Pericytes are multipotent cells present in every vascularized tissue in the body. Despite the fact that they are well-known for more than a century, pericytes are still representing cells with intriguing properties. This is mainly because of their heterogeneity in terms of definition, tissue distribution, origin, phenotype and multi-functional properties. The body of knowledge illustrates importance of pericytes in the regulation of homeostatic and healing processes in the body.In this review, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in the crosstalk between pericytes and endothelial or immune cells. We highlighted the role of pericytes in the pathogenesis of fibrosis, diabetes-related complications , ischemic organ failure, pulmonary hypertension, Alzheimer disease, tumor growth and metastasis with the focus on their therapeutic potential in the regenerative medicine. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed. Strong evidence for pericytes’ participation in physiological, as well as in pathological conditions reveals a broad potential for their therapeutic use. Recently published results obtained in animal studies showed that transplantation of pericytes could positively influence the healing of bone, muscle and skin and could support revascularization. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials.Critical to further progress in clinical application of pericytes will be identification of tissue specific pericyte phenotype and function, validation and standardization of the procedure for their isolation that will enable establishment of precise clinical settings in which pericyte-based therapy will be efficiently applied. They wed vessel . Despited vessel .Currently, a mature pericyte is defined as a “cell embedded within the vascular basement membrane” . AnotherHerewith, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in crosstalk between pericytes and endothelial cells (ECs) or immune cells. Additionally, we highlighted the role of pericytes in the pathogenesis of several diseases with the focus on their therapeutic potential in the regenerative medicine.Pericytes are heterogenous in terms of embryonic origin. Ectoderm-derived neural crest gives rise to pericytes in the central nervous system and thymus while in lung, heart, liver and gut, the mesothelium is the main source of pericytes. In most other organs, pericytes derive from the mesoderm; specifically, the sclerotomal compartment . InteresFor research purposes, pericytes were most usually isolated from bovine retina or brain since the highest density of pericytes to ECs has been observed in these organs . The othDue to the heterogeneity of pericytes, several markers were usually used for their identification Fig. : plateleMorphology of pericytes is determined by their localization and the content of α-SMA. Mid-capillary pericytes have lack of α-SMA and are elongated and more spindle shaped, while pre- and post-capillary pericytes contain varying amounts of α-SMA and are shorter and stellate-shaped . The typFrom their position on the outer surface of the blood vessel, pericytes interact with ECs, which reside on the other side of the basement membrane. The number and size of pericyte-endothelial contacts vary between tissues, and can increase up to 1000 for a single endothelial cell. The majority of these contacts are of peg-socket type, in which pericyte cytoplasmic fingers (pegs) are inserted into endothelial invaginations (pockets). Other contact morphologies include occluding contacts and adhesion plaques that strengthen adherence between ECs and pericytes. The occluding contacts are located at the edge of the pericyte processes and through them membranes of pericytes and ECs come very close to each other enabling straightway contact between these cells. The adhesion plaques, which provide adherence between the ECs and the pericytes, represent fibronectin-reach microfilament bundles attached at the pericyte plasma membrane and electron-dense material in the opposing endothelial cytoplasm. These are the sites where N-cadherin-based connections are formed between ECs and pericytes , 14, 25.Distribution of pericytes within the tissue microenvironment and their interaction with ECs are regulated by blood flow and oxygen content . The anaDuring embryonic development, PDGF-B is released from ECs and binds to PDGFRb, expressed on the surface of developing pericytes. As a result, PDGFRb-positive pericytes (or their progenitors) are co-recruited to the angiogenic sprouts . PostnatReciprocal orientation to the PDGF-B/PDGFRb signaling has an Angiopetin-1 (Ang-1)/Tie-2 paracrine loop where Ang-1 is produced by pericytes while Tie-2 is expressed on ECs. Ang-1 through the binding to the Tie-2 regulates maturation and integrity of ECs –30. Peri, during tumor angiogenesis [Another pathway recently implicated in pericyte recruitment is stromal-derived factor 1-a (SDF-1a)/CXCR4 axis which activation promotes pericyte migration in vitro and in vivoogenesis . SDF-1a ogenesis  and actiogenesis .A huge number of studies have demonstrated the pivotal role of transforming growth factor beta (TGF-β) signaling for regulation of pericytes and ECs proliferation and differentiation as well as generation of new blood vessels , 34–37. Interaction between pericytes and ECs is crucially important for the integrity and maintenance of the basement membrane of the vessel wall . The conAdditionally, pericytes mechanically regulate vessel wall integrity and serve as signaling mediators of ECs behavior. Pericytes in paracrine manner affect proliferation and maturation of ECs and are able to promote generation of new vessel sprouts when it is appropriate or to inhibit aberrant pro-angiogenic behavior of ECs when vessel sprouting is not required .Pericytes:ECs interactions are affected not only by biochemical factors such as ligand–receptor kinetics, but also through the pericytes’ exertion of mechanical forces that are communicated to nearby ECs through either direct strain or indirect mechanical stiffening of the underlying nonlinear elastic substrata . There iWhen mechanical strain applied to ECs, ECs are activated and re-enter the cell cycle. Pericyte contraction, resulting with the attendant strain of the ECs environment, serves as an early mechanical cue that promotes activation of ECs and development of capillary-like endothelial sprouting .Fluid shear stress induces up-regulation of “a disintegrin and metalloproteinase with thrombospondin motif 1 (ADAMTS-1)” in ECs, a metalloproteinase that is crucially important for vascular regression . PericytPericytes play an important role in intussusceptive angiogenesis, as well . By elecRecently, it has been found that pericytes may regulate the diffusion of cells and proteins from the vessel to the surrounding tissue, influencing the infiltration of the immune cells in inflamed tissues –58. InitMoreover, emerging evidence demonstrates the involvement of pericytes in modulation of immune response . PericytA fact that pericytes are cells with immunomodulatory characteristics and that most of them are derived from mesoderm, indicated their resemblance with perivascular mesenchymal stem cells (MSCs), multipotent, self-renewable cells that, upon injury, promote tissue repair by suppressing immune response and inflammation –72. The Since pericytes regulate angiogenesis and inflammation, they play an important role in the pathogenesis of fibrosis, ischemic organ failure, tumor growth and metastasis, and their number was significantly altered in several pathologies including diabetes and diabetes-related complications, pulmonary hypertension and Alzheimer disease.Pericytes may contribute to the development of fibrosis in two ways: directly by producing collagen  or indirPericytes are recruited into tumor blood vessels in PDGF-B/PDGFRb, HB-EGF/Erb and SDF-1a/CXCR4 dependent manner , 86, 87.Additionally, pericyte deficiency increases interstitial fluid pressure , which mOne of the earliest hallmarks of diabetes and related complications  is the loss of pericytes which causes regression of the microvasculature leading to leaking of fluids, leukocyte adhesion to the vasculature and hypoxia in the damaged area. Reduced number of pericytes seen in diabetic patients is a consequence of hyperglycemia-induced apoptosis of pericytes which mainly happens due to an increase in production of reactive oxygen species (ROS) that disrupt mitochondrial membrane of pericytes, resulting with the release of cytochrome C and the activation of the caspase-3 dependent apoptotic cascade. Another mechanism by which hyperglycemia-induced oxidative stress can cause pericyte loss is through the generation of advanced glycation end-products (AGEs). Through the binding to their receptors, expressed on the membrane of pericytes, AGEs induce apoptosis of pericytes, further contributing with their reduced number in diabetic patients .The dysfunction, degeneration and loss of pericytes in diabetic patients are crucially important for the development of peripheral vascular complications, including diabetic limb ischemia. Mi-RNAs are considered as critical regulators of gene expression in this condition. Hyperglycemia and ischemia induce increased expression of miR-503 in ECs which is, within extracellular vesicles and microparticals, distributed to the pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduced expression of EfrinB2 and VEGF-A, resulting with the impaired migration and proliferation of pericytes and consequent progression of diabetic limb ischemia .Diabetic retinopathy, a leading cause of blindness, is one of the most common complications of diabetes mellitus . During In similar manner as in diabetic retinopathy, hyperglycemia-induced alteration in number and function of renal pericytes results with the development of diabetic nephropathy, manifested by proteinuria, progressive decline in the glomerular filtration rate and increased arterial blood pressure. High glucose causes migration of peritubular pericytes away from the capillary into the interstitial space where they differentiate into collagen-producing myofibroblasts significantly contributing to the development of tubulointerstitial fibrosis and renal dysfunction.  It is asProlonged and incomplete wound healing, caused by dysfunction of pericytes and impaired angiogenesis, has been observed as a complication of diabetes mellitus . As a noHyperglycemia-induced apoptosis of pericytes contributes to the development of neuropathy and erectile dysfunction in diabetic patients. Reduced number of pericytes leads to the disorganization of ECs, resulting in decreased perfusion of peripheral nerves and consequent hypoxia. The hypoxia is, in turn, responsible for oxidative stress and apoptotic cell death of pericytes which results with microangiopathies of the endoneurial capillaries . SimilarPericytes have an important role in the etiology of ischemic organ failure . In the Pericytes have an important pathological role in the development of pulmonary hypertension. When compared to the vessels of healthy controls, an increased number of pericytes is found in pulmonary arteries of patients suffering from pulmonary hypertension. It was assumed that these additional pericytes serve as a source of smooth muscle-like cells leading to the excessive remodeling of the pulmonary vasculature, endothelial dysfunction and development of PAH .Strong evidence for pericytes’ participation in physiological, as well as in pathological conditions reveals a broad potential for the therapeutic use of these cells , 108. SePericyte-based therapy holds great potential to enhance the healing of injured muscles. Human pericytes  were able to produce myofibres contributing to the muscle regeneration after transplantation in mice with cardiotoxin-induced muscle damage . SimilarAlthough pro-fibrotic role of pericytes were well documented in animal models of chronic kidney injury and diabetic nephropathy , 102, peTransplantation of human adipose tissue-derived pericytes  protects against diabetic retinopathy in a mouse model by promoting angiogenesis and vascular support . This waPromising results of pericyte-based therapy have been observed in murine models of skin and bone injury, as well . The appThe body of knowledge illustrates the importance of pericytes in the regulation of homeostatic and healing processes in the body. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well known while their regenerative and immunomodulatory characteristics are still not completely revealed. An aberrant number or function of pericytes is associated with the development of fibrosis, diabetes-related complications, ischemic organ failure, pulmonary hypertension, Alzheimer’s disease, tumor growth and metastasis. Recent in vivo studies show that the transplantation of pericytes can positively influence the healing of bone, muscle and skin and can support revascularization in a mouse model of diabetic retinopathy. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials and until now pericytes were in regenerative medicine mainly used for repopulation of vascular grafts . Critica


