These adipose stromal cells (ASC) have been differentiated in a number of laboratories to osteogenic, myogenic, vascular, and adipocytic cell phenotypes. In vivo, ASC have been shown to have functional and phenotypic overlap with pericytes lining microvessels in adipose tissues. Furthermore, these cells either in paracrine mode or physical proximity with endothelial cells, promoted angiogenesis, improved ischemia–reperfusion, protected from myocardial infarction, and were neuroprotective. Owing to the easy isolation procedure and abundant supply, fat-derived ASC are a more preferred source of autologous mesenchymal cells compared to bone marrow MSC. In this review, we present evidence that these readily available ASC from minimally invasive liposuction will facilitate translation of ASC research into patients with retinal diseases in the near future.Retinopathies in human and animal models have shown to occur through loss of pericytes resulting in edema formation, excessive immature retinal angiogenesis, and neuronal apoptosis eventually leading to blindness. In recent years, the concept of regenerating terminally differentiated organs with a cell-based therapy has evolved. The cells used in these approaches are diverse and include tissue-specific endogenous stem cells, endothelial progenitor (EPC), embryonic stem cells, induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC). Recently, MSC derived from the stromal fraction of adipose tissue have been shown to possess pluripotent differentiation potential  Diabetic retinopathy (DR) is the most common vascular complication in patients with long-standing diabetes, and is the leading cause of blindness in working-age adults. The estimated prevalence in USA is 5.4% (~7 million) . Future Diabetic retinopathy develops as sustained metabolic dysregulation and inflicts progressive damage to the retinal microvasculature, increasing vascular permeability, and, in advance stages, leads to the aberrant proliferation of vascular endothelial cells . As the − hematopoietic stem cells (HSCs) from bone marrow injected directly into the mouse eye targeted activated astrocytes, and participate in normal developmental angiogenesis in neonatal mice or injury-induced neovascularization in the adult (hi cells via a HIF1α-mediated mechanism suggested to play a role in oxygen-induced retinopathy model (OIR)  . In contel (OIR) . Along tel (OIR) . Alternael (OIR)  have beeel (OIR) . Diabeteel (OIR) , 20–28, el (OIR) , 30. Theironment .in vitro and in vivo  that have been obtained from bone marrow, peripheral blood, cord blood as well as stem cells derived from other sources such as adipose tissue is expected to have an impact on cell therapy in eye diseases. For example, adult bone marrow MSC positive for CD90 have been shown to partially differentiate into photoreceptors  in vivo  and loca in vivo . Recentl in vivo . Differe in vivo . In sodi in vivo .in vivo by cooperation of ASC with endothelial cells . In particular, ASC are currently being investigated in clinical trials in several fields  and the emerging results of these trials will provide a great deal of data concerning the safety of ASC use  and bone marrow-derived CD34+ cells . While MSC are not a preferred choice as of today, early 2012, FDA approved a first of its kind clinical trial  cells in patients with advanced dry AMD; NCT01344993) for the use of embryonic stem cells (ES) for the treatment of AMD, an age-related retinal disease with loss of central vision. It was reported that two patients who received stem cells showed improvement in their vision and it is encouraging that during the observation period of 4 months neither patient lost vision  and one  ASC use . Unlike There are multiple challenges for cell therapies with MSC in DR.(1)Pericytes are mesenchymal in origin and express multiple cell surface markers  depending upon the tissue or the subpopulation derived from the tissues. This brings enormous heterogeneity in MSC, which may contribute to different outcomes in DR.(2)The heterogeneity in MSC may mandate us to purify and enrich a subpopulation to define differentiation with specificity to pericyte. Emerging data from pericyte progenitors from MSC engraft preferentially at perivascular location , 64. Fur(3)Route of injection may be of concern. In line with other cell therapies approved for DR, we chose to do intravitreal injections of ASC as it benefits from direct delivery of these cells into the eye close to the damaged retinal vasculature. Furthermore, unlike for endothelial progenitor cells, pericytes from abluminal side may yield quick results. However, we would need to evaluate the relative merit of intravenous, intraorbital, or sub-retinal injection of MSC in future studies as these routes are routinely used in clinical ophthalmology.(4)Well-characterized vasoregenerative cells that are ready for clinical application for human use is necessary. This may include a combination of MSC and CD34+ cells or other endothelial progenitor cells as one cell type alone may not help develop patented vessels. To this end, we have recently shown that ASC markedly enhanced retinal endothelial cell survival under hyperglycemic conditions; and in contact co-cultures, ASC formed robust vascular networks with retinal endothelial cells, much as with cord blood endothelial cells , 47. Eme(5)One of the challenges for MSC transplantation therapy for DR is the secretion of angiogenic growth factors produced by ASC, such as VEGF and HGF , which m(6)Another general challenge of stem cell-based treatments is the relative rudimentary characterization of derived cells. Most studies rely on a rather limited survey of extracellular markers rather than functional evaluation of the derived cells.Mesenchymal cells in particular ASC are preferred choices of cell therapy in ischemic and diabetic diseases. The ready availability of large numbers of autologous cells with the capabilities of facilitating repair of vascular and neurogenic tissues would be highly significant clinically for patients with retinal diseases such as AMD, DR, and retinitis pigmentosa. The resulting therapies would involve a minimally invasive procedure such as liposuction to harvest adipose tissue, followed by any processing required to obtain an appropriately defined and functionally consistent population of cells with the desired characteristics. Because of the extremely large numbers of cells available from such harvests, this processing might simply include isolation/separation steps in the absence of any need for expansion; or conversely might include culturing in the presence of either specific media, growth factors, or even genetic material that preferentially activate/suppress specific signaling events involved in competing differentiation pathways for the purpose of directing subsequent cellular behavior. Studies undertaken in rodent models will help determine if stem cells isolated from the adipose tissue can be used as vehicles for long-term, sustained delivery of therapeutic agents to eye tissues, or replace the diseased tissue with stem cells that can take their function. By evaluating this approach in the rodent model, we will be in a better position to determine whether such an approach should be tested in humans with a variety of retinal diseases.The Guest Associate Editor Ashay Dilip Bhatwadekar declares that, despite being affiliated to the same institution as author Gangaraju Rajashekhar, the review process was handled objectively and no conflict of interest exists. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Traumatic brain injury (TBI), defined as an alteration in brain functions caused by an external force, is responsible for high morbidity and mortality around the world. It is important to identify and treat TBI victims as early as possible. Tracking and monitoring TBI with neuroimaging technologies, including functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and high definition fiber tracking (HDFT) show increasing sensitivity and specificity. Classical electrophysiological monitoring, together with newly established brain-on-chip, cerebral microdialysis techniques, both benefit TBI. First generation molecular biomarkers, based on genomic and proteomic changes following TBI, have proven effective and economical. It is conceivable that TBI-specific biomarkers will be developed with the combination of systems biology and bioinformation strategies. Advances in treatment of TBI include stem cell-based and nanotechnology-based therapy, physical and pharmaceutical interventions and also new use in TBI for approved drugs which all present favorable promise in preventing and reversing TBI. Traumatic brain injury (TBI) is characterized as “an alteration in brain function, or other evidence of brain pathology, caused by an external force”  and is pIt wasn’t until 1976 that Graham Teasdale and Bryan J. Jennett came up with a method to objectively diagnose unconsciousness, as TBI may be associated with loss of consciousness. They established the Glasgow Coma Scale (GCS) . With thMild, moderate and severe TBIs are classified according to GCS scores of 13–15, 9–12, and 3–8, respectively. Severe injury causes not only permanent neurological deficits (20% of adults) but it has been shown that up to 14% remain in a vegetative state and 20%–40% of patients end up dying as a result of brain injury or secondary complications .etc. is more feasible and effective in diagnosis, prognosis and treatment guidance of TBI. At the genomic and proteomic levels, modern bioinformation helps to explore more specific and sensitive TBI-restricted biomarkers for early diagnosis and long-term prognostication. Multimodal neuromonitoring technology has been shown to play an important role in treatment of TBI, preventing secondary brain injury and promoting better patient outcome. Here we shall introduce the traditional monitoring methods including electrophysiologic monitoring, brain oxygen monitoring, intracranial pressure (ICP) monitoring, cerebral microdialysis and experimental brain-on-chip technology.Conventional neuroimaging methods, like CT and MRI, show advantages in detecting secondary injuries. However, newly developed structural and functional neuroimaging techniques such as diffusion-tensor-imaging, magnetoencephalography and single-photon-emission-computed-tomography improve accuracy and timeliness of diagnosis and prognosis in TBI. We will introduce and compare the most current methods used in clinical settings. Compared to advanced neuroimaging technologies, detecting molecular biomarkers in biofluid like blood, cerebrospinal fluid, urine, saliva, For the