the researchers of modern era. The term nanofluid was introduced by Choi Peristalsis is a well-known mechanism for fluid transport in physiology. In this mechanism sinusoidal waves travel on the walls of tube like organs of human beings propelling the fluid contained within the tube in the direction of their propagation. In physiology the principle of peristalsis is seen in the transport of food through oesophagus, movement of chyme in intestines, urine transport from kidneys to the bladder, bile transport in bile duct, transport of spermatozoa, vasomotion of blood vessels and many others. Peristalsis has proven very useful in fluid transport over short distance preventing the fluid from being contaminated. Subject to its utility, such mechanism has been adopted by the engineers in designing several industrial appliances including roller and finger pumps and peristaltic pumps in heart lung and dialysis machines. Latest hose pumps of several kinds operate through the principle of peristalsis. Peristaltic type flow is readily being used in the nuclear industry for the transport of corrosive fluids. Subject to such wide occurrence of peristalsis in physiology and industry many theoretical investigations are carried out in different flow configuration It is noticed from existing information on the topic that not much has been said yet about the peristaltic motion of nanofluids. Few recent investigations constructed such flow models see . In thesλ and amplitude Consider the peristaltic flow of copper-water nanofluid in a symmetric channel of width Wave geometry is of the formRelations for effective density, specific heat and thermal conductivity of nanofluid by Tiwari and Das The quantities from the laboratory frame Pressure gradient, pressure rise per wavelength, axial velocity and trapping are important quantities in the study of peristalsis. On the other hand the analysis of heat transfer phenomena is significant in the study of nanofluids. Hence the present section is prepared to analyze the behavior of pressure gradient, pressure rise per wavelength, axial velocity, streamlines, temperature and heat transfer rate at the wall for variation in different embedded parameters.Pressure gradient is studied through Pressure rise per wavelength versus flow rate is shown in the Effects of several flow parameters on axial velocity are shown in Trapping for different involved parameters is studied through Gr and Impact of several embedded parameters on temperature and heat transfer rate at the wall are examined through Gr and Br. Numerical values of heat transfer rate at the wall for variations in Heat transfer rate at the wall for variation in nanoparticle volume fraction is analyzed in Velocity and thermal slip effects on the peristaltic transport of copper-water nanofluid in an inclined channel are studied. Findings of present analysis indicate that the addition of copper nanoparticles reduces the pressure gradient. Increase in the value of nanoparticle volume fraction enhances the pressure rise in retrograde pumping region. Nanofluid with low concentration of copper nanoparticles possesses higher value of velocity at the center of channel. Velocity slip parameter has a decreasing effect on the maximum value of axial velocity. Trapping is reduced in presence of nanoparticles. Grashoff number and channel inclination angle have increasing effect on the temperature of nanofluid. Increase in nanoparticle volume fraction largely enhances the heat transfer rate at the wall.


The neocortex is unique to mammals and its evolutionary origin is still highly debated. The neocortex is generated by the dorsal pallium ventricular zone, a germinative domain that in reptiles give rise to the dorsal cortex. Whether this latter allocortical structure contains homologs of all neocortical cell types it is unclear. Recently we described a population of DCX+/Tbr1+ cells that is specifically associated with the layer II of higher order areas of both the neocortex and of the more evolutionary conserved piriform cortex. In a reptile similar cells are present in the layer II of the olfactory cortex and the DVR but not in the dorsal cortex. These data are consistent with the proposal that the reptilian dorsal cortex is homologous only to the deep layers of the neocortex while the upper layers are a mammalian innovation. Based on our observations we extended these ideas by hypothesizing that this innovation was obtained by co-opting a lateral and/or ventral pallium developmental program. Interestingly, an analysis in the Allen brain atlas revealed a striking similarity in gene expression between neocortical layers II/III and piriform cortex. We thus propose a model in which the early neocortical column originated by the superposition of the lateral olfactory and dorsal cortex. This model is consistent with the fossil record and may account not only for the topological position of the neocortex, but also for its basic cytoarchitectural and