LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient’s derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2–3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 ( Parkinson’s disease (PD) is the most common movement disorder and the second most frequent neurodegenerative disease affecting more than 6.5 million people worldwide , represeEssay on the Shaking Palsy and later on refined and expanded by Jean-Martin Charcot who named the disorder “malaldie de Parkinson” pars compacta (SNpc) located in the mesencephalon and the consequent striatal dopamine (DA) deficit that leads to the classical motor symptoms of the disease  in the  disease . In addi disease . The agg disease .The dramatic loss of DAn in the SNpc, even in early stages of the disease, suggests that the degeneration in this region starts long before the motor symptoms appear . In thisIn this scenario, it is now widely accepted that PD is not a movement disorder simply induced by the loss of the DAn in the SNpc. The SN is not the only damaged region in PD, nor the first affected one. Brain sites other than the SN, such as the cerebral cortex and the limbic system, have also been reported to be impaired in patients during the presymptomatic phase . In factParkinson’s disease was thought to be primarily caused by environmental factors, but research reveals that the disease develops from a complicated interplay of ageing, genetics and environment. In fact, the vast majority of cases occur sporadically and genetic forms of the disease account for about 10% of patients .In general, the average age of onset of PD is the late fifties, with a broad range from <40 to >80 years of age depending, among others, on its pattern of inheritance. Young-onset PD is commonly defined by an age of onset <45 years and >10% of these cases have a genetic basis; the proportion of genetically defined cases rises to >40% of those with disease onset before 30 years of age .The greatest risk factor for the development of neurodegenerative diseases, including PD, is ageing . IncidenGender has also been reported to be a risk factor for PD, with approximately a 3:2 male-to-female ratio. Sex hormones have been proposed to play a neuroprotective role in the disease. In case of female hormones, the antioxidant capacity of estradiol, for instance, has been proposed to prevent neurodegeneration . Interes2+ that promotes cell death and the promotion of oxidative stress responsible of cell damage, all hallmarks of PD pathogenesis.Other risk factors for PD are directly associated with environmental features are pesticide exposure, rural living, agricultural occupation, well-water drinking, prior head injury and β-blocker use. A special mention must be done for exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP), with similar structure of some herbicides that increase the risk of PD, due to its historical importance. Since its incidental discovery in drug abusers after inadvertent self-administration, MPTP has been widely used to induce PD in animal models . MPTP isIn contrast, tobacco smoking, coffee drinking, non-steroidal anti-inflammatory drug use, calcium channel blocker intake, and alcohol consumption have been associated with a decreased risk of PD development .Additionally, the incidence of PD seems to vary within different ethnicities. The prevalence of PD is high in Ashkenazi Jews of Israel, Inuit, Alaska native and native American populations  and onlyThere are two different classes of genetic contributions to PD: gene mutations directly associated to genetically inherited forms of PD and genetic variations, indirectly accounting for risk factors of disease.SNCA, the gene encoding for the α-synuclein protein, caused PD and the demonstration that α-synuclein was the major component of LB  and Parkin (PRKN) genes emerge amongst the most frequent forms of autosomal dominant and recessive forms of PD, respectively.The discovery of the molecular pathways orchestrated by proteins encoded by these genes associated with monogenic forms PD, have reinforced the notion that impaired mitochondrial and autophagy homeostasis are key events in disease etiology . In factWith respect to the second, genetic risk factors of PD account for the rest of 90–92% of non-inherited cases of PD, so-called idiopathic. They are caused by the complex interplay of an array of unknown factors, a part from the numerous genetic risk factors of PD see : modifyiThe definition of genetic and environmental cues in the development of PD is one of the novel areas of study in which growing and coming efforts should be focused and, probably, thanks to the development of new generation sequencing tools, the discovery of novel gens responsible of PD will arise, together with new putative genetic risk factors, thus reducing the number of idiopathic PD cases.locus and symbol have been described, together with the protein encoded by the gene and the function it exerts (the cell pathway governated), as well as the kind of PD associated to the genetic mutation or variation . Among these entities, LRRK2 and PRKN genes emerge amongst the most frequent forms of autosomal dominant and recessive inherited-forms of PD, respectively.post-mortem. In addition, by the time that clinical symptoms manifest, most of the cells targeted by PD have already been lost , which is currently only available een lost . Thus, ftly used .in vivo, partially reproducing the specific pathogenic events and behavioral outcomes of the disease. In fact, after the study of brain necropsies from PD patients, much of the current understanding of the etiology and the pathogenesis of PD has been obtained from the study of neurotoxin-based animal models  have been used to generate the most robust and clinically useful models of PD. The current gold standard animal model of PD is a toxin-based NHP induced model, which shows stable, bilateral clinical features that closely resemble idiopathic PD  and may The development of experimental models to elucidate disease etiology, find novel diagnostic/prognostic biomarkers and assay new therapeutic strategies remains as one of the most challenging gaps in PD research.The use of toxic or genetic animal models of disease has strengths as reproducing the complex interplay between different neural and non-neural brain cells directly in the target tissue of the disease, and the assay of different therapeutic approaches in physiologic context. Unfortunately, in parallel, animal models fail to recapitulate important hallmarks of PD as clinical and anatomopathological features. Other weaknesses, a part of ethical concerns, high economic and facility costs, are that most of them fail to reproduce the influence of aging, epigenetic, and genetic modifying factors characteristic of PD patients. Novel cell models overcome part of these limitations.Immortalized cell lines of neural origin, either animal or human, that can also be subjected to toxin exposition or gene editing, have been widely used to model PD . These cHowever, immortalized cell lines are also associated to important weaknesses including the presence of genetic instability or the high rate of glycolytic metabolism which pushes toward the use of patient-derived cell models .The fact that the greatest proportion of PD is of unknown cause and the urgent need to find novel biomarkers at the prodromal phase of the disease has encouraged the development of specific patient-derived models. The advantages of these patient-derived cell models is that they recapitulate PD pathogenicity at an individual basis, thus partially circumventing the drawbacks of animal and established cell line models . In thisin vitro by reprograming somatic cells from patients with the disease  shooting .Additionally, and despite being an exciting prospect for PD research, stem cell-derived neural lines and iPSC technologies have some other important inconveniences, including a considerable phenotypic variability unrelated to their genotype and their high maintenance costs and time-inefficiency . AdditioAs previously mentioned, accumulating evidences suggest that PD is a multisystem disorder rather than a solely dopaminergic motor syndrome that encompasses central and peripheral clinical features . In lineThe use of patient skin-derived fibroblasts has been widely utilized to model numerous diseases of metabolic, neurodegenerative, and lysosomal origin . For mitStudies in skin-derived fibroblasts from patients with sPD have thrown relevant and consistent information regarding molecular pathways altered in this type of neurodegeneration. A recent study showed that fibroblasts from sPD patients have higher growth rates, altered morphology, increased mitochondrial susceptibility to UV-exerted stress and autophagic alterations .SNCA gene expression up-regulation  and autophagic failure, emerge as key players in PD