The neurobiological mechanisms underlying alcohol addiction remain obscure. It is generally accepted that alcohol’s addictive property is associated with its ability to increase the activity of dopaminergic (DA) neurons in the ventral tegmental area (VTA) in the brain. These neurons are under the powerful control of synaptic inputs. Thus, the synaptic regulation of DA neurons is a key initial step in reward mechanisms leading to alcohol addiction. DA neurons receive major GABAergic afferents. Some drugs of abuse, such as opioids, stimulate VTA-DA neurons through suppression of GABAergic transmission - that is by disinhibition. Emerging evidence indicates that the rostromedial tegmental nucleus (RMTg), a recently defined structure with dense Mu-opioid receptor (MOR) immunoreactivity, is a major GABAergic afferent to DA neurons, and a key structure in MOR-dependent regulation of DA neurons . SubstanIn an attempt to address this issue, in a recent study, we measOur results are in line with a recent rat study showing that excitotoxic lesion of the RMTg using quinolinic acid increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion . Our resWe additionally found that intra-RMTg injection of DS increased locomotion of rats, implying that locomotion may normally be limited by the RMTg. Since it has been well documented that dopamine has a significant role in locomotion, and inhibition of RMTg neurons disinhibits VTA-DA neurons , we propThere are limitations of current study. For example, areas surrounding the RMTg having moderate levels of MOR expression could have been damaged by intra-RMTg DS injection. To minimize this risk, we injected DS of a small volume and a low dose. Despite these precautions, there were lesions outside the RMTg. Therefore, we cannot conclude that all the changes in alcohol-related behaviors induced by intra-RMTg DS injection were exclusively a result of RMTg cell damage. And while the current evidence suggests that increased dopamine may contribute to the hyperactivity of rats with RMTg ablation, direct evidence supporting this possibility is still lacking.In summary, we demonstrated that damage of RMTg MOR-expressing GABAergic neurons by DS increased the intake and preference for alcohol, boosted the expression and slowed down the extinction of alcohol CPP, and increased locomotion. These were not seen in rats receiving BS or vehicle injection. These results indicate that the RMTg plays an important role in the regulation of voluntary alcohol drinking and CPP, as well as locomotion.


Immunity, virulence, biofilm formation, and survival in the host environment are regulated by the versatile nature of density dependent microbial cell signaling, also called quorum sensing (QS). The QS molecules can associate with host plant tissues and, at times, cause a change in its gene expression at the downstream level through inter-kingdom cross talking. Progress in controlling QS through fungicide/bactericide in pathogenic microscopic organisms has lead to a rise of antibiotic resistance pathogens. Here, we review the application of selective quorum quenching (QQ) endophytes to control phytopathogens that are shared by most, if not all, terrestrial plant species as well as aquatic plants. Allowing the plants to posses endophytic colonies through biotization will be an additional and a sustainable encompassing methodology resulting in attenuated virulence rather than killing the pathogens. Furthermore, the introduced endophytes could serve as a potential biofertilizer and bioprotection agent, which in turn increases the PAMP- triggered immunity and hormonal systemic acquired resistance (SAR) in plants through SA-JA-ET signaling systems. This paper discusses major challenges imposed by QS and QQ application in biotechnology. This practice is an emerging trend in biotechnological approaches that harbors unprecedented potential for efficient control over virulent pathogens.The use of synthetic broad-spectrum fungicides/bactericides in plant disease management results in imbalances within the microbial community and the continuous evolution of multiple bactericide-resistant strains. Microbes with the ability to produce quorum quenching enzymes, which can degrade the wide-spread quorum sensing signals from pathogenic microbes, could be employed in development of sustainable methods of suppressing virulence expression and abolishing bacterial infection. Quorum quenching enzymes produced by endophytes have a more limited selection pressure for microbial survival than biocide treatments , degradative exoenzymes, horizontal gene transfer (HGT),  to activate plant virulence genes  and detection (via the LuxR-family proteins) of AHL signaling molecules. Schaefer et al.  screenedOryza sativa (rice) and Phaseolus vulgaris (bean) plant samples. These bimolecular analogs bind to signal receptors of bacteria, but they fail to do the signaling activity of AHLs, resulting in confusing bacterial populations. A thorough analysis using biosensors carrying the lactonase enzyme showed that rice and bean seed extracts contain biomolecules that lack lactones' typical ring of AHLs. Although Götz-Rösch et al.  in response to microbial infection. PAMPs are common in pathogens, non-pathogens, and saprophytes  are defective when grown in biofilms  communication mediated by peptide molecules (Chang et al., Rgg-class proteins are transcriptional regulators on the cytoplasmic membrane that act as receptors for intracellular signaling peptides. They are found in low-G+C-content, Gram-positive bacteria (Delisea pulchra, have a direct role in inhibiting AI-2 quorum sensing (Lennen, in vitro-produced AI-2 has a negative impact on biofilm density (Auger et al., Autoinducer AI-2 is a common signaling molecule used in both intra- and interspecies communication. It is a furanosyl borate diester molecule, unique due to the presence of boron in its structure (Pereira et al.,  Lennen, . Increasbiotization. Biotization in the rhizosphere region helps plants obtain more transition metals through siderophore production, which in turn increases plant immunity against phytopathogens. Other evidence also shows that plants with hyper-accumulation of metal have increased resistance to pathogens (Fones and Preston, R. solanacearum appears to alter its membrane architecture in complex ways during adaptation to life in the xylem (Poussier et al., in vitro conditions can be used for endophytic colonization in plants (Senthilkumar et al., Cross-kingdom interaction leads to specific adjustments and physiological adaptations in colonized eukaryotes (Hartmann and Schikora, Various quorum quenching endophytes that have been identified in plants with AHL-ase activity are presented in Table in vitro biotization are summarized in Figure So far there are no universal QQ bacterai to be used for all plants. Also, biotization has been shown to be limited by the absence of AHL-based quorum sensing in Gram-positive bacteria, instead inhibition of Rgg pheromone receptors could be employed (Cook and Federle, Biotization helps at various physiological and developmental stages in plants. It enhances induced biotic and abiotic stress resistance (Badosa and Montesinos, The quorum quenching mechanism can serve as a potential target for developing new antimicrobials to overcome microbial pathogenesis. Quorum quenching endophytes will attenuate virulence factors rather than kill the microbes, a feature that should hugely reduce the selective pressures associated with bactericidal agents that have led to the rapid emergence of resistance. Before engineering the quorum sensing pathway in native endophytes, it is important to ensure the presence of naturally available beneficial mechanisms in the host environment. The key to improving plant resistance to bacterial diseases in a changing environment may lie in creating biotized plants. Pesticide poisoning has been acknowledged as a serious problem in many agricultural communities of low- and middle-income countries. Efforts to develop a systematic and a sustainable approach to prevent and manage pesticide poisoning remain inadequate. Thus, the novel possibility of exploiting the quorum quenching endophytes may serve as a sustainable tool for plant disease management.GA, KA, and MM initiated the project. All the authors have made a substantial, direct, intellectual contribution to the work, and reviewed the final version of the manuscript.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.