High-grade glioma, particularly, glioblastoma, is the most aggressive cancer of the central nervous system (CNS) in adults. Due to its heterogeneous nature, glioblastoma almost inevitably relapses after surgical resection and radio-/chemotherapy, and is thus highly lethal and associated with a dismal prognosis. Identifying the cell of origin has been considered an important aspect in understanding tumor heterogeneity, thereby holding great promise in designing novel therapeutic strategies for glioblastoma. Taking advantage of genetic lineage-tracing techniques, performed mainly on genetically engineered mouse models (GEMMs), multiple cell types in the CNS have been suggested as potential cells of origin for glioblastoma, among which adult neural stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) are the major candidates. However, it remains highly debated whether these cell types are equally capable of transforming in patients, given that in the human brain, some cell types divide so slowly, therefore may never have a chance to transform. With the recent advances in studying adult NSCs and OPCs, particularly from the perspective of comparative biology, we now realize that notable differences exist among mammalian species. These differences have critical impacts on shaping our understanding of the cell of origin of glioma in humans. In this perspective, we update the current progress in this field and clarify some misconceptions with inputs from important findings about the biology of adult NSCs and OPCs. We propose to re-evaluate the cellular origin candidacy of these cells, with an emphasis on comparative studies between animal models and humans. Adult gliomas are the most common cancers of the central nervous system (CNS) . DespitePerspective, we review the current progress in the research of the cell of origin of glioma. Together with new findings in NSCs and OPCs from both rodents and large-brained mammals including humans, we propose to carefully re-evaluate the candidacy of several popular cell types that have been believed as the potential cells of origin of glioma in humans.A cell of origin is the normal progenitor from which all the neoplastic cells of a given type of cancer develop . IdentifKnowing the properties of neural cell types and their lineage relationship will help understanding their potential contributions to the etiology of human glioma. Neural cells in the adult CNS are grossly classified as neurons, astrocytes, oligodendrocyte precursor cells (OPCs), and oligodendrocytes. In addition to these lineage-committed progenitor and mature cells, specialized stem cells, termed adult neural stem cells (NSCs) exist within restricted regions such as the subventricular zone (SVZ) next to the lateral ventricle, and the subgranular zone (SGZ) of the hippocampus , in the Figure 1A). Therefore, although adult NSCs exhibit remarkable self-renewal potential and differentiation plasticity in culture , which were best studied in rodents, have been generally believed to be able to persistently self-renew, and give rise to multiple neuronal and glial cell types . Recent  culture , it rema culture .Figure 1A). By using a sensitive DNA-labeling approach to mark cells undergoing proliferation, bona fide self-renewable cell population in vivo. Given that OPCs make up 5–10% of all cells in the brain , we have shown that introducing p53 and NF1 mutations into NSCs did not evidently change the proliferation rate of pre-cancerous adult NSCs, but drastically promoted the over-expansion of descendant OPCs, arguing against a direct transformation of NSCs, at least in the context of this mutation combination . Unlike humans, but quite similar to rodents, dogs possess SVZ neurogenesis that persists into adulthood .Cumulative evidence suggests that the same cell of origin can give rise to the GBMs manifesting different molecular features and that distinct types of cells of origin can evolve in parallel to give rise to tumors resembling similar molecular features (see also For instance, OPCs have been previously considered to mainly give rise to oligodendrogliomas and proneural subtype of GBMs . HoweverImportantly, the evolution routes of a defined cell of origin may also affect the molecular features of brain tumors. The recurrent GBMs from the same patients frequently switched their molecular features when compared to their primary tumor counterparts . TherefoOwing to genetic lineage tracing techniques and other advanced biological methods, tremendous progress has been made in understanding the glioma cell of origin during the past decade. Now, a consensus has been made that several important cell types, particularly NSCs and OPCs, are capable of transforming at least in GEMMs. However, many fundamental questions remain unanswered. For instance, is there a universal cell type functioning as the cell of origin for all gliomas in humans? Or alternatively, do different cell types give rise to gliomas with distinct pathological identities? Can different mutations drive the same cell of origin to follow the same or distinct routes toward the final transformation? When exactly do human gliomas form? GEMMs will surely continue to serve as the most important tools to address these fundamental questions. Nevertheless, we should be aware of the difference between GEMMs and patients. Newer methods and the concept of comparative pathology could help us identify what really initiates this devastating form of cancer in humans.FS and CL wrote the manuscript. FS prepared the figure and the table.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Purpose: We present the clinical, paraclinical and therapeutic features in a patient with secondary congenital aphakia.Methods: A 2-year-old patient, diagnosed with congenital rubella syndrome including sensorineural deafness, congenital heart disease, intellectual disability, microcephaly, microphthalmia, and congenital cataract, presented to our clinic for the surgical treatment of cataract.Results: During the surgery, the absence of the lens’ cortex was observed, hence, the final diagnose was of secondary congenital aphakia. Surgery was then continued with a posterior capsulorhexis and an anterior vitrectomy, deciding to postpone the implantation of the posterior chamber intraocular lens. Aphakia can be congenital due to the intrauterine anomalies and acquired due to the surgical removal or trauma. Congenital aphakia is a rare anomaly, which can be associated with other important ocular disorders. It can be subdivided into two forms: primary and secondary congenital aphakia. Primary congenital aphakia results from the failed induction of the lens placode and therefore the lens is absent, whereas in secondary aphakia, the lens placode has developed but has been resorbed before birth (remnants of the lens such as the lens capsule are present) [1].The lens development begins in the 3rd- 4th week of gestation, when the thickening of the surface epithelial cells over the optic vesicle gives birth to the optic placode, which, after the process of invagination, becomes the lens vesicle. The latter contains a single layer of cells covered by a basal lamina, which will ultimately form the lens capsule. In the 3rd month, the primary lens fibers begin to fill the cavity from posterior to anterior . The rubella virus has an apoptotic effect on the primary lens fibers during pregnancy but it may persist in the lens three years postnatally [5].Although the rubella virus generally has a benign evolution in children and adults, it has important vital consequences if contracted cardiac defects, deafness, and mental retardation, especially if the infection occurs during the first trimester of pregnancy .The occlusion therapy of the patient’s amblyopia is the key for a good visual result in the future. Also, since the patient has a considerable risk of developing secondary glaucoma, the screening of glaucoma becomes an important step in evaluating the long-term outcome of the patient [


An effective method to monitor heavy metal stress in crops is of critical importance to assure agricultural production and food security. Phenology, as a sensitive indicator of environmental change, can respond to heavy metal stress in crops and remote sensing is an effective method to detect plant phenological changes. This study focused on identifying the rice phenological differences under varied heavy metal stress using EVI (enhanced vegetation index) time-series, which was obtained from HJ-1A/B CCD images and fitted with asymmetric Gaussian model functions. We extracted three phenological periods using first derivative analysis: the tillering period, heading period, and maturation period; and constructed two kinds of metrics with phenological characteristics: date-intervals and time-integrated EVI, to explore the rice phenological differences under mild and severe stress levels. Results indicated that under severe stress the values of the metrics for presenting rice phenological differences in the experimental areas of heavy metal stress were smaller than the ones under mild stress. This finding represents a new method for monitoring heavy metal contamination through rice phenology. With rapid development of the industry, rice paddies in some areas have been subjected to heavy metal pollution. According to the related statistics, more than 12 million tons of grains are contaminated in China every year . Heavy mAt present, most research on heavy metals in rice are carried out from the aspects of chlorophyll, leaf area index, cell structure  ,8,9, or Compared with methods based on traditional ground remote sensing and model simulation, extracting the rice phenological information through satellite remote sensing to monitor heavy metal stress is more convenient and direct. Knowledge of crop calendars and phenology is often a key element in vegetation interpretation. Since the 1970s, the potential of multi-temporal satellite observations to provide information on the phenological development of natural vegetation and crops have been recognized by many researchers ,23,24. PThe objective of this study was to explore the potential of evaluating heavy metal stress based on rice phenology extracted by remote sensing technology. In order to verify the effectiveness of using phenological characteristics to monitor heavy metal stress in rice, we compared and analyzed the phenological differences under mild and severe heavy metal stress by two kinds of metrics with phenological characteristics for proving that the specific phenological characteristics are effective indicators for monitoring heavy metal stress in rice. The findings are expected to assist in monitoring the heavy metal contamination of rice and measure the degree of regional heavy metal pollution from the perspective of phenology.Environmental Quality Standard for Soils in China [The city of Zhuzhou, in the Hunan Province, China, is an important commodity grain producing area and, simultaneously, is an old industrial base. From the industrial activity, the Xiangjiang River and its tributaries were contaminated. The