development. However, there are different schools of thought regarding the triggers of the disease. Two main hypotheses raised: according to the “protein depot cascade hypothesis,” alpha-synuclein and other misfolded proteins stored as protein depots in neurons are the cause of PD. Other stand for the “mitochondrial cascade hypothesis,” that foresees the origin of PD in a defect in the oxidative phosphorylation (OXPHOS) system. Interestingly, protein deposition and bioenergetics appear to be closely related. Thus, alpha-synuclein can reduce OXPHOS function and OXPHOS deficiency can increase alpha-synuclein production .In line with the “mitochondrial cascade hypothesis,” some primary mitochondrial diseases caused by monogenic mutations in mitochondrial-related genes that usually translate to OXPHOS deficiencies, clinically manifests as brain disease such as neurodegeneration and parkinsonism . In factThe study of mitochondrial contribution to PD and other neurodegenerative diseases has been widely validated by the use of cybrids . They alMitochondrial function is essential in almost all cells of the organism, but specially in neurons. There are different reasons to explain their dependence on proper mitochondrial function, controlled oxidative stress production and adequate mitochondrial replacement through autophagy.Neural metabolism is highly oxidative. Glucose is the obligatory energy substrate of the adult brain. However, under certain circumstances the brain has the capacity to use alternative blood-derived energy substrates, such as ketone bodies (during starvation or development)  and lactMetabolic oxidative activity of neurons explains they dependence on mitochondria to obtain energy. Noticeably, brain is one of the highest energy-demanding organs of the body due to the its intrinsic physiological activity. It is constituted by postmitotic cells (neurons) with less capacity for cellular regeneration compared to other organs. Thus, it is believed to be particularly vulnerable to mitochondrial dysfunction, ROS damaging effects and detrimental autophagic renewal of cell components, that may explain why is prone to manifest clinical evidences of mitochondrial, oxidative or autophagic alterations . This isIn this scenario, mitochondrial dysfunction, associated oxidative stress and autophagic development becomes critical for neuronal survival. Several lines of evidence have implicated mitochondrial dysfunction as a key element in PD pathogenesis. Reduction of mitochondrial CI activity has been reported in several tissues isolated from PD patients including the CNS . In addiUnfortunately, when postmortem brain tissue of PD patients is studied, most of DAn have disappeared , thus diAs previously mentioned, initial models of PD were developed by using MPTP, a mitochondrial neurotoxin that specifically targeted DAn in primates and mice which was discovered to produce parkinsonism in humans . MPTP-bain vitro abnormal accumulation of this protein has proven to lead to mitochondrial CI dysfunction and associated oxidative stress, importantly linking these two events that have been repeatedly reported in PD  is located in chromosome 12, contains 51 exons and spans a genomic distance of 144 kb that includes 7500 nucleotides of coding sequence. Up to date, about 80 “probably pathogenic” and seven pathogenic LRRK2 mutations have been described, being the G2019S (G2019S-LRRK2) the most frequent pathogenic mutation , which is also known as dardarin, from the Basque word “dardara” which means trembling. LRRK2 has the particular feature of encoding a leucine-rich repeat (LRR), a ROC-COR GTPase, a mitogen-activated protein kinase, and WD40 domains in the same protein  presents with a PD-typical phenotype with no sex association. A large systematic review of LRRK2-PD case reports that age of onset is around 57 years, with a mean disease duration of 10 years. The cardinal PD symptoms were reported with the following frequency: bradykinesia in 99%, rigidity in 99%, tremor in 88% and postural instability in 65%, while atypical signs of PD have been reported only anecdotally. In addition, autopsies of such patients showed prominent loss of melanized DAn in the SNpc , lipid rafts, microtubule associates vesicles, Golgi complex, and the endoplasmic reticulum , Mitofusin (MFN1) and 2 and optic atrophy1 (OPA1) . Thus, Ldynamics . This hypatients  and in dpatients . Such stpatients . In addipatients .LRRK2-fibroblasts at baseline and under conditions of pharmacological stress. The most common pharmacological approaches used to date include mitochondrial toxins such as MPTP, valinomycin, oligomycin, CCCP, and rotenone. As these approaches may mimic mitochondrial toxicity, they are far from dissecting the mitochondrial pathways affected under physiological conditions , with patients harboring G2019S-LRRK2-mutation and clinical manifested PD. Interestingly, fibroblasts of NMC showed an enhanced mitochondrial performance upon forcing mitochondrial oxidative metabolism with galactose and upregulation of autophagy . These fOther forms of PD have also been genetically associated to mitochondrial and autophagic imbalance, in this case through a recessive inheritance. This is the case of PRKN.PRKN is mapped to the telomeric region of the long-arm of chromosome 6. More than 170 different mutations have been identified throughout the sequence of this particularly large gene (1.35 Mb) ranging from point and missense mutations to large deletions or multiplications and small deletions/insertions (PRKN coregulated gene (PACRG) result in the same early onset parkinsonism phenotype  followed by three really interesting new gene (RING) finger domains (RING 0–2) separated by an In-Between-RING (IBR) domain in the COOH-terminal part, each of which bind two Zn2+   . PARIS rAmongst all the studies using skin-derived fibroblasts as a cell model for PRKN-PD, it is worth stressing that many of them have focused on studying mitochondrial function leading to controversial outcomes.PRKN-PD fibroblasts, while Alterations in the enzymatic activities of the MRC have been previously reported in PRKN-PD fibroblasts . MortiboMitochondrial membrane potential has also been widely explored as a general marker of mitochondrial integrity in PRKN-PD fibroblasts. While two authors were not able to demonstrate alterations in this parameter , others PRKN-PD fibroblasts studies but with controversial results  may partially account for the large variation obtained. For instance, the use of different high-resolution respirometry approaches in which oxygen consumption is measured from seeding fibroblasts or from cells in suspension. Similarly, assessing MRC enzymatic activities in intact cells or in mitochondrial enriched fractions may contribute to outcome disparities. Moreover, all the studies were performed in glycolytic conditions that may partially unveil mitochondrial deficits and contribute to controversy . In thisPRKN-PD fibroblasts has proved to be contentious, with several groups either describing similar defects or no apparent abnormalities. It would be of great importance that researchers join efforts on homogenization of protocols and analyzing a more significant number of PRKN-PD patient-derived cells in order to unveil if mitochondrial and autophagic dysfunction is a crucial event in PRKN-PD pathogenesis.In summary, the particular area of research focused on the study of mitochondrial function in Since the disseverment of PD, different therapeutic options have been developed to ameliorate the symptoms of PD. The first one to be developed was levodopa, in 1960, a precursor that is transformed to DA in the brain, supplying the amount of DA that degenerated neurons are not able to produce. Other medications include DA agonists and monoamine oxidase-B (MAO-B) or Catechol-O-methyltransferase inhibitors (COMT) inhibitors, selegiline, and rasagiline, that decrease the activity of MAO-B, enzyme responsible of degrading DA. There are also other options to severe cases who do not respond to DA based on the use of apomorphine and duodopa administered by pumps, surgical interventions or deep brain stimulation .However, these treatments are supportive, only control the symptoms of the disease, the neurodegeneration is not stopped or reversed, consequently, there are no curative treatments for PD.To unveil the pathophysiology of the diseases and develop new therapeutic strategies to reduce the impact of PD and find a cure is essential to develop novel models of disease.The experimental models herein discussed hold potential for the development of PD modifying therapies. The complementary assay of any potential candidate in different experimental models confers strength to the potential therapeutic efficacy before translation into the clinical settings. Patient-derived cell models offer usefulness either as platforms for