hodological features. This idea is also consistent with previous hypotheses that the peri-allocortex represents the more ancient neocortical part. The great advances in deciphering the molecular logic of the amniote pallium developmental programs will hopefully enable to directly test our hypotheses in the next future. The Neocortex is a pallial structure that is divided in multiple sub-regions and is made by six layers of distinct neuronal types. Despite more than a century of intense research and speculation, the evolutionary origin of this brain region is still unclear Reiner, . Early wNonetheless, subsequent work showed that during early development pallial progenitors of all tetrapods are regionalized into at least four conserved domains, referred as medial (MP), dorsal (DP), lateral (LP), and ventral (VP) pallium, that give rise to distinct radially migrating glutamatergic neurons  Segregation of functions, in which two sister cell types lose complementary parts of the gene modules of the former precursor cells. (3) Co-option of functions, in which the precursor cell co-opts the gene modules of an unrelated cell type  Expansion and Segregation: gene modules underlying specific functions of UL and DL were present in a single precursor cell in the ancestral DP derivatives and became segregated and subsequently refined in distinct sister cell types. In this case the temporal patterning of DP progenitors will be a mammalian innovation. (3) Spatial to Temporal patterning switch: DP progenitors co-opted the expression of gene modules specifying the neuronal types of other pallial regions , thus leading to the appearance of new cell types in the DP derivatives. The temporal patterning of neocortical progenitors may thus represent a patchwork of formerly spatially segregated developmental programs. In this case part of the neocortical cells may have a sister cell type in a different pallial domain.The specification of neocortical neurons depends on spatial patterning events delimiting the DP progenitors Figure , followeLacerta Muralis, a lizard. However, virtually identical cell types were observed in the LP and VP derivatives of both lizard and mammals thus supporting the spatial to temporal patterning switch hypothesis  is a microtubule associated protein involved in cytoskeletal dynamics during migration and differentiation of immature neurons . These authors raised the possibility that an independent progenitor domain giving rise to neurons of both dorsal and lateral cortex may actually exist in some living reptiles. In contrast to this interpretation however, Ulinsky reported that during development the layer II of the reptilian dorsal and lateral cortex is a continuous stratum of cells that is secondarily ruptured during differentiation (Ulinsky, Another interesting aspects of the hypothesis that the neocortex derived from the superposition of lateral and dorsal cortex, is that it may account for some hodological features that the UL shares with the olfactory cortex but not with the reptilian dorsal cortex. For instance, the olfactory cortex of tetrapods possesses homotopic projections to the contralateral hemisphere passing through the anterior commissure (Zeier and Karten, Ulinsky, . StartinUlinsky, . This crUlinsky, . AccordiUlinsky, . An intrUlinsky, .Several crucial questions remain regarding the emergence of the inside out-gradient of neurogenesis, the appearance of layer IV cells and the arrival of the collo-thalamic projections to the dorsal pallial derivatives.A hallmark of the evolution of the mammalian neocortex is the emergence of a SVZ in the DP (Martínez-Cerdeño et al., In this perspective, in the last years different authors have analyzed the pattern of expression of the sauropsid orthologs of genes expressed in specific neocortical layers (Nomura et al., in vitro (Suzuki et al., Surprisingly, early dorso-medial and dorso-lateral progenitors of the chick pallium were able to sequentially produce cells expressing DL and UL markers Nonetheless, these results introduce the intriguing possibility that an intrinsic temporal patterning mechanism specifying pallio-fugal, thalamo-recipient, and pallio-pallial neuronal types was present in pallial progenitors of the common ancestor of all amniotes or even vertebrates. This idea would be consistent with the fact that temporal patterning of primary progenitors is a major mechanism for generating neuronal diversity in Drosophila (Li et al., In conclusion, our understanding of the genetic logic of cell type specification in the neocortex and other pallial regions of amniotes is constantly growing and this will likely enable to test current theories of the evolution of the mammalian pallium. These analyses would be greatly helped by the comparison of the genetic fingerprint of more restricted cell populations and the layer II DCX+/Tbr1+ cells represent an attractive candidate for such analyses.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.