A 21-year-old pregnant female with no significant past medical history presented with acute onset headache and nausea as well as tonic-clonic seizures, then rapidly decompensated into a coma with complete absence of brainstem reflexes. The patient was ultimately diagnosed with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) and subsequent posterior reversible encephalopathy syndrome (PRES) with brainstem involvement. Emergent delivery and blood pressure control resulted in rapid and complete neurologic recovery. Posterior reversible encephalopathy syndrome (PRES), first described by Hinchey et al in 1996,A 21-year-old female with no significant past medical history presented to an outside hospital accompanied by her father, following two witnessed episodes of generalized tonic-clonic movement. Initial seizure activity was controlled with a single, appropriate dose of intravenous lorazepam; however, she quickly became obtunded and required intubation for airway protection. A bedside ultrasound revealed a previously unknown pregnancy of 32–35 weeks gestation. Basic laboratory evaluation demonstrated a mildly elevated serum creatinine and no other abnormalities. An emergent non-contrast head computed topography (CT) demonstrated findings of diffuse anoxic brain injury. With no signs of neurologic recovery the patient was transferred to a tertiary academic medical center.Upon arrival to the accepting institution the patient was tachycardic at 129 beats per minute and hypertensive with a blood pressure of 229/158 mm Hg. Initial physical examination revealed an unresponsive and gravid female, intubated and mechanically ventilated. Neurologic exam demonstrated the complete absence of a gag reflex with no active paralytic on board from the outside facility. Her pupils were non-reactive and she had no corneal reflexes; doll’s eyes phenomena were present. Invasive arterial monitoring and central venous access were rapidly acquired. Immediate hypertensive management with a continuous intravenous nicardipine infusion was initiated. The patient also received a concomitant magnesium infusion for seizure control. Complete laboratory analysis demonstrated transaminitis , thrombocytopenia , and anemia, consistent with HELLP syndrome.The patient underwent emergent cesarean section and a live female infant was delivered. Post-delivery repeat non-contrast head CT  revealed slender lateral ventricles and diffuse cerebral swelling; low-density areas were seen in the parieto-occiptal region as well as indistinct areas of the basal ganglia, putamen and thalamus , suggestFollowing delivery, the patient’s blood pressure continued to improve and the nicardipine infusion was discontinued. Antiepileptic therapy was initiated and the magnesium infusion was gradually tapered. Shortly thereafter, the patient’s brainstem reflexes began to return; six hours post-delivery the patient’s pupils were reactive and she demonstrated voluntary movement of all four extremities. Her neurologic status continued to improve over the next 16 hours and she was liberated from ventilatory support the subsequent morning.The subsequent neurological examination revealed no cognitive or reflexive deficits; she was able to ambulate and communicate appropriately. Her laboratory data began to improve and she was transferred to the postpartum unit the following day where she continued to recover. On hospital day six, the patient was discharged with a healthy baby girl.New-onset seizures, in the context of an unknown pregnancy, established the diagnosis of eclampsia in a patient with laboratory-confirmed HELLP syndrome resulting in a distinctly unusual presentation of PRES. PRES-induced brainstem areflexia and coma is a remarkable and unusual entity, representing one of the few rapidly reversible causes of catastrophic neurologic insult. HELLP syndrome has limited and non-specific neurologic findings, often with headache or blurred vision, similar to findings in eclampsia, making the distinction difficult without laboratory or radiographic evaluation.CPC-EM CAPSULEWhat do we already know about this clinical entity?We know the clinical presentation of PRES, but rarely see complete, rapid resolution of all neurology symptoms in patients presenting comatose without brainstem reflexes.What makes this presentation of disease reportable?This case is an unusual presentation of two potentially morbid conditions associated with pregnancy that need aggressive treatment stemming from rapid recognition.What is the major learning point?It supports aggressive treatments for this condition, as complete neurologic resolution is possible, as well as the use of other first line antihypertensive agents in pregnant patients.How might this improve emergency medicine practice?Further supports the notion in emergency medicine we need to think beyond a single diagnosis to explain all presentations, as occasionally 2 major pathologies present.This constellation of symptoms represents a neurologic emergency. Imaging in the form of a head CT most commonly reveals the development of vasogenic edema to support the diagnosis. The vasogenic edema is generally found in the posterior white matter of the cerebral hemispheres and is frequently seen in the parieto-occipital lobes bilaterally; however, it has been reported throughout the brain.The neurologic findings associated with PRES can be directly attributed to the vasogenic edema found on head CT. Although the presence of vasogenic edema is well documented with PRES, the inciting pathophysiology remains disputed. Early postulates suggested that intense cerebral autoregulatory vasoconstriction occurs in response to acute elevations in blood pressure. This vasoconstriction leads to decreased cerebral blood flow and resultant ischemia, which in turn causes edema in the watershed arterial regions. More recently, investigators proposed that the marked hypertensive state leads to forced vasodilatation through failure of the cerebral autoregulatory system resulting in hydrostatic extravasations of fluid into the interstitium.4While the pathophysiology of PRES remains controversial, there is a significant amount of literature detailing the multiple conditions that have been associated with the development of PRES. Most commonly, significant elevations in blood pressure are noted. Certain medications, especially cyclosporine, tacrolimus and other chemotherapeutic agents, have been associated with the development of PRES. Regardless of the etiology, the clinical prognosis is often excellent. Given appropriate supportive intensive care, control of hypertension, and removal of the offending agents, PRES is often completely reversible with minimal lasting neurologic deficits.PRES in the setting of eclampsia is a well-established occurrence;


Because they enable labeling of biological samples in a genetically-encoded manner, Fluorescent Proteins (FPs) have revolutionized life sciences. Photo-transformable fluorescent proteins (PTFPs), in particular, recently attracted wide interest, as their fluorescence state can be actively modulated by light, a property central to the emergence of super-resolution microscopy. PTFPs, however, exhibit highly complex photophysical behaviours that are still poorly understood, hampering the rational engineering of variants with improved performances. We show that kinetic crystallography combined with in crystallo optical spectroscopy, modeling approaches and single-molecule measurements constitutes a powerful tool to decipher processes such as photoactivation, photoconversion, photoswitching, photoblinking and photobleaching. Besides potential applications for the design of enhanced PTFPs, these investigations provide fundamental insight into photoactivated protein dynamics. Fluorescence microscopy is a key technique for cell biologists, relying heavily on the use of fluorescent proteins (FPs) as markers . FPs forThe dynamic properties of fluorescent proteins Aequora victoria GFP or from various Anthozoan marine organisms such as corals or anemones, providing fluorescent colours across the entire optical spectrum (450 to 650 nm) . T. T13]. TThe great difficulty in obtaining well diffracting photobleached IrisFP crystals prompted us to strongly reduce the illumination power used to photofatigue the samples. Experiments were thus repeated with a 10-fold lower power density, i.e., 10 W/cm², more typical of a standard widefield microscopy experiment. The same overall pattern of photo fatigue decay was observed, albeit on a longer time scale. However, unexpectedly, striking differences were observed in the electron density maps when compared to those obtained under high-intensity illumination d. The chAnother interesting observation is that the crystals photofatigued under these low intensity illumination conditions actually turned out to be even more degraded than when high-intensity illumination was used. This was attributed to the general oxidation of the protein, rapidly developing after the initial sulfoxidation of the two proximal residues Met159 and Cys171. Again here, only crystals in which a low-level of photobleaching was achieved could produce usable diffraction or Raman data, highlighting the delicate balance to be achieved between occupancy and crystalline quality when such experiments are attempted.So far, improvement of photostability in FPs has mainly proceeded empirically using e.g., directed evolution strategies . The strThe example of IrisFP demonstrates the potential of kinetic crystallography to elucidate the complex photophysical behaviours of fluorescent proteins, especially when used in combination with other complementary approaches that include optical spectroscopy, mass spectrometry, single-molecule imaging and theoretical calculations. Nevertheless, the multiple reaction pathways that fluorescent proteins may follow upon photon absorption, each with relatively low probability and each being potentially strongly influenced by experimental conditions, renders the comprehensive structural mapping of FP photophysics an extraordinary difficult task. Beyond our still limited understanding of light induced protein dynamics in general, it is clear that the prospect of engineering enhanced fluorescent proteins in a purely rational manner based on structural insight is still far ahead. As a matter of fact, the vast majority of popular fluorescent proteins used to date in cell biology labs have been obtained primarily by directed evolution approaches. A long route stands in front of us to bridge structural data, even recorded at the highest spatiotemporal resolution, with the ability to predict the effect of mutations in FPs. Particularly difficult are the combined effects of multiple mutations that typically display epistatic behaviour . On the