testing novel therapeutic approaches or for prompting the discovery of novel targets from disrupted pathways reported in these models.LRRK2-PD carriers, where the use of LRRK2 inhibitors has been proposed. They are currently being tested in clinical I trials. Unfortunately, their systemic action may unveil secondary effects, somehow bypassed by the targeting of specific neural effectors (as PAK6 or Rab GTPases) to modulate neural disrupted protein and organelle trafficking in PD , that still rank in experimental settings , disease modification through neuroprotection remains as the main milestone in PD research. Neuroprotection tested by pramipexole (CALM-PD), ropinirole (REAL-PD), and pramipexol (PROUD-PD) failed to establish disease modification . In thisAdditionally, aiming to support neuroprotection through the enhancement of neuronal viability, trophic factors are also being evaluated in PD, showing moderate or null therapeutic success. Of them, glial family ligands as glial derived neurotrophic factor (GDNF) and neurturin in preclinical studies demonstrated strong neuroprotection in multiple animal models. However, multiple clinical trials, including 2 phase II trials, failed to demonstrate their efficacy or showed significant side effects .Alpha-synuclein has become lately the major target for PD therapeutics. Initial preclinical efforts concentrated on synuclein-lowering treatments such as siRNAs directed against alpha-synuclein, that resulted toxic in animals. Novel attempts focused to disaggregate aggregated synuclein, facilitate its clearance by augmenting autophagy pathways, or using antibodies to prevent its propagation from the periphery to the brain and once in the brain across the neural axis. Vaccines against alpha-synuclein as both active and passive immunization approaches have been attempted. Active immunotherapy attempts to stimulate the immune system against specific antigens . PassiveProbably the next coming years will open future perspectives for the development of new supportive and curative therapies in PD, where personalized medicine, mainly based on genetic and molecular counseling, will help to direct specific PD patients to a wide panoply of therapies.The development of novel therapeutic options will depend of the efficacy of candidate compounds previously tested in preclinical settings and experimental models of disease, as the herein described, and the target of disrupted pathways, as the herein explained.LRRK2 and PRKN genes. These findings demonstrate the presence of molecular damage characteristic of the PD target tissue beyond the CNS and the usefulness of these patient-derived cells to model PD, models that can be metabolically upgraded to resemble neuron behavior and challenge mitochondrial and autophagic function by the use of galactose.Parkinson’s disease encompasses a wide panoply of genetic and molecular etiologies leading to common clinical manifestations. Different schools of thought differ in considering either mitochondria or protein deposition-cascade as the triggers of PD, but all they convey that PD pathogenesis is associated to the deregulation of both mitochondrial and autophagic clearance pathways, supporting its role in the disease. Mitochondrial dysfunction and their turnover through autophagy directly targets some types of PD  but also stand at the base of the rest of PD by providing the overdose of energy needed to support alternative deregulated pathways while maintaining oxidative stress levels within control ranges. Thus, proper mitochondrial and autophagic function protects against PD and exhaustion of mitochondrial and autophagy contributes to PD development, independently of the genetic base. These molecular alterations have been consistently reported in skin-derived fibroblasts from PD patients carrying mutations in Current research gaps in PD research stand for the development of novel therapeutic candidates aimed to promote healthy brain aging and avoid or even cure PD, probably based in personalized-medicine guided by genetic and molecular counseling. New generation sequencing will increase the number of genes responsible of familial PD and the number of genetic risk factors accounting for sporadic PD, thus unveiling molecular imbalances underlying PD. Novel compounds against these targets will be discovered in experimental settings and disease models to set the path for further clinical trial testing. Complementary models of disease will be needed to dissect the disrupted pathways in PD and design specific therapeutic targets, but the use of patient-derived cells such as fibroblasts is gaining in strength because they constitute platforms to model disease etiopathogenesis and try new therapeutic approaches in the genetic and epigenetic background of the patient.New challenges and potential developments in the field of PD entail the validation of these novel therapeutic candidates focused on modifying the course of PD through, among others, promoting mitochondrial and autophagic performance.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 more comprehensive understanding of the human ageing process is required to help mitigate the increasing burden of age-related morbidities in a rapidly growing global demographic of elderly individuals. One exciting novel strategy that has emerged to intervene involves the use of extracellular vesicles to engender tissue regeneration. Specifically, this employs their molecular payloads to confer changes in the epigenetic landscape of ageing cells and ameliorate the loss of functional capacity. Understanding the biology of extracellular vesicles and the specific roles they play during normative ageing will allow for the development of novel cell-free therapeutic interventions. Hence, the purpose of this review is to summarise the current understanding of the mechanisms that drive ageing, critically explore how extracellular vesicles affect ageing processes and discuss their therapeutic potential to mitigate the effects of age-associated morbidities and improve the human health span. There is a growing number of aged individuals in the global population. It is estimated that within the next few years, people aged 65 and older will outnumber children below the age of 5 for the first time in our history . It is pAgeing, either at the organismal or cellular level, can be defined by the loss of physiological function over time . Ageing It is important to recognise that not all individuals age at the same rate or in the same way . Indeed,Heterocephalus glaber) and how they are protected from oxidative stress and cancer, could assist in the development of strategies that prevent or slow down premature ageing. Additionally, the study of rougheye rockfish  and bowhead whale , which both have documented lifespans of >200 years, could potentially enhance our understanding of autonomous and non-autonomous cellular senescence during ageing [In this respect, the study of animals and how they mitigate some of the loss of physiological function, common to ageing and diseases of ageing in humans, may be of benefit. Interestingly, almost all of the diseases that affect humans have an equivalent in the animal kingdom . Hence, g ageing .Despite advances in geroscience, which have allowed us to better understand how we age, there is still a pressing need to better understand the mechanisms that drive ageing throughout the life course and not just in the latter half of life.A number of strategies appear capable of mitigating against the effects of age-related morbidities, with lifestyle factors such as nutrition, exercise, and other psychosocial factors impacting positively on health and ageing . The traOne novel approach that has been developed recently exploits the use of extracellular vesicle biology. Alterations in intercellular communication have already been identified as one of the hallmarks of ageing  and extrA component of physiological homeostasis has been attributed to the action of extracellular vesicles, which have proven roles in tissue maintenance and repair . ExtraceThe majority of previous research has focused on two distinct classes of extracellular vesicles: exosomes and microvesicles. Exosomes have a size range of 30–100 nm diameter and are released via multi-vesicular endosome fusion with the plasma membrane ,43,44,45Extracellular vesicles can be isolated from the cell culture media of numerous cell types or from body fluids primarily via centrifugation and ultrafiltration, while other isolation techniques have been critically reviewed elsewhere ,49. BrieExtracellular vesicles are a heterogeneous population whose molecular payloads have been shown to be dependent on the cell type of origin. Most notably, stem cell and cancer cell extracellular vesicles have been identified to have a distinct composition ,53. ThesExtracellular vesicles have