The nail unit is constructed by distinctly regulated components. The nail isthmus is a lately proposed region as a transitional zone between the most distal part of the nail bed and the hyponychium. It is difficult to recognize the nail isthmus in the normal nail, but it is easy to identify the region in nail disorders such as pterygium inversum unguis and ectopic nail. We describe structure and putative function of the nail isthmus via histopathologic features of pterygium inversum unguis and ectopic nail. The nail unit has distinct structure. The concept of the nail isthmus was recently proposed by Perrin in 2007 . The regThe nail isthmus is composed of two distinct parts. A histopathological study of the nail isthmus with a case of pterygium inversum unguis identified two substances: (i) a marked, highly eosinophilic, keratinized substance attaching the distal and visceral nail plate and (ii) a whorled, highly eosinophilic, keratinized substance into the horny layer of the finger tip Figures  and 3 44. The foThe highly eosinophilic structures are identical to semihard keratin. The nail apparatus is sequentially composed of soft keratin in the proximal nail fold, semihard keratin in the cuticle, hard keratin in the nail plate from the nail matrix and the nail bed, semihard keratin in the nail isthmus, and soft keratin in the hyponychium .Immunohistochemical study of the regional keratin and filaggrin in a case of ectopic nail showed keratin 1 (K1) and K10 expression in the suprabasal layers of the nail isthmus Figures , K14 in The nail isthmus showed two regions; a proximal and narrow part and a distal and wide part. The proximal and narrow region has supposed function as an anchor for the inferior border of the nail plate. The distal and wide region produces semihard keratins possibly against repeated trauma toward the separated area between the nail plate and the hyponychium. Pterygium inversum unguis may occur after a cerebral vascular event resulted in hemi-paralysis . EctopicThe nail isthmus expresses a profile of transitional keratins and is probably constructed by two regions. One is a proximal region producing a marked, highly eosinophilic, keratinized substance attaching the distal and ventral nail plate. The region produces a peculiar and thin compartment of pale and nucleated corneocytes via the granular layer and probably maintains the longitudinal ridge pattern of the nail bed. Another is the distal region producing a whorled, highly eosinophilic, keratinized substance and may protect the binding between the nail plate and the proximal nail isthmus from repeated trauma. The nail isthmus is one of the distinctly regulated regions of the nail apparatus. A recent proposal of the nail isthmus brings us to reevaluate the pathogenesis of the nail disorders. In the future, further study will elucidate more precise structure and function of the nail isthmus.


Protein-protein interaction (PPI) network analysis presents an essential role in understanding the functional relationship among proteins in a living biological system. Despite the success of current approaches for understanding the PPI network, the large fraction of missing and spurious PPIs and a low coverage of complete PPI network are the sources of major concern. In this paper, based on the diffusion process, we propose a new concept of global geometric affinity and an accompanying computational scheme to filter the uncertain PPIs, namely, reduce the spurious PPIs and recover the missing PPIs in the network. The main concept defines a diffusion process in which all proteins simultaneously participate to define a similarity metric ) to robustly reflect the internal connectivity among proteins. The robustness of the GGA is attributed to propagating the local connectivity to a global representation of similarity among proteins in a diffusion process. The propagation process is extremely fast as only simple matrix products are required in this computation process and thus our method is geared toward applications in high-throughput PPI networks. Furthermore, we proposed two new approaches that determine the optimal geometric scale of the PPI network and the optimal threshold for assigning the PPI from the GGA matrix. Our approach is tested with three protein-protein interaction networks and performs well with significant random noises of deletions and insertions in true PPIs. Our approach has the potential to benefit biological experiments, to better characterize network data sets, and to drive new discoveries. Current development in high-throughput measurement techniques such as tandem affinity purification, two-hybrid assays, and mass spectrometry have resulted in vast amounts of pertinent elements and the biological networks of their interactions As measurements cover different aspects of a biological systems with different characteristics of the PPI network Similar to the method in In addition, we are aware of the relationship between the GGA-method and Markov clustering (MCL) In The computation of a global geometric metric from the local metric by geometric embedding operators has been recently established in machine learning research field The diffusion metric revealed in a diffusion propagation process reflects the intrinsic and geometric relationship among data points in the embedded diffusion space. In practice, the diffusion metric is in a form of geometric distance (dissimilarity), called diffusion distance, which is represented by the Euclidean distance in the embedded space As the mapping function We introduce a new definition of geometric metric, called global geometric affinity (GGA), to overcome the weakness of current geometric based methods for PPI network. Different from the GGD, the GGA is in form of affinity (similarity), which is computed by the dot product of a pair of high-dimensional vectors (correlation coefficient). The Initialization of the weight matrix:Propagation process:The GGA reflects the internal affinity (geometric similarity) between node The parameter, The assumption of the correctness of geometry based approaches in analysis of PPI network is that a pair of proteins will be assigned an interaction if they are close in an embedded space whereas NPPIs correspond to points that are further away in that space In the original PPI network, we denote True positive (TP) functionFalse positive (FP) functionTrue negative (TN) functionFalse negative (FN) functionMatch functionGiven a threshold, the TP function measures the intersection between the new assigned PPIs set and the ground truth PPIs set, FP denotes the assigned edges which are not in the set of ground truth, TN denotes the intersection of new assigned NPPIs and ground truth of PPNs, and FN denotes new assigned PPIs in the ground truth of PPIs set. The match function evaluates how well the new assigned PPI network match with original local PPI network. From the mathematical point of view, we are about to solve the following optimization problem to find the optimal threshold value.The algorithm for solving the optimization problem is outlined below and We vary the threshold from minimum to maximum found in GGA matrix among all pairs of proteins.For a given threshold t, we compute true positive (TP) function, true negative (TN) function, false positive (FP) function and false negative (FN) function.Based on the values obtained from the previous step, we compute match function.The optimal threshold is the one with maximum match function value ) and specificity rate (TN/(TN+FP)), precise (TP/(TP+FP)) and recall (TP/(TP+FN)). To plot the ROC curve, the horizontal axis represents (1 - specificity), and the vertical axis represents sensitivity. To plot the PR curve, the horizontal axis represents recall, and the vertical axis represents precision.The ROC curves are shown in the Following the experimental setting in In this experiment, we demonstrate the performance of GGA-method in prediction of missing PPI and identification of spurious PPI in the noisy network. For an incomplete observed PPI network, we determine GGA for each pair of proteins in the network. We are interested in the pairs of proteins that have high GGA but are not connected in the observed network, and the pairs of proteins that have low GGA but are connected in the observed network. The first type of pairs of proteins are most likely candidates for missing PPIs, and the second type of pairs are most likely candidates for spurious PPIs. Our method is compared to MDS-methods in We assess the performance of our method from two perspectives according to the tests on three PPI networks . First, we want to compare the performance in identification of spurious PPI using our method with that of MDS-method. We evaluate the comparison by gradually increase the insertions of the false PPI and attempt to identify those links using the topology information remaining in the network. Second, we want to compare the performance in predictions of missing PPI using our method with that of MDS-method. We evaluate the comparison by gradually increase the deletions of the true PPI and attempt to predict them using the topology information remaining in the network. The comparison result is displayed in the We explain why MDS-method performs worse than GGA-method against insertion and deletion noise. The metric revealed by MDS is based on the shortest path traveled from one protein to another protein in the network To demonstrate the computation efficiency of GGA-method, we compare the computation time for both methods. The The Optimal Local Fitting algorithm (OLF) is used to determine the threshold for the PPI assignment from the GGA matrix. The test result is shown in the In the first test, we randomly insert the a certain amount of PPIs (Ins Ratio is In the first test, we randomly insert the a certain amount of PPIs (Ins Ratio is We analyze the results in The result for the first test is presented in the first three rows (labeled The result for the second test is presented in the second three rows (labeled The limitations of the current high-throughput measurements techniques inherently give rise to a large amount of spurious and missing PPIs. To clean the network, people often try to integrate multiple data sources, such as gene expression arrays and proteomics to improve the quality of PPIs in a network. Recently, geometric based approaches, which are only based on the topology of the PPI network, are very promising as those approaches are independent from other prior knowledge except for topology of the PPI network. However, the large amount of noisy PPIs poses a great challenge to the geometric based computational approaches. Robust geometric structural understanding methods are the prerequisite for capturing the intrinsic geometric structure which is hidden behind the noisy PPI network data.Biological data, like the PPI data, are often observed in an incomplete manner with high noise. Any method, if simply based on the metric of a small number of local PPI network, is likely to be overwhelmed by the noise and incompleteness. It is of great importance to place the data in a statistical model and take into account all the pieces of local information simultaneously, in order to generate the knowledge behind the overall global structure of the data. Globally consistent metric, like the global geometric affinity proposed in this work, measure the relationship considering the optimal arrangement of all the data samples. Therefore, even if the local incomplete and noisy pairs of PPIs are not able to reveal the internal global structure, given sufficient samples of PPIs and considering the entire set of pair-wise linkages simultaneously, our GGA-method is able to reveal the intrinsic metric hidden in the very noisy and incomplete PPI data. The excellent robustness against noise is highlighted by its good performance at a large number of insertions and deletions introduced.Biological experimental measurements are usually time consuming and costly. The computational approaches are proposed to benefit biological experiments and to better characterize network data sets by minimizing the use of the prior knowledge from biological experiments. In recent years, the geometric features of PPI network have been proven to provide new insights into the function of individual proteins, protein complexes and cellular machinery as a complex system. These approaches take advantage of the geometric characteristics behind the PPI network, which enables to evaluate the relationship among the protein-protein interactions and analyze the network characteristics. These approaches based only on the geometric topology formed by connections among proteins and has been recently developed to de-noise the observed PPIs network. The common hypothesis for these methods is that the existence of the geometric structure for PPI networks and the topology knowledge is crucial in determining the PPIs in the network The efficiency of a computational approach for most biological problems is vital in real applications due to the high-throughput nature of the data. The existing geometry based methods for the de-noising the PPI network, for example, MDS-method, are computationally expensive and even intractable for large and incomplete PPI networks. This is because these methods include the eigen-decomposition to compute the explicit embedding coordinates and then compute the global geometric distance. In our method, we completely decouple the global metric from the eigen-decomposition problem by proposing the GGA. The eigen-decomposition-free method give our method a distinct advantage that we can totally get rid of the issues caused by the eigendecomposition. Therefore, our proposed method is able to apply on the sparse and huge size PPI network and finish the de-noising in an efficient way. These virtues account for the superiority of our proposed in the real applications for de-noising PPI networks.This paper presents our first implementation, with very promising results in the completed tests. However, the noise properties in raw PPI data can be different from the simulated random deletions and insertions used in existing tests. The performance of our method and its general applicability in de-noising a PPI network generally confirm the robustness of our methods but still need further work to improve by testing more real challenging PPI data. The parameter of propagation step plays a critical role in looking through the geometric structure from multiple scales. Although we provide a probability based algorithm to determine the optimal parameter, we have not given a rigorous proof. In our future work, we will come up a good strategy based on this parameter to investigate the raw PPI network at different level of details. The OLF algorithm is proposed to numerically determine the optimal threshold without a closed form solution or proof to that optimization problem. Furthermore, GGA-method is a general method and applicable to a wide range of problem domains, for example, the reconstruction of the air transportation network.