Rapid-acting, non-irritating nasal treatment options for smoking cessation pharmacotherapy are lacking. The halt in development is due, in part, to difficulty in delivering compounds across the blood brain barrier. Recently, in both human and animal models, insulin was shown to be capable of being transported to the cerebrospinal fluid and various brain regions via the “nose-to-brain” pathway, which bypasses the blood brain barrier, but is not free of its own unique, though different from blood brain barrier, challenges. This review will first evaluate and critique pharmacokinetic and pharmacodynamic evidence of intranasal insulin  delivery. As intranasal insulin has been shown in clinical trials to be effective in reducing nicotine cravings, in the remainder of the review, hypothesis-generating literature for additional mediators  of smoking persistence will be reviewed. In particular, weight gain, impulsive behavior, and anhedonia have been shown to contribute to the inability to quit smoking. For each of these, after reviewing how the mediator promotes smoking, intranasal insulin literature from animal and clinical models will be critiqued in assessing whether a hypothesis may be generated that intranasal insulin may alleviate it, thereby potentially contributing to a successful smoking cessation outcome. Smoking remains the single most preventable cause of morbidity and mortality . Whereas, <2% of small compounds effectively cross the BBB, larger molecules and peptides are nearly impenetrable  through the olfactory epithelium in nasal cavity do so via olfactory sensory neurons  in that study underwent positron emission tomography before and after treatment. Placebo-assigned participants showed progressive hypometabolism —a typical feature of Alzheimer's disease progression. The effect was observed in several brain regions of placebo-treated patients while intranasal insulin-treated patients showed a significant dampening of the hypometabolic progression.Therapeutic intranasal delivery of insulin reaches CSF in humans , new quitters (quit ≤ 3years), and continuing smokers were 1.22 , 1.73 , and 1.31 , respectively. The risks were substantially attenuated after an adjustment for weight gain.Weight gain of nine pounds on average  and cocaine-amphetamine-regulated-transcript (CART) neurons as well as the orexigenic acting neuropeptide Y (NPY) and agoutirelated peptide (AgRP). The POMC neurons further synapse onto the second order neurons which contain the hippocampal melanocortin receptor 4 (MC4-R)—a seven-transmembrane G-protein coupled receptor. The resulting increase in the second order MC4-R signaling provides crucial inhibitory tone that restrains food intake. In fact, both nicotine (Mineur et al., In addition to the above-described insulin's effect on the homeostatic regulation, an additional, hedonic locus of insulin's effect on food valuation was recently evaluated in a human pharmacologic fMRI study (Tiedemann et al., Much progress has been made recently in defining related but clearly independent constructs of impulsive behavior. Criticized as being generally broad Cyders, , it is rChoice impulsivity in nicotine withdrawal research is highly dependent on trait impulsivity. Remarkably, both animal (Kolokotroni et al., The overlapping effect of nicotine and insulin is evident in rapid-response impulsivity. Just as nicotine reverses the detrimental response, so does insulin. Insulin robustly and swiftly induces the cell surface expression and function of dopamine transporter in dopamine terminals (Patterson et al., Anhedonia spikes within the first day of smoking cessation. It significantly predicts smoking cessation even after adjustment for related withdrawal symptoms such as, nicotine craving (Cook et al., Insulin's role in mood modulation is in the beginning stage of investigation in both animal and clinical models. There is clear evidence of the involvement of insulin in anhedonia—the brain insulin receptor knockout NIRKO mice exhibit depressive behavior due to overactive monoamine oxidase activity and a subsequent increased dopamine turnover (Kleinridders et al., Clinical administration of intranasal insulin for mood-related outcomes has resulted in mixed findings. Whereas, a study by Benedict et al.  in healtInsulin receptors are widely distributed throughout the brain (Kleinridders et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Stroke is one of the leading causes for disability worldwide. Motor function deficits due to stroke affect the patients' mobility, their limitation in daily life activities, their participation in society and their odds of returning to professional activities. All of these factors contribute to a low overall quality of life. Rehabilitation training is the most effective way to reduce motor impairments in stroke patients. This multiple systematic review focuses both on standard treatment methods and on innovating rehabilitation techniques used to promote upper extremity motor function in stroke patients. A total number of 5712 publications on stroke rehabilitation was systematically reviewed for relevance and quality with regards to upper extremity motor outcome. This procedure yielded 270 publications corresponding to the inclusion criteria of the systematic review. Recent technology-based interventions in stroke rehabilitation including non-invasive brain stimulation, robot-assisted training, and virtual reality immersion are addressed. Finally, a decisional tree based on evidence from the literature and characteristics of stroke patients is proposed. At present, the stroke rehabilitation field faces the challenge to tailor evidence-based treatment strategies to the needs of the individual stroke patient. Interventions can be combined in order to achieve the maximal motor function recovery for each patient. Though the efficacy of some interventions may be under debate, motor skill learning, and some new technological approaches give promising outcome prognosis in stroke motor rehabilitation. The World Health Organization (WHO) estimates that stroke events in EU countries are likely to increase by 30% between 2000 and 2025  after stroke are common with prevalence rates variously reported to be 11–85%  . In some cases, routine clinical treatments that have not been investigated in a randomized controlled way, are still included in the present systematic review if the trial demonstrated sufficient quality evidence. The scientific evidence of each stroke rehabilitation intervention is discussed and presented with a practical recommendation for clinicians working in the field of neurorehabilitation. A decisional tree according to the patient's characteristics is proposed based on scientific evidence available for the different interventions.lack of scientific evidence, if a total number of less than 500 subjects has been included in trials selected in the systematic review. A treatment modality is not recommended as a rehabilitation intervention because of a lack of effectiveness, if (1) it has shown non-superior (similar or inferior) efficacy compared to another rehabilitation intervention and (2) a sufficient amount of evidence is available, defined as a total number of at least 500 subjects included in trials selected in the systematic review. A treatment modality is recommended as a rehabilitation intervention, if it has shown superior efficacy compared to another rehabilitation intervention. A treatment modality is recommended as an adjuvant intervention for rehabilitation treatment, if it has shown superior efficacy in combination with another rehabilitation intervention compared to the other rehabilitation intervention alone. These recommandations as a rehabilitation intervention or as an adjuvant intervention only are issued if a sufficient amount of evidence is available, defined as a total number of at least 500 subjects included in trials selected in the systematic review.This manuscript is based on multiple systematic reviews. Twenty-six different rehabilitation treatment modalities were included and searched for with the following search terms: Bobath, Picard, Perfetti, muscle strengthening, isokinetic muscle strengthening, stretching, bilateral training, forced-use, motor skill learning, constraint induced movement, mirror therapy, motor imagery, motor imitation, movement observation, transcutaneous electrical nerve stimulation, neuromuscular electrical stimulation, positional feedback, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, deep brain stimulation, paired associative stimulation, antidepressants, botulinum toxin, robot-assisted, virtual reality, music. The 26 search terms were chosen by a panel of experts in neurorehabilitation . The systematic database search and article selection was performed by two independent investigators (SH and YB). Each of the 26 search terms was combined with the keyword “stroke” and with each of the following three keywords: “rehabilitation” or “intervention” or “recovery.” The search was performed by a hand search and by using the internet databases: medline and pubmed, retrieving articles from 1971 until May 2015, and yielded a total number of 5712 publications. Exclusion criteria at each stage of the review process are reported in a general prisma diagram. The outcome of this multiple review process includes randomized-controlled trials (RCTs), controlled trials, systematic reviews, and meta-analyses with a PEDro-score higher than or equal to 4  Neurofacilitatory approaches/multiple exercising approaches; (2) Isolated concepts; (3) Motor learning; (4) Interventions based on the hypothesis of mirror neurons and motor imagery; (5) Adjuvant therapies; and (6) Technology-supported training. For each chapter, results of the systematic review are highlighted and in the general discussion, a decisional tree is proposed for therapeutic intervention based on current scientific evidence.The systematic search yielded 5712 publications. After the systematic selection of articles following the general flowchart described in Figure Exercise therapy is a key element of stroke rehabilitation. Exercises performed after stroke may differ with regards to their objectives  or their technical characteristics . These specific elements of exercise therapy are described in a Supplementary Material The Bobath concept was developed by Berta and Karl Bobath. The Bobath treatment aims at normalizing tone and facilitate volitional movement through handling of specific points  in