Although emotional processing in words became a strong focus of research recently, less attention was given to the question of functional localization of emotion effects in the stream of visual word recognition directly. Here, the impact of emotional connotation of words on different processing stages of reading  is investigated. Or put alternatively: How is emotional valence represented within the linguistic representational system?From a psycholinguistic perspective there are at least two types of linguistic representations which are central to visual word recognition. These are lexical and semantic representations. It is a challenging endeavor to define the term lexical: Whether low-level lexical representations  should be differentiated from higher-level lexical representations , is for example an open issue. Furthermore, orthographic processing may comprise sublexical processing on the level of letters and syllables, and lexical processing on the level of the complete word form. The term semantic commonly refers to the meaning of words, presumed as internally represented concepts made of smaller elements of meaning organized by semantic similarity.In psycholinguistics separate lexical and semantic representations are presumed. Accordingly, most models of visual word recognition assume that lexical representations are retrieved  after basic low-level visual perception of line forms and colors, which then culminate in activation of semantic knowledge. Models of word recognition differ with respect to their assumptions about discreteness of the processing stages and to mechanisms of accessing the lexical and semantic representations. While early models of visual word recognition postulated discrete processing stages  components in visual word processing should first be considered irrespective of emotion. Higher-level lexical representation effects  are observed already 100-ms post-stimulus. Since word frequency is broadly accepted to be a lexical factor, such modulations imply that lexical access is underway already starting in the time course of the P1  emotional valence denotes whether a stimulus is being perceived and experienced as positive or negative, and (ii) arousal constitutes the intensity of the appraisal process. I will limit the article to discussion of valence effects which can be understood as the dimension that underlies the quality of emotional experience. Considering the time course of emotional valence effects three different components of the ERP were observed with words. Very early emotion effects have been observed in the time course of P1  exhibit a shorter latency to emotional than to neutral words (Kissler and Herbert, Taken together, it can be assumed that emotional valence is a semantic feature, possibly the first semantic feature to be retrieved from semantic memory when reading words. A growing body of evidence is pointing to a second possible locus of emotion in the lexical linguistic representations. The exact level of lexical representation and the underpinning learning mechanisms are open issues. The conclusion that emotional valence impacts word recognition on multiple stages and might be both part of lexical and of semantic representations is pinpointing future challenges for models of visual word recognition, that is, first, the need for integration of models that either have a focus on lexical or on semantic processing, and second, the integration and prediction of word dimensions like emotion within such models.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.


Most ofThe signal of dopamine neurons in classical and instrumental conditioning has been explained in terms of the temporal-difference (TD) algorithm. However it is not clear whether and, if so, how reinforcement learning can account for the dopamine signals in complex decision-making tasks with noisy sensory information and temporal uncertainty of the relevant task events, as is the case in the detection task mentioned above . We haveThe dopamine phasic activity predicted by the model matches the experimental data and the prediction of the psychometric curve is consistent with the animal performance. Furthermore, the model provides an interpretation of the condition-dependent dopamine response to the go cue instruction in terms of reward prediction error. Using Bayesian inference the model constructs an internal belief about the presence of the somatosensory stimulus. This belief reflects the confidence about the sensory perception and thus the value assigned to this perceptual judgment. The large belief in stimulus-present decisions represents a high degree of confidence in the sensory perception and a great expectation for future rewards. On the contrary, stimulus-absent choices reflect a small belief and consequently a larger uncertainty about the decision and the future reward. This computational description of belief agrees with the previous interpretation of the data  and desc


Some evidence suggests that women with primary dysmenorrhea (or painful period) often have traumatic experience with parental attachments, but the exact relationship between styles of the parental bonding and the detailed aspects of the disorder is unclear.From university-student women, we invited 50 primary dysmenorrhea patients and 111 healthy volunteers to undergo tests of the functional and emotional measure of dysmenorrhea (FEMD), the Family Relationship Questionnaire (FRQ), and the visual analog scale for the pain intensity experienced.Besides the high scores of the FEMD functional and emotional scales, the dysmenorrhea patients also scored significantly higher than the healthy controls on the FRQ scales of paternal dominance and maternal abuse. In patients, the FEMD Emotional scale was negatively predicted by the Paternal Freedom Release scale and the FEMD functional scale was positively predicted by the Maternal Dominance scale.Inappropriate parental bonding or chronic traumatic attachment styles have respective relationships with the functional and emotional disturbances experienced by the primary dysmenorrhea patients.


Due to the imminent growth of the world population, shortage of protein sources for human consumption will arise in the near future. Alternative and sustainable protein sources like insects, such as mealworm, are now being explored for the production of food and feed. Before novel products can be launched on the market the assessment of food safety is vital. One of the key aspects of food safety is the risk of the development of food allergy. Food allergies specifically have a significant impact on the quality of life of allergic patients and their daily functioning, and they may even be life-threatening. TNO together with the University Medical Center Utrecht (UMCU) developed a risk assessment strategy to assess the allergenicity of novel proteins, in accordance to the European Food Safety Authority (EFSA) guidelines to assess the safety of Genetic modified organisms. Using this strategy the safety of mealworm (Tenebrio molitor L.) proteins for use in human consumption was assessed. In this study, 15 shrimp allergic patients were tested on their allergic reaction to mealworm proteins. For this purpose different in vivo (skin prick tests) and in vitro tests (immune blot and basophil activation) were used. In all tests a positive reaction to mealworm extracts was seen. This indicates that shrimp allergic patients are at risk for developing allergic reactions when consuming food containing mealworm proteins. Double blind placebo controlled food challenge will have to confirm this in the coming months.