Cardiac surgeries are sometimes followed by significant blood loss and transfusions may be necessary. However, indiscriminate use of blood components can result in detrimental effects for the patient. In this study, we evaluated the short-term effects of the implementation of a protocol for the rational use of blood products in the postoperative period of cardiac surgery.P <0.05 was considered statistically significant.Between April and June 2011 an institutional protocol was implemented in a private hospital specialized in cardiology to encourage rational use of blood products with the consent and collaboration of seven cardiac surgery teams. Clinical and demographic data of patients were collected, and the use of blood products and clinical outcomes during in-hospital period 6 months before and after implementation of the protocol were analyzed. The protocol consisted of an institutional campaign with educational intervention in the surgical, intensive care and anesthesiology teams aiming to spread the practice of blood transfusion based on clinical goals , as well as making routine prescription of epsilon aminocaproic acid (EACA) intraoperatively. Comparisons between categorical variables were performed with the chi-square test and P <0.001). Clinical outcomes related to blood transfusion are presented in Table After 3 months of implementation of the protocol, the use of EACA rose from 31 to 100%. The surgeries requiring any blood transfusion were 67% before the implementation of the protocol, and 40% in the subsequent months of the same year after implantation (The rational use of blood products associated with infusion of ε-aminocaproic acid has the potential to reduce the number of blood transfusions in postoperative of cardiac surgery, which can impact the risk of complications.


The role of the amygdala in regulating emotional neural processing has been well-acknowledged by both animal and clinical studies LeDoux, , particuThe role of the lateral amygdala in the retrieval and maintenance of fear-memories formed by probabilistic reinforcement” published in Frontiers in Behavioral Neuroscience, Erlich and colleagues (In an interesting article “lleagues  provide lleagues  and clinlleagues . HoweverThe main outcome of this study is the demonstration that lateral amygdala activity is essential to the expression of fear-behavior in probabilistic paradigms and that CCK2 receptor activation may lead to impaired recovery from fearful memories. This is the first demonstration of this role and sheds light on new therapeutic targets in the modulation of the fear response in a post-encounter approach.Yet, the most remarkable finding reported by Erlich and colleagues is the role of lateral amygdala in the encoding of uncertain information using a probabilistic presentation of the aversive stimulus. It has been well-characterized that the lateral amygdala has a paramount role and is the neuroanatomical substrate (Phelps and LeDoux, In conclusion, the findings reported by Erlich and colleagues represent an appealing topic of investigation from both behavioral and pharmaceutical points of view in that it provides a rationale of developing in the future chemical compounds that, by manipulating lateral amygdala function in particular through the modulation of CCK2 receptors, may ameliorate negative and aversive emotional states.


Vascular variations of the penis are very rare. Awareness of its variations is of utmost importance to the urologists and radiologist dealing with the reconstruction or transplants of penis, erectile dysfunctions, and priapism. We report an extremely rare variation of the artery of the penis and discuss its clinical importance. The artery of the penis arose from a common arterial trunk from the left internal iliac artery. The common trunk also gave origin to the obturator and inferior vesical arteries. The artery of the penis coursed forward in the pelvis above the pelvic diaphragm and divided into deep and dorsal arteries of the penis just below the pubic symphysis. The internal pudendal artery was small and supplied the anal canal and musculature of the perineum. It also gave an artery to the bulb of the penis. The artery of the penis is the distal continuation of the internal pudendal artery after the origin of its perineal branch. It runs anteriorly below or above the inferior fascia of urogenital diaphragm to reach the area just below the inferior pubic ligament, where it terminates by dividing into deep and dorsal arteries of the penis . Artery During dissection classes for undergraduate medical students, a rare variation in the origin and course of the artery of the penis was noted. The variation was found in an adult male cadaver aged approximately 70 years. The left internal iliac artery did not divide into anterior and posterior divisions. The main trunk of the internal iliac artery gave iliolumbar, lateral sacral, superior gluteal, middle rectal, and superior vesical arteries. In addition to these arteries two common trunks arose from it. The first common trunk bifurcated into inferior gluteal and internal pudendal arteries, whereas the second common trunk gave two inferior vesical arteries, obturator artery, and the artery of penis . The artA detailed knowledge of origin, course, and distribution of the vessels of the penis is essential during the planning, management, or surgical treatment of erectile dysfunctions and trauma of the penis. Internal iliac artery embolization is standard selective technique in arresting the bleeding from the penis and perineal region. Instead of this procedure, a superselective embolization of the internal pudendal artery with a stainless steel mini coil can be done to preserve the blood supply from the uninjured branches of the internal iliac artery . HoweverTraumatic laceration of penile arteries may result in high flow priapism caused by a pathologically increased arterial flow to the cavernous bodies. Clinically, it is identified as a persistent painless erection with a flaccid glans that results within hours or days after blunt perineal trauma –9. PatieAs per our knowledge, this is the first report on combined origin of artery of the penis, obturator artery, and inferior vesical arteries from a common trunk above the pelvic diaphragm. What makes the case unique is the forward course of artery of the penis in relation to the pelvic surface of the levator ani muscle, prostate, and puboprostatic ligaments. Its iatrogenic injuries are possible in any procedure involving prostate and bladder. The artery might get injured in pelvic fractures as well. Hence, this report might be useful for the radiologists, orthopaedic surgeons, and urologists working in and around the pelvic cavity.


Since then, antibiotics have represented virtually the only effective treatment option for bacterial infections. However, their efficacy has been seriously compromised by over-use and misuse of these drugs, which have led to the emergence of bacteria that are resistant to many commonly used antibiotics. Bacteria present three general categories of antibiotic resistance: acquired, intrinsic and adaptive  and/or peptidoglycan biosynthesis, and act synergistically with the antibiotic. Authors conclude that cell shape alterations likely disturb the influx/efflux machinery of Gram-negative bacteria and thereby enable the accumulation of otherwise excluded antibiotics. This finding provides an attractive strategy to combat the intrinsic antibiotic resistance of Gram-negative bacteria and can aid the development of new therapies that enhance the activity of existing antibiotics against them.The combination of these antibiotic resistance mechanisms has led to the emergence of multidrug-resistant pathogens, which are a serious threat for medical care. Among other strategies, the discovery or development of new antibiotic agents had been thought to be a solution to overcome the deficiencies of the existing ones. However, development and marketing approval of new antibiotics have not kept pace with the increasing public health threat of bacterial drug resistance. An alternative to the development of new antibiotics is to find potentiators of the already existing ones, a less expensive alternative to the problem  inhibition of antibiotic resistance elements; (ii) enhancement of the uptake of the antibiotic through the bacterial membrane; (iii) direct blocking of efflux pumps; and (iv) changing the physiology of resistant cells  (Kalan and Wright, et al., et al., et al., In conclusion, the use of antibiotic adjuvants has two beneficial outcomes: enhancement of the antimicrobial effect and reduction of the occurrence of mutations that result in resistance. In this context, efforts to find such molecules should be intensified. Since environmental organisms are the source of most resistance genes and antibiotics (D'Costa None declared.