treatment of TBI, we shall focus on updated information about stem-cell based and nanotechnology-based therapies like perfluoro-carbons and polyethylene-glycol-functionalized hydrophilic-carbon-clusters and also cover the physical and pharmaceutical interventions like hypothermia and hyperbaric oxygen preconditioning. New uses in TBI treatment for approved drugs like progesterone and lithium are also discussed.Advances in technology include but are not limited to: single-nucleotide polymorphisms, global gene expression approach, microarray techniques, mass spectrometry, wide genomic, transcriptomic, proteomic and epigenomic profiling approaches, gene interaction hierarchy, and Ingenuity Pathway Analysis program. Through these technologies, a substantial amount of genetic factors have proven to be implicated in the pathogenesis of brain trauma. Evaluating the influence of polymorphisms on TBI helps to better understand the individual variations in outcomes, aids in the triaging and management of TBI patients, and ultimately contributes to genetic profile-based personalized interventions .Clinical outcomes following TBI are determined by both multiple genetic elements and acquired environmental risk factors. TBI triggers a series of pathophysiological processes including neuroinflammation, oxidative stress, excitotoxicity, apoptotic cell death, neurodegeneration, reparative processes, synaptic plasticity, and neurotransmitter alterations ,8. AdditO-methyltransferase (COMT), BCL-2, neuroglobin (NGB) and IL-1β [Genetic association studies are useful tools in investigating possible relationships between gene polymorphisms and disease outcome. With the microarray techniques, Michael and colleagues  detectednd IL-1β . Geneticnd IL-1β .Previous studies investigated genetic variants involved in various molecular pathways initiated after TBI, including oxidative stress, neuroinflammation, excitotoxicity, apoptotic cell death, neurodegeneration, reparative processes, synaptic plasticity, and neurotransmitter alterations ,8,9. GivGene expression and epigenetic-epigenomic approaches studies have been conducted on nonhuman TBI models to understand the pathophysiology and recovery process after TBI. With a global gene expression approach, Di Pietro and colleagues found that gene expression regulation in rat hippocampus was determined by the severity of injury, and the associated pathways that were altered the most were those involved in inflammation, immunity, and neurodegeneration . A candiBioinformatic analysis tools allow for both identification of key molecules and elucidation of their interactions. It made the utilization of microarray data more practical and easily replicable. Based on a database built from published scientific literature, Ingenuity Pathway Analysis (IPA) software is designed to depict direct and indirect gene interactions and to assign genes to specific biological functions and canonical pathways . When comiRNAs are small RNA (~22 nts) molecules that are expressed intrinsically and play an key role in regulating gene expression. miRNAs have proven to be important mediators of the massive molecular and cellular changes that occur in both short and long-term periods post TBI. In a study of rodent TBI models, deep sequencing identified eight upregulated and thirteen downregulated miRNAs at 24 h post-injury, whereas three were upregulated and thirteen downregulated at day 7 post-injury . MicroarMechanical force is one of important determinants in TBI, and Weber and colleagues proposed how mechanical shear stresses could modulate vascular homeostasis through microRNA regulation of target molecules, like phosphatase and tensin homologprotein (PTEN) . They coTBI accounts for one third of all injury-related deaths . SeventyAs discussed above, miRNAs expression pattern altered significantly in response to TBI, and miRNAs play key roles in signal transduction, transcriptional regulation, mechanotransduction, proliferation, and differentiation initiated by TBI. These altered miRNAs thus seem to be good candidate biomarkers for TBI. Redell and colleagues compared the plasma miRNA profiles between severe TBI patients  and healthy volunteers. They concluded that decreases in the levels of miR-16 and miR-92a, and increased levels of miR-765, were good markers of severe TBI at 25–48 h after injury . A simplStudies of CSF from TBI rats found a significant increase in levels of miR-let-7i as early as 3 h post-injury . PredictIn addition, miRNA levels also change following TBI treatment, suggesting the use of miRNA as a prognostic biomarker. As will be discussed in the treatment section, hypothermia is one of the most promising treatments for TBI due to its ability to attenuate prolonged neurological deficits and improve functional outcomes ,32,33. IThe permeability of the blood-brain-barrier (BBB) is increased following TBI and results in the exposure of brain-specific proteins  and their break down products (BDPs) to peripheral circulation immune system components, allowing the self antigen/immune cell interaction to activate the immune response post TBI. In the case of TBI, neuronal and glial cells at and around damage sites release brain-derived cell-type-specific proteins into the peripheral blood stream, leading to a subsequent increase in the formation of autoantibodies against these cells . SeveralThe presence of these autoantibodies may represent putative long-term biomarkers possibly correlated to injury severity as well disease prognostic indicators that may be the center for potential neurotherapeutic targets see . It is cetc. related reviews are recommended [Clinical proteomics aim to identify suitable biomarkers for diagnosis or prognosis of a disease. The current available protein and gene biomarkers are regarded as early generation biomarkers and in some regards show low specificities and sensitivities. These early generation biomarkers, however, are well studied and some of them have already been applied in clinical practice. We will give a brief overview on them. Representative biomarkers are derived from acute neuronal, axonal, astroglial and endothelial injuries or secondary inflammatory and reparative processes such as inflammation, oxidative stress, excitotoxicity, and other host-derived pathophysiological mechanisms . In partommended .Though numerous candidate biomarkers have proven a positive association with TBI outcome, they showed low specificity or sensitivity when used individually. Combining biomarkers into a panel may provide more information than individual biomarkers . In a stThe progressive increase in TBI brings with it more variable and complex long-term neurological disorders. The heterogenetic and multifactorial nature of secondary responses in TBI make it difficult to find cellular biomarkers for diagnosis, prognosis and management of TBI. It is imperative to find more accurate TBI-specific markers to take the place of CNS-restricted markers. Systems biology strategies can be applied to probe and analyze the crosstalk between different molecular signaling pathways that regulate the secondary cellular response through computational models, which integrate the diverse data sets. Feala and colleagues described opportunities for applying this methodology to existing TBI data sets to identify new biomarker candidates and gain insights about the underlying molecular mechanisms of TBI response. For instance, they manually compiled a list of 32 protein biomarker candidates from the literature, and then applied network and pathway analysis to recover known TBI-associated mechanisms and produce new hypothetical biomarker candidates. The combination of neuroproteomics with systems biology and other molecular biology techniques will be ideal tools for discovering well-validated TBI-specific biomarkers .Although great progress has been made with the aid of advanced technologies, the need for transitioning from research-based experimental screening with mass spectrometry to fast and reliable diagnostic instrumentation is imperative for the use of biomarkers in the clinical setting.The essential aims of neuroimaging after TBI are to assist in prevention of secondary damage, to emphasize favorable biomarkers with potential for neurodegenerative disease detection, and to obtain prognostic information about long-term outcome. Neuroimaging methods such as computerized tomography (CT) and magnetic resonance imaging (MRI) which are identified as conventional neuroimaging techniques and are generally used for the initial clinical evaluation and acute vital management of intracranial problems following TBI . CT is gDiffuse axonal injury (DAI) determines long-term cognitive and neuropsychiatric outcomes following mild TBI, both hemorrhagic and non-hemorrhagic. Shearing axonal lesions are located in the major white matter tracts, spreading from the surface to deeper structures ; howeverAdvanced structural neuroimaging techniques are susceptibility-weighted-imaging (SWI), diffusion-weighted-imaging (DWI), diffusion-tensor-imaging (DTI) and high-definition-fiber-tractography (HDFT). Advanced functional neuroimaging methods include MR spectroscopy, functional MR imaging, SPECT and magnetoencephalography .American Journal of Radiology in 2015 concurred that advanced neuroimaging techniques show promising results in group comparison analyses; however, there is still lack of evidence supporting the routine clinical use of advanced neuroimaging for diagnosis and/or prognostication at the individual patient level [These techniques are beneficial for finding abnormalities in the brain related to long-term traumatic sequelae and the focus of ongoing research is to identify structural and functional correlations while analyzing fiber tracts . The Ament level .Listed below  are the Susceptibility-Weighted Imaging (SWI) combines both magnitude and phase data to increase the contrast between hemorrhage-related blood products and the surrounding brain parenchyma, thereby allowing usefulness in detection of small amounts of altered blood and blood products on neuroimaging . GlushakA study by Ryan and colleagues aimed to investigate the utility of SWI as a biomarker for prediction of outcome and recovery of social cognition after pediatric TBI, and concluded that SWI in the acute phase of injury may be a useful indicator of not just the severity of brain injury, but may also assist clinicians to identify children at elevated risk for poor social cognitive function in the post-acute recovery period .Shaken baby syndrome, now called abusive head trauma  have greEarlier studies that used MRI imaging to detect traumatic microbleeding