This paper analyzed the relationship between some indicators of reproductive history and body fatness in relation to the timing of the menopause transition in Hungarian women using survival analysis after controlling for birth cohort.Data on menstruation and reproductive history were collected during the personal interviews in a sample of 1932 women (aged 35+ years). Menarcheal age, the length of menstrual cycles and menstrual bleedings, regularity of menstrual cycles, number of gestations, lactation, the ever use of contraceptives, menopausal status and age at menopause were used as indicators of reproductive history. The body fat fraction was estimated by bioelectrical impedance analysis. Body fatness was also estimated by dividing women into obese and non-obese categories (considering body mass index and waist-to-hip ratio). Survival analyses were used to analyze the relationship between the indicators of reproductive history and body fatness during the menopausal transition.Only the menarcheal age among the investigated reproductive life characteristics showed secular changes in the studied decades in Hungary; the mean age at menarche decreased by approximately 2.5 months per decade from the 1920s until the 1970s. Ever use of hormonal contraceptives, a relatively long cycle length in the perimenopausal transition and higher parity were all related with lower risk of early menopause. Later menarcheal age, normal length of menstrual cycle or bleeding in the climacterium, irregular bleeding pattern and postmenopausal status were associated with a higher amount of body fatness, while never use of contraceptives, regular menstruation, postmenopausal status and relatively early menopause were associated with a higher risk of abdominal obesity.This report confirms that age of menarche is not significantly predictive of age at menopause but prior use of oral contraceptives, longer mean cycle length and smaller number of gestations all are. In addition, age of menarche, irregular bleeding pattern before the climacterium, length of menstrual cycles and bleedings during the climacterium and postmenopausal status were associated with obesity during the climacterium. The age at menopause is a distinctive milestone in female reproductive life since it indicates not only the increased risk of morbidity and premature mortality due to the decreased level of sex hormone levels but also a biological marker of overall ageing and general health status. Menopause is universal and shows little variation in the timing of its occurrence (~50 years) across contemporary human populations and has remained mainly constant over the last 100 years in developed societies .Previous studies on the onset of natural menopause have revealed that its variance is determined mainly by the interactions of multiple genes through control of the ageing processes of the neuroendocrine system , 5, and The main purposes of this study were to analyze (1) the relationship between the age at menopause and the other characteristics of reproductive life in Hungarian women and (2) the relationships between body fatness at the time of menopause and reproductive life characteristics. The secular changes of the studied reproductive variables were analyzed only in those women who never used hormonal contraceptives, since the use of this kind of contraceptives can significantly modify the natural characteristics of menstrual cycles.Since it was confirmed by many epidemiological surveys  that theAccording to our hypothesis, the age at menopause is influenced not only by extrinsic factors (e.g. by socioeconomic factors) but also by the factors of the reproductive life; therefore, the relationship between the age at menopause and the other main characteristics of reproductive life  was presupposed.The possible advancement in timing of puberty was hypothesized to be accompanied by the earlier onset of menopause due to the positive secular socioeconomic changes and the earlier onset of reproductive life and a decrease in the number of gestations per women over recent decades.Since the transitions between prereproductive, reproductive and postreproductive stages are accompanied not only by the changing levels of female sex hormones but also by significant changes of metabolic status and body structure, a hypothesis of a relation between the risk of obesity/abdominal obesity and the characteristics of reproductive life was proposed as well. The characteristics of reproductive life that can be related to higher level of female sex hormones  were supposed to increase the risk of obesity in the menopausal transition because these reproductive life parameters were considered as indicators of a lifelong higher level of sex hormones.By considering the main purposes of the study and the results of the former menopause studies, the following hypotheses were posed:Subject recruitment was done by using multilevel multistage sampling so as to obtain subjects that represented the diverse types of settlements  as well as the age distribution of Hungarian women [The main purposes of the Hungarian Menopause Study were (1) to analyze