Although there are significant numbers of people displaced by war in Africa, very little is known about long-term changes in the fertility of refugees. Refugees of the Mozambican civil war (1977–1992) settled in many neighbouring countries, including South Africa. A large number of Mozambican refugees settled within the Agincourt sub-district, underpinned by a Health and Socio-demographic Surveillance Site (AHDSS), established in 1992, and have remained there. The AHDSS data provide a unique opportunity to study changes in fertility over time and the role that the fertility of self-settled refugee populations plays in the overall fertility level of the host community, a highly relevant factor in many areas of sub-Saharan Africa.To examine the change in fertility of former Mozambican self-settled refugees over a period of 16 years and to compare the overall fertility and fertility patterns of Mozambicans to host South Africans.Prospective data from the AHDSS on births from 1993 to 2009 were used to compare fertility trends and patterns and to examine socio-economic factors that may be associated with fertility change.There has been a sharp decline in fertility in the Mozambican population and convergence in fertility patterns of Mozambican and local South African women. The convergence of fertility patterns coincides with a convergence in other socio-economic factors.The fertility of Mozambicans has decreased significantly and Mozambicans are adopting the childbearing patterns of South African women. The decline in Mozambican fertility has occurred alongside socio-economic gains. There remains, however, high unemployment and endemic poverty in the area and fertility is not likely to decrease further without increased delivery of family planning to adolescents and increased education and job opportunities for women. Africa is home to about a fifth of the world's refugees, most of whom have been victims of forced migration .‡ HoweveWar and resettlement can place both upward and downward pressure on fertility in the short term. Upward pressure may come from the desire to replace those lost in war, while downward pressure on fertility may come from the disruption of life and relationships caused by war . StudiesHowever, most studies on refugee fertility are conducted in refugee camps and the situation may differ for refugees not living in camps. Populations that settle in host countries without residing in camps are likely to be different from those in refugee camps since they are not served directly by aid programs. Many studies of the fertility of self-settled refugees exist in developed countries with vital registration systems. However, studies of self-settled refugee populations in Africa where vital registration systems are lacking are rare. Prospective data from the Agincourt sub-district in Mpumalanga Province in rural northeast South Africa provide an opportunity to examine the change in fertility of self-settled Mozambican refugees over a period of 16 years (1993–2009) and to examine their impact on overall fertility levels in the area. Earlier research using data from the Agincourt health and socio-demographic surveillance site (AHDSS) found that Mozambican refugees in Agincourt contributed to a noticeable increase in the average number of children borne  by women in the 1980s measured retrospectively through birth histories . Subsequapartheid regime to the spectre of rapid population growth among the African population. The programme provided free modern contraceptives in public health clinics, including oral and injectable contraceptives , Gazankulu, where African South Africans were resettled as part of the apartheid regimes strategy of ‘separate development’  and the level of fertility measured by the TFR are used to examine fertility trends. The latter is defined as the average number of children that a woman would have by the end of her reproductive life if the current age pattern of fertility were to remain unchanged. Descriptive statistics are used to describe changes in the age pattern of fertility over time. A discrete time event framework is used to evaluate women's progression from a first to a second birth within five years and smoothed survival curves are presented. Other socio-economic trends are examined by estimating levels of employment, household wealth, and formal education.Fertility levels were quite different in the two populations during the 1990s, with Mozambican women maintaining higher fertility than South Africans. Thereafter, the two populations increasingly exhibit similar fertility levels, converging from 2000 when the confidence intervals around the fertility estimates for the two groups started overlapping. The convergence of total fertility of the two population groups is driven primarily by the decline in fertility among Mozambican women to the levels of South African women. This suggests that Mozambican women were adopting fertility behaviours similar to those of the host population. To test this hypothesis we compared age-specific fertility rates and the timing of first and second births between the two populations at the beginning and end of the observation period.However, by 2009, Panel B of The age-specific fertility rates suggest similarly high levels of adolescent fertility for Mozambican and South African women. Further analysis of the age distribution of first births for Mozambican women  shows inFurther analysis also suggests lower contraceptive use by Mozambican women prior to their first birth. At the time of their first birth, Mozambican women consistently reported lower contraceptive use prior to conceiving than South African women. Five per cent of Mozambican women compared to 9.5% of South African women with first births from 1995 to 1999 reported using contraception at some time before their first birth. These figures were 23% and 28%, respectively, for first births occurring from 2003 to 2005. High adolescent fertility has been a source of concern in South Africa and so it is important to recognise the lower use of contraception before a first birth as well as the increase in the percentage of first births to adolescents for Mozambican women .Previous research on the fertility of host South Africans has shown that fertility decline for African South Africans has been driven by significant widening of birth intervals explained primarily by increases in the use of modern contraception . Wide biThe changes in age-specific fertility rates, timing of first births and extended first birth intervals indicate that Mozambican women are achieving lower fertility by adopting patterns of childbearing typical for South African women in Agincourt.To further explore the fertility decline and the convergence of fertility in the two populations, we examine select socio-economic factors that may be ‘underlying’ drivers of the decline in the TFR among the Mozambicans. Increases in education, labour force participation and income have been found to reduce fertility –22. HistPanel B of An analysis of the labour force participation of women of reproductive ages shows that formal employment increased slightly during the past decade for South Africans (from about 28% in 2000 to 30% in 2008) but decreased for Mozambicans (from about 27% to 23% over the same period). The very high unemployment of both groups suggests limited formal economic opportunities for women, which might have contributed to the recently observed stall in fertility decline.Education and wealth indicators suggest that over the period of study Mozambican women's status improved and converged with that of South African women. However, these gains are relatively modest and Mozambican women remain disadvantaged, particularly in relation to formal employment, within the relatively poor population of the rural setting.Approximately 20 years after the civil war in Mozambique, demographic characteristics of self-settled refugees of Mozambican origin in Agincourt are converging with those of their South African hosts. While the TFR in Mozambique itself has remained near 5 , the MozThe findings of this study suggest adaptation of the Mozambican refugees in the AHDSS to the fertility patterns of their host community. Adaptation theory states that exposure to cultural norms and local costs of childbearing will lead migrants to change their fertility behaviour to converge with that of natives in the destination . This apThe adaptation of Mozambican refugees to the lower fertility regime in South Africa has important implications for many areas of sub-Saharan Africa hosting refugee populations. The adaptation of Mozambicans in South Africa is likely facilitated by a shared language and culture. Self-settled refugees are also probably more likely to be exposed to and adjust to the local norms of childbearing compared to refugees living in camps.Access to contraception through the South African health system is a key component of the decrease in fertility of Mozambicans. Another important component is the improvement in socio-economic status partly attributable to access to education and host government social grants. Reducing the economic disadvantage of refugees and integrating refugees into local programmes and services encourages adaptation and can compensate for other factors that may otherwise increase the fertility of refugees such as poverty, lack of education, and lack of reproductive health services. Integration encourages adaptation and will likely benefit host communities by lowering the fertility of refugees.Overall fertility decline in Agincourt over the past few decades has been driven primarily by the decline in fertility of Mozambican women. South African women's total fertility declined primarily in the early 1990s and has been wavering around 2.5 since 1995. Fertility decline has also been minimal for Mozambican women since 2002. With fertility decline stalling in both groups it remains to be seen if fertility will go below replacement level (2.5 in South Africa) as predicted by earlier research . FurtherFindings presented here suggest a few areas of future intervention that would be helpful in settings such as Agincourt. The pattern of childbearing in Agincourt shows that delaying first births could reduce overall fertility rates. Others have argued that family planning programmes in South Africa need to be reoriented to address the contraceptive needs of adolescents before first births . Since cIn other settings, increasing access to family planning and reproductive health programmes for all women has been shown to improve women's economic and health outcomes and to enhance economic growth . HoweverThe primary limitations of our study are data driven. We do not have information on important variables such as prospective data on marriage, fertility desires, or detailed information on contraceptive use, to run models examining the proximate determinants of fertility.