been identified as key mediators of paracrine signaling, both in physiological and pathological states associated with ageing . They caExosomes can mediate the removal of cytotoxins from cells. For instance, as a branch of the endolysosomal pathway, they can contribute to cellular homeostasis by removing misfolded or unwanted proteins and cytoplasmic DNA, both of which can be targeted to multivesicular bodies and released via exocytosis ,64. ThusNumerous studies have suggested that endogenous or exogenous stress can affect the amount or content of secreted extracellular vesicles ,38,58,67Extracellular vesicles may also play a role in promoting another hallmark of ageing, namely increasing genomic instability, through the transfer of retrotransposons . ExtraceExtracellular vesicle secretion has also been shown to change with age and disease. For instance, aged rat mesenchymal stem cells (MSCs) secrete more exosomes than their young counterparts. However, these vesicles have a lower content of anti-inflammatory miRNAs  and thusToxoplasma, among others [Extracellular vesicles have also been implicated in the spread of a number of other diseases, for instance by shuttling toxic protein aggregates or misfolded proteins, including those involved in Alzheimer’s disease and prion diseases ,58,60,81Overall, extracellular vesicles have been implicated both in physiological and pathological ageing, and it is essential that we further comprehend their biology. Additionally, it is important to distinguish and understand the roles that different extracellular vesicle subclasses play during ageing.Although once thought to be cell debris, there is now solid evidence to indicate that extracellular vesicles play a vital role in intercellular communication, stem cell regulation, and critically tissue regeneration ,86,87,88Human induced pluripotent stem cells (iPSCs) have been used as a source of microvesicles for therapeutic applications. These iPSC-derived microvesicles were able to confer iPSC regenerative attributes to adult somatic cells, through the transfer of their molecular payloads, comprising a series of RNAs, miRNAs, and proteins. As a result, the iPSC-derived microvesicles exerted proliferative and protective effects on cardiac MSCs, while also enhancing their differentiation potential, by impacting on their transcriptome and proteomic profile. These microvesicles were also capable of transferring exogenous transcripts from genetically modified iPSCs. Hence, future therapeutic strategies can benefit from the genetic enhancement of the content of extracellular vesicles . These oMoreover, the therapeutic potential of MSCs and their extracellular vesicles has been investigated in vitro for the treatment of acute lung injury and acute respiratory distress syndrome- ,93,94. TMicrovesicles derived from mouse embryonic stem cells have also been explored as a novel therapeutic intervention for the regeneration of the retina. The microvesicles can transfer RNAs and miRNAs to Müller cells, inducing pluripotency and allowing them to differentiate into cells of retinal lineage .The therapeutic potential of microvesicles and exosomes for the development of interventions that can treat damage in the nervous system has also been discussed elsewhere . Indeed,In the instance of renal recovery following damage or age-related dysfunction, microvesicles of MSC origin can be protective following glycerol-induced, ischemia-reperfusion and cisplatin-induced acute kidney injury. This effect has been particularly attributed to the horizontal transfer of mRNA and miRNA molecules ,107,108.Finally, extracellular vesicles have been implicated in mediating the systemic benefits of exercise. Following exercise, muscle and other tissues increase the release of microvesicles and exosomes into the circulation, transferring a series of factors, termed exerkines . They inStudying the role of extracellular vesicles, in cell-to-cell communication and in the context of physiological and pathological ageing, will enhance our understanding of the ageing process and the mechanisms underpinning the spread of allostatic load across the human body. Additionally, understanding the associated mechanisms of action, during maintenance of organismal homeostasis and tissue regeneration throughout the life course, could prove beneficial for the development of novel cell-free therapeutic interventions that could improve the health span and combat age-related loss of function and diseases.Extracellular vesicles and specifically microvesicles are in clinical trials or moving into clinical development on a number of fronts . In comp


The gastrointestinal tract is the first physiological barrier against food contaminants, as well as the first target for these toxicants. As prominent food and feed contaminants, mycotoxins frequently come into contact with the intestinal mucosa, and awareness of their potentially deleterious effects is increasing ,2. Even Fusarium toxins, DON and zearalenone (ZEN), at supposedly non-toxic levels. Substantial data have been assembled on the damage caused by mycotoxins to a number of histological structures and functions of the intestinal tissue. Mycotoxins, with chemical structures as diverse as aflatoxins, ochratoxin, and deoxynivalenol (DON), have been shown to impair intestinal permeability in species as different as humans, fish, and pigs, removing any remaining doubt about global mycotoxin-driven alteration of the intestinal barrier function ,5,6. TheEnteric neurons involved in many regulatory processes, connected with all aspects of intestinal physiology, have also been underestimated, and the question of whether mycotoxins could target the enteric nervous system (ENS) deserves attention. Makowska et al.  demonstr1. Reddy et al. [Lactobacillus genus, suggesting that members of this genus could play a key role in the detoxification of dietary DON and ZEN in pigs. Also in pigs, dietary fumonisin B1 (FB1) was shown to hinder the age-related dynamic of fecal microbiota, starting from 15 days of exposure [An overview of the detrimental effects of mycotoxins on the intestine could not ignore the gut-hosted microbiota that are now regarded as a fully fledged organ associated with the gut . Yang ety et al.  analyzedexposure . The emergence of the intestine as a critical target for mycotoxin toxicity concurrently raises the question of the suitability of current regulations to protect against alterations of this organ. Maruo et al.  concludeSaccharomyces cerevisiae boulardii strain CNCM I-1079. These authors reported that applying the yeast significantly reduced the overall impact of DON on the transcriptome, and specifically reversed a number of signaling pathways triggering inflammation, oxidative stress, and lipid metabolism. Likewise, the oxidative stress and mitochondrial apoptosis induced by ZEN in pig intestinal epithelial cells were reported to be alleviated by application of N-Acetylcysteine [Clostridium sp. WJ06 strain as a DON detoxification strategy in pigs also appears to be of potential interest, as Li et al. [Fusarium mycotoxins in piglets. These authors showed that providing functional hydrogen to the pig gut could protect the animal against the imbalance of intestinal communities of microbiota, and protect it from a reduction in the production of short-chain fatty acids and a higher rate of diarrhea induced by a mix of Fusarium mycotoxins. Conversely, despite their broadly acknowledged gut health promoting action, chito-oligosaccharides had no remediating effect against the intestinal toxicity of DON [Finally, the unavoidable presence of mycotoxins in animal feed, despite continuing efforts to keep the risk under control, calls for the implementation of new detoxification strategies, whose efficacy still needs to be assessed . To thatcysteine . Dietaryi et al.  showed ti et al.  exploredy of DON .This special issue contains original contributions that advance our knowledge of the intestinal toxicity of mycotoxins. Most of the studies focus on fusariotoxins, but the toxicity of aflatoxins and ergot alkaloids is also addressed. Mycotoxin toxicity is investigated on different cellular targets , markers , and the intestinal bacterial flora. The use of the pig model was recurrent in in vivo studies, making it possible to envisage dual valorization of the present findings in biomedical and agricultural research. An original contribution on salmon provides useful information for this breeding species, which remains poorly investigated in the field of mycotoxicology. The outcomes of this special issue improve the characterization of the deleterious effects of mycotoxins on the intestine and identify potential solutions to mitigate these effects. The different detoxification strategies described here will certainly attract the attention of the scientific community.