the nature of menopausal transition in Hungary; (2) to analyze the manner in which the onset of menopause and the length of menopausal transition are affected by the nutritional status and body composition, lifestyle and socioeconomic background of women; (3) to estimate the influence of genetic and endocrinological factors on reproductive ageing process by comparing autophagic activity and the female sex hormone levels in women being in different menopausal status; and (4) to identify the most important intrinsic and extrinsic risk factors that can lead to early or late menopause.Study volunteers included 1932 Hungarian women aged between 25 and 94 years , number of pregnancies , number of live births with or without lactation, age at which any irregularity of menstrual cycle length commenced, age at the last menstrual cycle and age at menopause were collected during the personal interviews. The questionnaires were constructed by considering the WHO and Stages of Reproductive Aging Workshop (STRAW) recommendations on collecting data on reproductive life characteristics in women , 13.Subjects were divided into four groups of premenopausal, early and late perimenopausal and postmenopausal on the basis of their menstrual cycle characteristics by considering the WHO and STRAW recommendations , 13  using the WHO cut-off points of BMI [The body fat fraction was estimated by bioelectrical impedance analysis . Subjects were divided into nutritional status categories  were used to analyze the data. Initially, analyses were undertaken using only one independent variable  and those that were significant were entered into a multivariate analysis . The omnibus test was used for testing the overall fit of Cox regression models.The statistical analyses were done by using SPSS v. 20. Hypotheses were tested at the 5 % level of random error.All subjects were asked to give their written informed consent to participate in the study. All attendants were provided by detailed information on the main purposes of the study and on all examinations before their approval. The participation was voluntary and anonym in the study. The research objectives, the research methodology and the questionnaires were approved by the National Human Research Ethics Committee (108/2011) and the Hungarian Scientific Research Fund (EIK-1001/2011).The main limitations of the study were the cross-sectional study design and the retrospective data collection . The personal interviews helped to diminish this methodological limitation of the study. The menopausal status and the reproductive life characteristics, especially the characteristics of the menstrual cycles, can be estimated more accurately by longitudinally. Moreover, the menopausal status can be estimated more accurately by following the complete STRAW staging system for ovarian ageing including menstrual and qualitative hormonal criteria . AlthougMenarcheal age showed a significant positive secular change between the 1920s and 1980s: the mean age of menarche decreased by birth cohorts from the age of ~14.0 years to 12.7 years  the ever use of contraceptives, long menstrual cycles and higher number of gestations related to lower risk of earlier menopause, while (2) later menarcheal age, normal length of menstrual cycle or bleeding in the climacterium, irregular bleeding pattern and the postmenopausal status were associated with higher prevalence of obesity and (3) the never use of contraceptives, the regular menstruation, the postmenopausal status and relatively earlier age at menopause increased the risk of abdominal obesity in the studied sample. Overall, the characteristics of reproductive life were found to have significant influence on the onset of the menopausal transition. Moreover, the presented results suggest that the risk of obesity is also related to the reproductive life parameters.Contrary to expectations, the results from this study suggest there is no relationship between age of menarche and age at menopause. The results of the present study add to a growing body of literature showing that prior use of oral contraceptives, longer mean cycle length and smaller number of gestations are all associated with later age of menopause.Our results also confirm those from previous studies showing that the later age of menarche, the irregular bleeding pattern before climacterium, the normal length of menstrual cycles and menstrual bleedings in the climacterium and the postmenopausal status were associated with a higher risk of obesity in climacterium.By considering the relationship between the reproductive life characteristics and body fatness distribution in the menopausal transition, these findings confirm—beyond the never use of hormonal contraceptives—the formerly evidenced association that the menopausal status was related to abdominal obesity.Recent studies have shown that variation in age at menopause and the other biological characteristics of the menopausal transition, e.g. body structural changes, are associated with several factors, such as genetic, reproductive, socio-demographic and certain behavioural, lifestyle influences , 5, 57.