order to guide patients through the initiation and completion of intended tasks Bobath, . Both thn = 475) and 2 systematic reviews/meta-analyses (at least n = 209) (Supplementary Table The systematic review yielded 8 RCTs (n > 500) indicating the non-superiority of Bobath therapy, at present, there are insufficient arguments for integrating Bobath therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence (n = 40) and showing no difference in motor outcomes between Perfetti's method and standard occupational therapy with regards to hand and arm impairments , at present, there are insufficient arguments for integrating Perfetti's method into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (The systematic review with the search term “Picard” did not yield any publications matching the inclusion criteria.n < 500), at present, there are insufficient arguments for integrating Picard rehabilitation into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  have been fully described and their effects tested. These isolated rehabilitation concepts will now be discussed.Muscle strengthening techniques are progressive active exercises against resistance for the paretic arm. These exercises can be performed against a manual resistance (exerted by the therapist) or using weight-bearing apparatus. Muscle strengthening and endurance training in stroke rehabilitation for long have been decried for their supposed induction of spasticity, but now have been recovered as an essential part of the rehabilitation programs offered to brain-lesioned patients  comparing strengthening exercises of the upper limb either to strengthening exercises of the lower limb or to standard therapy. The total number of subjects in these reviews could not be retrieved. There is moderate-quality evidence indicating that strengthening exercises are useful for increasing UE impairments (strength), without or with poor improvement at the level of disabilities, in acute, subacute, and chronic stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of muscle strengthening, muscle strengthening exercises appear to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments.Based on a sufficient amount of evidence , at present, there are insufficient arguments for integrating isokinetic muscle strengthening into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and 2 systematic reviews (n = 1384). There is moderate- to high-quality evidence indicating that stretching is similar to control rehabilitation approaches for treating upper limb impairments  and disabilities in subacute and chronic stroke. No significant effects were found of stretching in comparison with control interventions with regards to passive range of motion, pain or activities of daily living. While manual passive stretching has not been proven effective, physical contentions have shown interest for the treatment of spasticity. Gains of range of motion, with an impact on spasticity and motor impairments have been observed through the use of long-term contention, , notably after injection of botulinum toxin A  indicating the non-superiority of stretching therapy, at present, there are insufficient arguments for integrating stretching into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence , 1 controlled trial (n = 23) and 7 meta-analyses/systematic reviews (at least n = 2240). There is moderate- to high-quality evidence that bilateral arm training (non-device assisted or device-assisted) is similar or inferior to unilateral arm training or to standard rehabilitation treatment. Any gains are specific for the task that is being trained (motor impairment) and do not extrapolate to upper extremity disabilities in daily life. The efficacy of bilateral arm training does not appear to be specific for a post-stroke phase. One study (n = 24) indicates that bilateral training may improve spasticity in chronic stroke  indicating the non-superiority of bilateral training, at present, there are insufficient arguments for integrating bilateral training into stroke rehabilitation with a view to improving UE motor impairments or disabilities.At present, it appears that bilateral training, though based on neurophysiological evidence, does not hold up its promise for clinical purpose. Based on a sufficient amount of evidence . However, in contrast with constraint-induced movement therapy , forced-use is not associated with specific motor skill learning techniques. Restraint of the non-paretic upper extremity is performed without specific training, or using usual care.n = 96). There is moderate-quality evidence that forced-use is similar to standard rehabilitation therapy or to bimanual training with regards to UE motor impairments or disabilities. Randomized controlled studies of forced-use of the UE after stroke are needed.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating forced-use into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (Constraint-induced movement therapy (CIMT) is a therapeutic approach that applies motor skill learning principles to stroke rehabilitation. CIMT is a specialized task-oriented training approach. Its specific strategy is to induce motor learning  and neuroplasticity  with intensive blocks of training. In contrast with forced-used (solely based on the idea of immobilization of the non-paretic arm without specific intervention), CIMT requires both functional training of the affected arm with gradually increasing difficulty levels, and immobilization of the patient's non-affected upper extremity. The original high-intensity protocol of CIMT highlights: (1) repetitive task-oriented practice of the paretic upper limb for 6 h/day during 10 consecutive weekdays; (2) skills achieved in the clinical setting to be translated to the patient's daily real-world environment; (3) constraint of the non-paretic upper extremity to promote the use of the paretic upper extremity during 90% of the waking hours , 1 controlled trial (n = 41) and 12 systematic reviews/meta-analyses (n = 6187).The systematic review  is superior to standard rehabilitation approaches, with regards to upper extremity impairments and disabilities. CIMT appears as beneficial in acute (with a lower dosage regimen), subacute and chronic post-stroke phases. Effects of CIMT may persist till 12 months after training. CIMT can be recommended for stroke patients after 3 months, either in its original design or in modified forms, especially if hand movement is possible. In patients without active hand movement, further studies are needed to confirm the benefit of CIMT. Under 3 months after stroke, the dosage of CIMT needs to be lowered.n = 20) describes the application of motor skill learning outside the context of CIMT  indicating the superiority of constraint-induced movement therapy, at present, CIMT appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor outcome (impairments and disabilities); taking into account the above-described recommendations.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating motor skill learning techniques other than CIMT, into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  networks . This trial gives moderate-quality evidence indicating that movement observation is similar to a “sham” procedure with regards to UE motor impairments and disabilities (except the box and block test which was significantly better till 5 months after exposure). More RCTs are needed to ascertain this conclusion.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating movement observation into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence . Data show that the basic brain circuitry underlying motor imitation coincides with the circuitry active during movement observation. A direct mapping of an observed action and its motor representation seems to occur through interactions in this circuitry , at present, there are insufficient arguments for integrating graded motor imitation therapies into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and 4 systematic reviews (n = 1134). There is moderate-quality evidence that mirror therapy is superior to sham therapy, control therapy  or standard rehabilitation treatment (Supplementary Table The systematic review (Supplementary Table n > 500) indicating the superiority of mirror therapy, at present, mirror therapy appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  is a training method that calls for cognitive rehearsal of activities for the explicit purpose of improving performance of those activities. The movement is not actually produced but is, instead, imagined by the individual  and 5 systematic reviews/meta-analyses (at least n = 1266). There is moderate-quality evidence that mental practice with motor imagery in combination with another rehabilitation treatment is superior to the other rehabilitation treatment alone with regards to upper extremity impairments and disabilities. Mental practice with motor imagery appears as beneficial in the subacute and chronic post-stroke phase.The systematic review (Supplementary Table n > 500) indicating the superiority of mental practice with motor imagery, at present, mental practice with motor imagery appears to be valuable and could be integrated into stroke rehabilitation strategies with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  sensory electrical stimulation; (b) muscle (or motor) electrical stimulation.TENS corresponds to the electrical somatosensory stimulation of a peripheral nerve through the use of cutaneous electrodes. In function of the stimulation, TENS is categorized into high-frequency TENS and low-frequency TENS corresponding to respective stimulation frequencies of 80–100 and 1–5 Hz. High-frequency TENS elicits sensory responses, whereas low-frequency TENS may elicit motor contractions as well. For the latter reason, literature on low-frequency TENS will be discussed in the following section . Electroacupuncture is an electrical stimulation technique based on the application of electrical current at low frequencies (2–3 Hz) during acupuncture needling. The exact mechanisms of action of TENS on motor recovery after stroke are unknown. Most likely, a long-term potentiation-like mechanism in the excitatory glutamatergic connections between the primary sensory and motor cortices mediates the direct effects of repetitive transcutaneous electrical nerve stimulation on corticospinal excitability and motor performance  and 1 systematic review (n = 446). There is moderate-quality evidence that high-frequency TENS (100 Hz) in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairments and disabilities. High-frequency TENS appears as beneficial in the subacute and chronic post-stroke phase. Spasticity appears to diminish with high frequency-TENS.The systematic review  in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairment. Further RCTs are needed to ascertain this conclusion.n > 500) indicating the superiority of high-frequency TENS, at present, high-frequency TENS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairments and disabilities.