In eukaryotic organisms clathrin-coated vesicles are instrumental in the processes of endocytosis as well as intracellular protein trafficking. Hence, it is important to understand how these vesicles have evolved across eukaryotes, to carry cargo molecules of varied shapes and sizes. The intricate nature and functional diversity of the vesicles are maintained by numerous interacting protein partners of the vesicle system. However, to delineate functionally important residues participating in protein-protein interactions of the assembly is a daunting task as there are no high-resolution structures of the intact assembly available. The two cryoEM structures closely representing intact assembly were determined at very low resolution and provide positions of Cα atoms alone. In the present study, using the method developed by us earlier, we predict the protein-protein interface residues in clathrin assembly, taking guidance from the available low-resolution structures. The conservation status of these interfaces when investigated across eukaryotes, revealed a radial distribution of evolutionary constraints, i.e., if the members of the clathrin vesicular assembly can be imagined to be arranged in spherical manner, the cargo being at the center and clathrins being at the periphery, the detailed phylogenetic analysis of these members of the assembly indicated high-residue variation in the members of the assembly closer to the cargo while high conservation was noted in clathrins and in other proteins at the periphery of the vesicle. This points to the strategy adopted by the nature to package diverse proteins but transport them through a highly conserved mechanism. Intracellular transport of biomolecules is an important event for the functioning of a cell. Both, endocytic as well as exocytic pathways of trafficking in eukaryotic cells involve formation of caged vesicles that communicate between the organelles of the same cell or to the exterior of the cell Clathrin, a cytosolic protein, was identified as the major component of CCVs and hence the name Protein-protein interactions play a crucial role in maintaining the structural integrity and functional state of the assembly In the present analysis, we have made use of these low resolution cryo-EM fitted models to gain better insights onto the protein-protein interactions made by clathrin chains. Towards this, we have used the method developed by us earlier, that can predict protein-protein interactions interface residues with high sensitivity and accuracy, starting from low resolution structures providing Cα atom positions only Protein-protein interaction interfaces of the components of CCV were recognized using accessibility criterion. As can be seen in the The homologues of human clathrin chains as well as adaptins were identified across eukaryotic organisms by carrying out sequence search using PSI-BLAST 1] Tree construction- Using the multiple sequence alignments mentioned above, the phylogenetic trees were constructed for clathrin chains as well as the components of the adaptor protein complexes. The tree constructions were carried out using PHYML programme 2] Correlation of genetic distances- Using the trees constructed as mentioned above and the multiple sequence alignments mentioned previously, the genetic distance matrices of n×n orthologous sequences was computed using TREE-PUZZLE Structure of clathrin cage. As mentioned earlier, there is no structure available for the intact assembly of clathrin coated vesicles. The structures that resemble the overall assembly closely are the two cryo-EM structures of empty clathrin cage, with or without part of auxilin J domain Adaptor proteins. Out of the four different types of adaptor proteins structural information is available for only two complexes namely adaptor protein 1  Apart from the above mentioned structures that were used in the main analysis, a number of other structures were used as supporting structures to confirm our predictions. The complete list of the structures analyzed is given in the Recognition of protein-protein interaction interface in case of clathrin cage was a twofold problem; a] The structures available for the clathrin cage provide positions of only Cα atoms and hence recognition of interface was a non-trivial task and b] To further add to the complexity, the structural models comprise eighteen polypeptide chains . Using the standard method harboring accessibility criterion the residues of adaptor protein subunits involved in protein-protein interactions were recognized. Two structures available of the cores of adaptor protein AP1 (PDB code 1w63) The above mentioned structures lacked the appendage region in the beta chains of both the adaptins. This gap in the information was filled by analyzing the high resolution structures of these regions namely the PDB ids: 2iv8 In a given polypeptide chain the residues participating in protein-protein interactions are often conserved better over the course of evolution compared to their non-interface solvent exposed regions. The residues identified as interface residues in case of clathrin chains when tested for residue conservation were also found to be better conserved compared to the non-interface, surface exposed residues of the same chain as shown in the When conservation of interface residues were compared between different components of the assembly it was observed that the interfaces were maximally conserved in clathrin heavy chain with B chains of adaptor proteins ranking next. Minimum residue conservation was observed in the interfaces of the chains of the adaptor proteins that directly interact with the cargo receptors (μ chains of both the adaptor protein complexes). To investigate this observed pattern further and to attain a quantitative picture, a detailed analysis of evolutionary constraints over these protein chains was carried out subsequently.Using the multiple sequence alignments obtained using ClustalW, phylogenetic trees were constructed using PHYML, which constructs maximum likelihood tree based on the alignment. Comparative analysis of the constructed phylogenetic trees unfolded some of the interesting facets of the evolutionary divergence pattern amongst the subunits of the two prominent hubs of the clathrin coated vesicle assembly namely clathrins and adaptor protein complexes. The orthologous sequences that were compared were taken from the identical set of organisms. The key observations of the analysis were as follows;1] When the functionally equivalent subunits of the two adapter proteins were compared, it was observed that the B chains, that interact with clathrin heavy chain directly, showed identical clustering pattern (as shown in the 2] Between the two A chains of the adaptors it was noted that the sequence of the A chain of the AP1 is largely conserved across eukaryotes while that of AP2 much diverged. This difference can be attributed to the differences in the modes of biological actions of the two complexes. AP1 largely operates between golgi complex to endosomes while AP2 operates at plasma membrane. Thus, it can be imagined that AP2 caters to larger variety of cargo and hence, to a larger variety of accessory proteins compared to AP1.To investigate the possibility of correlated evolution between the subunits of adaptins and clathrin heavy chain, genetic distance matrices were constructed using TREE-PUZZLE. Comparison was carried out between the matrices of adaptor protein subunits and that of clathrin heavy chain and Pearson correlation coefficients were computed. As shown in the Thus, if different components of the Clathrin coated assembly can be imagined to be arranged in spherical fashion with clathrin heavy chain being at the periphery and the cargo molecules at the center of the sphere, as depicted in the The structures of clathrin coat with and without auxilin peptide bound to clathrin heavy chain are the only available structures that represent the intact clathrin coated vesicle assembly the best. However, these structures were solved at very low resolution and provide Cα atom positions only. Hence, deriving in-depth knowledge about the residues participating in protein-protein interactions had been a difficult task. Recently, we have developed a method which can perform the above mentioned task with high accuracy and sensitivity Adaptor proteins interact with almost every member of the vesicle and the tasks are very well shared by all the four subunits of the adaptin complex. Every subunit comprises two distinct interacting interfaces namely the one for interactions within the adaptin complex to form core and the other to interact with its non-adaptin interacting partner. The interfaces holding the subunits of the complex together seemed to be located largely towards the center of the polypeptide while in case of α and β subunits the appendages towards the N-termini harbored the interfaces holding the accessory proteins and clathrin heavy chain respectively. The interface residues inferred in the present analysis showed better residue conservation over their non-interface, surface exposed counterparts, thus validating our findings.Owing to the functions performed by the assembly, the importance of the assembly to almost all the eukaryotic organisms can very well be imagined. Such assemblies will have a few commonalities such as the presence of clathrin like molecule to form cage in order to carry the proteins safely from place to place. However, due to the varying sizes and natures of the cargo there will be significant changes in the structures of the assembly. In order to understand the evolutionary trends in the components of clathrin vesicles detailed phylogenetic analysis was carried out and data was compared across the members of the assembly. In an organism, if members of the vesicular assembly can be imagined to be arranged in a sphere with the clathrin heavy chains being at the periphery while the cargo were being at the center, the adaptor proteins will occupy the space in between, connecting the two layers. This is the simplified model to visualize the arrangement of the components of clathrin coated vesicles. Here, we are not differentiating clathrin coated pits from plaques as elegantly shown by Saffarian et.al experimentally In conclusion, an extensive and non-trivial task of interface determination from a low resolution structure of clathrin coat, followed by a systematic sequence analysis and visualizing the results in the context of 3D structure, enabled us to dissect out a complex pattern of radial distribution of evolutionary constraints. Given the low resolution structures, such an analysis can be extended to other large biomolecular assemblies in the cell that play crucial roles in various cellular pathways.


Escherichia coli and Bacillus subtilis are the most thoroughly studied cell division mechanisms. The earliest visible event in cell division is the formation of a Z ring by FtsZ, a tubulin like protein, at the future septum site. The Z-ring appears to be an accurate marker for the position of the division site and is furthermore recognized by set of cell division proteins—the divisome. At least two distinct mechanisms contribute to the placement of the division machinery: nucleoid occlusion and the Min system. The mechanism of Min system action is fundamentally different in both model organisms [reviewed in Barak and Wilkinson . This is likely accomplished by DivIVA switching its binding partner from MinJ to the DNA-binding RacA protein  of MinCD (Jamroskovic et al.,


In some hospitals, urinalysis is done routinely for all patients scheduled for cardiac surgery. Occasionally pyuria or bacteria is reported in the microscopic urinalysis of these patients that are clinically asymptomatic for urinary tract infections.We were seeking answer to this question: is the presence of a different number of bacteria in preoperative microscopic urinalysis of asymptomatic patients scheduled for cardiac surgery indicative of potential postoperative complications and as a result, a good reason to postpone the operation?We conducted a retrospective cross-sectional study based on the review of the medical records of 1165 patients who underwent open-heart surgery.One hundered and fifty one patients were eligible in our established criteria. There were no significant difference between their demographic characteristics and the same number of randomly selected patients with normal urinalysis who had underwent open-heart surgery. In the bacteriuria group, two patients, and in the control group, three patients had an infection at the operation sites in the post-operative period, which was not a significant finding between two groups (P = 0.503).We recommend that in the absence of symptoms of urinary tract infection, urinalysis is not necessary and not cost beneficial in the preoperative evaluation of patients scheduled for open-heart surgery. Open-heart surgery is one of the major operations in which the use of cardio-pulmonary bypass circulation by extracorporeal devices causes wide-spread of pathophysiological changes in the vital organs of the human body during and following the operation. Because of these vast changes in the mechanical, physiological and biochemical functions of the patient's body in perioperative period, the operation team especially anesthesiologists and cardiac surgeons need comprehensive preoperative evaluations of patient's status. In some hospitals such as our hospital, urinalysis is one of the laboratory tests that is done routinely prior to cardiac surgery routinly. The urine culture does not include routine laboratory tests in the absence of any symptom of urinary tract infection in the preoperative assessment of the candidates for open-heart surgery and it is only ordered when symptoms of urinary tract infection are presented. Occasionally pyuria or bacteria is reported in the microscopic urinalysis of patients who are clinically asymptomatic for urinary tract infection. There are some references regarding preoperative management of asymptomatic bacteriuria in different kinds of surgeries such as joint operations , 2. HoweThe urinary tract is normally sterile except for the flora in the last few centimeters of the distal urethra, which is varied and reflects the existence of digestive flora , the skin flora , and the genital flora  . AsymptoWe were seeking an answer to this question: is the presence of a different numbers of bacteria in preoperative microscopic urinalysis of asymptomatic patients scheduled for cardiac surgery an indicator for the likelihood of postoperative complications and a reason for postponing the operation?We conducted a retrospective cross-sectional study based on medical records of Ahvaz Imam Khomeini hospital. We reviewed the medical charts of 1165 patients who underwent open-heart surgery between March 2010 and March 2012. We enrolled the medical charts of patients that were asymptomatic for urinary tract infections, but had bacteriuria with or without pyuria in microscopic urinalysis and compared them with the same number of randomly selected patients with normal urinalysis who had underwent open-heart surgery in our hospital during the same period as the control group. In microscopic urinalysis, microorganisms are usually reported as "none", "few", "moderate" and "many" present per high power field (HPF). We included those medical charts that had "moderate" or "many" bacteria in urinalysis reports. Men normally have fewer than two white blood cells (WBCs) per HPF; and women normally have fewer than five WBCs per HPF in urinalysis  were eligible according our established criteria and compared with the same number of randomly selected patients with normal urinalysis who had underwent open-heart surgery in our hospital during the same time duration. The demographic characteristics between two groups are presented in Bacteria are common microorganisms in urine specimens because of their abundant normal microbial flora of the vagina or external urethral meatus and because of their ability to rapidly multiply in urine standing at room temperature. Therefore, microbial organisms found in all but the most scrupulously collected urines should be interpretive in view of clinical symptoms. The most accurate test for bacteriuria is urine culture. The most commonly used tests for detecting bacteriuria in asymptomatic persons are dipstick urinalysis and direct microscopy . Microsc