main heavy metals in this area are cadmium (Cd), plumbum (Pb) and arsenic (As). Four rice fields adjacent to the Xiangjiang watershed in Zhuzhou were selected as experimental fields , and eacl sample  and variin China , the depin China . In thesIn this study, 16 CCD images from the small sun-synchronous satellites, HJ-1A/B, which are used for monitoring and forecasting environmental and natural disasters, were adopted as the remote sensing data covering four experimentation areas in the entire growing season of rice paddies (dated from 13 June to 29 September 2013). The HJ-1A/B satellite can cover a ground swath 700 km wide, and two CCD sensors were loaded on satellites which formed a constellation to constitute an observation network that covered China and its surrounding areas on a two-day-repeat cycle. The CCD sensors captured ground features with a 30 m pixel resolution at a nadir angle in the visible bands. These CCD images consisted of the following four channels: band 1: 0.43–0.52 μm (blue waveband), band 2: 0.52–0.6 μm (green waveband), band 3: 0.63–0.69 μm (red waveband), and band 4: 0.76–0.90 μm (near-infrared waveband). Wang et al.  integratThe time is expressed as the day of the year (DOY) in this paper. Among the 16 images , there were two images in June (DOY168 and DOY181), four images in July , five images in August , and five images in September . All of the 30 m multispectral CCD images were processed prior to use, and the specific process can be summarized as: (1) radiometric-calibration was performed for each band, and the four bands of each scenes were packed; (2) the CCD images were clipped to obtain a subset The extraction of vegetation phenological information by remote sensing are mostly based on the vegetation indices time-series curves, that is, the vegetation indices of time-series using remote sensing images are analyzed by smoothing and parameter analysis of the vegetation indices to extract phenological information while reflecting seasonal characteristics of vegetation community for temporal-spatial analysis ,34,35,36NDVI is the most widely used vegetation index for monitoring vegetation phenology. EVI, the enhanced vegetation index based on NDVI, is applied increasing widely. To a certain extent, the two VIs can reflect the comprehensive situation of the land cover types from pixels in corresponding regions. The periodic increase and decrease of the VIs value of the region is a typical performance of the vegetation growth cycle, which can be used to determine the vegetation growth and overall situation. Additionally, the differences of VIs among different regions can reflect the vegetation, soil type, precipitation, topography and land use, and so on . Thus, tectively .Due to the presence of cloud, shadow, and other factors, the time-series EVI data still had a lot of noise, so they need to be filtered and reconstructed before application . In the Many researchers performed the studies about the fidelity performance and the capability of keeping main characteristics on the three algorithms for vegetation phenology detection. Wang, Xin, and Shu  used EVIAfter the original data were smoothed, the temporal profiles of EVI were obtained. Next, according to the characteristics of EVI time-series curves, the specific phenological periods were extracted. The rice growth period was from transplanting time to harvest time. Remote sensing in rice using optical satellite sensors exploited the phenological characteristics of the rice life-cycle. About one to two weeks after transplanting, the rice turned into the tillering period. In the tillering period, due to the development of rice root and leaf systems, EVI rapidly increased until the heading period when the vegetative development of rice reached its maximum, and rice growth becomes a descending stage where EVI decreases gradually, due to the nutrients transferred into the seeds. During the maturation period, due to the loss of most of the chlorophyll, the leaves rapidly withered, and the vegetation index was minimized in the harvest period . As ment0) [max) was used to estimate the active tillering period; and (3) similarly, at the end of the maturation stage, EVI declines rapidly due to leaf senescence [min) to detect the maturity period (mid-September). According to the characteristics of rice growth stages described above, the identification of rice growth and development period can be detected through the vegetation index of remote sensing image time-series.Based on the analysis method of first derivative, we selected the appropriate indicators to identify the rice growth stage: (1) due to a high level of LAI and biomass in the heading period (mid-August), this period will have the maximum EVI corresponding to the value of FD (FD0) ,47; (2) 0) . Thus, tnescence . Hence, As the four experimental areas were from different places, there were differences in the specific transplanting period (mostly in mid-June) and the definition of phenological periods by traditional methods, therefore, we could not identify the delay and advance for the specific phenological period. To detect the impact of heavy metals in soil on rice phenology, we selected the date-intervals, which meant the lengths of time between different phenological phases and eliminated the impact of different planting time, as the heavy metal stress metrics of rice phenology to extract the same differences under varied heavy metal stress levels. The specific metrics are calculated as follows :(3)L1=DOTo further analyze the effect of heavy metal concentration on rice phenology, the differences between L1 and L2 under same heavy metal stress were taken as a measure, that is, the variation tendency of two adjacent phenological intervals (between the tillering period and heading period and between the heading period and maturity period) under different heavy metal stresses was analyzed, and the formula is as follows:The dates of the tillering, heading, and maturation periods can be extracted by remote sensing data using the phenology monitoring algorithms, as the EVI time-series reflect changes in the morphological and physiological condition of the rice during the rice growth cycle . The timIn this study, approximately 50 pixels from CCD images were extracted in each of the four experimental areas to fit the time-series of the EVI and extract phenological periods by pixel, before averaging the pixel information in the same experimental area. max, FD0, and FDmin) of smoothed EVI temporal profiles, three phenological periods  in the four experiment areas were obtained and averaged, respectively. According to first derivative (FD) analysis  were selected as the metrics to present the phenological differences under stress. Different concentrations of heavy metals had distinct effects on the rice different growth stages. As shown in Different characteristics of rice growth status presented different responses under heavy metal stress. Based on the time-series curves constructed by the EVI values obtained from the remote sensing images, the trend and abundance of curves can reflect the size of rice growth season. This study presents a new methodology for monitoring heavy metal stress in crops based on crop phenology with remote sensing technology. The methodology was identified through extracting rice phenological differences under mild and severe heavy metal stress levels by the EVI time-series, which was obtained from HJ-1A/B CCD images and fitted with asymmetric Gaussian model functions (AG). With first derivative (FD) analysis, three phenological periods  were detected, and then two kinds of metrics with phenological characteristic: date-intervals and time-integrated EVI were constructed and compared in the four experimental areas. The results indicated that the phenology is an effective indicator for monitoring heavy metal stress in rice.It is critical that phenological differences under different heavy metals stress are measured. In this study, we selected the EVI time-series, which were composed of CCD images, to define three key phenological periods. CCD images from HJ-1A/B have high temporal-spatial resolution were obtained, but due to the monsoon climate, the cloud-free remote sensing data during the growth phase of the paddy rice was limited. Compared with other remote sensing data commonly used for monitoring vegetation phenology, CCD data represents the value of the day unlike AVHRR and MODIS remote sensing data of usually eight or 16 days of synthetic products, which means any one of the images were compounded by the optimal algorithm between eight days or 16 days. Thus, we can obtain better and closer to the true value of smoothed curves of the EVI time-series that also contributed to detect phenological differences under the two heavy metal stress levels. Some studies found that the crop growth under heavy metal stress becomes slower comparing with non-contaminated conditions ,51,52,53This study provides a new way to monitor heavy metal pollution in agriculture through remote sensing technology. Compared to traditional ground-based methods used to monitor heavy metal stress, remote sensing is a simple and convenient resource. Furthermore, the analysis of phenology presented here concerned the effects of temperature, climate, rainfall, and so on. In this study, the results of the metrics’ analyses clearly indicate that heavy metal stress is also an important factor that affects phenological changes. At present, in the case of serious heavy metal pollution, when investigating the phenological changes of terrestrial ecosystems, it is necessary to consider the impact of heavy metal pollution in heavy metal contaminated areas. However, it is necessary to declare that the relationship between the phenological differences and stress metrics found in this study are specific to the selected phenological periods studied , and the results might differ for other phenological periods monitored, other types of data used, other smoothed functions, other measures of phenological period estimation, and other stress metrics. Thus, when the metrics are applied to other areas or other crops, another comparative analysis should be undertaken. Furthermore, the values of the metrics presented in this study ought to be proved. In conclusion, the generality of this finding in other areas and crops require further research.Our results are limited by the selected phenological extraction method’s sensitivity and fidelity and the metrics used, but under the severe stress level, the length of time between the tillering period and the maturation period was around 49 days, and the integral areas of the EVI time-series during the tillering and maturation periods was about 32. These were identified via the statistical properties, and a comparative analysis of the metrics is an important indicator of monitoring phenological differences under mild and severe stress levels to fully investigate heavy metal stress levels of rice paddies based on extracting phenological periods from EVI time-series curves by remote sensing data and the fitting method. Meanwhile, it should be pointed out that, in this study, two kinds of metrics were qualitatively analyzed, and the performance of the metrics could be further tested through detailed quantification using measured data and more detailed procedures. The results in this paper could be further verified by collecting field observation data. In addition, more rice phenology periods, like the transplanting periods and panicle development, should be extracted to analyze the phenological differences by means of ground-based spectrometers.max, FD0 and FDmin) of smoothed EVI temporal profiles. Two kinds of metrics with phenological characteristics, date-intervals and time-integrated EVI, were constructed to detect rice phenological differences under varied heavy metal stress. The comparison of the two kinds of metrics indicated that the values of the metrics for presenting rice phenological differences under severe stress in the four experimental areas were smaller than the ones under mild stress. It has been proved that it is feasible to use remote sensing technology to monitor the rice phenological variations caused under different heavy metal stress, and measured the rice phenological differences with the two kinds of metrics under mild and severe heavy metal stress. This conclusion strongly supported the theory that phenology is one of the sensitive indicators of environmental change. Thus, phenology could be a useful indicator for heavy metal stress in rice plants.In this study, we monitored rice phenological differences under mild and severe heavy metal stress levels using remote sensing technology for exploring the potential of evaluating heavy metal stress based on rice phenology by remote sensing. We used the EVI time-series smoothed with AG function to represent the status of plant growth. Three phenological periods  were detected through first derivative (FD) analysis (FD