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating electroacupuncture as an adjuvant therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  over a muscle (neuromuscular endplate) induces muscle contractions at stimulation frequencies of 10–50 Hz. NMES can be used to elicit simple muscle contractions as a passive technique or can be actively triggered by electromyographic activity (EMG-NMES) or by limb position (position-triggered NMES)  and 4 systematic reviews (n = 2293).The systematic review  in combination with rehabilitation treatment is superior to the rehabilitation treatment alone with regards to upper extremity impairment. There is no effect of low-frequency TENS on UE disabilities. Low-frequency TENS does not appear to influence upon spasticity. Further RCTs are needed to ascertain this conclusion.There is moderate-quality evidence that simple/passive NMES in combination with rehabilitation is superior to the rehabilitation treatment alone with regards to upper extremity impairment . There is no effect of simple/passive NMES on UE disabilities. Treatment effects have been described in acute and subacute stroke patients. Simple/passive NMES does not appear to influence upon spasticity.There is moderate quality evidence that EMG-NMES in combination with rehabilitation treatment is similar to the rehabilitation treatment alone or to passive NEMS with regards to upper extremity impairment . However, it is difficult to dissociate EMG-NMES' effects from those of the rehabilitation treatment. There is no effect of EMG- NMES on UE disabilities. Further RCTs are needed to explore the efficacy of EMG-triggered neuromuscular electrical stimulation.The systematic review with the search term “positional feedback” did not yield any publications matching the inclusion criteria.n > 500) indicating the superiority of passive neuromuscular electrical stimulation, at present, passive NMES appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairments.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating low-frequency TENS, EMG-NMES or positional feedback-NMES as an adjuvant therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence  and transcranial direct current stimulation (tDCS) influence the function of the corticospinal tracts by modulating the corticomotor excitability , 4 controlled trials (n = 97) and 5 systematic reviews (n = 1173).The systematic review  is superior to sham rTMS with regards to improving upper extremity impairments. There is no effect of rTMS alone on UE disabilities. Differential effects on UE impairment are obtained according to the type of rTMS that is used  indicating the superiority of repetitive transcranial magnetic stimulation, at present, rTMS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome , taking into account safety guidelines and the differential effects of stimulation protocols.Based on a sufficient amount of evidence (n < 500), at present, there are insufficient arguments for integrating theta-burst stimulation or paired associative stimulation as an adjuvant therapy into stroke rehabilitation with a view to improving UE impairments or disabilities.Based on a lack of evidence  and 4 systematic reviews/meta-analyses (at least n = 455).The systematic review  is superior to sham tDCS with regards to improving upper extremity impairment. There is no effect of tDCS alone on UE disabilities. Differential effects on UE impairments are obtained according to the type of tDCS that is used (for details: Supplementary Table n > 500) indicating the superiority of transcranial direct current stimulation, at present, tDCS appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome , taking into account safety guidelines and the differential effects of stimulation protocols.Based on a sufficient amount of evidence (The systematic review with the search term “deep brain stimulation” did not yield any publications matching the inclusion criteria.n < 500), at present, there are insufficient arguments for integrating deep brain stimulation as an adjuvant therapy into stroke rehabilitation with a view to improving UE impairments or disabilities.Based on a lack of evidence  and noradrenaline reuptake inhibitors (NARI) are the best studied drugs in stroke patients. Other types of drugs have also been assessed for their effects on upper extremity paresis: stimulants (amphetamines and methylphenidate), dopaminergics (levodopa), methylphenidate, trazadone, and nortriptyline , 1 controlled study (n = 64), 1 case-control study (n = 508) and 2 systematic reviews/meta-analyses (n = 5380). There is moderate- to high-quality evidence that antidepressant therapy by SSRIs or NARIs in combination with conventional rehabilitation treatment  potentiates the effect of the rehabilitation treatment alone with regards to UE impairments or disabilities. Treatment effects have been described in acute and subacute stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of antidepressants drugs, at present, antidepressant drug therapy appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor outcome (impairments and disabilities), in depressed as well as undepressed acute stroke patients.Based on a sufficient amount of evidence , 1 controlled study (n = 59) and 4 systematic reviews (n = 4456). There is moderate- to high-quality evidence that botulinum toxin is superior to placebo treatment with regards to UE impairment (spasticity). However, no effect is observed on UE disabilities. There is moderate- to high quality evidence that botulinum toxin in combination with rehabilitation treatment  is superior to placebo treatment in combination with rehabilitation treatment with regards to UE impairment (spasticity). Any effect on UE disabilities appears to depend on the type of concomitant rehabilitation treatment, and not on botulinum toxin itself. Short-term (1–3 months) treatment effects of botulinum toxin on spasticity have been described in acute, subacute and chronic stroke patients.The systematic review (Supplementary Table n > 500) indicating the superiority of botulinum toxin injection, at present, botulinum toxin appears to be valuable by itself with a view to improving UE motor impairment (spasticity) and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view of improving UE motor disabilities.Based on a sufficient amount of evidence , 1 controlled trial (n = 47) and 6 systematic reviews (n = 2587). There is moderate-quality evidence that robot-assisted therapy for the paretic UE is similar or inferior to standard rehabilitation treatment. Any gains that are obtained are specific to the task that is being trained (motor impairment) and do not extrapolate to upper extremity disabilities in daily life. The efficacy of robot-based therapy of the paretic upper extremity does not appear to be specific for a post-stroke phase.The systematic review (Supplementary Table n > 500) indicating the non-superiority of robot-assisted therapy, at present, there are insufficient arguments for integrating robot-assisted therapy for the paretic upper extremity into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a sufficient amount of evidence  frequently is based on the interaction with a two-dimensional virtual environment presented on a computer or television screen.Virtual reality immersion techniques are based on the conjunct use of a computer-generated three-dimensional graphical environments Riva,  and visuThe so-called “serious gaming” may increase patient's adherence and self-management, aid physical and psychological recovery, and enhance patient's and clinician's knowledge in a range of contexts  and 4 systematic reviews (n = 760). There is moderate-quality evidence that virtual reality is similar to standard rehabilitation treatment with regards to UE impairment and disabilities. There is moderate-quality evidence that virtual reality combined with another rehabilitation treatment  is superior to the other rehabilitation treatment alone with regards to UE impairments and activities. Treatment effects have been described in chronic stroke patients.The systematic review . There is moderate-quality evidence that serious gaming is superior to standard rehabilitation treatment or recreational therapy with regards to UE impairment (only two RCTs available). However, further RCTs are needed to ascertain treatment effects of virtual immersion and serious gaming.n < 500), at present, there are insufficient arguments for integrating virtual reality (without another rehabilitation treatment), virtual immersion or serious gaming into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence (n > 500) indicating the superiority of virtual reality as an adjuvant therapy, at present, virtual reality combined with another rehabilitation treatment appears to be valuable and could be integrated as an adjuvant therapy into stroke rehabilitation strategies with a view to improving UE motor impairment and disabilities.Based on a sufficient amount of evidence (Neurologic music therapy (NMT) aims at improving cognitive, sensory and motor function in neurological patients through the therapeutic application of music. Passive music-supported therapy includes auditory-motor synchronization, an entrainment function with rhythmic auditory cueing of movement execution as well as motivational aspects  and 2 systematic reviews (reporting the same results on n = 41). There is moderate quality evidence that passive music-supported therapy is similar to standard rehabilitation treatment with regards to UE impairment. There is moderate quality evidence that active-music supported therapy is superior to standard rehabilitation treatment with regards to UE impairment. Further RCTs are needed to ascertain these conclusions. Treatment effects have been described in acute, subacute and chronic stroke patients.The systematic review (Supplementary Table n < 500), at present, there are insufficient arguments for integrating passive or active music-supported therapy into stroke rehabilitation with a view to improving UE motor impairments or disabilities.Based on a lack of evidence .Rehabilitation approaches recommended as a main rehabilitation intervention on the basis of current evidence for improving UE motor outcome, are: muscle strengthening exercises (impairments), constraint-induced movement therapy (impairments and disabilities), mirror therapy (impairments and disabilities), botulinum toxin (as an intervention Rehabilitation approaches recommended as an adjuvant therapy (combined with another rehabilitation treatment) on the basis of current evidence for improving UE motor outcome, are: mental practice with motor imagery (impairments and disabilities), high frequency-transcutaneous electrical nerve stimulation (impairments and disabilities), passive neuromuscular electrical stimulation (impairments), repetitive transcranial magnetic stimulation (impairments), transcranial direct current stimulation (impairments), SSRI and NARI antidepressants (impairments and disabilities), botulinum toxin (as an adjuvant intervention: disabilities), virtual reality (impairments and disabilities).Rehabilitation approaches that are not recommended on the basis of current evidence because scientific data do not show their efficacy for UE motor outcome, are: Bobath concept, manual passive stretching, bilateral training , robot-assisted therapy for the paretic upper extremity (task-oriented).Rehabilitation approaches that are not recommended on the basis of current evidence because there is insufficient scientific data available with regards to UE motor outcome, are: Perfetti method, Picard method, isokinetic muscle strengthening, device-assisted stretching , motor skill learning techniques (other than CIMT), movement observation, motor imitation, electroacupuncture, low-frequency TENS, electromyography-triggered neuromuscular electrical stimulation, position-triggered neuromuscular electrical stimulation, theta-burst stimulation, paired associative stimulation, deep brain stimulation, virtual immersion, serious gaming, passive music-supported therapy, active music-supported therapy. Large RCTs are needed to confirm preliminary data in these fields.According to the stage of stroke, some rehabilitation concepts may be more appropriate than others. In acute stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement therapy (with a lower dosage regimen), mirror therapy, passive neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, SSRI and NARI antidepressants, botulinum toxin.In subacute stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement, mirror therapy, mental practice with motor imagery, high frequency-transcutaneous electrical nerve stimulation, passive neuromuscular electrical stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, SSRI and NARI antidepressants, botulinum toxin.In chronic stroke patients, the following rehabilitation approaches have been studied and are recommended: muscle strengthening exercises, constraint-induced movement therapy, mirror therapy, mental practice with motor imagery, high frequency-transcutaneous electrical nerve stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, botulinum toxin, virtual reality.For some neurorehabilitation approaches, the severity of initial motor deficit may impact upon the feasibility and effectiveness of the intervention. This is apparent for muscle strengthening exercises, constraint-induced movement therapy and virtual reality interfaces.The following neurorehabilitation approaches may modulate the degree of spasticity: botulinum toxin , and in a lesser way: repetitive transcranial magnetic stimulation, high frequency-transcutaneous electrical nerve stimulation and transcranial direct current stimulation.The following neurorehabilitation approaches that are effective upon the UE motor outcome, do not impact upon the degree of spasticity: muscle strengthening exercises, passive neuromuscular electrical stimulation, mirror therapy, constraint-induced movement therapy, virtual reality.The decisional tree proposed in this manuscript Figure  is basedThis systematic review may present some limitations. Though the investigators aimed at providing a large overview of current rehabilitation techniques for the UE, the specified choice of search terms may have excluded clinical rehabilitation strategies that are unusual in Western-European countries. This review does not include some recent technological advances making their way into clinical rehabilitation such as brain-computer interface based technologies , but subsequent improvements of motor impairment do not transfer to improving motor disabilities in activities of daily living. As an example, the lack of effectiveness of bilateral arm training  stands in contrast with the significant improvement of motor impairments and disabilities by constraint-induced movement therapy applying the premises of goal-oriented motor skill learning techniques. It can be hypothesized that a functional bimanual intensive training without constraint  as a postdoctorate clinical master specialist.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.


Scars are a natural and unavoidable result from most wound repair procedures and the body’s physiological healing response. However, they scars can cause considerable functional impairment and emotional and social distress. There are different forms of treatments that have been adopted to manage or eliminate scar formation. This review covers the latest research in the past decade on using either natural agents or synthetic biomaterials in treatments for scar reduction. Scar tissue forms in injured areas of human bodies and replaces cells that have been destroyed. It appears either inside the body or on the skin. Scar tissue on the skin looks different from the surrounding area; while inside the body, scar may cause adhesion between tissues and organs or fibrosis. Scar causes functional impairment and emotional distress, thus the pre- or post-scar managements are important .A scar is caused by the overgrowth of a tissue after an injury, burn, or surgical incision, demonstrating an exuberant healing response which determines type of scars: hypertrophic and keloid. Hypertrophic scars do not extend beyond the wound borders while keloid scars do. Hypertrophic scars are more favorable than the keloid scars clinically as they are more manageable in treatment and are often more spontaneous in regression. In a keloid scar, thicker and more irregularly arranged collagen often with pain is observed. For a hypertrophic scar, however, patients encounter thinner and more parallel arranged collagen in scars. Moreover, hypertrophic scars arise in all races with low probability in young and aged people . Keloid Wound healing is an intricate and dynamic process of devitalized and damaged cellular constructs and tissue layers replacement that normally occurs through the scar tissue formation. Wound healing process of a human adult can be classified into three distinct phases: (1) inflammatory, in which damaged and dead cells, along with pathogens or debris, are cleared out via the phagocytosis. Platelet-derived growth factors are released that cause the cells migration and division during the proliferation; (2) proliferation or new tissue formation and angiogenesis, collagen regeneration, growth of granulated tissue, epithelialization, and wound contraction occur; (3) remodeling stage, in which collagen is orientated along tension lines, and non-viable cells are removed by apoptosis. A number of growth factors and cytokines have been reported to be involved in the wound healing procedure through different biochemical pathways .Scar formation is a prevalent, undesirable consequence of most wound healing events, along with significant psychological, emotional, and social problems –6. It isIn addition, many different techniques to treat scars have been developed, including laser therapy, diverse types of sutures, and radiation therapy. However, fewer methods have been surveyed for cutaneous scar prevention. For instances, Barbed sutures as a self-anchoring and knotless option were evaluated in surgery clinically and were shown to provide comparable performance and safety as compared to conventional wound closure techniques . SpencerNumerous documents have been found on wound treatments, but not much of them considered a scarless healing or scar minimization . PharmacNaturally derived materials have long been used as a substantial source of medicines. Natural materials are still considered as ideal sources for a broad range of diseases. Pycnogenol, an extract from French maritime pine bark containing a mixture of procyanidins, was reported as a wound healing accelerator and scar formation reducer. Pycnogenol was suspended in a polyacrylic acid hydrogel and tested in vivo. Pycnogenol was found to decrease oxidized ascorbate and, consequently, to provide inhibitory effect on matrix metalloproteinases and to support collagen matrix formation. .Relaxin was tested on rodent wound healing: Juvenile pigs were used for an investigation of scar reduction and cosmetic outlook because of their similar healing mechanism to human. It was demonstrated that wounds treated with relaxin have less granulation and inflammation, and more well-knit collagen framework, representing that relaxin boosts the normal wound repair procedure by increasing angiogenesis, reducing scar formation and granulation tissue, and contributing to a well-organized collagen structure .Astragalus membranaceus (AR) incorporated in a hydrophilic foam dressing is effective in increasing the closure of rats’ acute open wounds. AR was found to suppress inflammation and promote basal cell proliferation, angiogenesis, and linear alignment of the granulation tissue and, consequently, to result in faster wound healing procedure [The effect of natural materials on decreasing the scar size has been illustrated in many studies. Han and colleagues reported that topically applied extract from the root of rocedure .Chen et al. further revealed the healing and anti-scar effects of astragaloside IV on the wound cure improvement in vitro and in vivo. It was reported that astragaloside IV can inhibit the transforming growth factor beta 1 (TGF-β1) secretion and improve healing. In addition, it can regulate collagen type I/type III ratio in the remodeling phase to reduce scarring .Li et al. examined the effect of crocodile oil in enhancing wound healing process and decreasing scar formation in rats. They found that crocodile oil significantly decreased the messenger ribonucleic acid (mRNA) expressions of TGF-β1and Smad3, which are the key cytokines that play a role in accelerated wound healing and less scar formation .Another natural therapeutic agent which has been found to have anti-inflammatory and antioxidant characteristics, curcumin, was recently tested on rabbit