Presently the training in tricuspid valve (TV) surgery is difficult due to limited exposure of the TV, 3D complexity of TV components and repair procedures. Therefore we propose a portable simulator for cardiac trainees and junior surgeons to be proficient in TV surgical techniques and to minimize the learning curve. The simulator can be used for an unrestricted number of procedures. It is made with the lowest possible fidelity focusing on availability and cost-containment of the exercise.The TV simulator was made from a sponge that can be placed inside of any box or on any board. The simulator can be equipped with a drain pipe for minimal invasive purposes. The rings and valves were made from available materials. The sponge was covered with a surgical tape for effective manipulation.The self-construction of the TV simulator results in improvement of the understanding of 3D TV anatomy. The usage of the sponge results in effective creation of TV components with similar properties to TV tissue. The usage of the simulator results in performing of all surgical procedures including TV ring annuloplasty, De Vega plasty, bicuspidization of the tricuspid valve, Edge to Edge, neo artificial chordae, pericardial augmentation of the leaflets and TV replacement as well. Unrestricted number of procedures can be performed after covering the sponge with surgical tape. Flexibility and cavity of the drain pipe allow the trainees to use the simulator for minimal invasive also.The surgical skills in TV surgery can be improved by usage of low fidelity simulator in classic and minimal invasive techniques. The high cost of the training residents and junior surgeons in TV surgery can be reduced effectively through the use of this low cost simulator and its accessories . The familiarity in performing surgical procedures results in reducing time consumed in the operation room and reduction of the learning curve.


Important advances in the development of smart biodegradable implants for axonal regeneration after spinal cord injury have recently been reported. These advances are evaluated in this review with special emphasis on the regeneration of the corticospinal tract. The corticospinal tract is often considered the ultimate challenge in demonstrating whether a repair strategy has been successful in the regeneration of the injured mammalian spinal cord. The extensive know-how of factors and cells involved in the development of the corticospinal tract, and the advances made in material science and tissue engineering technology, have provided the foundations for the optimization of the biomatrices needed for repair. Based on the findings summarized in this review, the future development of smart biodegradable bridges for CST regrowth and regeneration in the injured spinal cord is discussed. The corticospinal tract (CST) is considered the ultimate challenge to demonstrate if a repair strategy is succesfull in regeneration of the injured mammalian spinal cord. It all started from the observations made after the use of peripheral nerve grafts into the lesioned spinal cord: a significant regrowth of CNS axons was noted, although various population of axons tracts including the CST did not respond  and, in particular, the spinal cord has already been a major challenge for neuroscientists for many decades. The complexity of the spinal cord with its many ascending and descending fiber tracts, the numerous spinal cell populations, the inter-connectivity between various levels of the spinal cord combined with the characteristic response after an injury in the adult, as well as the variability in the location and impact of the lesion in the clinical situation, makes the development of appropriate repair strategies very complex and difficult. Furthermore, in most cases of human SCI, there is a significant loss of spinal cord tissue and cavity formation is an important obstacle, impeding axonal regeneration  is related to material science and tissue engineering technology. Here, most know-how is based on studies on repair after peripheral nervous system (PNS) injury. Although autologuous peripheral nerve grafts still result in a superior regenerative performance or “gold standard” for peripheral nerve repair  into the spinal cord of the rat is characterized by two phases, which both occur postnatally: a white matter tract formation on the one hand and the spinal gray matter target innervations on the other. Both phases are closely related and have been shown in various anterograde tract-tracing studies  molecules and myelin-associated proteins may act as outgrowth inhibitory molecules and be implicated in the outgrowth and restriction of CST pioneer fibers to leave the DF during their descent , in the environment of the vDF upon and during the arrival of the first CST pioneer fibers, is important for guidance. For correct target innervation (back-branching of fibers) and contact formation of the CST fibers, both outgrowth stimulating as well as outgrowth inhibitory molecules including various CAMs, EphA4, growth associated protein 43 (GAP-43), chondroitin sulphate proteoglycans and identified (NT-3) (or as yet unidentified) neurotrophins are needed. The know-how on cells and molecules involved in CST outgrowth during development is important in the design and creation of optimal bridging structures, which are used to enhance and direct the regrowth of injured CST fibers in adult mammalian spinal cord.A damaged peripheral nerve is able to regrow its axons through the distal stump, mainly via the bands of Bungner that are composed of tubes of basal lamina enclosing Schwann cells (SC). A prerequisite for this regrowth of injured PNS axons is the presence of a physical continuity. Hence, in large peripheral lesion gaps, many bridging materials have been tested to allow and stimulate the regrowth of injured fibers. In contrast to the injured PNS axons, those of the CNS fail to regenerate, although local sprouting can occur. The pioneering work of Ramon Y Cajal  indicateA variety of biodegradable natural polymers have been used as implants and cell carriers for repair after SCI. Among them collagen type I and alginate have received most attention.Developmental studies have shown that environmental factors such as extracellular matrix molecules (ECM) components  are transiently expressed during periods of axonal elongation  using collagen as a vehicle that is not sufficient for CST regrowth and re-establishment of functional connections. Although collagen can serve as a bridge to connect the rostral and caudal portions of the injured spinal cord , which is a very promising approach in repair and bridging the injured spinal cord. Future research should be aimed at the creation and transplantation of aliginate-encapsulated cells producing substantially more of the neurotrophic factor.Synthetic biodegradable implants tested for spinal cord repair include matrigel matrix, fibrin and fibronectin (mats) and poly .Matrigel is a soluble basal membrane extract of the Engelbreth-Holm-Swarm tumor cell line. It forms a nonporous hydrogel at room temperature and the matrigel matrix contains laminin, collagen IV and heparin sulphate proteoglycan, as well as growth factors such as insulin growth factor-I (IGF-I). The implantation of Matrigel alone into the injured spinal cord does not stimulate regeneration of injured axons Bunge , an effeAmong those cells most often used for transplantation are the Schwann cells (SC) Bunge . The usecomplete transection) did result in an improved cell survival, the additional use of fibrin glue and acidic fibroblast growth factor (aFGF) was needed to demonstrate regrowth of injured anterogradely labeled CST fibers  cells, in particular Schwann cell implantation, have shown promise in overcoming many of the obstacles facing successful repair of the injured spinal cord including the successful survival of transplanted cell (or cell suspensions). The implantation of Schwann cells as cell suspensions with in situ gelling Matrigel but also with collagen as a vehicle, after spinal cord contusion significantly enhances long-term cell survival but not proliferation, as well as improvement of graft vascularization and the degree of axonal in-growth over the standard implantation vehicle   was injected into the lesioned site. Five weeks after transplantation, the application of Matrigel and hBMSC-SC resulted in a reduced cystic cavitation and at the same time promotion of the functional recovery  has been studied using Matrigel-containing vascular endothelial growth factor (VEGF). With the use of Matrigel as a vehicle, exogenous vascular endothelial growth factor (VEGF165), either as recombinant protein alone or combined with an adenovirus coding for VEGF165, was applied into the lesion gap of the transected spinal cord  is noted but at the same time there is an absence of re-entry of the CST fibers into the host in areas distal to the transplant. The latter maybe in part related to the presence of CSPGs, which inhibit axon growth.As already discussed see “”, the adDespite significant improvements in design of fibrin gels/mats and controlled delivery of neurotrophins (like NT-3), a major disadvantage of the fibronectin mats and fibrin gels is their relatively rapid degradation. Hence, timing of the implantation of (the presently available) fibronectin/fibrin bridges into the lesioned spinal cord is important; timed implantation at chronic stages may result in significant regeneration of injured CNS fibers including the CST.The aliphatic polyesters derived from lactide, glycolide and E-caprolactone are completely resorbable and biocompatible in the central nervous system  with the main aim to re-create a continuum for regrowth of injured CST fibers may result in significant ingrowth into the bridge and re-entry of injured CST fibers into the host. The use of PLGA nanoparticles for a controlled and sustained release of neurotrophins is a very promising development in the field of biomatrices and bridging the injured spinal cord and has already resulted in improved hindlimb motor function in SCI rats. Follow-up studies are needed to demonstrate the effect of local delivery of the PLGA nanoparticles encapsulating neurotrophins on CST regrowth.Polyethylene glycol (PEG) is a highly water soluble polymer and has served as a therapeutic agent to reconstruct the phospholipid bilayers of damaged cell membranes (or fusogenic activity). Based on this fusogenic property, the systemic intravenous application of 30% PEG in rats that underwent 35-g clip compression at cervical eight (C8) resulted in a reduced neurofilament degradation and apoptotic cell death in the lesion area finally resulting in a modest neurobehavioral recovery after SCI : the injection of SWNT-PEG into the lesion at T9 1 week after a complete transection decreased the lesion volume, did not increase reactive gliosis and at the same time increased the number of neurofilament and anterogradely labeled CST fibers in the lesion , the intravenous application has been shown to result in axonal preservation and a significant neurological recovery after spinal cord injury. PEGylation of neurotrophins, functionalization of carbon nanotubes with PEG, or the development of injectable hydrogel scaffolds based on PEG are interesting and important improvements in design of successful biomatrices and bridges for repair of injured spinal cord, including the CST.The use of degradable biomatrices for implantation into the lesioned mammalian spinal cord has led to interesting and important findings on CNS regeneration in general and also in view of CST regrowth. As can be deduced from the approaches chosen, the implementation of factors and or cells important during the development of the spinal cord and combined and/or integrated into a biodegradable matrix often formed the fundaments of repair strategies. With respect to the injured CST, main efforts have been taken to bridge the lesion based on the re-creation or reconstruction of a 3-D alignment of outgrowth promoting cells , as this typical structure is known to be present and important during guidance and development of this tract. Furthermore, bridging the lesion and stimulation of the regrowth of injured CST fibers is often triggered by application of the neurotrophin-3 (NT-3), a molecule also known to be important during the development of this tract.In general, it can be concluded that various approaches have led to a significant ingrowth of anterogradely labeled regrowing CST into the bridges. It is difficult to compare the quality of the various bridges used but at the present moment not one single approach stands out. Furthermore, the major drawback of all bridges currently used and developed is the fact that no re-entry of CST fibers from the graft into the host tissue is noted. It is here where most research should be focused at. Despite the fact that various degradable biomaterials in themselves do not enhance the formation of scar tissue or even minimize the impermissiveness of the host tissue, the CST axons do not re-enter; obviously, the CST fibers like it too much in the graft and are not triggered (enough) to re-enter the host. Here, various aspects, based on our developmental know-how, might be directive and inform us about which approach should be taken in future design of CNS bridges and CST regrowth. The presence of neurotrop(h)ic molecules but also the 3D alignment of the glial cells during development, is restricted in time and only needed during the various phases of CST outgrowth. In future designs of bridges and biomaterials, mimicking a developmental CST environment is of the utmost importance; not only the presence of the cue needed for regrowth but equally important is the disappearance or decrease in concentration of the guidance molecule after some time. If we again use the developmental CST as the most optimal model needed for regrowth of injured CST fibers in the adult mammalian spinal cord, we have learned that the development of the CST tract is characterized by cellular interactions, which are changing during the spinal outgrowth in place and in time. It has been shown, for instance, that for spinal target innervation the most common mechanism used is collateral formation or back-branching, a phenomenon, at least to my knowledge that has never been observed (or studied) in regrowing injured CST fibers. This back-branching occurs after a waiting period of several days at a defined spinal level and the neurotrophin NT-3 might be important, although the precise mechanism underlying the formation of the CST-collaterals is not yet known. Whereas the injured CST axons should be triggered to re-enter the host tissue, it should be stressed that the failure of (CST) axons to re-enter the distal spinal host tissue maybe in part related to the presence of the so-called glial scar, including the chondroitin sulfate proteoglycans (CSPGs), which inhibit axon growth (Fawcett and Asher ON (“ingrowth of CST fibers into the bridge”) and (maybe even more important!!) an OFF mode . In this, the use of a bridge does not stand alone: the formation of a continuum based on outgrowth promoting capacities not only related to the bridge but also including the rostral and caudal host tissue  point of motor restoration, the regeneration of individual fiber systems is needed in order to develop an optimal repair strategy and motor recovery. In this respect, one important question needs to be addressed: what is the relationship between an anatomically observed response related to the function repair and recovery of function? Or, do we need all injured (CST) fibers to regenerate?With respect to the CST, the question of which behavioral deficits are due to CST lesioning in adult rats is still not fully answered. Although the transection of the CST in the rat leads to, for instance, a loss of contact placing, the role of this tract in the control of distal and proximal limb movements is still not fully understood. The good news is that it has been documented that a very low percentage of regrowing fibers at the anatomical level may account for a complete recovery of the placing reflex (Bregman et al.