There is a growing recognition about the effects of traumatic experiences on mental health worldwide. With ongoing conflicts, natural disasters, interpersonal violence, and other traumatic events it is estimated that approximately 70% of the global population have been exposed to at least one lifetime traumatic experience. Research shows a substantial proportion of survivors, especially in low- and middle-income countries, would have a posttraumatic stress disorder (PTSD). During recent decades effective evidence-based treatments for PTSD have been developed. However, there are significant barriers to mental health services and trauma-informed treatments are not easily available for trauma survivors. From the perspective of social psychotraumatology several core barriers to trauma treatments were identified, including the lack of acknowledgment, and avoidance of disclosure. The need for cultural sensitivity in PTSD treatments, the potential of alternative ways of treatment delivery, and the involvement of non-professional volunteers are proposed as directions for future developments in the field. Even though we wish our world was safe and secure, traumatic experiences are inevitable companions of human existence. Research suggests that the majority of a population are exposed to traumatic events in a lifetime, and that this is true worldwide. A recent epidemiological study revealed that even in high-income countries, such as the United States of America, 95% of the population experienced at least one lifetime traumatic event , and aboStudies also demonstrate a remarkable resilience in coping with traumatic experiences. A majority of survivors successfully cope with traumatic experiences, utilizing inner resources, and social support from their social network. However, some survivors may have severe adjustment impairments after traumatic events. Since the inclusion of the Posttraumatic Stress Disorder (PTSD) in the Diagnostic and Statistical Manual of Disorders (DSM-III) in 1980, PTSD has now become one of the most common diagnoses among mental health professionals . Still, This paper aims to discuss barriers for effective PTSD treatments, primarily in low- and middle-income countries, and identify several important future directions for reducing the burden of PTSD in traumatized populations.PTSD has a high cost for societies and there is worldwide demand for effective treatments of PTSD. Over the last few decades a number of evidence-based PTSD treatments have been developed . Howeverbarriers for dissemination and delivery of effective PTSD treatments for traumatized populations important for health care policies were identified:Acknowledgment of survivors. Across many cultures trauma survivors may experience stigmatization, and a lack of acknowledgment. The negative role of the lack of social acknowledgment has been demonstrated in several studies recently [recently ,11. Negarecently .Avoidance and trauma disclosure. One of the core PTSD symptoms is avoidance. Survivors with PTSD symptoms very often avoid disclosure of traumatic experiences, and trauma reminders, and may be reluctant to seek help. Studies on the disclosure of trauma have revealed that it is a significant predictor of PTSD symptoms [symptoms ,13,14. ILimited resources. Evidence suggests that psychological treatments  for trauma survivors are the most effective treatments for PTSD [for PTSD . Howeverfor PTSD .Ongoing conflicts and disasters. It is extremely difficult to provide PTSD treatments in a country with an on-going conflict or even war. Findings from studies in post-conflict areas also indicate that the PTSD rates in these countries are significantly higher and could reach up to 40% in the general population [pulation .The treatment gap in mental health is worldwide . Based oCultural sensitivity. We have substantial evidence of the cross-cultural validity of the PTSD diagnosis. However, there is a need for cultural sensitivity in PTSD treatment [reatment . More crAlternative models of health care. There are a growing number of studies providing evidence that Internet-based interventions can be similarly as effective as traditional face-to-face treatments [eatments . Global eatments .Involvement of non-professional volunteers. We will not have enough available trained professionals in evidence-based trauma treatments worldwide in the near future. We need to revise our concepts of mental health care delivery and utilize volunteers and other non-professionals who can disseminate effective self-help programs and assist in addressing the psychological needs of trauma survivors. Global train-the-trainers programs can facilitate training of volunteers and non-professionals to deliver treatments, possibly in self-help.Therefore, several future directions for the traumatic stress field of research which are relevant for national and international health care developments that could contribute to reducing the gap of untreated PTSD in traumatized populations are proposed:The burden and the cost of traumatic events and PTSD are increasing. Only several barriers for trauma treatments were identified in this paper, and a few directions based on the current status of the traumatic stress field of research were proposed. Health care policy makers should be informed about the role of the social factors of PTSD, such as the importance of the social acknowledgment of survivors. However, the active role of international organizations, such as the World Health Organization (WHO), is also crucial for influencing health care policies on the regional and national levels. With the increasing body of evidence about the resilience of survivors, and the findings on the effectiveness of trauma-focused treatments, we could hope that positive changes are possible in the near future in overcoming barriers to treatment of trauma-related disorders.


The deliberations and conclusions of a Hinxton Retreat convened in September 2015, entitled “Mechanisms to reverse the public health neglect of snakebite victims” are reported. The participants recommended that the following priority actions be included in strategies to reduce the global impact of snake envenoming: (a) collection of accurate global snakebite incidence, mortality and morbidity data to underpin advocacy efforts and help design public health campaigns; (b) promotion of (i) public education prevention campaigns; (ii) transport systems to improve access to hospitals and (iii) establishment of regional antivenom-efficacy testing facilities to ensure antivenoms’ effectiveness and safety; (c) exploration of funding models for investment in the production of antivenoms to address deficiencies in some regions; (d) establishment of (i) programs for training in effective first aid, hospital management and post-treatment care of victims; (ii) a clinical network to generate treatment guidelines and (iii) a clinical trials system to improve the clinical management of snakebite; (e) development of (i) novel treatments of the systemic and local tissue-destructive effects of envenoming and (ii) affordable, simple, point-of-care snakebite diagnostic kits to improve the accuracy and rapidity of treatment; (f) devising and implementation of interventions to help the people and communities affected by physical and psychological sequelae of snakebite. Snakebite is a medical emergency that annually kills over 95,000 people residing in some of the world’s most disadvantaged subsistence farming communities, and leaves over 300,000 surviving victims with permanent physical disabilities, stigmatising disfigurements and chronic mental morbidity ,2,3. It While there have been a number of efforts to address this issue by some individual governments, civil society groups and members of the snakebite research community, a more globally-coordinated, multi-faceted approach is vital to achieve significant, sustained progress to reduce the medical and socioeconomic burden of snakebite. Here, the outcomes of a Wellcome Trust-funded Hinxton Retreat organised by the authors in September 2015, entitled “Mechanisms to reverse the public health neglect of snakebite victims” are summarized. This 36 participant workshop was organized to combine the breadth of knowledge, opinion, and experience of key physicians, scientists and advocates working on tropical snakebite in Africa , Asia , Latin America , Oceania , and Europe  with the fiscal, political and advocacy power of civil society groups and funding agencies—Médecins Sans Frontières (MSF), Drugs for Neglected Diseases initiative (DNDi), Global Snakebite Initiative (GSI), Health Action International (HAI), AMREF Health Africa, the World Health Organization (WHO) and the Wellcome Trust.The first session of the workshop was an overview of the diverse factors limiting access to effective healthcare for tropical snakebite victims. As summarised below, poverty and limited government investment in snakebite management were described as ever-present themes at each level that snakebite affects its victims.Poor subsistent farmers are at greatest risk of snakebite  because Rural snakebite victims typically gain access to health centres many hours 6+) after the bite ,6, which+ after tWith the exception of charity-managed hospitals, most rural, remote health centres are under-resourced in many tropical countries. Antivenom treatment requires hospitalisation for a minimum of 24 h. Thus, while these health centres or dispensaries are closest to snakebite victims, they are often unable to provide effective clinical care because they lack the required clinical staff, hospital beds, equipment, effective antivenom and training in snakebite management. Snakebite victims are therefore often referred to a more centralised hospital, invoking further delay of treatment.The very limited availability of effective, affordable and safe antivenom in much of rural sub-Saharan Africa and Asia, and in some regions of Latin America, is the most important contributor to this tropical disease burden . AntivenThese financial, clinical and logistic complexities of antivenom treatment and the lack of accurate epidemiological data perhaps explain the typically limited government investment in effective antivenom purchase and distribution to rural communities in greatest need. The lack of robust regulatory control of antivenom efficacy also leads to widespread availability of less expensive but weakly or ineffective antivenoms throughout sub-Saharan Africa—which exacerbate the problem.Snakebite victims may need to be hospitalised because (i) of severe neurological, haemorrhagic, coagulopathic, renal, cardiac, or myotoxic manifestations of envenoming; (ii) antivenom must be intravenously administered; (iii) cure is complicated to assess; (iv) the frequent need to observe and treat patients for antivenom-induced adverse effects; and (v) extensive tissue necrosis subsequent to envenoming by some species requires surgical debridement or amputation to prevent spread of life-threatening sepsis. Effective hospital management of snakebite therefore requires specific clinical and surgical training—medical education that is often lacking in these remote, under-resourced regions.Post-treatment care rarely exists but is greatly needed to manage the