ear wounds, suggesting that the systemic administration of curcumin improves lesion repair and reduces scarring. Curcumin was found to suppress TGF-β1/SMAD pathway and extra cellular matrix (ECM) production in primary keloid fibroblasts and reduce pro-inflammatory cytokines, interleukins , which directly decrease hypertrophic scarring .Honey, a traditional medical ingredient known for thousands of years, was reviewed for its healing and anti-microbial capacities. Honey stimulates monocytes (MM6 cells) to secrete cytokines, tumor necrosis factor alpha (TNF-α) and IL-1 and IL-6, which triggers the immune reaction to infection. Honey helps collagen IV degradation via the matrix metalloproteinases 9 (MMP-9) stimulation during the reepithelialization phase of wound healing . PreviouOn the other hand, some scientists are interested in modulating and stimulating wound healing signal pathways by using bioactive substitute such as proteins, enzymes, or growth factors. c-Ski is a tissue repair-related gene that is mostly expressed in fibroblasts during the cell proliferation stage of wound healing; Liu et al. suggested that c-ski is capable of controlling scarring in wound repair by modulating fibroblast functions. They studied the effects of c-Ski on skin fibroblast proliferation, collagen type I secretion, and myofibroblast differentiation . The samShi et al. worked on Jun amino-terminal kinases (JNK) signaling to mediate healing of corneal wound via expression of connective tissue growth factor, thus demonstrated that JNK can potentially serve as a new strategy to help in corneal scar reduction . The effRecently, wound healing and scarring was studied from a membrane repair gene, MG53 point of view. The study established that MG53 can be a facilitator of injury repair and inhibitor of myofibroblast differentiation and an effective means for promoting scarless wound healing .Generally speaking, the pharmaceutical products studied for their effects on promoting wound healing and scar formation do not have strong evidence to support their efficacy. On the one hand, more studies are necessary to examine their efficacy and biochemical mechanism in terms of the roles they played in wound healing and scar management. On the other hand, these pharmaceutical products have to be used in combination with dressing or scaffolding biomaterials in wound care, which will be discussed in the next section.To improve the traditional scar management, new advanced wound dressings have been developed to increase wound healing capacity. The biomaterials composed of natural polymers and bioactive molecules briefly summarized in Table A number of biopolymers derived from natural resources have been used in wound care for reducing scar formation. As described by Hu et al., fetal tissue heals rapidly without scarring due to the higher levels of hyaluronic acid (HA) in ECM as compared to adult tissues. Therefore, they observed that HA strand grafts enhanced wound closure rate and reduced the scar area remarkably by reducing TGF-β1 level in the wound . InjectaGenipin cross-linked gelatin (GCG) and collagen sheets were analyzed on minimizing invasion and scarring of the nerve and open wound healing in vivo. It was reported that GCG can be a beneficial aid for scarless nerve regeneration and lead to desirable nerve functional recovery .Czaja et al. studied microbial cellulose and its effect on patients with second-degree facial burn. Compared to a standard technique with moist gauze dressing and ointment, the dressing considerably promoted the healing rate in deep facial burns. A decrease of pain and reduction of scar tissue formation were also observed for wounds treated by the microbial cellulose dressing. The moist environment created using the dressing facilitates necrotic debris removal, new cell migration and growth, and prompted reepithelialization .Another trial was done on collagen membrane cross-linked with glutaraldehyde as a wound dressing for surgical defects of the oral mucosa. Based on the study, it was an excellent wound graft material for oral scar reducing; however, there was some contraction and moderate scarring in some patients who lost their collagen membrane early. This graft was reported to control infection in primary healing stage and to reduce growth of granulation tissue, leading to less scarring and short healing duration .Electrospun nanofibrous dressings composited of silk fibroin/gelatin and cellulose acetate have been examined in vivo and in vitro to prove their functionality in mimicking skin regeneration and in reducing scar formation , 39. WouRecently, there have also been work that employed wound dressings incorporated with drugs or bioactive molecules to enhance their capacity in scar management. It was demonstrated that the genipin-modified collagen sheets are effective in reducing scars in first- and second-degree burns , 41. ColKim et al. developed a polyvinyl alcohol–sodium alginate gel-matrix-based wound dressing structure containing nitrofurazone, which performs a positive healing and less scarring effect as compared with wound dressing without nitrofurazone. The drug-loaded hydrogels, as a biodegradable and nontoxic polymeric matrix, keep wound moist and prevent secondary damage when dressings are changed. They show mild positive effects on inflammatory phase and create reduced wound size with new epithelium noted at the edge of the defects .A multifunctional acellular biologic scaffold was combined with wound dressings which has selective delivery and release of shielded biomaterials and bioactive substances. It can be used in wounds or damaged tissues for scarolysis and eliminating dead debris. It was suggested that these scaffolds help in vascularization, blood vessel formation and keep body temperature .In addition, Morton and Philips investigated a wound dressing which decreases scar formation by keeping moisture in the wound . Some coOther groups reported efficiency of electrospun nanofibers and hydrogels for the treatment of diabetic ulcers. Particularly, nanofibrous meshes immobilized with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), and dressings composed of polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and agar were studied to reveal their efficacies in reducing scarring –48.In the past year or two, more advanced approaches have been employed in the prevention and minimization of scars. Some in vitro biomaterial membranes studies specialized in scar prevention application such as ginsenoside Rg3-loaded electrospun poly(lactic-co-glycolic acid) (PLGA) fibrous membranes as cutaneous wound cover . As a reIn another study, Norfloxacin-loaded collagen/chitosan scaffold was found to enhance the rate of wound healing with unnoticeable inflammation and scarring by controlling infection which contribute to lower inflammation, higher new cell growth and faster wound closure .Blount and Harding developed a bioelectric dressing and tested it in vivo, resulting in faster wound epithelization and improved scar appearance. Specifically, a single-layer dressing was constructed from a polyester fabric containing elemental silver and zinc microcells held in position by a biocompatible binder which produced microcurrent using conductive fluid. The created microcurrent promoted collagen synthesis and reepithelialization rate , 52.There has also been a large amount of work involving the use of biomaterials incorporated with viable cells (including stem cells). Such tissue engineering approaches for scar management will be discussed in the next section.Cell therapy combined with scaffolding biomaterials have been employed in tissue engineering approaches for wound care and scar management.Zaulyanov and Kirsner reviewed Apligraf, a bi-layered bioengineered skin substitute, the first of its kind approved by the US Food and Drug Administration (FDA) for treating venous leg ulcers and diabetic foot ulcers. The graft is developed from neonatal cells and may stimulate a more fetal-like scarless wound healing, therefore may result in better cosmetic appearance .In another research, clinical outcomes of cultured epithelial autografts were investigated on facial skin defects. Although the cell cultures of an epithelial autograft did not fully meet the demands of the patients, especially in the younger patients with facial skin defects, it did reduce and improve scarring. As a result of using the autograft, faster vascularization, epithelial cells proliferation and migration have been observed in wounds .To date, there have been extensive studies on tissue engineering and stem cells application in wound treatment and scar decreasing. Dermal and epidermal substitutes have been developed to help facilitate reepithelialization but still fail to reconstruct the appearance of the skin to its pre-wounded state . CellulaScientific findings in wound and scar management were highlighted by developing biological treatments with fetal cell therapy –59. FetaThere has also report on the capacity of mesenchymal stem cells (MSCs) in attenuating scar formation during wound healing by promoting angiogenesis and modulating the inflammatory responses . WilliamPolyhydroxybutyrate-co-hydroxyvalerate constructs loaded with adipose-derived stem cells (ASCs) were shown to maintain the wound moisture and assert appropriate mechanical properties to endure wound contraction. Furthermore, exudate and inflammatory cell infiltration were found to promote the structure degradation and, consequently, improve scarless repair. The scaffold was found to promote expression of VEGF and bFGF with the presence of ASCs for appropriate blood vessel formation and played an important role in scar formation management by regulation of TGF-β1, α-SMA, and TGF-β3 .In this review, we have covered the methods and technologies in scarless wound healing in the past decade. Extensive studies have been concentrated on treatment rather than prevention and minimizing of postsurgical and traumatic scars; however, here, we have discussed several investigated ways and wound managements which are more likely to provide better cosmetic outcomes by scar reduction. Generally, understanding different types of treatments in human wound healing process in order to perfectly regenerate their missing cell and tissue may propose strategies and methods for maximizing healing benefits and decreasing scarring. To attain these goals, future research should aim to identify critical factors in tissue repair and regeneration. It is plausible that this will pave the way forward in future developments for more advanced methods that will tackle the problems of scarring.