Caudovirales (viruses) and Basidiomycota, Ascomycota, and Candida albicans (fungi) are revealed to be increased in IBD. The deconvolution of the gut microbiota in IBD lays the basis for unveiling the roles of these various gut microbiota components in IBD pathogenesis and being conductive to instructing on future IBD diagnosis and therapeutics. Here we comprehensively elucidate the alterations in the gut microbiota in IBD, discuss the effect of diets in the gut microbiota in relation to IBD, and illustrate the potential of manipulation of gut microbiota for IBD therapeutics. The therapeutic strategy of antibiotics, prebiotics, probiotics and fecal microbiota transplantation will benefit the effective application of precision microbiome manipulation in IBD.In the twenty first century, the changing epidemiology of inflammatory bowel disease (IBD) globally with increasing disease incidence across many countries relates to the altered gut microbiota, due to a combinatorial effect of environmental factors, human immune responses and genetics. IBD is a gastrointestinal disease associated with a gut microbial dysbiosis, including an expansion of facultative anaerobic bacteria of the family Enterobacteriaceae. Advances in high-throughput sequencing enable us to entangle the gut microbiota in human health and IBD beyond the gut bacterial microbiota, expanding insights into the mycobiota, virobiota and helminthes.  Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative disease (UC), are proposed to result from an inappropriate immune response to the gut microbes in a genetically susceptible host. It is a chronic inflammatory disorder of the intestinal tract of an unknown cause. The incidence of IBD has increased in the western world since the midst of the twentieth century  tract, it reaches an upper level in the colon of 10Firmicutes and Bacteroides, and increases in the Gammaproteobacteria  strains, were isolated from ileal CD biopsies  infection against the development of autoimmune diseases, including IBD  and to mitigate intestinal inflammation , including acetate, propionate, and butyrate. SCFAs have been shown to exert multiple beneficial effects on mammalian energy metabolism. They are the primary energy source for colonic epithelial cells  infection  , a highly effective therapy for recurrent Two placebo-controlled trials of FMT on patients with UC have shown conflicting results with one study demonstrating the importance of the donor effect. It was documented that some patients with UC experienced fevers and increased levels of C-reactive protein post-FMT . Importantly, the microbial diversity increased and persisted after FMT (Paramsothy et al., A recent multicenter, double-blind, randomized, placebo-controlled trial showed that intensive-dosing, with multidonor FMT induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes related to the outcome (Paramsothy et al., It has been reported that 30–50% of the donor's bacterial microbiota persist in the recipient after FMT (Li et al., The long-term consequence of FMT in treating diseases remains unclear. In the future, FMT will be likely substituted by the use of defined microbial consortia. It was proven in animals that such an approach was feasible and effective for the treatment of IBD (Atarashi et al., Efforts to date have effectively characterized the diverse constituents of the human gut microbiota in health and IBD. Bacterial microbiota is the most studied gut microbiota component though the function and strain-level resolution studies are still lacking. Beyond that, the under-studied gut microbiota components, viruses and fungi, and their inter-kingdom interactions with gut bacteria may have high impact in human health and IBD. These studies are still in its infancy. In summary, understanding the complexity of this gut ecosystem will require thorough mechanistic studies involving sophisticated molecular microbiologic techniques and animal studies to better define the role of different gut microbes in IBD pathogenesis and disease evolution. Precise interpretation of the cause and consequence of these microbial alterations will also require integration with host genetic polymorphisms and gene expression to allow proper comprehension of microbial-host interaction. Although microbe-based therapeutics is appealing, effective application of probiotics, prebiotics, antibiotics and FMT will require a personalized approach to identify defined subsets of patients that will benefit most from such a strategy.TZ and SN devised the concept, acquired data, and wrote 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.


Detailed knowledge of anatomy is an essential part of surgical practice. However, there are many drawbacks in anatomy education that make many residents feel inadequate when they start performing surgeries. Cadaveric dissection courses aim to close the gap between the anatomic knowledge and surgical practice. This review focuses on the role of cadaveric dissection on surgical education, and additionally states the panel decision of the Surgical Anatomy and Technologies Association on the proper use of cadavers. This review covers the concept of cadaveric dissection in terms of teaching anatomy and post-graduate surgical training.rd century before Christ, the first human cadaveric dissections were performed in Greece by Herophilus of Chalcedon and Erasistratus of Chios to understand the whole body from the viewpoint of anatomy and physiology. However, religious and moral attitudes and taboos towards physicians and medical schools had many detrimental effects on the scientific value of cadaver-based education.Cadaveric dissection has been the main teaching modality in anatomy education since the ancient times. In the 3. Medical students gain knowledge and strengthen theoretical data through visualization of real anatomic structures. Additionally, by practicing on cadavers they touch and feel the anatomic relations more efficiently. Owing to the role of cadaveric dissection in generating a three-dimensional (3D) perspective, and providing an easy way of understanding and recalling anatomic structures, the literature indicates that cadaveric dissection is one of the most powerful ways of teaching topographic and regional anatomy,4.Cadaveric dissection is the traditional way of teaching anatomy after theoretical lessons and discussions on the atlas images.Recently, there has been a trend shift in modern anatomy education, and many novel options are used in teaching anatomy. Cadaveric dissection and didactic lessons with atlas images constitute the traditional methods; however, 3D simulation technologies, virtual/augmented reality, 3D printed materials, simulation/training models, and radiology-based comparative illustrations form the new methodologies in current anatomy education. Nevertheless, cadaveric dissection is not the sole method of teaching anatomy and it should be complemented by other innovative educational tools. In this way, medical students and residents will be better equipped and well prepared for future medical activities.Post-graduate anatomy education is the core praxis in improving surgical and technical knowledge for surgery residents. Simulation-based education with hands-on courses and cadaveric dissections focus on a detailed practice of surgical procedures prior to live patient operations, consequently an increase in confidence levels and surgical skills of residents will be noticed.The problem beyond the inadequacy in anatomy education for surgery residents gave rise to the wide use of cadaveric courses in many surgical disciplines. Giving the opportunity to residents to attend these cadaveric courses will improve the educational quality during the first steps of learning surgical procedures by raising self-confidence and better surgical skills.Cadaveric dissection under the supervision of senior surgeons and anatomists will develop a practical competency in the field of minimally invasive surgery, gynecology, gynecologic oncology, and urogynecology, even if in obstetrics, and also for the management of complications reported the positive effect of procedure-oriented cadaveric courses, which target teaching specific operations to improve operative confidence and surgical technique. Some advanced surgical procedures could be observed or performed for the first time at the cadaveric courses, which deeply enhance anatomic knowledge and may also provide a higher level of autonomy to perform procedures independently.Sharma et al. and Lim et al. showed that the best improvements were observed in hysterectomy and salpingo-oophorectomy procedures for gynecology practice. Both basic and advanced surgical procedures can be performed on cadavers and the use of fresh frozen cadavers instead of traditional embalmed ones make it easy to learn the general objectives of a surgical operation in which a special and tailored practice is needed. Simulation of surgical scenarios, identifying the steps of new techniques, and teaching the tips and tricks of advanced surgical procedures are effectively performed by using fresh frozen cadavers for postgraduate surgical education.Post-course surveys showed that improvements in surgical skills, which are transferrable to the operating room, were essentially maintained by cadaveric dissections,14. Safe implementation of surgical procedures with regard to vascular and neural structures was also studied for transvaginal tape and sacrospinous ligament fixation operations in urogynecology literature,16.Previously, a newer surgical method used in urogynecology practice, transobturator tape procedure, was widely discussed in cadaveric illustration studies,18,19. Soft-preserved cadavers, which are prepared using phenol, alcohol, and glycerol, were used by Barton et al. during a gynecologic oncology cadaveric course, and the need of such a cadaveric anatomy education during gynecologic oncology fellowship was the objective result of the end-course evaluation.Additionally, the complex structure of pelvic anatomy and the pathway of the ureter