chronic psychological  and physThe historical categorisation of snakebite as an accident/injury rather than a tropical disease, the fact it cannot be eradicated, the lack of accurate data evidencing the medical and socioeconomic disease-burden, its complex and expensive treatment, and competing tropical health priorities have combined in the nearly universal public health neglect of snakebite victims by governments and International Health Agencies. Worldwide, snakebite kills approximately 270–340 people every day—one fifth the number of people that die from malaria. In India, snakebite kills half the number of people that die from HIV . In AfriThe tragedy is that snakebite victims, despite their high rates of death and suffering, do not benefit from the generous national and international investment provided to reduce the disease burden of malaria, HIV, lymphatic filariasis, schistosomiais, and several other tropical diseases such as Buruli ulcers, trypanosomiasis and leishmaniasis that pose a lower threat of death, physical disability and psychological morbidity than snake envenoming . Snakebite is a legitimate Neglected Tropical Disease ,13, whic(i)reduce snakebite incidence and increase access to effective health care;(ii)improve the clinical management of snakebite before, during and after hospital care;(iii)apply scientific innovation to devise novel, effective, affordable and safe snakebite therapies and rapid diagnosis;(iv)implement an effective snakebite advocacy initiative.After the above overview of the snakebite burden in Africa, Asia and Latin America, the participants were next tasked with identifying key strategic, and achievable, interventions to:The following sections describe the priority objectives identified during the workshop , and the progress achieved since the retreat or prior exemplars of effective practice in these key areas.A clear need was identified for public health and social research programs to capture data evidencing the medical, social and economic impact of snakebite envenoming. The avenue to achieve this would be collaborative  and medical charities) community- and hospital-based surveys recording snakebite incidence, mortality and morbidity data  in formats that can be utilized by health economists to generate health impact assessments. This information, collected for nations or regions, was identified as a critical step to (i) assess local, national and regional therapeutic needs; (ii) establish baseline data for determining the medical, health economic and sociological impact of preventative interventions; and perhaps, most importantly, (iii) to provide governments with the data they need to implement or approach International Health Agencies and philanthropic donors to fund evidence-based intervention strategies.The social research programs would benefit from inclusion of studies to better understand snake ecology and behaviors dictated by rural poverty, identify especially vulnerable groups, such as indigenous communities, and determine the impact of snakebite on these groups, together with understanding the social and cultural contexts in which snakebites occur and their implications for prevention and appropriate management.Data from studies conducted in India ,14, BangThere was broad consensus that motorcycle transport has proved very effective in reducing snakebite deaths in some settings —and shouKenSERS) in Baringo County. This is based upon mobile telephone activation of specially-designed, inexpensive motorcycle ambulances to speed rural snakebite victims to hospitals equipped with appropriately trained clinical staff provided with effective antivenoms. Success of the KenSERS pilot project will provide an affordable ambulance template to improve snakebite victims acquiring rapid access to effective treatment throughout sub-Saharan Africa (s-SA), and globally.The workshop was informed of an emergency response system designed to meet the specific needs of Papua New Guinean snakebite victims that contained many valuable aspects that could be implemented globally. Since the retreat, the Kenya Snakebite Study Group established in 2015 has acquired funds to trial the Kenya Snakebite Emergency Response System  and avoid harmful practices that increase the likelihood of snakebite. These would require MoH involvement and ideally incorporate the cultural stature of local traditional healers, and, importantly, with other local civil society initiatives and be part of universal health coverage. Education campaigns at the community level need to respect the cultural backgrounds. It was considered important that the education campaigns include a strategy of approaching the media, with the aim of targeting governments, public health authorities, international health agencies and foundations, and other philanthropic donors and stakeholders to acquire the political support and funding for consolidating a long-term, sustainable strategy to reduce snakebite incidence, mortality and morbidity.Significant efforts have been performed in several countries. For instance, in Costa Rica, an active community education program has been underway for several decades, directed to rural areas of high snakebite risk, including indigenous communities. Likewise, an ongoing project in Papua New Guinea involves snakebite prevention campaigns at the local community level. A successful project was developed in Nicaragua, with the support of the Pan-American Health Organization (PAHO) aimed at developing integrated actions between the MoH and local traditional healers.Clinical research groups urgently need to establish clinical trials networks for collecting data post-treatment—unified under an international coordinating body. The task for this body will include (i) identifying standard metrics and protocols for evaluation of antivenom effectiveness at all levels from phase 1 dose-finding through to Randomised Clinical Trials, to generate consensus on endpoint measurement and safety assessment; (ii) providing guidance on endpoints; (iii) agreeing upon the most valuable prospective observational data using standardised and specific case definitions; and (iv) promoting clinical research aimed at identifying poorly known clinical manifestations of envenoming by some snake species in various regions of the world.It was also acknowledged that there exists an urgent need for systematic programs to teach basic aspects of diagnosis and clinical management of snakebite envenoming at university, hospital and local health center levels. This should include the publication and wide distribution of guidelines and algorithms for clinical management of envenoming. The use of new Information and Communication Technologies offers opportunities to reach health staff in remote settings of high snakebite incidence.The freely available WHO guidelines for the clinical management of snakebite in Africa  and AsiaResearch into the development of first aid methods that are practical, effective and affordable at the community level was identified as another priority.The WHO snakebite-management guidelines also include effective first aid recommendations. The Papua New Guinean emergency response system includes specific training modules on effective first aid that could be valuably adapted for other regions. It is encouraging that recent research  indicateThe existence of some antivenoms in sub-Saharan Africa of known ineffectiveness ,25,26 anThe WHO took the opportunity of this workshop to publicly announce the launch of a prequalification scheme of antivenoms for sub-Saharan Africa , whereinEchis ocellatus from various regions [Dendroaspis polylepis [In addition to a sustained international cooperative effort in the preclinical testing of antivenom efficacy being performed in Latin America for many years , it was regions ,30,31 anolylepis . It was Workshop presentations highlighted that antivenom production globally consisted of over 45 manufacturers with variant output capacity, QC-testing facilities, government sponsorship, market , and that the recent, highly-publicised market failure of the Sanofi Pasteur antivenom (Fav-Afrique) illustrated the fiscal challenges that some companies face. Regional strategies to significantly increase antivenom availability need to consider this manufacturing heterogeneity, and many of these laboratories need to upgrade their technological platforms, infrastructure, good manufacturing practices (GMPs) and staff training; some also require urgent re-analysis of the venom mixtures used for immunization. Concerted dialogue between manufacturers, governments and regional WHO regional offices is necessary to effect the changes needed to increase the quality and quantity of antivenoms manufactured by these laboratories. Technology transfer programs for antivenom production, from established laboratories to countries that do not produce antivenoms, but have the requisite technological capacity, were also considered an important objective.The workshop predicted that antivenom–efficacy tests will provide evidence and identify regions with serious therapeutic deficiencies. A strategy needs to be urgently formulated to provide funds to existing manufacturers (with spare manufacturing capacity) to produce antivenoms to meet the immediate needs of these regions see also .The organization of regional networks of antivenom manufacturers developed in Latin America in the last decade  constituIt was recognized that the long-term physical and psychological impact of snakebite in poor rural communities is another priority for the snakebite community, and requires research to (i) measure medical and socioeconomic impact and (ii) devise locally appropriate strategies to reduce this impact. It was also clear that implementing these measures requires expertise from medical charities assisting victims of other medical emergencies, such as landmine accidents, survivors of which suffer similar disabilities as snakebite victims. The attention to the psychological sequelae of snakebite victims is a highly neglected area that demands urgent research and attention.The recent research describing the chronic psychological impact of snakebite in Sri Lanka ,35 and IThe selection of venoms included in the mixture to immunize animals for antivenom production is often made on an empirical basis. The technologies of proteomics, together with information on the epidemiology of snakebites and the identification of the most relevant venom toxins to be neutralized , allow fA vast volume of information has been generated in the past decade defining the protein composition of venoms of the most medically-important snakes , and on It was agreed that innovative science, allied with contemporary technical platforms, has strong potential to overcome the poor dose-efficacy , thermostable, inexpensive and polyspecifically effective therapy, which, ideally, could be applied in field conditions rapidly after the bite.Encouraging results on small peptide enzyme-inhibitors , fucoidaIn the absence of diagnostic tools, physicians’ treatment decisions rely upon the victim’s description of the snake (but distinguishing harmless or weakly-venomous snake species from life-threatening species is notoriously inaccurate) and signs of local and systemic envenoming, which may develop slowly and vary greatly . There was broad agreement that the provision of Point-of-Care diagnosis  would significantly improve the accuracy and outcome of clinical management of snakebite victims and should be a research priority, particularly in some regions of the world where a ‘syndromic approach’ to diagnosis of envenoming is difficult. The development of an epidemiological diagnostic tool, designed to identify envenoming by snake species, was considered valuable but of a lower priority than the Point-of-Care clinical tool.Recent research on molecular diagnosis of snake bite  providesThe consensus view was that, while all the above research concepts hold considerable therapeutic and diagnostic promise, practical implementation is years away. There is therefore a compelling and urgent need for national and international health