failed to demonstrate correlation with functional outcomes . SWI enaWang Xuan and colleagues studied SWI combined with conventional MRI and CT images to prospectively analyze mild TBI patients 1 year post TBI. Their results showed SWI detected microbleeds that went undetected on conventional MRI and CT images. Microbleed lesions detected by SWI on the frontal, parietal, and temporal lobes may correlate with higher incidence of depression after TBI .Diffusion-Weighted Imaging (DWI) with its known functions such as measuring patterns of water diffusion based on surrounding temperature, structures, and tissue damage . Areas wReduced ADC values in the corticospinal tracts and corpus callosum have also been observed in concussed athletes compared to controls. Galloway and colleagues attempted to predict TBI outcomes using DWI and reported that apparent diffusion coefficient values of both specific regions and the entire brain could be used as an outcome predictor in pediatric cases of severe TBI . Hudak aIn the early stages of TBI, diffusion of water molecules can be affected by axotomy and myelin degradation associated not only with increased ADC values but also post-traumatic cytotoxic edema with reduced ADC values ,89. The The fact that ADC values are high in the subacute phase indicates a massive increase in the extracellular water content of the tissue, reflecting the progressive loss of proteins in the extracellular matrix combined with cellular degeneration and increased diffusion of water molecules ,92. HåbeDiffusion imaging methods have clinically influenced the improvement of TBI as a result of their ability to detect the effects of injury upon white matter structural integrity . DiffusiHberg and colleagues in 2014 conducted a detailed clinical research study with 78 healthy and 73 chronic TBI patients. He outlined not only injury mechanisms, but also neuroimaging and clinical measures from the acute and early phases after injury and its impact on white matter FA, MD, and tract volumes in the chronic phase of TBI, and how white matter integrity in the chronic phase is associated with different outcome measures. They concluded that FA was the primary determinant of injury severity and mechanism, and diffuse axonal injury of any grade led to lower FA in the thalamus and brainstem. Minor effects on MD were observed in severe TBI associated with low cerebral perfusion pressure (below 70 mmHg).Studies have shown FA several standard deviations below a control group average reflects the number of regions with “abnormally” low white matter integrity, and correlates with measures of trauma severity and cognitive dysfunction . A numbeFA has been proposed as the most feasible biomarker of traumatic axonal injury and one of the best indicators of TBI severity. The most powerful applications of DTI techniques involves the specific analysis of particular regions of interest which are selected based on known or suspected tendency to demonstrate a particular pathological state . In addiHigh Definition Fiber Tractography (HDFT), tracks fibers from the cortex to subcortical targets with high resolution . It alsoHDFT applies diffusion spectrum imaging, which has a high angular resolution than release tractography to navigate complex fiber crossings. Thus, HDFT provides high-resolution details of axonal pathways and projection fields that allow exposure of specific location and degree of damage . Shin anFunctional MRI (fMRI) assesses brain function based on relations between neuronal activity and the resultant hemodynamic responses described as neurovascular coupling ,117. fMRvs. post-injury design in athletes. Their results indicated that prolonged exposure to sub-concussive hits resulted in hypoactivation within the left middle and superior temporal gyri, left middle occipital gyrus, and bilateral cerebellum during a working memory task, which correlated with decreased working memory performance in the non-concussed high school football players [fMRI is usually performed while the patient completes a neurocognitive task, placing an increased demand on the brain, thus showing differences in local perfusion in real time. Abnormal brain activation patterns detected by fMRI correlate with a broad range of neurocognitive and functional deficits in patients with prior traumatic coma, including memory impairment and motor dysfunction . In a co players .Resting-state fMRI (RS-fMRI), a recent form of fMRI, is based on the analysis of spontaneous low-frequency fluctuations in the BOLD signal in the absence of any external task. Thereby, it focuses on functionally related brain regions at rest . One of Nathan and colleagues designed a descriptive study that aimed to understand how functional connectivity of the resting state DMN varies between healthy controls and mTBI subjects differs. They reported that mTBI patients had a decrease in DMN connectivity within regions of the left inferior temporal lobe, right precentral gyrus, and left caudate nucleus. They also demonstrated significant correlations between a variety of neuropsychological test measures and data from DMN connectivity maps of TBI subjects in cerebellar and cortical regions. Their results show the ability to correlate markers of emotional response within the cerebellum. fMRI is sensitive to changes in neural function following TBI and is an effective technique for understanding the neural basis of cognitive-behavioral dysfunction and investigating recovery of function .Magnetoencephalography (MEG) detects magnetic fields generated by currents flowing in neurons through a group of sensors surrounding the head ,130. AbnHuang and colleagues detected sensitivity of MEG for analyzing resting-state MEG data and found abnormal delta-waves in 84.5% for all mild and symptomatic TBI patients . MultiplThe role of MEG in diagnosis and prognosis is still limited because of the variety of incomparable approaches and absence of standard protocols for MEG analysis. MEG applications require improvements before becoming clinically relevant. More studies are needed to examine the utility of MEG as a prognostic and predictive neuroimaging method for TBI.Magnetic Resonance Spectroscopy (MRS), a molecular-based neuroimaging technique that reflects intracellular metabolic status as evidence of microscopic injury . Common Metabolites such as lactate (Lac) (generated as a result of anaerobic glycolysis) and glutamate (excitatory amino transmitter) might suggest evidence of energy dysfunction, membrane turnover, and inflammation as a result of injury . The relVarious studies indicate that NAA levels and NAA/creatinine ratios are reduced in TBI as a result of neuronal loss and/or dysfunction. Reduced NAA levels are predictive of long-term functional outcomes in TBI. Twelve athletes who had sustained sports-related concussions were compared with healthy controls within 6 days of injury. The NAA/Cr levels were significantly reduced in the primary motor cortex and, to a lesser extent, in the dorsolateral prefrontal cortex when compared to healthy controls . Sports-Govind and colleagues conducted a study during the subacute period following TBI. They studied not only the associations of metabolite indices with neuropsychological test results, but also differences in metabolite ratio distributions. Hemispheric lobes and tissue types were evaluated relative to those of age-matched controls. Significant metabolite alterations were present in locations remote from, or in the absence of any MRI-observed traumatic lesions, and significant correlations were found between metabolite measures .Brain perfusion single-photon emission computed tomography (SPECT) imaging is a functional nuclear imaging technique performed to assess regional cerebral perfusion by using 99 mTc ethyl cysteinate diethylester (ECD) as tracer .SPECT scans can display areas of impaired brain function following TBI including not only focal cerebral blood flow (CBF) reduction near the focal site of injury, but also asymmetrical hypoperfusion in the prefrontal, temporal, and parietal or occipital lobes. In addition, a decreased CBF in the anterior temporal poles was observed ,147. SPESome early studies compared the value of CBF SPECT imaging to anatomical findings on MRI or CT in TBI patients. Ichise and colleagues  conducteSPECT can detect brain activation changes during complex cognitive tasks in patients with chronic symptoms following TBI . HattoriDuring the last decades, multimodal neuromonitoring technology has made great progress. It has been shown to play an important role in treatment of TBI, preventing secondary brain injury and promoting better patient outcome.Continuous intracranial pressure (ICP) monitoring is widely used clinically after severe TBI. Although clinical studies in ICP monitoring overall showed controversial results, recent trials indicate lower mortality and better outcome in patients with monitored and controlled ICP. The Brain Trauma Foundation recommends with level II evidence to treat ICP above 20 mmHg ,160,161.Two established invasive methods are the application of an intraparenchymal microsensor and the intraventricular catheter. The intraventricular catheter is considered the gold standard, since it measures global ICP and allows drainage of cerebrospinal fluid as treatment or administration of drugs. Intraparenchymal ICP monitors, on the other hand, are frequently used as a first-line monitoring method and are considered to be safe and of equal accuracy to intraventricular measurements ,163,164.ICP is frequently used in TBI treatment to calculate the cerebral perfusion pressure (CPP) involving the patient’s mean arterial pressure. With level II and III evidence the Brain Trauma Foundation recommends to maintain a CPP threshold between 50 and 70 mmHg ,162. ICPThe future in monitoring seeks for noninvasive methods with equal accuracy as invasive techniques. Neuroimaging, as described in the previous section, can be considered as noninvasive single point of time of ICP evaluation. Recent studies showed possible ICP estimation by measuring the optic sheath diameter using ultrasound  or magneCerebral autoregulation stands for the regulation of the cerebral blood flow by dilation and constriction of cerebral arterioles in response to changes of cerebral perfusion pressure. In neurocritical patients a dysregulated autoregulation of pressure flow or reactivity has been linked to poor outcome. Developing the best correlating monitoring coefficient for tailored treatment and prognosis is a central research topic in TBI .Currently known indices using further monitoring methods with promising results are shown in In 2007, brain