There were multiple errors in the Author Contributions statement. The second author (YL) was incorrectly included in the list of authors who "Wrote the paper." In addition, the first author (XC) should be included in the list of authors who "Wrote the paper."


TheVirtualBrain (TVB) is the first integrative neuroinformatics platform for the modeling of full brain network dynamics. TVB simulator, written in Python, enables the systematic model-based inference of neurophysiological mechanisms on different brain scales that underlie the generation of macroscopic commonly used neuroimaging signals . In the framework of TVB we build full brain network models by incorporating biologically realistic large scale couplings of neural populations. The couplings within the network are captured by the space-time structure of the connectivity matrix, which defines the connection strengths and time delays via signal transmission between all network nodes. Researchers from computational, theoretical and clinical neuroscience can benefit of this tool. The web interface allows users without programming knowledge to access a powerful computing platform as well as visualization and analysis tools. Users with strong programming skills benefit of all the advantages provided by the Python programming through a shell interface.We propose TVB as a novel computing tool for large-scale brain simulations. TVB is the solution to tackle systematic parameter space exploration, allowing to rapidly gain insights of the full brain dynamics repertoire as a function of structure. It moves away from the investigation of isolated regional responses and considers the function of each region in terms of the interplay among brain regions. Full brain simulations open the possibility for the exploration of the consequences of pathological changes in the system, enabling us to identify and potentially counteract those unfavorable processes.


The Eating Disorders Program (EDP) based at Royal Melbourne Hospital offers inpatient, day patient and outpatient services to adults from western Melbourne and regional Victoria and receives over 150 referrals per year. Despite streamlined referral processes to the program and access to training for front line clinicians, there are still gaps in the management of eating disorders in the community. Most affected are patients who have been discharged from the inpatient or day programs and those from regional centres.The EDP set up a pilot outreach service in 2013 following extensive service mapping and needs analysis. There were two initial goals; individualised community treatment for patients in recovery phase of their eating disorder and a consultation liaison role to advise local and regional clinicians and inpatient units in effective management of eating disorders.The outreach service consisted of a multi-disciplinary team supported by the EDP. The goals of treatment for individual work were improved quality of life, weight restoration and decreased eating disordered behaviour. The consultation liaison role aimed to reduce the need for admission to specialist beds and build the capacity of local clinicians.This presentation aims to describe the background, setup and outcomes of this new service.Care in Inpatient and Community Settings stream of the 2013 ANZAED Conference.This abstract was presented in the