agency support and investment in the production, efficacy-testing and delivery of conventionally-manufactured antivenoms to those regions in greatest need, particularly in sub-Saharan Africa.The overarching objective of the meeting was the formulation of a plan to reduce snakebite death and disability, especially in tropical countries of high snakebite incidence. There was unanimous agreement that (i) the future success of the priority actions identified during the workshop required effective advocacy at each level ; and (ii) that the snakebite community’s attempts at advocacy urgently needs to be supplemented with advocacy professionals and organizations. A very positive and unique aspect of this workshop was the presence of key NGO representatives who contributed significantly to the discussions and to the development of future plans.We report here that action was immediately taken after the retreat to scale-up the role and capability of the Global Snakebite Initiative (GSI); with Health Action International (HAI) being co-opted to run the GSI Secretariat and tasked with devising an effective advocacy strategy based around a ‘theory of change’ that is likely to include many of the same objectives discussed at this workshop. Furthermore, the GSI Board of Directors was expanded to include representatives of sub-Saharan Africa and Asia.Another important progression was the initiative supported by GSI, HAI and MSF and sponsored by the government of Costa Rica and co-sponsored by the governments of Afghanistan, Angola, Bangladesh, Burkina Faso, Cameroon, Chad, Gabon, Guinea, Kenya, Nepal, Nigeria, Pakistan, Papua New Guinea, Philippines, Senegal, and Uganda to run a snakebite-focused Side Event at the World Health Assembly in Geneva, May 2016. This event, attended by 140 people from many countries, proved a powerful opportunity to raise awareness of the public health burden of snakebite, the plight of snakebite victims and a strategic plan to reverse this. The event attracted the attention of the media and many organizations, which now needs to be exploited to maintain this advocacy momentum. Encouraging the WHO to upgrade the profile of snakebite either within the Neglected Tropical Diseases or Essential Medicines departments is an essential prerequisite to gaining the support of other International Health Agencies and donors.An independent film company, funded by the Lillian Lincoln Foundation, is preparing an hour-long documentary focusing on the plight of rural snakebite victims, and was invited to the retreat to conduct interviews and gain background information. A five-minute film extracted from this documentary was presented at the WHA Side Event and released online , which hThe considerable progress made in the past year reflects the value of collaboration with new partners with distinct skills, and illustrates the enthusiasm that exists at many levels to achieve the aims of the workshop. This will be vital because the priority objectives identified during the workshop are daunting in their diversity, geographic and technical scope and need for coordination—particularly as funds to implement these have yet to identified. Therefore, a multi-component, inter-sectorial and inter-disciplinary approach, involving stakeholders in many different realms, should be implemented. The workshop’s conclusion that s-SA should be the focus of pilot projects of some of these new initiatives seems sensible and meets an urgent need. The greatest challenge to making these actions sustainably successful will be coordination and acquiring the cooperation and support of national Ministries of Health, International Health Agencies and civil society groups.There was considerable workshop discussion as to the optimal strategy to overcome this challenge, and the need for an organization to coordinate efforts at the global level was emphasized. GSI is the only snakebite-focused charitable organization with a global remit and, as such, received support from the workshop participants as the most appropriate agency to undertake this role. This represents a formidable commitment. As described above, GSI has responded to this challenge by forming effective collaborative relationships with organizations including the WHO, HAI, MSF and others, as well as with Permanent Delegations of several governments in Geneva. It is expected that GSI will expand its scope of activities, its collaborative network and its coordinating role in the near future. In parallel, independent initiatives of various sorts in different regions of the world and promoted by a variety of actors need to be supported and implemented at all levels of action . The combination of decentralized activities at many levels and GSI-coordinated initiatives is expected to catalyze an outburst of activities aimed at improving the management of snakebite victims to significantly reduce deaths and morbidity.(a)Collection of accurate global snakebite incidence, mortality and morbidity data to underpin advocacy efforts and help design of effective public health strategies.(b)Promotion of (i) public education campaigns aimed at reducing snakebite incidence; (ii) ambulatory/transport systems to improve access to hospital treatment; and (iii) establishing regional antivenom-efficacy testing facilities to ensure that antivenoms provided to the hospitals are effective and safe.(c)Explore funding models for investment in the production of antivenoms to address existing deficiencies in some parts of the world.(d)Establish (i) a global system for training in effective first aid, hospital management and post-treatment care of snakebite victims; (ii) a clinical network to generate treatment guidelines and metrics and (iii) a clinical trials system—to improve the clinical management of snakebite before, during and after hospital care.(e)Develop (i) novel, polyspecifically-effective and safe treatments of the systemic and local tissue-destructive effects of envenoming and (ii) an affordable, low-technology, point-of-care snakebite diagnostic kit to improve the accuracy and rapidity of treatment.(f)Devise and implement intervention strategies to help the people and communities affected by physical and psychological sequelae of snakebite in order to reduce the extent of social suffering caused by this disease.In conclusion, the Hinxton Retreat participants recommended that the following highly summarised, priority actions be included in this strategy to reduce the global impact of snakebite envenoming:


Cisplatin has a well-established role in the treatment of broad spectrum of malignancies; however its use is limited because of cisplatin-induced nephrotoxicity (CIN) which can be progressive in more than 50% of cases. The most important risk factors for CIN include higher doses of cisplatin, previous cisplatin chemotherapy, underlying kidney damage and concurrent treatment with other potential nephrotoxin agents, such as aminoglycosides, nonsteroidal anti-inflammatory agents, or iodinated contrast media. Different strategies have been offered to diminish or prevent nephrotoxicity of cisplatin. The standard approach for prevention of CIN is the administration of lower doses of cisplatin in combination with full intravenous hydration prior and after cisplatin administration. Cisplatin-induced oxidative stress in the kidney may be prevented by natural antioxidant compounds. The results of this review show that many strategies for prevention of CIN exist, however, attention to the administration of these agent for CIN is necessary. Cisplatin is important chemotherapeutic agents used to treat solid tumors, including head, ovarian and neck, and testicular germ cell tumors, which its use is limited because of cisplatin-induced nephrotoxicity (CIN) that can be progressive in significant percent of patients. In the early trials prior to the use of preventive measures, the amount of acute renal failure (ARF) incidence resulting from this drug was observed in more than 5o% of cases. It is recommended that preventive measures must be used in all patients treated with cisplatin and aim of this mini-review is evaluation of these preventive measures.Renal toxicity involves kidneys free radical production and increase, utilization of antioxidant defense mechanisms, and also acute renal tubular cells necrosis that leads to reduce glomerular filtration rate (GFR) and kidney dysfunction. Beside the pathological mechanisms involve rise of upregulation of transforming growth factor-β, endothelin-1, augmentation of oxidative stress, necrosis, apoptosis and increase in macrophage/monocyte infiltration into the renal cortex and medulla . The search was performed by using combinations of the following key words and or their equivalents; cisplatin, cisplatin-induced nephrotoxicity.Cisplatin (cis-diamminedichloroplatinum II) is an antineoplastic agent drug, which is used in the treatment of a broad spectrum of malignancies including head and neck, esophagus, bladder, and metastatic testis, ovarian, breast and non-small cell lung cancer ,2. Cispla) increase plasmatic levels of blood urea nitrogen and creatinine, (b) decrease calcium uptake, ATP content and electrochemical potential, (c) depletion of the NADPH and glutathione (GSH) as an antioxidant defense, (d) oxidation of cardiolipin, sulfhydryl and aconitase enzyme, (e) increase activity of the apoptosis executioner including caspase-3 were prevented by DMTU (Generation of reactive oxygen species (ROS) and vasoconstriction in the renal microvasculature is responsible for the cisplatin-induced renal tubular injury. Moreover the S3 segment of the proximal tubule in the outer stripe of the outer medulla are selectively injured by cisplatin, as manifested by both apoptosis and necrosis. There have been a number of studies that interestingly reported, reactive nitrogen species (NOS) have also been involved in cisplatin-induced renal toxicity. Cisplatin intensifies the production of nitric oxide and peroxynitrite in renal tissues. Peroxynitrite stimulate changes in the function and structure of lipid peroxidation, chemical cleavage of DNA, proteins and reduction in cellular defenses by oxidation of thiol pools . Cisplat by DMTU . One stu by DMTU .Many of sulfur-containing compounds have been reduced the nephrotoxicity of cisplatin without inhibiting or decreasing its antitumor effect in patients with non-small cell lung cancer, metastatic breast cancer, ovarian cancer and metastatic colon cancer . In animThe most significant clinical manifestation of cisplatin nephrotoxicity is acute and chronic impairment of renal function, which are associated with major morbidity and mortality among these patients . ThromboThe standard approach for prevention of CIN, which must be used in all patients treated with cisplatin is the administration of lower doses of that in combination with intravenous hydration prior and after chemotherapy administration. Although, the doses of cisplatin are not lowered in the treatment of malignancies such as small cell lung cancer and testicular germ cell tumors. The lower doses of cisplatin in conjunction with newer chemotherapy agents have been developed for palliative settings such as non-small cell lung cancer. Chemotherapy regimens with the lower doses of cisplatin have minimized the incidence of nephrotoxicity without lowering the therapeutic efficacy of cisplatin .2, received a solution consisting of 1000 ml of isotonic saline plus 20 mEq of potassium chloride (KCL) and 2 grams of magnesium sulfate (MgSo4). They administered a minimum of 1000 ml of this solution over 2 to 3 hours prior and a minimum of 500 ml over the 2 hours after the cisplatin injection. The prescribed dose of the solution was to establish a urine flow of at least 100 cc/hour for two hours before and after chemotherapy. According to the results of this study, the amount of ARF incidence resulting from this drug in patients, who were hydrated with the mentioned protocol was 6.6% which is significantly less than the reported prevalence of this side-effect in patients, who are not hydrated  have been completely observed by the authors.None.