I read with interest the excellent article on sudden cardiac death risk stratification with electrocardiographic (ECG) indices by Dr. Gimeno-Blanes and his colleagues in the recent issue of Frontiers in Physiology . As the authors pointed out, it differs from the spectral method and while there are commonalities, there are critical differences in the approach and in the clinical evidence supporting the two methods. The MMA method employs the noise-rejection principle of recursive averaging. The algorithm continuously streams odd and even beats into separate bins and creates averaged complexes for each bin. These complexes are then superimposed, and the maximum difference between the odd and even complexes at any point within the JT segment is identified for every 15 s and reported as the TWA value. The highest TWA levels within the entire 24-h period are recorded for each subject and used for analysis of risk for sudden cardiac death or cardiovascular mortality. The established TWA cut-point of 47 μV indicates a positive TWA test. Inspection of the TWA template permits verification of the waveform and provides opportunities for insights into the pathophysiology, as distinct patterns are associated with differing disease states. Samples of the rhythm strip and QRS-aligned template are provided  method. We have studied this parameter in our laboratory for more than two decades. The MMA methodology has run the complete gambit from development through clearance by the United States FDA and a recent positive coverage decision by Center for Medicare and Medicaid Services  and Beth Israel Deaconess Medical Center  and licensed to GE Healthcare, Inc. .


Historically, the semen analysis results are the foundation on which clinicians base their decision for treatment for a given couple. It has, however, become clear that semen parameters are insufficient for the determination of male fertility potential. A continuous search for better markers of male fertility has led to an increased focus on testing of sperm chromatin integrity in fertility workup and ART. Sperm DNA damage is a useful biomarker for male infertility diagnosis and prediction of assisted reproduction outcomes. It is associated with reduced fertilization rates, embryo quality and pregnancy rates, and higher rates of spontaneous miscarriage and childhood diseases. Successful fertilization of the human oocyte from spermatozoa with damaged DNA may lead to paternal transmission of defective genetic material with adverse consequences to embryo development. Sperm DNA fragmentation has shown to be an independent predictor of success in couples undergoing intrauterine insemination (IUI). The speaker will discuss the conflicting reports on the role of sperm DNA fragmentation in relation to fertilization, pre-embryo development and pregnancy outcome in The speaker will provide a summary of the most recent studies in the literature in the field of sperm DNA damage in the clinical setting. He will discuss current laboratory tests and the accumulating body of knowledge concerning the relationship between sperm DNA damage and clinical outcomes. Next he will talk about the pros and cons and clinical applicability of the current sperm DNA fragmentation assays and the biological significance of sperm chromatin damage in the male germ line. Finally, as sperm DNA damage is often the result of increased oxidative stress in the male reproductive tract, the potential contribution of antioxidant therapy in the clinical management of this condition will be debated.


The progressive increase in incidence in cow's milk proteins allergy (CMPA) in the past decades required primary prevention strategies for children at high-risk. Evidence of the role of gut microbiota in promoting the maturation of the immune system during early life encouraged supplementing the diet with probiotics in order to facilitate tolerance and delay or prevent sensitization. The efficacy of this strategy has not been consistently proven . Breastf


The hopes placed in the new treatment regimens for tuberculosis (TB), with the emergence of rifampicin were partially shaded by the side effects which were frequently recorded, able to impose temporary or definitive abandonment of this tuberculostatic.The patient to be presented illustrates relapse of TB infection, in the context of significant comorbidities: chronic renal failure, uremic stage, in chronic hemodialysis program; primary hyperuricemia with urate nephropathy; stage II arterial hypertension with very high cardiovascular risk.In the absence of clinical, definite biological and morphological criteria, the diagnosis of drug hepatopathy relies predominantly on causal relationship between the drug administration and the occurrence of the therapeutic accident. Non-hepatitis jaundice  occurred after 2 weeks of daily tuberculosis treatment, suggesting the involvement of rifampicin in the conjugation of bilirubin and conjugated bilirubin excretion in the bile. The peculiarity of the case: In the patient presented, the fundamental mechanism behind the cholestatic syndrome consisted of: compromising the active transport of bilirubin through the liver cell, without being present the reflux of bile constituents  in the circulation.Adverse reactions to drugs due to their frequency and harmfulness have opened a new nosology chapter in modern medicine. Adverse effects of tuberculostatic drugs affect in a negative way both the management and the dynamics of TB infection.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