were also demonstrated in cadaveric studies for surgical education.In addition, management of complications is a major requirement that a resident needs to learn during the surgical training period; however, it is not easy to observe these kinds of cases all the time. Cadaveric courses can mimic complications through simulations and this yields a higher practice level and competency for less common procedures and real-life conditions,23,24.In practical obstetrics, cadaveric education increased the ability to manage surgical cases where a serious episiotomy tear or a massive peripartum bleeding occurred evaluated the effectiveness of laparoscopic cadaveric dissection after starting the residency program of obstetrics and gynecology to overcome the deficiencies in anatomy education; the course produced satisfactory results for the participants and also allowed video recording, which could spread the educational materials to non-active participants.Minimally invasive gynecology, with the advantage of video recording, especially in the laparoscopic technique, is a well-known surgical practice to popularize the surgical approach and maneuvers to a widespread population, and this is also valid for teaching and demonstrating anatomic structures. Cundiff et al.,28,29,30.Other surgical branches also benefit from cadaveric courses; residents, fellows, junior surgeons, and new consultants gain experience and improve skills with confidence. Cadaveric courses are also the approved method of surgical education to share knowledge in brain surgery, plastic surgery, orthopedics, general surgery, urology, vascular surgery, and other branches. Cadaveric courses will lead to improvement of surgical outcomes by means of identifying proper anatomical landmarks, practicing more without any stress of the operation room in a comfortable environment, and teaching the basis of a new modification in a surgical approachSurgical Anatomy and Technologies Association (SATA) organized a panel titled “Ethical and Proper Use of Cadavers in Surgical Education” during the First National Anatomy and Cadaveric Dissection Symposium of SATA, which was held at Kars, Turkey, in March 2018. More than 50 participants attended this interactive session, which was conducted by three mentors  who were proficient in surgery and anatomy. The role of cadaveric dissection in surgical education was discussed in many aspects.The final decisions on the Ethical and Proper Use of Cadavers in Surgical Education:-The scientific committee of cadaveric courses should be consisted of phyicians and anatomists, a multidisciplinary/advisory board.-Cadaveric courses without the integration of anatomy departments and anatomists will give harm to an effective education.-Dissection subgroups will improve the surgical education both for mentors and residents.-A certification program should be formed to train the teachers of cadaveric surgical education (“teach the teachers”).-Number of participants per cadaver during the cadaveric dissection courses should be defined according to the aim and tasks of the course to maintain a cost-effective and educational activity.-Criteria of a well-designed cadaveric course should be established with respect to the training aim, ethics, and health conditions of the environment.-Cadaveric dissection laboratories should be high quality to preserve the health conditions of the participants and laboratory personnel.-A rotation program to anatomy departments should be implemented to surgical residency education to improve anatomic knowledge..Despite the higher costs of cadavers, if used effectively and properly, by conducting small but meticulous dissections, cadaveric courses will produce successful educational results in a cost-effective manner. However, measurements of the validity and effectiveness of these gains are lacking during surgical operations, as such there is a need for further studies in this areaIn conclusion, to gain surgical skills, experience, and confidence before performing a procedure on a live patient, hands-on cadaveric courses should be an integrated part of surgical education during residency and the post-graduate period. Fundamentally, these courses should be planned under the supervision of an advisory board consisting of both surgeons and anatomists with limited numbers of participants to allow each attendee achieve the final goals of the course.


Habitat valuation can provide an objective basis for the prioritisation of conservation and restoration actions. The attribution of fisheries production to particular habitat units is an important measure of value, but is difficult to estimate. Using the case study of habitat use by juvenile banana prawns in a tropical estuary, we assessed the potential to produce valid value estimates at two spatio-conceptual scales: estuary reach and whole estuary. Additionally, we also explore the potential to produce meaningful value estimates at the scale of whole estuary contribution to the offshore fisheries stock. A diversity of potential and actual sources of error and logical problems means that quantification at any scale is at best of uncertain validity and produces estimates that are likely to produce unreliable results if treated as quantitative inputs to production models. Estimates for the whole estuary were the most viable, although still requiring substantial assumptions that may or may not be reasonable in particular situations. Estimates for individual habitats required the unreasonable assumption of limited prawn movement, while estimates of contribution of an estuary to the fishery required difficult-to-obtain and usually unavailable information. Because low occupancy habitats can have trophic value, we also used stable isotope analysis to assess the importance of mangroves and saltmarshes to prawn nutrition. No particular habitat was of critical trophic importance, again suggesting that the habitat-production link is most usefully assessed at the whole-of-estuary scale. While valuable and required to support targeted ecosystem management and protection and restoration efforts, valid estimates of the contribution of particular units to fisheries are likely to be unachievable in many situations. Estuaries and coastal wetlands have always been important to human societies, fulfilling a variety of ecological services that are critical to human livelihoods and food security such as fisheries production, providing nursery grounds for important species, and filtering and detoxification . AlthougFenneropenaeus merguiensis, Penaeidae) is one of the most important fishery species in tropical northern Australia, where its biology and ecology have been researched extensively. Juvenile F. merguiensis are strongly associated with mangrove estuaries ),F. merguiensis example, we could consider three different types or stages of estimates  eststimates , (ii) esstimates , and ; estimation of growth rates and natural mortality during residence in different habitats and during different life-history stages; identification of the trophic importance of the habitats accessed throughout ontogeny; and characterization of the effects of the different environmental parameters, such as temperature and salinity, on e.g. growth rates, mortality and movement. These data should then be combined with detailed habitat, topographic, bathymetric and hydrologic mapping, with analyses of tides and inundation patterns, with long-term data on environmental parameters  and with fisheries catch and effort. It is clear that developing authoritative, robust and reliable estimate value would necessarily involve a very high, long-term, research effort, and could only be  feasible in the case of highly valuable fisheries such as the penaeid prawn fisheries in the Gulf of Mexico, USA (see  and 76]76]). EveF. merguiensis this would be in the offshore adult population)  . This isulation) .Added to the difficulties associated with valid data collection and parameter estimation, are the critical limits placed on estimation by the presence of pervasive complexity that puts limits on what is possible to predict . For insF. merguiensis there is still a substantial deficit in the information needed to make precise species-productivity links, with substantial research still needed before the available broad-scale biomass estimates can be converted to valid estimates of total biomass and production. In the example studied, a diversity of potential and actual sources of error and logical problems means that quantification at any scale is at best of uncertain validity and produces estimates that are likely to produce unreliable results if treated as quantitative inputs to production models. In fact, such estimates are probably best treated as indices of relative numerical and biomass densities. Moreover, given the level of uncertainty attached to the estimation of ‘average’ biomass density, and the range of assumptions that need to be made, it is unclear if such estimates are of substantially greater value than simple measures such as Probability of Encounter [Even for a well-studied species such as ncounter . It is eResults from the present study have substantial implications for conservation, restoration and management of tropical coastal wetlands, and of the fisheries that rely on them. The manifest difficulties in determining and assigning value to individual habitats, the vast amount of information needed to support viable estimates, and the uncertainty of current paradigms , impliesS1 TableFenneropenaeus merguiensis captures (number and weight of prawns per net) for the downstream (DS), mid-estuary (MS) and upstream (US) reaches of Alligator Creek during each of the eleven trips.Data on (XLSX)Click here for additional data file.S2 TableFenneropenaeus merguiensis size structure for each trip (T1-T11) for the downstream (DS), mid-estuary (MS) and upstream (US) reaches of Alligator Creek. Data was binned into 5 mm size classes.(XLSX)Click here for additional data file.S3 Table13C) and nitrogen (δ15N).Carbon (δ(XLSX)Click here for additional data file.