oxygen monitoring was added into the Brain Trauma Foundation guidelines with a level III evidence to treat brain tissue oxygen tension thresholds below 15 mmHg. In the past decade several studies showed a correlation between low brain oxygen levels and higher mortality rate and unfavorable outcome ,183. ComA non-invasive way to assess real-time regional cortical oxygenation is with NIRS (near-infrared spectroscopy). It is most frequently used in cardiovascular surgery to detect cerebral oxygenation changes during surgical cardiac arrest during cardiopulmonary bypass. NIRS is non-invasive, but has a number of limitations causing highly variable results and, therefore, is only used for restricted indications . Track cThe heterogeneous entity of TBI makes generalizable equations and overall studies difficult. Recently a new method for predictive analysis after TBI with symbolic regression modeling has been introduced. Symbolic regression was used as a computational framework to study the dynamic parameters of ICP, brain temperature and brain tissue oxygen to generate equations from real-time data. This may lead to development of dynamic smart monitoring devices that continuously collect data and redefine individual critical boundaries with constant improvement of accuracy .Electrophysiology is a well-established non-invasive diagnostic method for neurological monitoring, prognostic and follow-up evaluation and also for neuromodulatory therapy after TBI. In experimental settings it has been broadly used in models of neurological diseases and in cerebral hypoxia and cardiac arrest models ,192. In Especially in mild cases of TBI electrophysiology monitoring proved to be superior to standard clinical evaluations only in detecting cerebral dysfunction ,195. TheIt should be briefly mentioned at this point, that besides monitoring, EEG may play a role in treatment of brain injury. Young TBI-patients showed improvement in cognitive functions and concussion symptoms. Additionally, thalamo-cortical connection in follow-up MRI was increased after EEG neurofeedback therapy .Since the early 1990s, cerebral microdialysis has become an established neurochemical monitoring method to analyze low molecular weight biomarkers and to measure metabolic energy crisis or cellular distress in brain tissue after injury and ischemia ,200,201.Treatment of glucose levels measured by microdialysis is controversial. Available data demonstrate hyperglycemia is common in TBI patients and is related to poor outcome. However, current clinical trials have not proven any benefit of tight cerebral glucose controlled treatment. So far, monitoring of cerebral glucose has only proven to detect and predict infarction risk depending on the position of the microdialysis catheter . DespiteOne cornerstone in intracranial microdialysis research is focused on lactate and the lactate-pyruvate-ratio (LPR). Although lactate has been considered to be an excellent biomarker for oxygen deprivation, the mechanism of brain lactate metabolism and shuttling remains poorly understood in case of TBI . LactateIn stroke models, disruption of ion homeostasis especially in the neurogliovascular unit has shown to be pathophysiologically involved in development of cerebral edema and, therefore, increased morbidity and mortality after ischemia ,221,222.In an experimental TBI model to explore the cerebral ionic profile, microdialysis probes were inserted into matrices and perfused with mock cerebrospinal fluid. With this method the actual ionic concentration in the extracellular fluid may be calculated based on the concentration in the microdialysate . ElevateAiming for technical catheter improvement, a recent paper introduced a surface modified microdialysis catheter coated with PluronicF-127. This method have shown promising results in improving accuracy and precision of protein biomarker sampling in a porcine brain injury model .Overall microdialysis is a promising method to offer sampling and measuring metabolic mechanisms, tissue biomarkers and pharmacokinetics in almost any human tissue and organ ,228.A new innovative technology to monitor changes at the level of axonal and neuronal networks has been recently introduced. The brain-on-a-chip device is an experimental strain injury model that maintains three dimensional cell architecture. It has been used to visualize hippocampal axonal response and biochemical changes induced by diffuse axonal injury after TBI. Changes in the mitochondrial membrane potentials have shown to lead to axonal degeneration ,230.Stem cell-based therapy has been tested and has been well-documented for years in various disease models  and espe6.1.1. “Biobridges” Paved by Stem CellsTajiri and colleagues proposed a theory of stem cell-paved formation of “biobridges” in experimental models of TBI. Rats subjected to TBI were intracerebrally transplanted with SB623 . One month after TBI, they observed notable increases in endogenous cellular proliferation as well as immature neural differentiation in the peri-injured cortical areas and subventricular zone, along with a stream of migrating cells along the corpus callosum of SB623 transplanted TBI rats. Furthermore, at 3 months post-TBI, they observed enhanced cellular proliferation and neural differentiation in peri-injured cortical areas of SB623 transplanted TBI animals, accompanied by a solid stream of neuronally-labeled cells migrating not only along but also across the corpus callosum from the subventricular zone to the impacted cortex. TBI rats, which had not received mesenchymal stromal cells, exhibited, elevated cellular proliferation; however the newly formed cells were “trapped” within the subventricular zone (SVZ) and cerebral cortex and did not migrate to the impacted cerebral cortex. Likewise, these animals showed a 2 and 9-fold upregulation of the matrix metalloproteinase-9 (MMP) activity and expression, respectively, at 1 and 3 months post-TBI. MMP-9 was upregulated in the TBI group, but reverted back to sham levels at 3 months post-TBI. To provide further evidence that the implanted stromal cells facilitated the formation of the biobridge, Tajiri and colleagues used primary rat cortical cells grown both alone and co-cultured with stromal cells either in the presence or absence of the MMP-9 inhibitor and revealed, by using migratory cell assay, enhanced migration of primary rat cortical cells with stromal cells, while these were suppressed by treatment with the MMP-9 inhibitor .in vitro and in vivo experimental methods. MSCs were cocultured with human umbilical vascular endothelial cells. At 2 and 24 h after injury MSCs was administered intravenously and rats were sacrificed 3 days after TBI. These results showed that MSCs exert a potent stabilizing effect on human vascular endothelial cells by increasing VE-cadherin expression and enhanced VE-cadherin/β-catenin interaction. Consistent with this, intravenous administration of MSCs increased VE-cadherin levels in brain homogenates and decreased TBI-associated enhanced BBB permeability. In addition, Pati and colleagues examined the interaction between tissue inhibitor of matrix metalloproteinase-3 (TIMP3) and mesenchymal stem cells due to regulation of blood brain barrier integrity 24 and 72 h post TBI. Results showed knockdown of TIMP3 in MSCs fully abrogates the protective effects of these stem cells on BBB permeability after TBI by reducing occludin-1 and VE-cadherin expression in the penumbra. In addition, following intravenous recombinant TIMP3 (rTIMP3) application after TBI, BBB integrity was preserved by increasing the expression of Occludin-1 and VE-Cadherin [Disruption of the blood brain barrier and vascular neuronal network following TBI often leads to uncontrolled inflammation and tissue damage ,235. PatCadherin .TBI consists of a primary insult resulting from a mechanical force inflicted on the head, and is amplified by a secondary insult that increases reactive oxygen species (ROS) production, excitatory amino acid release, energy consumption, and disturbed calcium homeostasis . Li and in vitro, as well as increasing the expression of GFAP, a gene related to mature astrocytes, indicating that factors expressed by MSC could induce differentiation of NSC in vivo [Cellular injury following TBI is mostly related to an excessive inflammatory reaction near the injured area . Galinda in vivo . Zhang a in vivo .Bedii and colleagues performed an experiment to investigate the long-term effects of progenitor cells on microglia/macrophage phenotype and on the cognitive and motor functions of rodents after TBI. Each group was given two doses of its assigned multipotent adult progenitor cell therapy (MAPC) concentration at 2 and 24 h after controlled cortical impact (CCI) injury. They found improvements in average cognitive function as measured by Morris water maze (MWM) performance and motor function revealed by posture on the balance beam, and these were accompanied by localized reduction in numbers of activated microglia 120 days after injury. Both 24 to 120 h after TBI, MAPC treatment alters the ratio of proinflammatory microglia/macrophages to anti-inflammatory microglia/macrophages in dentate gyrus .Park Katya and colleagues designed a study of white matter protection and microvascular integrity of endothelial progenitor cells (EPC) after TBI . They exDue to current advances in nanotechnology, neuroscience research has initiated application of nanotechnology as novel bioengineering therapies for the treatment of nervous system injuries including TBI. Our discussion includes newly-developed nanomaterials instead of reviewing the well-studied nanomaterial like sealants, fusogens, chitosan and hydrophilic, nonionic polymers .2 and CO2 [PerfluoroCarbons are formed of carbon and fluorine and emulsions and can easily be dissolved in large quantities of gases, including O and CO2 . Previou and CO2 . Zhengwe and CO2 . The usein vitro [in vitro study to evaluate the characteristics of PEG-HCCs designed specifically to address cerebrovascular dysfunction that accompanies TBI. The authors concluded that PEG-HCCs maintain antioxidant capacity sufficient for biological relevancy and targeting oxidatively stressed brain endothelial cells. When targeting the brain, they preserve their ability to alleviate oxidative stress in cultured brain endothelial cells [PEG-HCCs are a class of biologically compatible carbon-based nanovectors which can be loaded with hydrophobic drugs, and when mixed with an antibody forms a noncovalent formulation capable of targeted drug delivery in vitro . Marcanoal cells .Cell membrane repair mechanisms, advances to crossing the blood