Although the kidney has capacity to repair after mild injury, ongoing or severe damage results in scarring (fibrosis) and an associated progressive loss of kidney function. However, despite its universal significance, evidence highlights a population based heterogeneity in the trajectory of chronic kidney disease (CKD) in these patients. To explain the heterogeneity of the CKD phenotype requires an understanding of the relevant risk factors for fibrosis. These factors include both the extrinsic nature of injury, and intrinsic factors such as age, gender, genetics, and perpetual activation of fibroblasts through priming. In many cases an additional level of regulation is provided by epigenetic mechanisms which integrate the various pro-fibrotic and anti-fibrotic triggers in fibrogenesis. In this review we therefore examine the various molecular and structural changes of fibrosis, and how they are influenced by extrinsic and intrinsic factors. Our aim is to provide a unifying hypothesis to help explain the transition from acute to CKD. When a mild or an acute kidney injury (AKI) occurs, tissue repair mechanisms are usually able to restore function. This wound repair consists of consecutive but overlapping events; inflammation, extracellular matrix (ECM) synthesis (fibrogenesis), resolution, regeneration, and remodeling . While tIf repair mechanisms are disrupted, or the injury-causing stimulus persists, AKI can progress into a chronic disorder, characterized by non-recoverable organ remodeling and scarring (fibrosis) . HistoloIn this review we focus on the pathogenesis of tubulointerstitial fibrosis due to its universal significance, and resemblance to fibrosis in general.de novo expression of alpha-smooth muscle actin (αSMA) with an activated phenotype. This so-called myofibroblast is characteristically hyperproliferative, contractile and fibrogenic. Similar phenotypic transitions occur in tubular epithelial cells  and interstitial fibrosis . Damaged tubules also release cytokines and pro-fibrotic signals that activate adjacent fibroblasts . The othal cells  and glomal cells , highligAt the molecular level, fibrogenenic cell activation is a predominantly cytokine driven process. Signals can be specific to the injury or derived from the uremic milieu systemically. Regardless, in each case the AP1 transcription factor c-Jun seems to be a central molecular mediator of fibroblast activity in multiple organs .Figure 1).Since the landmark studies of Border and colleagues demonstrating a role for transforming growth factor beta 1 (TGF-β1) in glomerulosclerosis , a multiFigure 1). Recent findings also suggest that the paracrine fibroblast growth factor 23 (FGF23) signaling may be relevant to fibrogenesis. FGF23 was originally described as a bone-derived member of the endocrine FGF family known to regulate mineral handling. Circulating levels of this hormone rise early in chronic kidney disease (CKD) and are predictive of disease progression. Whilst the factors driving this increase from bone are partially understood, de novo expression in the kidney has also been noted following injury, leading to speculation about its functional significance in this context   and angi context . Trying in vitro .Figure 1) is borne out in epidemiological studies which show that the likelihood of progression in humans can be modeled by variables including age, gender and baseline renal function , meaning that we have robust and reproducible experimental models to investigate specific risks for progression of fibrosis.The importance of several modifiable and unmodifiable risk factors .While risk estimates based on the above factors allow accurate discrimination of those who are likely to progress over a 5-year period , they doEpigenetics refers to stable changes in gene activity that are heritable in cell division, but do not involve changes in the DNA sequence . EpigeneOften referred to as a second genetic code, epigenetic regulation of renal gene expression involves multiple mechanisms including post-replicative DNA methylation , RNA intEpigenetic regulation can occur via direct modification of genomic DNA. In this case DNA is methylated by the attachment of a methyl group to the 5′ position of cytosine residues in specific regions of DNA where cytosine and guanosine are separated by a single phosphate group (CpG sites). CpG methylation generally leads to transcriptional repression of genes . Interesin vivo by selectively inhibiting myofibroblast proliferation  which are small (19–25 nucleotides) RNA molecules that cleave or translationally repress targeted mRNA, and are well-described in kidney disease  and tranferation .Recent attention has focused on the significance of post-translational histone modifications (marks) in the kidney. Nucleosomes consist of chromosomal DNA wrapped around core histone subunits . These histones also have a flexible N-terminus tail of amino acids that extends from the nucleosome and can be post-translationally modified by phosphorylation, sumoylation, ubiquitination, acetylation (Ac), and methylation (Me). Modifications to the amino acid Lysine (K) on H3 and H4 histone tails have proven to be particularly relevant in fibrogenesis. Acetyl groups are added by the actions of various acetyl transferases (HAT) and removed by histone deacetylases (HDAC), with net enrichment a balance between the activities of these enzymes. Likewise, methylation is under the control of various methyl transferases (MHT) and their corresponding demethylases (HDM). Unlike acetylation however, more than one methyl group can be added meaning that histones can be mono- di- or tri- methylated. These histone modifications are docking sites for various proteins including co-activators, co-repressors, chromatin remodeling proteins. Their interaction with specific gene promoters form a pattern that regulates transcription . Enrichmin vivo . A better understanding of specific modifiable risk factors will excitingly provide new targets for therapeutic intervention.While the kidney can recover from acute and limited damage, critical illness or a persistent injury leads to a complex chain of direct and indirect sequelae resulting in chronic progressive renal impairment without repair. Severe and ongoing injury, influenced by susceptibility and epigenetics, leads to priming, feed-forward induction, and perpetual activation of fibroblasts, and a failure to return to tissue homeostasis through repair. This model provides a unifying hypothesis helping explain the transition from AKI to CKD (TH, SH, and ES contributed to writing of manuscript, gave final approval and are responsible for the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BHA and handling Editor declared their shared affiliation, and the handling Editor states that the process met the standards of a fair and objective review.


Plants have endogenous biological clocks that allow organisms to anticipate and prepare for daily and seasonal environmental changes and increase their fitness in changing environments. The circadian clock in plants, as in animals and insects, mainly consists of multiple interlocking transcriptional/translational feedback loops. The circadian clock can be entrained by environmental cues such as light, temperature and nutrient status to synchronize internal biological rhythms with surrounding environments. Output pathways link the circadian oscillator to various physiological, developmental, and reproductive processes for adjusting the timing of these biological processes to an appropriate time of day or a suitable season. Recent genomic studies have demonstrated that polymorphism in circadian clock genes may contribute to local adaptations over a wide range of latitudes in many plant species. In the present review, we summarize the circadian regulation of biological processes throughout the life cycle of plants, and describe the contribution of the circadian clock to local adaptation. CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), PSEUDO RESPONSE REGULATOR (PRR) family genes, TIMING OF CAB EXPRESSION 1 (TOC1), GIGANTEA (GI), EARLY FLOWERING (ELF) genes, and LUX ARRHYTHMO (LUX), which form multiple interlocked negative feedback loops  genes, LIGHT-REGULATED WD (LWD) genes, and NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED (LNK) genes have also been identified  and the bean Phaseolus vulgaris, stomatal conductance is higher during the day than at night  for photoperiodic flowering  achieved genome-wide identification of the direct regulations of clock-output genes by some of the core clock components (Ezer et al. As described above, polymorphism in the circadian clock genes may contribute to the adaptation to local environments. Indeed, many domesticated crops contain mutations in the core clock genes, resulting in the optimized flowering time (Nakamichi