FOXP2 involved in specific language impairments and neuroligin genes (NL-3 and NL-4) involved in autism spectrum disorders. Knockout of FoxP2 leads to reduced vocal behavior and eventually premature death. Introducing the human variant of FoxP2 protein into mice, in contrast, results in shifts in frequency and modulation of pup ultrasonic vocalizations. Knockout of NL-3 and NL-4 in mice diminishes social behavior and vocalizations. Although such studies may provide insights into the molecular and neural basis of social and communicative behavior, the structure of mouse vocalizations is largely innate, limiting the suitability of the mouse model to study human speech, a learned mode of production. Although knockout or replacement of single genes has perceptible effects on behavior, these genes are part of larger networks whose functions remain poorly understood. In humans, for instance, deficiencies in NL-4 can lead to a broad spectrum of disorders, suggesting that further factors  contribute to the variation in clinical symptoms. The precise nature as well as the interaction of these factors is yet to be determined.Comparative analyses used to reconstruct the evolution of traits associated with the human language faculty, including its socio-cognitive underpinnings, highlight the importance of evolutionary constraints limiting vocal learning in non-human primates. After a brief overview of this field of research and the neural basis of primate vocalizations, we review studies that have addressed the genetic basis of usage and structure of ultrasonic communication in mice, with a focus on the gene  A classic theme in natural philosophy is the question of what distinguishes our own species from others , particuFoxP2 with particular regard to its impact on structural properties of vocalizations, whereas the second study set assessed the importance of neuroligin genes on the usage of vocalizations. For comparative purposes, we will make some reference to research on bird song, another important study system to elucidate the foundations of vocal learning.The purpose of the present review is to explore ways in which genetic studies in mouse models can contribute to a better understanding of the evolution of human communication. One specific aim is to elucidate the limitations in vocal communication of non-human primates. We therefore begin with a review of the vocal communication of non-human primates, including the neural circuits underlying call usage and structure. This background knowledge is essential to understand the derived features of neural circuitry in the human lineage that are seen as a precondition for vocal learning in our own species and to place the studies of mouse ultrasonic vocalizations (USVs) into an appropriate context. We begin this central part with a brief introduction to the structural and functional properties of mouse USVs, and then summarize the results of two exemplary sets of studies. The first study set focused on the effects of Language in general is characterized by a set of features that distinguish it from other means of communication  involves a number of different subsystems, contributing to different degrees in the initiation of vocalization and the structural properties of the calls. In a recent review, The second vocalization control pathway described in the The role of the basal ganglia in controlling motor output has long been recognized . Recent The most important derived feature in the human lineage regarding the ontogeny of speech appears to be the evolution of the direct pathway from the motor cortex to the motoneurons, enabling volitional control over the oscillations of the vocal folds. Together with the intricate coordination of breathing and articulation, this feature allows for the precise control over speech production. The role of the basal ganglia in the modulation of vocal behavior, in contrast, appears to be an ancestral feature. The detailed investigations of the brain mechanisms underlying vocal control now call for the elucidation of the genes that might be involved in the reorganization of the brain that enabled humans to talk .USVs occur in a wide range of taxa such as rats  as well Interest in mouse vocal behavior goes back quite some time  were able to show that females emit USVs during social encounters with intruding females. The number of calls seemed to be modulated by the motivational state of the emitter during the estrous cycle, and there was a positive correlation between the number of calls and the time spent by the resident sniffing the intruder female  confirmeThe above overview describing some key questions in the evolution of language debate, as well as the most significant features of mouse USVs, serves as the framework for the following section that reviews exemplary studies addressing specific genes that have been implicated in language impairments and socio-cognitive deficits.FOXP2 gene was identified in a British family whose specific language impairments appeared to be inherited in an autosomal dominant fashion (FOXP2 gene (FoxP2 appears to be highly conserved . Analyses of the evolution of the FoxP2 gene in primates have identified two amino acid substitutions  believed to have become fixed in the human lineage after its separation from the chimpanzee and which appear to have been subject to positive selection  affecting the DNA binding domain of the protein, is truncated due to a nonsense mutation (R328X) or is disrupted by a chromosomal rearrangement, the development of speech and language is impaired  and not in males who sang to females (directed singing)  ; this waFoxP2 support the view that this gene is closely linked to vocal behavior. The different clades of echolocating bats show significant changes in the FoxP2 gene sequence  hypothesized that this pattern of gene modification is related to the fact that bats rely on extremely precise vocalizations for predation. Mice homozygous for non-functional FoxP2 alleles produce significantly fewer isolation calls than their wild-type (WT) littermates ; the WT mouse FoxP2 protein can be used as a model for the ancestral version of the human FoxP2 protein  and vasopressin – hypothalamic neuropeptides excreted by the neurohypophysis . Mice laThe usage of ultrasonic vocalizations appears to also be influenced by the dopaminergic reward system involved in a variety of behaviors, including affective responses, positive reinforcement, foraging and sexual behavior . To giveAs mentioned early on, our research interest lies in the elucidation of the evolution of communicative behavior with special emphasis on the evolution of speech. Because of the link between communicative behavior and the development of perspective taking and mental state attribution in human children, genes that have been implicated in autism spectrum disorders (ASD) are of particular interest. Typical symptoms of ASD are social deficits such as impairments in the ability to take the perspective of others, language deficits, as well as restricted interests . These fWe focused on the vocal communication of NL-3 and NL-4 KO mice and analyzed the ultrasonic vocalizations of male mice during courtship behavior. We found in both cases a significant reduction in the number of USV calls . Indeed,The rare cases where the KO male mice uttered calls showed that both WT and KO mice were able to produce the same call types . AlthougOther mouse models for autism have reported a very different pattern in terms of the structural property of calls. Mice of the BTBR T+ tf/J strain, which exhibit social abnormalities and repetitive behaviors, were found to have an abnormal vocal repertoire (The case studies reviewed here indicate that the ultrasonic vocalizations of mice appear to constitute a valuable readout in studies of the genetic foundations of social and communicative behavior, perhaps even giving some preliminary clues to the evolution of speech. Call rates, durations and response consistencies, in particular, appear to be sensitive variables in studies of genes involved in the modulation of social behavior. However, to date the interaction of different factors that contribute to variation in the propensity to vocalize remains largely unclear.Before we can fully understand how different genes contribute to changes in the structure of vocalizations, we need to develop a better understanding of the sound production mechanisms. For instance, how are mouse calls with ‘pitch jumps' being produced, what role do non-linear phenomena play and what is the contribution of the vocal tract filtering (FoxP2 gene show significant differences in the local architecture of the striatum is in-line with the view that this area is important in the fine-grained control of motor behavior. However, in addition to changes at the synaptic and local level, there is also a global reorganization of the fiber tracts that connect the brain areas involved in motor sound production and perception (Despite the present optimism regarding the value of ultrasonic vocalizations in transgenic mice as readouts in clinical studies, some important restrictions apply in terms of their applicability to study the foundations of human speech. It is of utmost importance to be aware of the differences in the neural circuitry underlying innate vs. learned vocalizations. In other words, in the FoxP2 studies in mice reviewed here, the effects of genes are studied largely in the context of innate behavior. The ultimate goal is to understand a learned mode of vocalization production because only in this context will we enhance our understanding of the origins of speech. The finding that laboratory-produced mice carrying the human variant of the rception .We are just beginning to grasp the complexity of the genetic networks contributing to regulations between vocal and social behavior. Studies on the genetic foundation of mouse ultrasonic vocalizations can help to put some pieces of the puzzle of language evolution in the proper place. At the same time, other issues such as the understanding of the link between mental state attribution and language and its role in the evolution of speech still remain largely elusive.


Over the past five decades ovarian cancer has been of considerable interest to clinical cancer investigators due to the fact that it is among the most chemosensitive of all solid tumors . Unfortutargeting biological pathways relevant in a particular tumor type  and even within a specific patient with that type of cancer . Research in this arena in ovarian cancer remains in its early stages although a number of quite exciting developments have recently been reported in the peer-reviewed medical literature that suggest the realistic potential that this novel general class of drugs will soon become important components of “standard-of-care” in the management of this difficult malignancy. In recent years there has been a particular focus in the cancer research community to discover and subsequently develop clinically active drugs that are capable of specifically  In this special issue, investigators from around the world have contributed to this literature by summarizing a number of important developments. In the papers of this special issue, an initial discussion of the role of surgical cytoreduction in the malignancy is followed by an overview of the management of recurrent ovarian cancer and the relevance of molecular abnormalities in specific ovarian cancer subtypes. This is followed by several excellent and comprehensive overviews of the possible roles of targeted therapy in ovarian cancer, the potential impact of antiangiogenic drugs, epidermal growth factor and PARP inhibitors, disruption of insulin and glucose pathways, and novel treatments affecting histone deacetylase and metastatic colonization, as well as an innovative approach to immunotherapy in the malignancy. The peer-reviewed papers in this special issue provide important insight into both the current and future management of epithelial ovarian cancer.M.MarkmanM.MarkmanJalid SehouliJalid SehouliCharles F. LevenbackCharles F. LevenbackDennis S. ChiDennis S. Chi


In a recent review article we reconsidered the hypothesis that neurogenic vasodilatation is a key factor in the genesis of the headache of the migraine attack according to an updated and critical analysis of past and current literature. Cited papers span from pioneering studies in experimental animals of more than a century ago, to very recent investigations in humans in whom vasodilatation of cranial arteries has been accurately measured with highly sophisticated and reliable techniques. Results of neurovascular imaging studies have strongly corroborated previous pharmacological acquisition with antagonists of the calcitonin gene-related peptide receptor. Findings from clinical trials with these drugs underlined the role of neurogenic vasodilatation in migraine. In a comment to our review , Elliot On the other hand, we acknowledge that the complex pathophysiology of migraine and the mystery that still covers the initiating factors/mechanisms of the migraine attack should cast caution in refusing the contribution of triggers located in the central nervous system.