brain barrier, drug delivery to the injured brain, and nanostructure scaffolds for neural tissue engineering will be deterministic in the use of nanotechnology interventions as a prospective TBI treatment strategy.Prophylactic interventions involving methods of preconditioning (PC) may help individuals at high risk for brain injury or as a preoperative treatment for brain surgery, reducing the impact of primary and secondary brain damage . For theHyperbaric oxygen therapy (HBOT) has been defined as a neurotherapeutic method for brain repair, providing oxygen-enriched air to patients in a closed chamber pressurized above one atmosphere absolute (1ATA). The combination of hyperoxia and hyperbaric pressure leads to significant improvements in tissue oxygenation as well as mitochondrial metabolism with anti-apoptotic and anti-inflammatory effects ,259,260.Wang and colleagues demonstrated that HBOT administered 2 days post injury resulted in significantly reduced overall neurological deficit scores and decreased neuronal apoptosis in brain tissues, and proposed the effective window for HBOT was 12 h post TBI . Harch aHarch and colleagues in 2010 reported dramatic improvement in a series of 15 patients treated with HBOT 1.5 in a clinical trial of military acquired TBI . MultiplDiscussions continue regarding the effectiveness of HBOT, but recent publications regarding the cognitive benefits of HBOT leave the medical community with an opportunity to pursue and conduct further research into its therapeutic benefits for the growing population of TBI.N-methyl-d-aspartate) is known as the main excitatory amino acid in the central nervous system and its activation is one of the mechanisms of brain damage after TBI. Glutamatergic excitotoxicity contributes to primary and secondary damage [Glutamate  include increased excitability, induction of mild oxidative stress, modulation of bioenergetics, ionic homeostasis and the modulation of glutamatergic transmission within non-excitotoxic levels. Although the neural mechanisms involved in NMDA preconditioning are not completely understood, literature has shown that there exists a time–dependent approach of NMDA-PC and that it is maintained up to 48 h after administration , showingAlterations in memory, cognitive, and mood impairments require a better understanding, and studies on the glutamatergic system are of paramount importance to clarify questions to reverse the pathologic cellular cascade underlying the progression of cell death. Prophylactic interventions involving PC may help individuals at high risk for brain injury or as a preoperative treatment for brain surgery . For theErythropoietin (EPO) is a 34-kDa glycoprotein hematopoietic growth factor belonging to the type I cytokine superfamily , with reThe effects of EPO on animal models proved to have positive effects on neuroprotection following TBI. EPO and analogs can reduce lesion volume and improve neurobehavioral outcomes in animal models of TBI. Due to recent clinical trials supporting the use of EPO associated with reduced mortality in trauma patients  and findClinical trials on the efficacy of EPO treatment in patients with TBI yield conflicting results, and without rigorous, fine-tuned, and detailed preclinical evaluation, it is unlikely that novel neuroprotective drugs will prove effective when tested in large, time-consuming, and expensive human clinical trials. Because of its promising results in preclinical studies, it is important to improve the methodological quality of pre-clinical studies in order to efficiently progress towards EPO treatment in humans.de novo or from precursors in the brain [Progesterone (PG) is a well-known hormone that functions primarily on the reproductive system. Recent decades have given new hope to its use besides its function as sex hormone. It has been found to act in several models of TBI, serving as a neuroprotector . Thus, ihe brain . This nehe brain .PG has been tried in clinical trials due to its pluripotential role after multiple animal studies supported its use in TBI. Phase II clinical trials have shown improvements in patients with TBI after treatment with PG including decreased mortality rate and increased functional independence scores when compared to placebo or healthy controls, respectively in moderate and severe TBI ,301. ProIn 2007, Wright and colleagues started ProTECT III, but found that after stratification of the patients based on severity of injury, no improvements in recovery were noted after giving progesterone or placebo to patients within four hours of injury, continuing treatment for 96 h, and the study was stopped . AnotherIn conjunction with this and other reports, the dynamics of TBI stretch beyond a monotherapeutic approach to target single receptors or specific mechanisms ,305, andRecently, the literature reveals more options in TBI treatment with the use of antioxidants in the clinical setting in the near future.2+-homeostasis and posttraumatic LP and calpain mediated cytoskeletal damage [The first antioxidant to mention is U-83836E a non-steroidal compound that functions as a lipopolysaccharide (LP) inhibitor and free radical destroyer. It not only decreases posttraumatic LP and preserves mitochondrial respiratory function, but also has calcium buffering capacities . Its capl damage . These aMelatonin has been well studied in the field of circadian rhythms and sleep; its functions in the brain also give it neuroprotectant qualities. It acts as both a direct scavenger of free radicals and an indirect regulator of endogenous enzyme expression . AdvantaTempol, a stable membrane permeable nitroxide, has a 1 h to several days treatment window to achieve mitochondrial protection  and locoResveratrol, known to be present in high amounts in red wine and grapes, has since early 2000 emerged as a potential antioxidant with neuroprotective effects. Resveratrol shows promising abilities as a neuroprotective agent in TBI models, possibly inhibiting lipid peroxidation ,319,320.Since 1943, inducing hypothermia as a treatment in which body temperature is kept at 32–34 °C has been applied in various brain injuries aiming to decrease brain metabolism and reduce neuronal swelling . InterveEven though the mechanisms responsible for the actions of hypothermia in the treatment of TBI remain to be elucidated, mild induced hypothermia seems to have an association with the expression connexin-43 and glutamate-transporter-1 in the hippocampus following TBI in rats. Mild hypothermia improved TBI induced brain edema and neurological functional deficits, and it is accompanied by down regulation in expression of connexin-43, normally increased after TBI, and upregulation of glutamate-transporter-1 levels that are normally decreased following TBI . In accoA review by Cochrane and colleagues concluded that there is no evidence that induced hypothermia is beneficial in the treatment of traumatic head injury . In addiThere are two large ongoing trials of long-term hypothermia for TBI. One is the Eurotherm 3235 trial in Europe . RewarmiCR8 is a CDK (cyclin-dependent kinase) inhibitor and second-generation analog with promising therapeutic potential . It has Cell cycle activators and their role in increased neurodegeneration and chronic neuroinflammation now face a strong opponent. CR8 is able to fight the pathophysiology of TBI, and combat the S-phase induction of cells that happens with CCA induced TBI as seen in the LFP model . In concStatins are 3-hydroxy-3-methylglutaryl coenzyme A (HMGA) reductase inhibitors, and not only act to reduce cholesterol, but influence both the acute and chronic phases of TBI ,359,360.Studies show improvements in behavior and histology with atorvastatin and simvastatin. Atorvastatin has a longer half-life and active metabolites for greater protection against neuronal death than simvastatin . DespiteAccording to studies done by Ramirez and colleagues 2011 simvastatin is the most effective statin. It has the power to decrease inflammation , increasin vitro experiments, but quantitative data shows that simvastatin significantly increased neuron populations. In addition, previous studies have shown that simvastatin inhibits the activation of microglial cells and astrocytes after TBI [Plausible explanations for neurologic recovery lies in the understanding that simvastatin may enhance proliferation and neurogenesis as shown in cultured neural cells, and is able to increase the expression of notch-1 proteins, demonstrated in chronic simvastatin treatment . In addifter TBI .Currently, atorvastatin is undergoing a phase II clinical trial with a 7-day regimen in order to help fill in the gaps regarding efficacy of treatment in the months following TBI. Though the effects of chronic administration of statins are still unknown in the literature, its ability to decrease neuronal cell loss and control inflammation are favorable and offer a novel therapeutic strategy for acute TBI after closed head injury.Neuroinflammation is one of the major causes for increased neuropathology and neurobehavioral changes after single or repeated exposures to blast activity ,372,373.Neuroprotective in nature, and acting across multiple pathways, lithium serves as a potential therapeutic agent for treatment of neurological deficits and damage, as well as neuronal protection and functional recovery after TBI . PatientTBI often leads to not only acute injury but also long-term neurodegeneration, and is one of the major risk factors for developing Alzheimer’s disease (AD). A strong indication of AD or neurodegeneration includes the presence of Beta amyloid (AB) peptide deposits, and these deposits increase after TBI in animal models and in patients with head trauma . BecauseRegulation of histone deacetylase (HDAC) inhibition regulation is neuroprotective in nature through its ability to restore histone acetylation levels and correct transcriptional deficits in various models of brain disorders, specifically TBI rodent models ,404,405.TBI research literature is published every year in great quantity and animal models of TBI are essential to clarify underlying injury mechanisms, to assess the safety and efficacy of novel therapies prior to clinical trials  and to bTBI is a complex and heterogeneous disease that requires personalized tracing, monitoring and treatment in clinical practice according to the severity, course, age, gender and co-morbidities associated with injury. An individual specific therapeutic option would benefit TBI victims to achieve the ideal structural restoration preserving lives and decreasing not only costs but also long term comorbidities associated with this condition.