Dear Editor,An 81-year-old man was referred to our department for investigation of right-sided painful ophthalmoplegia. He had a history of chronic obstructive pulmonary disease and benign prostatic adenoma. The anamnesis revealed the use of mycophenolate mofetil (an immunosuppressant drug) for a few months, following a suspicion of rheumatoid mono-arthritis. Clinical evaluation showed a reddish right upper eyelid, chemosis of the right eye, a slight proptosis and diplopia caused by a palsy of the right abducens nerve (VI). The pupils were equal and reactive. Visual acuity was normal.Orbital and skull-base MRI Figure  was perfThe orbital apex is a region loaded with muscular, nervous and vascular structures, amongst others, including the origin of the extraocular muscles as well as the optic nerve. The cavernous sinus is the structure of the skull-base with the densest concentration of critical vascular and neural structures. It contains the oculomotor, trochlear and abducens nerves, as well as the first and second divisions of the trigeminal nerve, the internal carotid artery and its nervous plexus. These two anatomical regions therefore establish important links between the skull-base and the orbital and facial areas, leading to various clinical symptoms depending on the involvement of each structure in the pathological process .A radioclinical presentation such as the one described in our patient raises the possibility of multiple etiologies: vascular , inflammation , infection (aspergillosis) or tumour (primary or metastatic) .Tolosa-Hunt syndrome is an idiopathic granulomatous inflammation of the cavernous sinus and/or the orbital apex/superior orbital fissure . The diaConsidering the use of immunosuppressant drugs by our patient and the absence of other significant systemic signs, the presumptive diagnosis of orbital aspergillosis was retained. It was therefore decided to start a treatment with oral administration of voriconazole . Within a few days, ocular symptoms and pain decreased.Following the increasing use of antibiotics, corticosteroids, chemotherapy, and due to the increasing prevalence of diabetes in the population, more and more cases of orbital aspergillosis have been reported. It is thereby a diagnosis that we should not neglect when confronted to a painful ophthalmoplegia.It is nonetheless important not to disregard other serious and possibly life-threatening conditions such as rapidly evoluting vascular abnormalities (aneurysms and fistulae) or tumours  .


The ankle brachial index (ABI) is widely used in clinical practice as a non-invasive method to detect the presence and severity of peripheral arterial disease (PAD). Current guidelines suggest that it should be used to monitor potential progression of PAD in affected individuals. As such, it is important that the test is reliable when used for repeated measurements, by the same or different health practitioners. This systematic review aims to examine the literature to evaluate the inter- and intra-rater reliability of the ABI.A systematic search of MEDLINE, EMBASE and CINAHL Complete was conducted to 20 January 2019. Two authors independently reviewed and selected relevant studies and extracted the data. Methodological quality was determined using the Quality Appraisal of Reliability (QAREL) Checklist.Fifteen studies of ABI reliability in a range of patient populations were identified as suitable for inclusion in the review: seven considered inter-rater reliability, four intra-rater reliability, and four studies evaluated both inter- and intra-rater reliability. Inter-rater reliability was found to be highly variable, with intraclass correlation coefficients (ICC’s) ranging from poor to excellent (ICC 0.42–1.00), while intra-rater also demonstrated considerable variation, with ICCs from 0.42–0.98. Meta-analysis was not possible due to the lack of statistical information reported.Results of included studies suggest the inter- and intra-tester reliability of the ABI is acceptable. However, inconsistencies in obtaining systolic pressure measurements, calculating ABI values, and incomplete reporting of methodologies and statistical analysis make it difficult to determine the validity of the results of included studies. Further research, with more consistent reliability methodology, statistical analysis and reporting conducted in populations at risk of PAD is needed to conclusively determine the ABI reliability. Peripheral arterial disease (PAD) describes the process of progressive atherosclerosis affecting arteries, most frequently in the lower limb. The prevalence in the general population has been estimated at up to 19% in people over the age of 55 years . The preDue to the high risk of concurrent cardiovascular morbidity, mortality and lower limb complications associated with PAD, accurate and reliable diagnostic testing methods are required for screening and ongoing monitoring , 6. EarlThe ABI is widely used to screen for PAD in different clinical settings and by different health professionals, from general medical practitioners to specialist vascular technicians , 10. RelGiven that the ABI is the recommended method for screening for the presence and progression of PAD, it is important that it is reliable. Therefore, the aim of this review was to systematically evaluate the literature to determine the inter- and intra-rater reliability of the ABI in adults.A search of relevant biomedical journal databases from the University of Newcastle library website was performed to identify studies that consider the reliability of ABI measurement from database inception to January 2019 using MEDLINE (1946+), EMBASE (1947+), and CINAHL Complete. Truncated versions of some search terms were used to ensure that relevant studies were included  statement . The folHand searching of the reference list of appropriate articles was also conducted.p-value). Given the expectation for a high degree of study heterogeneity, we believed a fixed effect meta-analysis would generally not be appropriate so we aimed to only pool estimates using a random effects approach provided there were at least 5 studies [All abstracts obtained were assessed independently by SC and SL for inclusion. There were no instances of disagreement between reviewers, so arbitration by a third person (VC) was not necessary. Data extraction was performed by SC and SL. It was pre-determined that a meta-analysis of reliability outcomes for inter- and intra-rater reliability would be conducted provided there were sufficient studies that report the estimator of interest, and a measure of uncertainty for this estimator  Checklist and qualitative methodological assessment . All fulA total of 1703 articles were retrieved, of which 36 were identified as suitable for full-text review. Twenty-one papers were excluded based on the exclusion criteria  overall than women, whilst gender was unreported in four studies [The 15 studies in this review included a total of 916 participants, with data collected from a combination of one and both lower limbs . Two studies did not state the number of limbs included , 53. Ele studies , 49, 50. studies , 57, how studies , 56, one studies  and one  studies , 55, 57  studies ; two stu studies , and two studies , 56.TablThere was little consistency in the training and qualifications of the raters used, with experience ranging from students , 47 to eThe quality of studies was variable with regard to reported blinding of raters, order of examination and the time between repeated measurements, with no study clearly addressing all of these variables. While most studies used appropriate statistical measures of agreement, reporting of results was frequently incomplete and the true extent of reliability could not be determined Table .Table 3QA number of the eligible papers identified lacked sufficient data relating to the main outcomes to allow for inclusion in a meta-analysis. For example, the paper by Chesbro et al.,  providedInter-rater reliability results are included in Table Other estimates of reliability reported in included studies were coefficient of variation between raters , 49  [Of the remaining studies, one demonstrated statistically significant differences in ABI between raters in a population with severe PAD and in those with no disease, which did not occur in