The symbiotic co-habitation of bacteria in the host colon is mutually beneficial to both partners. While the host provides the place and food for the bacteria to colonize and live, the bacteria in turn help the host in energy and nutritional homeostasis, development and maturation of the mucosal immune system, and protection against inflammation and carcinogenesis. In this review, we highlight the molecular mediators of the effective communication between the bacteria and the host, focusing on selective metabolites from the bacteria that serve as messengers to the host by acting through selective receptors in the host colon. These bacterial metabolites include the short-chain fatty acids acetate, propionate, and butyrate, the tryptophan degradation products indole-3-aldehyde, indole-3-acetic, acid and indole-3-propionic acid, and derivatives of endogenous bile acids. The targets for these bacterial products in the host include the cell-surface G-protein-coupled receptors GPR41, GPR43, and GPR109A and the nuclear receptors aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and farnesoid X receptor (FXR). The chemical communication between these bacterial metabolite messengers and the host targets collectively has the ability to impact metabolism, gene expression, and epigenetics in colonic epithelial cells as well as in mucosal immune cells. The end result, for the most part, is the maintenance of optimal colonic health. Over millions of years, humans have co-evolved with microorganisms through co-habitation. Adult human harbors microflora that is equal or even greater than their human cells in number ,2. TheseBecause of its close proximity to the bacteria, the colon is the most influenced organ as the result of this co-habitation. The presence of bacteria in the colon is absolutely necessary for optimal colonic health; normal bacteria in the colon offer protection against inflammation and cancer. As such, the beneficial effects of colonic bacteria are undeniable. Any imbalance in the normal density and phylogenetic composition in colonic bacteria, generally referred to as dysbiosis, is detrimental to colonic health ,16,17,18The relationship between the host and the microbiota could fall into three categories—parasitism, commensalism, and mutualism—depending on the specifics of the interaction. In parasitism, one of the co-habitants gets the benefits, while the other is harmed. In commensalism, one of the co-habitants reaps the benefits, while the co-habitation is neither beneficial nor harmful to the other partner. In mutualism, both partners get the benefits from the co-existence. The relationship between the host and the colonic bacteria falls under the third category, mutualism. The benefits to the bacteria as a result of this co-habitation include the availability of the colonic lumen for colonization and proliferation and provision of the nutrients by the host necessary for survival and growth. The host also benefits from the relationship ,26,27. CDysbiosis in the colon is a critical determinant in the pathogenesis of IBD. Research on colitis induction in germ-free mice with introduction of specific strains of bacteria has shown that microbial dysbiosis, rather than genetic factors, is the major factor for IBD pathogenesis. Many genetically-engineered mouse models that develop spontaneous colitis in the presence of bacteria in the colon are resistant to colitis when raised under germ-free conditions ,34. ThisThe communication between colonic bacteria and the host could be contact-dependent as well as contact-independent. The phylogenetic composition of the microflora in colonic lumen is not exactly the same as that of the microflora on the surface of the colonic epithelium. Which bacterial strains adhere to the colonic epithelial cells depends on multiple factors such as the presence or absence of cell-surface receptors for a given strain, ability of bacterial strains to traverse the thick mucin present on the luminal surface of the epithelial cell layer, as well as susceptibility of the bacterial strains to the bactericidal and bacteriostatic actions of the various molecules secreted by the epithelial cells and mucosal immune cells. The physical contact followed by insertion of specific bacterial proteins into the epithelial cell membrane could elicit signaling changes in the epithelium as a means of communication. Another mode of communication, probably more prevalent than the former, is through metabolites released into the lumen from live bacteria or from dead bacterial cells. The colon provides a favorable environment for anaerobic microbial growth, resulting in fermentation by resident bacteria of dietary constituents that reach the colon. The microbiota population in the colon is highly variable depending on the intestinal physiology, substrate availability, oxygen tension, and pH . As a re+/SCFA− symport, and Na+/SCFA− symport [Among these bacterial metabolites responsible for communication between the bacteria and the host, short-chain fatty acids (SCFAs) have received the most attention ,43,44,45 symport ,47,48,49 symport ,51,52. T symport ,54,55,56As the cell-surface receptors for SCFAs are located on the lumen-facing apical membrane of colonic epithelial cells (see below), the luminal concentrations of these agonists are physiologically relevant. SCFAs are low-affinity agonists for these receptors, and the normal luminal concentrations of these bacterial metabolites are in the millimolar levels, sufficient to activate these receptors from the luminal side. However, some of the molecular targets for these metabolites are either inside the cells  or on the surface of the immune cells located in the lamina propria. Therefore, concentrations of these metabolites inside the colonic epithelial cells and in the lamina propria are relevant to impact these molecular targets. The intracellular target HDAC is inhibited by butyrate and propionate at low micromolar concentrations. There are effective transport systems for SCFAs in the apical membrane of colonic epithelial cells  , thus maLactate is another bacterial metabolite that is important to colonic health but has received much less attention than the SCFAs. Lactobacilli that generate lactate as a fermentation product form a significant constituent of normal bacterial flora in the colon. As such, in addition to the dietary sources of lactate from yogurt and other dairy products, bacterial metabolism constitutes an important source of lactate in the colonic lumen ,59.Bacterial metabolites arising from protein catabolism are receiving increasing attention in recent years, particularly the metabolites resulting from tryptophan degradation ,61. This+-coupled SCFA transporter SMCT1 (SLC5A8) in the colon [Even though the beneficial effects of colonic bacteria and their metabolites on the host have been recognized for a long time, it was not until recently that we began to understand the molecular mechanisms that underlie this important biological phenomenon. This was true even in the case of SCFAs for which there is a long history of investigations focusing on the role of these bacterial metabolites as the molecular link between colonic bacteria and the host. Inhibition of histone deacetylases (HDACs) by the SCFA butyrate is an exception; HDAC is probably the first molecular target discovered for bacterial metabolites in the colon to provide a mechanistic insight into the communication between colonic bacteria and the host . HDACs ahe colon . HDACs bIn the past decade, we have witnessed a burgeoning of literature describing identification of new and novel molecular targets in the colon for bacterial metabolites ,51,60,61G-protein-coupled receptors are seven transmembrane domain–containing proteins involved in cellular signaling; most of them are expressed on the cell surface to interact with extracellular signals and transmit the signals into the cells via second messengers. The human genome encodes ~700 G-protein-coupled receptors. Even though physiological agonists have been identified for many of these receptors, a significant number of them still remain as orphan receptors with no information on the identity of their agonists. In the last decade, however, a distinct class of these “orphan” receptors has been found to be activated by normal physiological metabolites, which were never considered as signaling molecules; these include long-chain fatty acids, the ketone body β-hydroxybutyrate, the ubiquitous metabolite lactate, and the citric-acid-cycle intermediate succinate. Many of these metabolites are also found in the bacterial kingdom and hence are present in colonic lumen; consequently, if these receptors are expressed on the lumen-facing apical membrane of colonic epithelial cells, bacterial metabolites serve as the agonists for these receptors rather than the metabolites arising from the host metabolism. Examples of this category include GPR81, GPR91, GPR43, and GPR41 . In someEC50 value in low millimolar range) [GPR109A was originally identified as a high-affinity receptor for the B-complex vitamin niacin (nicotinic acid) ,88,89. Tr range) ,73. Acetr range) ,73. The Upon ligand binding, GPR109A couples through the Gi pathway in most tissues, resulting in decreased levels of cAMP inside the cells ,88. The GPR43 was discovered in a cluster of four novel GPRs located in close proximity to CD22 on human chromosome 19  and thenThe exact biological role of GPR43 under normal physiological conditions remains controversial with regard to whether the receptor suppresses or promotes inflammation and carcinogenesis in the colon. Several studies have demonstrated that the receptor plays a role in promoting inflammation and cancer ,97,98,99In contrast to GPR109A, which is expressed only in colonic epithelial cells, GPR43 is expressed in epithelial cells and in enteroendocrine cells, particularly L-cells ,104,105.GPR41 is also a receptor for SCFAs: all three SCFAs activate the receptor . HoweverGPR81 is a cell-surface, G-protein-coupled receptor for the ubiquitous metabolite lactate  whereas There are bacterial metabolites other than the SCFAs that are also important for the communication between the host and colonic bacteria and hence for optimal colonic health. These include tryptophan metabolites and bile acids . While tAhR is expressed in colonic epithelial cells and functions as a suppressor of inflammation and carcinogenesis ,108,109.PXR and FXR are also nuclear receptors and they are also activated by various xenobiotics. However, the endogenous agonists for these receptors are steroids and bile acids, respectively . The bacColonic bacteria generate tryptophan metabolites via protein metabolism. In contrast, the short-chain fatty acids are generated via fermentation of carbohydrates that reach the colon mostly in the form of dietary fiber. However, the quantity and quality of dietary fiber can potentially impact the generation of tryptophan metabolites because fiber as the source of carbon and energy is a major determinant of the composition of bacterial species in the colon. It has been documented that restriction of sugar in the diet promotes expansion of Lactobacilli species that possess enzymatic machinery to generate selective tryptophan metabolites to activate AhR and stimulate IL22 production . This cyThe symbiotic relationship between colonic bacteria and the host is undeniable, and this mutually beneficial coexistence is made possible through effective communication between the two partners in this co-habitation. The primary mode of this communication is chemical, mediated by specific bacterial metabolites that elicit their biological effects on the host by activating selective molecular targets in the host colon. Some of these molecular targets  are located on the lumen-facing apical membrane of colonic epithelial cells where they have direct access to bacterial metabolites generated in the lumen. Some are located intracellularly , and there is evidence that the bacterial metabolites generated in the lumen enter the colonic epithelial cells, many of them via selective transporters expressed in the apical membrane of these cells. Mucosal immune cells present in the lamina propria also express the same molecular targets as in colonic epithelial cells for these bacterial metabolites, but it is questionable if all of these metabolites reach lamina propria at concentrations sufficient to act on these targets in immune cells. This question seems particularly appropriate for SCFAs because these metabolites are actively metabolized in colonic epithelial cells. This might not be an issue for tryptophan metabolites. Taken collectively, there is an overwhelming evidence for active dialogue between colonic bacteria and the host with selective bacterial metabolites functioning as messengers. The end result of this chemical communication is the tolerance of colonic bacteria by the host immune system, which is obligatory for the symbiosis. A beneficial byproduct of this co-habitation and symbiosis is the maintenance of optimal colonic health with a decreased risk of colonic inflammation and carcinogenesis.