Globally, trauma represents a growing and significant burden of disease. Many health systems have limited metrics with which to guide development and appropriately inform policy and management decisions with regard to trauma related health care delivery.This paper outlines the establishment of need for improved trauma related metrics in the country of Bhutan and the process of development of a trauma registry at Jigme Dorji Wangchuck National Referral Hospital to meet that need.Trauma registries are important tools allowing health systems to respond to the shifting burden of disease; successful establishment of a trauma registry requires an understanding of the health system and broad institutional support. This project outlines the concepts and process involved in establishing a trauma registry at Jigme Dorji Wangchuck National Referral Hospital Thimphu, Bhutan (JDWNRH) as a model for the country of Bhutan. A need for improved emergency medical care was established by the Royal Government of Bhutan and collaborating partners and improved trauma related metrics were identified as critical to informed development.Recent changes in the understanding of trauma related outcomes and demographics have led to a trend in international policy, funding and programmatic implementation emphasizing trauma care and injury prevention in the developing world  with limited health and economic infrastructure, Bhutan faces significant challenges with regard to health care delivery  of the United Nations Injuries and the burden of injuries on the health care system are increasing in Bhutan, resulting in the prioritization and need for increased data on the part of the MoH. Data from the Monthly Morbidity Report (MMR) presented in the 2009 Annual Health Bulletin shows total number of Injuries and Poisoning increasing from 19,117 in 2004 to 26,330 in 2008, and increase of 37.7%. In addition the number of deaths attributed to Injuries and Poisoning increased from 13 in 2004 to 30 in 2008, an increase of 130%. This data correlates with global studies of trends that show dramatically increasing rates of injuries and associated death and disability .While in Bhutan the two staff members helped build a core group of staff, the ‘trauma team’ focused on the development and implementation of the trauma registry. This group included management, clinical staff and administrators involved in hospital services related to trauma patients. Definitions were agreed upon and the data points were chosen based on addressing the important elements of demographics, prehospital care, vital signs representing clinical condition, mechanism or nature of injury, treatment and disposition. A trauma registry form was developed and piloted with subsequent implementation in September 2010.Establishment of the trauma registry at JDWNRH was met with some specific challenges. First, while there was interest in the benefits of the registry, as evidenced by MoH efforts and a previous attempt at establishing a registry several years earlier, clinical workload and commitment of resources hindered the process. Communication between the MoH and clinical staff with regard to data use and priority setting was not clear. Arrival of trauma patients occurred at several venues  requiring many staff to be trained and adding logistical difficulties. Three clinic departments – the emergency department, orthopedics, and forensics – represented the bulk of trauma patients and were trained to administer the registry. The data processing was conducted by the medical records office and staff of the trauma team with the goal of eventually transferring the data to the MoH for further analysis and use in policy and management decision making. Document flow through the hospital was a great challenge, requiring layers of shifting responsibility.  concerning policy implications of data points was also likely an important limitation. Implementation of the paper trauma registry before the planned implementation of the computerized medical record was necessary but less than ideal. Finally, given the limited number of clinical staff the untoward affect of using staff time to develop a tool of unclear clinical significance and longevity was of great concern.The project outlined above represented initial attempts to confront the unmet needs of the people of Bhutan and desire of the government to improve health outcomes with regards to trauma and emergency care. Many of the challenges facing Bhutan’s goals for improving emergency medical care are similar to those found in other resource poor settings: economic and logistical challenges to scaling up care, lack of trained health care personnel and limited training opportunities, and difficulty prioritizing interventions and health care systems investment. Improved metrics as a goal of this project, has potential to confront some of the limitations inherent within systems with limited resources. In addition, given Bhutan’s reliance on partners for development, the country’s ability to guide its development may be influenced by external priorities. Improved metrics may allow the MoH greater ability to influence development partners towards more impact driven interventions.


Because of the rapidly increasing prevalence of obesity among children worldwide and the realization that this global epidemic is closely related to changing life style, especially relating to diet and exercise, research in the effects of exercise on children's health and the effects of children's health on their ability to exercise becomes timely and imperative. Promoting scientific researching in the field of exercise medicine in children has therefore been the primary motive behind this special issue of the International Journal of Pediatrics which is dedicated to publishing important works in the field. To the great satisfaction of our team of editors, a great number of good quality research results were submitted to the issue from all four corners of the world which indicates a strong interest in this very important field of medicine worldwide. The first section of this issue contains cross-sectional population studies that provide evidence confirming the strong correlation between obesity and lack of activity in children of different populations and different age groups . Furthermore, a 12-month interventional study from Sweden showed that longer exercise periods performed by school age boys resulted in more muscle mass and increased muscle strength (the fourth paper). The second section of the issue contains several articles studying the different genetic, environmental, parental, and other psychosocial factors that can potentially affect children's level of exercise activity. These articles collectively provide evidence for the variety and complexity of factors that affect children's predilection or exercise . They also identify potential areas for future intervention to promote exercise early in life (the ninth paper). One example of such opportunities involves the use of video gaming. Even though the overuse of video gaming has been largely blamed for the decreasing level of physical activity in children, the case might be completely reversed with the recent advent of interactive video gaming which tends to be preferred by children over conventional video gaming and is associated with higher level of physical activity (the tenth paper). The third section deals with research relating to exercise in children with known chronic illness such as diabetes, cystic fibrosis, neuromuscular diseases, arthritis, and congenital heart diseases with emphasis not only concerning the limitations these illnesses impose on children's ability to exercise and become physically fit but also on how increased fitness in these patients can modulate their disease process and therefore on ways exercise can be performed and promoted .The fourth section discusses hemodynamic responses to exercise in children as compared to adults (the seventeenth paper) and explores the hormonal and inflammatory profile of overweight and normal weight children and relates them to cardiovascular fitness (the eighteenth paper). The fifth and final section has one article which evaluates the validity of different accelerometeric measurements used in exercise research to objectively grade level of physical activity as compared to the gold standard of directly measuring energy expenditure (the nineteenth paper).We hope that this special issue will contribute substantially to the existing body of knowledge of this new and growing field of exercise medicine in children and to stimulate further needed research.Mutasim Abu-HasanMutasim Abu-HasanNeil ArmstrongNeil ArmstrongLars B. AndersenLars B. AndersenMiles WeinbergerMiles WeinbergerPatricia A. NixonPatricia A. Nixon


Malaria is still one of the most important infectious diseases in the world. The disease also is a public health problem in south and southeast of Iran. This study programmed to show the correlation between regular malaria microscopy training and refresher training courses and control of malaria in Iran.Three types of training courses were conducted in this programme including; five – day, ten – day and bimonthly training courses. Each of the training courses contained theoretical and practical sections and training impact was evaluated by practical examination and multiple-choice quizzes through pre and post tests.Distribution pattern of the participants in the training and refresher training courses showed that the most participants were from Sistan & Baluchistan and Hormozgan provinces where malaria is endemic and most cases of the infection come out from these malarious areas. A total of 695 identified individuals were participated in the training courses. A significant conversely correlation was found between conducting malaria microscopy training courses and annual malaria cases in Iran.Conducting a suitable programme for malaria microscopy training and refresher training plays an important role in the control of malaria in endemic areas. Obviously, the decrease of malaria cases in Iran has been achieved due to some activities that malaria diagnosis training was one of them. Malaria is still one of the most important infectious diseases in the world and is a life threatening in the malarious areas. According to the report of WHO, 216 million malaria cases with an estimated of 655000 deaths were officially recorded in 2010 . On the Malaria is a public health problem in south and southeast of Iran. The annual reports of Communicable Disease Centre (CDC) show that the number of malaria cases from 19129 cases in 2001 has been decreased to 2656 cases in 2011  the School of Public Health, TUMS, Iran has been designated as a research and training focal point of malaria programs including malaria microscopy. Three types of training courses were conducted in this programme including:The objectives of the training course for the first and second items were to strengthen the knowledge of participants in the field of malaria microscopy and for the third item were to train the malaria microscopy for new eligible participants. Each day of the courses covered seven training hours .Training impact of the courses was evaluated by practical and multiple –choice quizzes through pre and post tests.This study was designed as a retrospective study to consider the number of participants, their geographical distribution, and their academic grades, quality of the training and also the influence of a decade (2001 – 2011) malaria microscopy training courses on the control of malaria in Iran.The refresher training courses were designed for microscopists and laboratory technicians and the bimonthly course was conducted for eligible high school graduated students.Theoretical subjects including: Introduction to malaria microscopy, malaria parasites, life cycle and morphology of human plasmodia, morphology of blood cells, antimalarial drugs and treatment of uncomplicated malaria, drug resistance in malaria parasites and Rapid Diagnostic Tests (RDTs). The theoretical subjects were presented according to the basic malaria microscopy . This se: blood collection, preparing thick and thin blood smears and staining them with Giemsa stain, detection of malaria parasites, differentiating between human plasmodia, artifacts, counting malaria parasites, keeping and storing the examined slides, recording the results and preparing relevant reports. The practical subjects were performed according to the standard operating procedures (SOPs) of WHO manuals . According to this table most of the courses were conducted at the Bandar-Abbas Health Research Station in Hormozgan Province.The Correlation between conducting malaria microscopy training courses and annual malaria cases in Iran is illustrated in In addition to well adopted administrative and vector control activities, prompt case finding in malaria infection and accurate treatment of the disease plays an important role in control and elimination of malaria. On the other hand, on time treatment of malaria infection depends on the exact and swift diagnosis of malaria parasites.Although clinical signs particularly in malarious areas can guide the physicians to suspect malaria infection, it is not sufficiently sensitive and specific. Due to avoiding presumptive treatment for malaria in cases come out with fever, the current WHO recommendation emphasizes on the systematic testing of all fever cases . DetectiAlthough some other methods such as PCR, Quantitative Buffy Coat (QBC), Indirect Fluorescent Antibody (IFA) and light microscopy can be used for diagnosis of malaria parasites, among them light microscopy is the conventional and method of choice for malaria case detection of malaria parasites in the most of malarious areas.In the light microscopical method prompt and exact diagnosis also depends on two principles; well trained and skillful microscopists and good materials and equipments. The latter is usually available in the markets, but rearing the competent microscopists takes time and needs adequate expenditures. Such aim can be achieved with designing a reasonable programme. The results of this study show that employing the trained malaria microscopists in their right place will lead to the desirable results . FindingPreparing a suitable programme for training and refresher training courses in the field of malaria microscopy can have a considerable impact on the knowledge and competency of the microscopists and laboratory technicians as well as plays an important role on control of malaria in endemic areas.Obviously, the decrease of malaria cases in Iran has been achieved due to some activities that malaria diagnosis training was one of them.