Nodular thyroid disease affects thousands of people in Poland. Tumors of the thyroid account for about 1% overall human cancers. Thyroidectomy is the most common surgical operation in endocrine tumors. Operative therapy for benign thyroid nodules is recommended for: progressive increase in nodule size, substernal extension, compressive symptoms of the neck, the development of thyrotoxicosis and patient therapeutic prevalence. In Poland thyroidectomy is the fifth surgical procedure and comprises about 25000 operations yearly. Reduction of surgical injury with simultaneous retention of current safety and radical nature of surgical intervention forces the work into a relatively small operating field. Electric devices enabling the achievement of full and lasting haemostasis during thyroidectomy supplant traditional surgical method  with no impact on the incidence of perioperative complications, while at the same time allowing to shorten the duration of the procedure. The haemostatic effect is associated with generation of heat, which apart from the intended result may bring about thermal tissue injury. During the surgical procedure it is important to determine the thermal spread around the active tip of electric devices in the operating field during thyroidectomy, and the safe temperature range during the operation to protect important structures of the neck. The mean safe distance of the active tip of an electric device from important anatomic structures is 5mm minimally and depends on the device type, time of operation and its power settings. All the modern techniques of vessel sealing are associated with generation of heat and its spherical spread, which causes thermal injury to the surrounding tissues. Their mode of operation through, among others, structural changes in collagen and elastin, leads to durable connection of sealed vessel walls and tissue structures. These systems enable a safe sealing of vessels of up to 7 mm in diameter.In conclusions: In the cases analyzed by the author concerning the thyroidectomy techniques, it is recommended to replace electric devices with ligatures or clips or human fibrinogen in place near the laryngeal nerves, parathyroid glands and the trachea. The decision of the change of the method of haemostasis maintenance in the vicinity of crucial structures has been left to the surgeon.


This paper is a country case study for the Universal Health Coverage Collection, organized by WHO. Gemini Mtei and colleagues illustrate progress towards UHC and its monitoring and evaluation in Tanzania.Please see later in the article for the Editors' Summary This paper is part of the PLOS Universal Health Coverage Collection. This is the summary of the Tanzania country case study. The full paper is available as Supporting Information file Achieving universal health coverage (UHC)—defined as access to needed health services to all and protection against financial risks arising from paying for health services Immediately after independence in 1961, Tanzania adopted a free health care policy that lasted until the early 1990s when user fees were reintroduced, accompanied by exemptions and waivers for the poor The assessment of progress in financial protection used data from the National Household Budget Survey 2007, the Strategies for Health Insurance for Equities in Less Developed Countries (SHIELD) survey 2008, and the National Panel Survey (NPS) 2010/2011. Access indicators were derived from the analytical report prepared for medium term review of the health sector strategic plan 2009–2015. Indicators were selected on the basis of availability of data, their priorities in the health sector strategic plans, and the degree to which the indicator addresses a critical health system problem in Tanzania . The study uses the framework presented in Out-of-pocket (OOP) payments account for about 2% of people's income. About 2% of the population incurs catastrophic health care expenditures and 1% becomes impoverished because of OOP payments. Although the observed levels of incidences of catastrophic events and impoverishment are still low in Tanzania compared to other low- and middle-income countries The burden of OOP payments is significantly large among the poorest segment of the population as indicated by the negative Kakwani index  targets by 2015. Although the proportion of households owning insecticide treated nets is large, malaria prevalence among outpatients is still high at 34% Click here for additional data file.


Periodontal disease, a bacterially mediated inflammatory disease of the gingival and adjacent periodontal attachment apparatus, represents, after dental caries, the leading cause of tooth loss among adults in developed countries due to the destruction of the periodontal ligament and the loss of the adjacent supporting bone, the tissues which support the teeth  is more rational than one that is disease specific  and serotonin (5-hydroxytryptamine 5-HT) has been reported in depression studies  axis and further determines cortisol and adrenal disturbances, as well as immune dysfunction and excessive secretion of proinflammatory cytokines  of poor oral hygiene and halitosis, frequent characteristics of patients with periodontal disease (Morita and Wang, Periodontal disease is also one of the leading causes of edentulousness due to the inflammatory destruction of the tooth supporting tissues: the periodontal ligament and the alveolar bone (Kassebaum et al., Finally, periodontal disease may contribute to the onset of depression through different pathways:An interdisciplinary approach in psychoimmunology and periodontology has been used to highlight the biological and psychosocial mechanism and mediators of the depression and periodontitis connection, in order to call attention to potential new therapeutic strategies for both depressed individuals and periodontal disease patients.The author confirms being the sole contributor of this work and approved it for publication.