Editorial on the Research TopicNeuropeptides and Behavior: From Motivation to PsychopathologyThe discovery of the involvement of neuropeptides with behaviors other than regulatory motivated ones took place in the mid-1960s with David de Wied’s first report on the influence of stress hormones, such as ACTH and arginine vasopressin (AVP) infused intra-cerebroventricularly, on memory , oxytocin (OT), corticotropin-releasing hormone/factor (CRH/CRF), orexin, melanin-concentrating hormone (MCH), prolactin, and opioids have been associated with depression, anxiety, drug addiction, eating, and social disorders.Pomrenze and colleagues used a transgenic rat that expresses CRH immunoreactive neurons, and they were able to show that this rat is a useful tool to study CRH projections, mainly from the central nucleus of the amygdala and the bed nucleus of the stria terminalis. CRH is the primary mediator of the hypothalamic–pituitary–adrenal axis stress response, subjected to plasticity and adaptations in cases of chronic stress exposure. Herman and Tasker presented a review of the mechanisms involved in the adaptations of the stress response at the level of the paraventricular nucleus of the hypothalamus, including the enhancement of CRH and AVP production, reduced glucocorticoid negative feedback activity, and increased excitatory neurotransmission at the CRH neurons. These converging alterations lead to increased CRH activity, characteristic of a number of stress-related psychiatric disorders.Quadros and colleagues presented a comprehensive review on the role of CRF and urocortin systems (and their related elements), in alcohol-induced escalated aggression, and in the transition from alcohol use to dependence, due to the direct modulation of CRF on the brain reward system.In recent years, dysregulation of extra-hypothalamic CRF systems has gained attention in the context of alcohol use disorders. Kawakami and co-workers showed that expression of behavioral sensitization can be blocked by naltrexone, an antagonist of the μ and, to a lesser extent, of the κ opioid receptors, in a sex-dependent manner, with greater efficiency in males than in females.In mice, chronic administration of low doses of ethanol produce a stimulatory action, inducing a phenomenon known as behavioral sensitization, which reflects neurobiological modifications in the reward system. Keil and colleagues explored the involvement of the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway in anxiety and depressive disorders, by means of amygdala hyperactivation induced by stressful conditions. PKA is involved in the regulation of a myriad of intracellular signals triggered by distinct neurotransmitter systems related to alertness, mood, and acute and social anxiety. This mechanism of plasticity could be important for the proposition of new therapeutic strategies for conditions that afflict the human population.Machado and Suchecki reviewed the neuropeptidergic and hormonal mechanisms involved in sleep induced by stressful situations. In Wellman and coworker’s original article, escapable shock, a model of controllable stress, increased REM sleep, whereas inescapable shock reduces this sleep stage. CRF blocked this positive response to controllable stress, whereas astressin, a CRF receptor 1 antagonist, restored sleep to control levels.Stress recruits numerous neuromodulators and neuropeptides that provide optimal coping conditions and adaptive responses. One such response is increased sleep time, especially of REM sleep, after a stressful event. Torterolo and colleagues’ review with special emphasis on recent electrophysiological recordings and optogenetic stimulation. The authors argued that the greatest firing rate of MCHergic neurons occurred during REM sleep and remote stimulation of those neurons induced sleep. The authors also focused on MCH projections to the dorsal raphe nucleus and the potential role of MCH in the pathophysiology of depression.Melanin-concentrating hormone was the focus of Thorsell and Mathé presented an overview of NPY action on anxiety and stress response, and potentially post-traumatic stress disorder and depression. The authors discussed genetic and epigenetic findings of importance for NPY function and regulation and proposed that the modulation of NPY-ergic activity within the brain constitute potential targets for intervention in affective and alcohol use disorders.Neuropeptide Y and its receptors have a key role in central control of energy homeostasis, sleep, circadian rhythm, memory, and neuronal plasticity. Torner highlighted the role of PRL in neurogenesis and stress responses in the male brain. The author showed strong argument supporting the hypothesis that alterations in the PRL system due to stress or exposure to substances or other conditions that reduce neurogenesis may contribute to maladaptive responses and pathological behavioral outcomes. The author discussed the effects of PRL on neurogenesis and neuroprotection and their potential contribution to the onset of psychopathological states such as depression.Circulating hormones are also key players in motivation and behavioral adaptations. Among the most versatile of them is prolactin (PRL). Acevedo-Rodriguez and colleagues presented data showing that steroid hormones differentially modulated stress responses and altered OT receptor expression. The authors emphasized the role of estrogen receptor β activation and suggested a role for OT in this estrogen receptor β-mediated anxiolytic effect.Oxytocin is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons are part of the magnocellular neurosecretory system, releasing OT into the posterior pituitary to promote labor and lactation. However, OT neurons also project to other brain sites and regulate homeostatic processes, social recognition, and fear conditioning. OT also decreases neuroendocrine stress signaling pathway, anxiety, and depression-like behaviors. Cabral and colleagues focused on the importance of mechanisms associated with the permeability of the blood brain barrier (BBB) and the interplay among delicate anatomical interfaces that have the potential to alter physiology and behavior. Authors used ghrelin, a hormone produced by the stomach with important role in energy homeostasis and motivated behaviors. Ghrelin receptors are widespread in the brain, but the accessibility of the hormone is strikingly low. This neuroendocrine issue is discussed in light of the dynamic control of the BBB.The function of neuropeptides and hormones is modulated by neuronal plasticity, synaptic strength, and morphological changes. Woelfle and colleagues discussed the effect of TCAP  and the LPHN ligand–receptor system in anxiety, stress, and mood disorders. The teneurin TCAP protein binds and activates the LPHNs, a family of adhesion-associated GPCRs, to regulate numerous neurological and physiological activities. The long-lasting effect of exogenous TCAP and the current molecular model of ligand–receptor interaction suggest a role in neuronal plasticity and behavioral modulation.Another aspect discussed in this issue is the crucial role of synaptic strength and interaction in physiology and behavior. Understanding the interplay between neuropeptides and hormones in the control of motivation and behavioral responses is highly relevant for human’s physical and mental health. Clearly, research in this field is advancing at a rapid pace. The articles in this eBook highlight novel findings and unanswered questions for future investigation.DS and CE participated as editor of 5 papers, each, of the 13 published in this Research Topic. They jointly wrote the present editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Much attention has focused on the immune recovery of donor T cells following hematopoietic stem cell transplantation (HSCT). Termed immune reconstitution, a better understanding of the dynamics of the functional recovery of immune cells following HSCT has important implications both for fighting infections and, in the allogeneic setting, for providing antitumor activity while controlling graft-vs.-host disease (GVHD). The immune cells involved in immune reconstitution include antigen-presenting cells, B lymphocytes, natural killer cells, and, in particular, T lymphocytes, the immune cell that will be the subject of this review. In addition, T cells can play an important role in the process of engraftment of hematopoietic stem cells. The evidence for a T cell tropic effect on hematopoietic engraftment is both direct and indirect, and comes from the clinic as well as the research lab. Animal models have provided useful clues, but the molecular mechanisms that govern the interaction between donor stem cells, donor T cells, the host immune system, and the stem cell niche remain obscure. This review will describe the current published clinical and basic evidence related to T cells and stem cell engraftment, and will identify future directions for translational research in this area.