In DSM-5, the classification of posttraumatic stress disorder (PTSD) has broadened its scope. The stressor criterion is more explicit with regard to events that can be qualified as a traumatic experience. Moreover, the specifier “with dissociative symptoms” was introduced for individuals experiencing depersonalization or derealization. However, this extension does not fully cover the more profound symptomatic expressions and developmental trajectories of severe and lasting (childhood) abuse and neglect, nor their impact on the development of self and interpersonal functioning as described for personality disorders . During the last decades a number of concepts have been suggested to describe these more profound phenomena: type II disorder , complex PTSD , enduring personality change after catastrophic experience , PTSD related to childhood abuse , complex posttraumatic self-dysregulation , disorders of extreme stress, not otherwise specified , and developmental trauma disorder . However, from a developmental perspective, the etiological role of trauma in complex PTSD is anything but simple. Pre-trauma factors are significant (genetic vulnerability) and what happens after the trauma has the biggest impact (context)! Unfortunately, none of these concepts were incorporated within the new version of the official APA classification system.With respect to the treatment of PTSD, cognitive behavioral therapies currently dominate the field of treatment approaches. Imaginary exposure and Eye Movement Desensitization and Reprocessing (EMDR) are straightforward evidence-based interventions, widely available to diminish symptoms like intrusive distressing memories, hyper arousal, flash backs, dreams, and nightmares. The aim is to reduce these symptoms within a short period of time.The majority of PTSD patients (Type I) are characterized by failed prefrontal inhibition of limbic activity. In contrast, however, in the dissociative subtype  PTSD high prefrontal activation in conjunction with inhibited limbic activation was found.In complex PTSD, clinicians and patients struggle with long-standing and multifaceted problems , more eclectic approaches are needed integrating emotion regulation and interpersonal functioning strategies as well as psychodynamic understanding. Especially when childhood sexual or physical abuse was long lasting, repetitive, and induced by attachment figures, and when emotional support was lacking, the impact on personality development can be so devastating that other treatment efforts are necessary to establish a trustful therapeutic relation as a starting point for cautious exploration. Evidence-based psychotherapeutic models for (borderline) personality disorders all describe efforts to treat PTSD symptoms within such a specific psychotherapeutic frame of reference. Most of these treatments are intensive  and long lasting (years). In dialectical behavior therapy (DBT), the initial phase of treatment explicitly focuses on stabilizing by diminishing para-suicidal and self-destructive behaviors, as well as treatment-interfering behaviors. Individual cognitive treatment is combined with skill training to improve emotion regulation. As soon as the patient is skilled and stabilized , DBT will next focus on the treatment of PTSD, using cognitive behavioral approaches like imaginary exposure. During transference focused psychotherapy (TFP), in the mid-phase of treatment, the theme of abuse will be activated within the transference (split self and object representations centered around aggression and hatred). Identification with both victim and perpetrator is elaborated, and sexual and aggressive impulses should be disentangled, with the purpose of resolving inner conflicts, fostering identity integration, and enhancing adaptive functioning. Also in schema-focused therapy (SFT), the treatment of trauma and PTSD is not part of the initial phase of treatment. The first phase of treatment involves identifying maladaptive schemas and building up adaptive capacities . Enough social support is a prerequisite to focus on specific former traumatic experiences. SFT describes specific strategies for treating traumatic experiences, like experiential techniques and imagination with rescripting. In mentalization-based treatment (MBT), the concept of mentalizing is used to broaden the perspective on trauma treatment. Mentalizing goes offline when defensive (fight–flight–freeze) responses become activated, promoting rapid responses to imminent danger. In particular, the impact of “attachment trauma” on emotion regulation and mentalizing reflects a dual liability (extreme distress plus impaired development emotion regulation capacities). Later in life, trauma-triggered hyperactivation of the attachment system, and the failure to mentalize, induces primitive modes of thought: psychic equivalence mode, pretend mode, and teleological mode. According to the MBT treatment, model treatment involves far more than processing traumatic memories. Treatment helps the patient to help the self to mentalize trauma and relationship conflicts, in order to develop more secure attachments. The patient uses the therapist as a mirror to understand the self: a “surrogate prefrontal cortex (PFC)”; it provides a buffer between feeling and action: a “pause button”, an opportunity for the patient to reconstruct his or her narrative within a safe and containing environment (first priority), and grounded in reality. In this way, the therapist often becomes the “object of hope.”What these evidence-based treatments for (borderline) personality disorder have in common is their clear contract setting, their supportive common factors, their efforts to first stabilize their patients before exposing them to traumatic memories, their focus on maintaining a trustworthy therapeutic relationship, and their efforts to tailor psychotherapeutic strategies toward specific vulnerabilities and capabilities to regulate emotions and control (self-destructive) impulses. So, in complex PTSS and personality disorders, the central therapeutic task is NOT specifically to work with the content of traumatic events, but rather involves supporting a mentalizing stance in relation to the meaning and effect of trauma. The focus is primarily on the patients’ mind, not on the event, on the process rather than the content. Over and beyond the holding environment of the therapeutic relation, phase specific and carefully tailored, symptom-focused approaches like exposure and EMDR can reduce typical PTSD symptoms.


AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T  and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by “omics” and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients.Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3 Autoimmune hepatitis (AIH) is an immune mediated liver disease; however its exact trigger and the underlying mechanism by which AIH develops are still not fully understood although genetic, dietary, and environmental factors seem to play an important role. AIH is characterised biochemically by the presence of elevated serum transaminase levels, histologically by interface hepatitis and the presence of plasma cells, and serologically by increased levels of immunoglobulin G (IgG) with presence of either elevated anti-nuclear antibodies (ANA) or anti-smooth muscle antibodies (ASMA), soluble liver antigen (SLA), and anti-actin or anti-liver-kidney-microsomal antibodies (anti-LKM) –3. Type The prevalence of AIH appears to vary between different regions of the world based on ethnic origin. A report from the United Kingdom  indicateAIH can affect any age groups . It is mIn some patients, AIH can coexist with other autoimmune biliary conditions such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), also known as overlap syndrome . PatientThe pathogenesis of AIH is a complex process and the exact aetiology is still unknown although genetic and environmental factors play an important role . AIH can∗0301 is the principal risk factor for type 1 AIH among Caucasian Northern European adults and is associated with poor prognosis . Th. ThhighCSeveral studies support the clinical application of Treg in type 1 AIH. Investigators have reported changes in Treg frequencies in AIH patient peripheral bloods , 72; how+ Treg cells  as these Tregs have an epigenetically stable FOXP3 locus with stable Treg lineage [Antigen-specific Tregs are anticipated to have greater efficacy and to overcome the possible risk of nonspecific immunosuppression. But until we identify the antigen for type 1 AIH, polyclonal functional GMP Treg in sufficient quantity is the feasible preparation to administer in the treatment of AIH patients. In the future, with advances toward flow sorting and chip sorting technology, isolation of antigen specific Treg subset based on markers including latency-associated peptide (LAP) and glycoprotein-A repetitions predominant (GARP) could be a potential option . Future  lineage . Analysi lineage .+ T cells, CD8+ T cells, and NK/NKT cells [Once the Tregs are administered intravenously, it is expected that they will migrate to the site of liver inflammation with their homing chemokine receptor CXCR3. The functional capacity of tissue infiltrating Treg is essential to control the ongoing hepatitis by suppressing the effector cells in the inflamed liver. Tregs are dependent upon the cytokine IL-2 for their expansion, survival, and function and owing to their high expression of the high affinity IL-2R alpha chain, CD25, they are sensitive to lower doses of IL-2 compared to effector CD4KT cells . We haveKT cells . FurtherKT cells . Thus weKT cells , GvHD [7KT cells , and typKT cells , 81. AccCurrently Treg therapy is highly expensive due to the clinical reagents, GMP clean room facilities, new technology, and isolation equipment required for generation of the final sterile cell therapy product. Increasing application of GMP grade Treg therapy together with improved understanding of the functional biology of Treg over the coming years will hopefully lead to streamline production of a more economical, practical, clinic based cell therapy. This would facilitate regular application of autologous Treg infusion as novel but standard therapy for patients with AIH in the future offering them freedom from life-long immunosuppression.There has been only gradual progression made in the diagnosis and management of autoimmune hepatitis over the last three decades. It is still challenging to tackle the treatment nonresponder, fulminant presenters, and biliary overlap patients. With the advance of genomic, proteomic, metabolomics, and immune profiling, it is prudent to stratify these patients to provide personalized treatment depending on individual multi-OMICs profile. Increasing understanding in immune-pathogenesis of both innate and adaptive responses in AIH patients' blood and importantly in the inflamed liver tissue will pave the way for new therapies.A novel concept of restoring tolerance with regulatory T cells infusion without requiring life-long global immunosuppression will soon be available in some centres. Adoption of these emerging diagnosis and treatment options is necessary for up-to-date management of patients with AIH.Exploring causative triggers and antigens and lack of representative animal model still remains a challenge and many investigators are attempting to tackle these aspects to dissect the underlying mechanism. European and global collaborations are necessary to collect a significant number of AIH patients for deeper understanding of immunopathology and to explore new therapies for this rare, immune mediated liver disease.


This systematic review aims to evaluate evidence on the effectiveness of sexual and reproductive health (SRH) interventions delivered in humanitarian crises.Crisis affected low-income or middle-income countries.Crisis-affected populations in low-income or middle-income countries.Peer-reviewed and grey literature sources were systematically searched for relevant papers detailing interventions from 1 January 1980 until the search date on 30 April 2013. Data from included studies were then extracted, and the papers’ quality evaluated using criteria based on modified STROBE and CONSORT checklists.Primary outcomes include, but are not limited to, changes in morbidity, mortality, sexually transmitted infection (STI) diagnosis or gender-based violence. Secondary outcomes include, but are not limited to, reported condom use or skilled attendance at birth. Primary outputs include, but are not limited to, condoms distributed or education courses taught.Of 7149 returned citations, 15 studies met the inclusion criteria. Only one randomised controlled trial was identified. The remaining observational studies were of moderate quality, demonstrating limited use of controls and inadequate attempts to address bias. Evidence of effectiveness was available for the following interventions: impregnated bed nets for pregnant women, subsidised refugee healthcare, female community health workers, and tiered community reproductive health services.The limited evidence base for SRH interventions highlights the need for improved research on the effectiveness of public health interventions in humanitarian crises. While interventions proven efficacious in stable settings are being used in humanitarian efforts, more evidence is required to demonstrate the effectiveness of delivering and scaling-up such interventions in humanitarian crises. Broad search strategy including peer-reviewed and grey literature.Rigorous assessment of the quality and strength of evidence.Only quantitative studies are included.No meta-analysis was possible so a narrative summary of the results is provided.Humanitarian crises can increase vulnerability to poor sexual and reproductive health (SRH) outcomes among affected populations due to reduced access to SRH services and supplies, damaged health facilities, depleted human resources, increased exposure to sexual violence, and increased impoverishment and related risk-taking.4–6The responsibility of humanitarian actors to respond to the SRH needs of those affected by conflict and natural disasters has been increasingly recognised over the past two decades. Following the 1994 International Conference on Population Development in Cairo,It is important to gauge the evidence on the effectiveness of SRH interventions specifically in humanitarian contexts because the ability to deliver SRH services in such contexts may be different due to issues such as insecurity, limited financial and human resources, and population mobility.To address these evidence gaps, the aim of this systemic review is to evaluate the evidence on the effectiveness of SRH interventions delivered in humanitarian crises. This study is part of a larger project evaluating the evidence on the effectiveness of interventions on a range of health outcomes in humanitarian settings.11This systematic literature review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Search terms for sexual and reproductive health were based on the standardised definition from the International Conference on Population and Development in 1994. SRH refers to “the constellation of methods, techniques and services that contribute to reproductive health and well-being by preventing and solving reproductive health problems.” International guidelines on reproductive health in conflict-affected situations include reproductive activities on family planning, HIV/AIDS and sexually transmitted diseases, maternal and newborn health, and sexual and gender-based violence.14For the purposes of this review a humanitarian crisis is defined as a serious disruption of the functioning of a community or a society causing widespread human, material, economic or environmental losses which exceed the ability of the affected community or society to cope using its own resources, necessitating a request to national or international level for external assistance. The disaster situation may either be man-made  or a natural phenomenon . Although crises can affect all countries, only studies from low-income or middle-income countries were included in this study. The majority of humanitarian crises occur in these countries, and the resources available to address them are very different in high-income countries. For these reasons, the study team included only papers from low-income and middle-income countries.The specific search terms (see online supplementary annex 1) were generated by the authors and then supplemented by searching for other search strategies used in previous systematic reviews on similar topics.Peer-reviewed journals and grey literature reports were included. We searched for peer-review published literature across three databases: EMBASE, Global Health and MEDLINE. Grey literature was searched using online sources: R4D, Reproductive Health Response in Crisis Consortium (RHRC), Medecins Sans Frontiers (MSF) Field Research, UNFPA, RAISE Initiative, IAWG, Save the Children, The International Rescue Committee (IRC), CARE, International Committee of the Red Cross (ICRC), International Planned Parenthood Federation (IPPF), AIDS Alliance and Marie Stopes International (MSI). Searches were complemented by screening the reference lists of papers for potentially relevant studies. Experts on SRH service delivery and research were also consulted to identify any additional research not found during the systematic search.All returned citations were downloaded into an Endnote library and a standard data-screening process was applied . PrimaryOwing to the heterogeneity of study outcomes, interventions and methods, a descriptive analysis was chosen over a meta-analysis. The findings were synthesised by main SRH outcomes . These themes were developed iteratively after thematic analysis of the studies’ stated aims and primary reported health outcome of interest.The quality of reporting in the included studies were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Consolidated Standards of Reporting Trials (CONSORT) checklists, which