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. The reviewer PV and handling Editor declared a current collaboration and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Synthetic biology is an ever-expanding field in science, also encompassing the research area of fungal natural product (NP) discovery and production. Until now, different aspects of synthetic biology have been covered in fungal NP studies from the manipulation of different regulatory elements and heterologous expression of biosynthetic pathways to the engineering of different multidomain biosynthetic enzymes such as polyketide synthases or non-ribosomal peptide synthetases. The following review will cover some of the exemplary studies of synthetic biology in filamentous fungi showing the capacity of these eukaryotes to be used as model organisms in the field. From the vast array of different NPs produced to the ease for genetic manipulation, filamentous fungi have proven to be an invaluable source for the further development of synthetic biology tools. Saccharomyces cerevisiae because of its vast toolkit in making different genomic manipulations  promoter, the pXyl xylose inducible promoter  in the fungus resulting in the activation of this silent gene cluster. This HAT, GcnE, part of the Saga/Ada complex was also found to play a role in the regulation of different NPs and in a further study it was shown that when specific amino acids on the histone tail of H3 were replaced mimicking acetylation or non-acetylation it affected the production of different NPs  gene and overexpression of the transcription factor in the native host. The native promoter was then used with an unknown PKS that was found to produce the antituberculosis agent pyrrolocin , thus creating a fungal expression system with the native promoter and transcriptional activator is advantageous  synthase, which is a PKS, was coexpressed with the A. nidulans phosphopantetheinyl transferase (PPTase) gene and resulted in yields of 6-MSA as high as 2.2 g/L . Up until now, much work has been done to understand the mechanisms of these enzymes in both fungi and bacteria . A lot oBesides the work on NR-PKS there has also been a lot of work on highly reducing PKS (HR-PKS) in filamentous fungi. These PKSs are also of interest because they come in different modes of reduction leading to a wide range of chemical diversity. Early studies also focused on the understanding of these complex enzymes and especially on the PKS responsible for the statin, lovastatin , the mycSynthetic biology for the discovery and understanding of fungal NPs is an ever-evolving field. With the advancement of the different techniques presented herein the possibilities are endless for the production of novel/bioactive NPs. Additionally, with the rapid discovery in different genome editing and genetic manipulation tools such as the bacterial derived CRISPR-Cas9 system , these cThe 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.


Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the  The human biogenic amine transporters (BATs) represent important drug targets for the treatment of many psychiatric diseases such as depression, anxiety, obesity, drug abuse, obsessive compulsive disorder, attention deficit hyperactive disorder, and schizophrenia . They arAquifex aeolicus, LeuT, was published -methamphetamine, cocaine and the cocaine analog RTI-55 as well as SNRIs, NET-specific reuptake inhibitors (NRIs) and SSRIs bound. For the first time it is accordingly possible to directly compare the binding of substrates to that of different types of inhibitors in a DAT structure.Importantly, in May 2015 an arsenal of new crystal structures of dDAT with various ligands bound were published . These nSeveral models have been published describing the binding of substrates, antidepressants, psychostimulants and mazindol to either of the human BATs using homology models constructed based on the structure of the bacterial homolog LeuT .Herein, we compare the binding of drugs to dDAT  and LeuBThe structure of the dDAT protein compared to a homology model of the human DAT previously published  is shownThe homology models of hDAT, hNET, and hSERT are compared with the dDAT crystal structure by alignment of the central binding site residues Figure . For theD-amphetamine and (+)-methamphetamine bound  derived compounds. The binding of PP and an analog has been studies computationally using homology models of hDAT and hSERT . The recne bound . In Figune bound . As can ne bound . The binne bound . This co+ group, most likely caused by subtle differences of the phenylalanine within the aromatic lid. The overall location of cocaine in The binding of cocaine has previously been studied through homology modeling both of hDAT  and hSERS-citalopram was previously biochemically validated to bind in the central S1 site of hSERT . A large number of published homology models of the human BATs  have beeWe observe that the early models of the human BATs constructed based on the bacterial homolog LeuT are in excellent agreement with the subsequent crystal structures, but importantly to note is that these predictions require careful selection of ligand binding modes combined with the consideration of more than top docking poses. This provides us with great confidence in the ability to use extensive modeling combined with experimental validations to provide initial insight to drug binding to proteins. Although the computational docking models are able to predict the binding of compounds to the BATs, a substantial limitation of the static models is the inability to predict the difference in function between the drugs. To understand the function, non-static methods such as molecular dynamics simulations  or electThe dDAT structure has been seen to possess a pharmacology profile resembling hNET more than dDAT  which shThe 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.