are commonly used for reporting the quality of observational and trial studies.see online supplementary table S2 and annex 2). No studies describing interventions aimed exclusively at responding to or preventing gender-based violence in crisis settings were identified. One intervention described the inclusion of gender-based violence topics but did not include any measurements to assess its influence.11In total 7149 citations were returned from peer-reviewed sources, two from grey literature libraries and three from expert recommendations. After screening, 15 studies meeting our inclusion criteria were selected  communities in Port Loko, Sierra Leone evaluated by a case-series design, found promising trends in improved knowledge, attitude and behavioural changes .24et alWorking in Tanzania with Rwandan refugees, Mayaud et alA fourth study by Reid 3) than those who received no or non-treated nets .Nine studies evaluated interventions focused on improving maternal, newborn and child health outcomes. One double-blind randomised control trial evaluated the efficacy of permethrin-treated bed nets compared with untreated nets or no bed net.Three studies focused on increased community education, involvement, and birth preparedness and planning.et al used an ecological study design to evaluate a programme with Afghan refugees in Pakistan which aimed to reduce maternal and neonatal mortality by increasing the use of emergency obstetric care through improving community knowledge about skilled delivery and obstetric danger signs. They observed that the maternal mortality ratio dropped from 291 to 102 per 100 000 live births from the first to the fifth year of the programme (95% CI 181 to 400). Neonatal mortality also decreased from 25 to 20.7 per 1000 births from the first to the seventh year, however no CIs were reported.Purdin et al evaluated a birth-preparedness package in Nepal using a case-series design. The intervention was a multilevel community education and healthcare response, seeking to reduce maternal and neonatal mortality and increase use of health services. Comparing endline to baseline surveys among mothers of infants, health behaviours improved—including not putting anything on the umbilical cord, wrapping the baby immediately after birth and delaying bathing (p=0.000). Attending at least one antenatal visit, making financial and transport preparations also improved (p=0.000). Breastfeeding within an hour of birth was not statistically improved (p=0.06). Of the seven chosen indicators, only the use of a skilled attendant at birth remained unchanged (p=0.55).29McPherson Five studies attempted to improve maternal and neonatal health through system strengthening and capacity building.An initiative in Makeni, Sierra Leone, assessed the impact of numerous hospital-based improvements including hiring a new medical officer with training in obstetrics and a second medical officer who would receive obstetric training.et alOrach et alTwo studies were identified that evaluated the impact of CHWs on reproductive and maternal health services.et alMullany Of the 15 studies, 14 were assessed for quality of reporting using the STROBE checklist and the only randomised controlled trial (RCT)28The STROBE assessment allowed specific analysis of common areas of low-quality reporting. For these studies, three broad themes emerged: confounding, bias and appropriately reporting findings. Confounding factors were, on the whole, not clearly described or discussed. Only two studies attempted a control,The review identified only 15 studies on the effectiveness of specific SRH interventions in humanitarian settings that met the inclusion criteria. Interventions resulting in improved health outcomes included the use of impregnated bed nets for pregnant women,Other significant gaps included that few studies looked directly at provision of or access to family planning. Many of the interventions were based on education in some format. While undoubtedly a core part of programming in these settings, relatively few studies looked at, for example, scaling up service delivery and only one study conducted an economic evaluation.The strength of the evidence identified for this review was variable but generally low. Only one of the papers was able to demonstrate a causative association through a randomised controlled trial,What may explain this limited evidence? First, there are clearly many logistical challenges to conducting research in humanitarian settings given the high levels of insecurity, scarcity of resources, and population movements. However, higher quantity and quality of research has been conducted in such settings for other health outcomes such as mental health and communicable diseases.This systematic review has a number of limitations. To be included in this study, papers needed to fit within relatively narrow criteria. The strict study design criteria excluded qualitative studies which form a rich part of the literature in this field. However, by including only studies demonstrating quantitative change over time, we expected to derive a specific level of evidence to inform our conclusions. Additionally, only papers written in English and French were included. Owing to the disparate intervention types, indicators and methods used in the included studies, we were unable to conduct a meta-analysis. The STROBE and CONSORT checklists were used to assess the quality of reporting in studies, but more specialist quality assessment tools such as the Cochrane Collaboration's tool for assessing risk of bias and the Newcastle Ottawa Scale would have provided more in-depth reviews of quality.35This review found some evidence to support increased access and demand creation for family planning services through CHWs, healthcare subsidies and discussions within literacy groups. Education-based interventions also suggest positive results relating to HIV-avoidant behaviours. Involving communities in maternal and child health and birth preparedness programmes, as well as refurbishing clinics and hospital facilities, was also associated with increased positive health outcomes. However, the types of study design, limited use of statistical data, and weak quality mean caution needs to be exercised when interpreting results. While interventions proven efficacious in stable settings are being used in humanitarian efforts, more evidence is required to demonstrate the effectiveness of delivering and scaling-up such interventions in humanitarian crises.


Stem cells play an important role in tissue repair and cancer development. The capacity to self-renew and to differentiate to specialized cells allows tissue-specific stem cells to rebuild damaged tissue and cancer stem cells to initiate and promote cancer. Mesenchymal stem cells, attracted to wounds and cancer, facilitate wound healing and support cancer progression primarily by secreting bioactive factors. There is now growing evidence that, like mesenchymal stem cells, also tissue-specific and cancer stem cells manipulate their environment by paracrine actions. Soluble factors and microvesicles released by these stem cells have been shown to protect recipient cells from apoptosis and to stimulate neovascularization. These paracrine mechanisms may allow stem cells to orchestrate wound healing and cancer progression. Hence, understanding these stem cell-driven paracrine effects may help to improve tissue regeneration and cancer treatment. IntroductionParacrine effects of stem cells in tissue regenerationParacrine effects of stem cells in cancerConclusions1.et al on hair follicle stem cells suggests that the more adult stem cells are present in the injured area the faster the wound is healing , a multipotent stromal progenitor cell residing preferentially in bone marrow and adipose tissue ,7. MSCs It is now well accepted that, also in cancer, stem-like cells, so-called cancer stem cells (CSCs), exist –21. ThesThere are many ways by which cells can communicate in a paracrine manner. One way is by proteins, such as growth factors or cytokines. MSCs secret a plethora of such proteins ,29,31 so2.Cardiac stem cells have been shown to improve recovery of the myocard from ischemia. This has been linked to their ability to differentiate to cardiomyocytes to replace the damaged cells. However, a recent report demonstrated that the differentiation potential of these cells alone was not sufficient for this repair . The carBesides cardiac stem cells, mesenchymal stem cells (MSCs) are able to improve post-ischemic recovery of the myocard . It was Additionally, MSCs may stimulate angiogenesis in the infarcted myocard. MSC-derived CM was shown to activate endothelial cells and to increase capillary density in the infarcted heart ,56. AmonThere are at least two more stem/progenitor cell types, the bone marrow-derived endothelial progenitor cell (EPC) and the skeletal muscle-derived stem cell (MDSC), which were shown to be capable of cardioprotection ,63. WhenIn a recent study, the cardioprotective activities of cardiac stem cells, MSCs and EPCs were compared. Most effective in inducing myocyte differentiation and tube formation were cardiosphere-derived cells, a population of cells that contained cardiac stem cells and supporting cells . Compareet al asked the question if transplantation of cardiac and mesenchymal stem cells into the infarcted heart would change the cocktail of secreted factors  to improve survival of cardiomyocytes; and ii) to stimulate neovascularization .in vitro  have been reported to stimulate proliferation and to inhibit apoptosis of cisplatin-injured proximal tubular epithelial cells . This efIn chronic kidney disease, exosomes from MSCs brought no improvement . However+ haematopoietic stem cells. The CM from these cells injected into the tail vein significantly increased liver repair and animal survival by blocking caspase 3-dependent apoptosis of liver cells. Among the 32 factors identified in the CM of the CD34+ stem cells were a number of cytokines, including members of the CXCL chemokine family, known to be involved in wound healing. Liver regeneration is closely linked to CXC receptor 2  (CD133 (Tregs) . These a (Tregs) , it is l (Tregs) . In addi (Tregs) , was fou (Tregs) . Interes (Tregs) . On its  (Tregs) . This in+ glioma CSCs secret substantial amounts of VEGF which leads to enhanced endothelial migration and tube formation , a cytokine present in colon cancer and absent in normal colon, was blocked by an IL-4 specific antibody , it is reasonable to assume that CSC-secreted PAI-1 may also affect cell motility.In addition, breast CSCs may themselves be a provider of bioactive soluble factors. Comparative transcriptome analyses by serial analysis of gene expression, cDNA microarray and next generation sequencing of CD44er cells ,108. Aloer cells , is a seer cells ,111. Siner cells   cells either to fill the gap that has been caused by cell loss or to fuel tumor growth, respectively. Now, a new theme is emerging which ascribe to these stem cells an additional regulatory function in tissue maintenance or tumor progression. The so-called damage-associated molecular pattern (DAMP) after acute kidney injury may be a good example that shows how much stem cell-derived factors are involved in tissue repair . It seemIn general, knowing that paracrine effects of stem cells strongly contribute to tissue repair and cancer may help to find new ways of therapeutical interventions to facilitate tissue regeneration and to improve cancer treatment, respectively.