those participants with mild to moderate PAD , suggest values) .Intra-rater reliability results are included in Table The findings of this review are that the inter- and intra- tester reliability of the ABI across a number of mixed populations appears to be acceptable, however statistical tests of reliability in included papers were heterogeneous and levels of statistical reporting were inconsistent and incomplete. This makes interpretation of the reliability of the ABI in the context of clinical detection, evaluation and ongoing monitoring of peripheral arterial supply challenging, and prevented meta-analysis. For example, where studies lack 95% confidence intervals for ICCs, the validity of interpretation of the value is reduced as it fails to provide the lowest level of reliability that it represents. Similarly for coefficient or estimate of variation, values between 3.2 and 15.8% were reported.. Whilst this is considered an acceptable level of variation for many clinical tests, for the ABI it can represent a range of values that may indicate both normal and pathological results; which could reduce the ability of ABI to reliably determine the presence and extent of PAD. For example, assuming a variation of 15%, an ABI of 1.0 (which is considered ‘borderline’ when ABI is used as a screening tool ) could rFurther complicating the interpretation and generalisability of the inter- and intra-rater reliability results of included studies was the heterogeneity of participant populations. Whilst the majority of studies included older people with PAD risk factors or suspected PAD, three studies also included healthy participants , 16, 52,Methodological differences between studies is also likely to have contributed to variable reliability outcomes, with automated oscillometric devices demonstrating marginally better reliability than manual assessment using Doppler , 55, whiTwo papers identified the presence of diabetes mellitus as a factor that may affect reliability of the ABI , 51, howWhile the search methods employed in this study were designed to be robust, there may be some evidence that was not captured, for example unpublished data. Further limitations to this study are the inability to perform meta-analysis in order to obtain a quantitative analysis of the available reliability data for the ABI, and the inability perform any sub-analyses relating to individual populations such as those with diabetes, or methods of measurement such as automated or manual methods. Furthermore, there has been some disagreement in the literature about which pressure measurement should be used to calculate the ABI , 62, witResults of included studies suggest the inter- and intra-tester reliability of the ABI is acceptable. However, inconsistencies in obtaining systolic pressure measurements, calculating ABI values, and incomplete reporting of methodologies and statistical analysis make it difficult to determine the validity of the results of included studies. Further research of ABI reliability using a more consistent approach to study design and implementation and more detailed reporting of results in populations with vascular pathology and at risk of PAD is required. Based on current available data clinicians should ensure they interpret ABI results in the context of other vascular assessment findings, and patient management is not based upon this measurement alone.


Autophagy (ATG) and the Ubiquitin Proteasome (UP) are the main clearing systems of eukaryotic cells, in that being ultimately involved in degrading damaged and potentially harmful cytoplasmic substrates. Emerging evidence implicates that, in addition to their classic catalytic function in the cytosol, autophagy and the proteasome act as modulators of neurotransmission, inasmuch as they orchestrate degradation and turnover of synaptic vesicles (SVs) and related proteins. These findings are now defining a novel synaptic scenario, where clearing systems and secretory pathways may be considered as a single system, which senses alterations in quality and distribution  of both synaptic proteins and neurotransmitters. In line with this, in the present manuscript we focus on evidence showing that, a dysregulation of secretory and trafficking pathways is quite constant in the presence of an impairment of autophagy-lysosomal machinery, which eventually precipitates synaptic dysfunction. Such a dual effect appears not to be just incidental but it rather represents the natural evolution of archaic cell compartments. While discussing these issues, we pose a special emphasis on the role of autophagy upon dopamine (DA) neurotransmission, which is early affected in several neurological and psychiatric disorders. In detail, we discuss how autophagy is engaged not only in removing potentially dangerous proteins, which can interfere with the mechanisms of DA release, but also the fate of synaptic DA vesicles thus surveilling DA neurotransmission. These concepts contribute to shed light on early mechanisms underlying intersection of autophagy with DA-related synaptic disorders. Remarkably, a loss of UNC51 apart from impairing ATG initiation also dampens the axonal transport of SVs. In fact, a loss of UNC51 impairs the activity of UNC76 kinesin adaptor protein  Endocytosed SVs are locally recycled in order to replenish the ready-releasable pools for a further round of exo/endocytosis. (ii) Endocytosed SVs can be targeted by the retromer complex, which recycles SV-components by trafficking them back to the Trans Golgi Network for reuse , Parkin and LRRK2, which co-chaperon SVs’ trafficking and DA release by interacting physically with Rabs, SNAREs and Endophilin-A (Burré et al., In the light of the tight interconnection of ATG with the secretory pathway, the findings revised in the present manuscript suggest that an impairment of ATG at the synapse may occur early, in parallel with SV cycle-related alterations. The hub linking ATG and DA release may be the tight interplay between ATG and innumerous proteins of the secretory pathway, which regulate both SV-cycle and ATG. This is supported by evidence showing that, mutations or dysfunctions of Rabs, SNAREs and Endophilin-A, which directly affect ATG, associate with several DA-synaptic disorders ranging from PD to drug addiction and schizophrenia (Drouet and Lesage, FL and FB wrote the article and made the artwork. SG contributed to important intellectual content. LR contributed to the literature review and artwork. FF: coordinator of the article. He participated in drafting the article. He participated in critically revising the article.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.


Academy for Multidisciplinary Neurotraumatology (AMN), the Foundation of the Society for the Study of Neuroprotection and Neuroplasticity (SSNN), the Journal of Medicine and Life (JML) and partners.The 2019 Congress of the Academy for Multidisciplinary Neurotraumatology took place between April 11-12 in Cluj-Napoca, Romania, organized by the This educational event brought together specialists from multiple related domains of research and clinical practice – neurology, neurosurgery, psychology, neurorehabilitation, neuroproteomics, biomarkers study, and others – who shared their vast experience in neurotraumatology and related fields in various presentations and workshops.medical doctors, patients, physicians, nurses, therapists, public health experts, and clinical researchers.The event set the stage for two days of intensive talks and debates between 150 participants from 7 countries, on a broad range of problems in clinical neurotraumatology and neuroscience, promoting the integration of new scientific information via keynote lectures, teaching-oriented workshops, and round table discussions. A rich and diverse audience of healthcare professionals interested in this steadily expanding and multidisciplinary field attended the event: Exciting lectures on a diverse set of topics were covered in five presentation sessions, one round-table discussion, and five interactive group workshops.In the opening, Professor Dafin F. Mureşanu from Romania, AMN’s Secretary-General, President of the European Federation of Neurorehabilitation Societies (EFNR), provided first-glimpse results from the CAPTAIN II study in traumatic brain injury (TBI). This is the first clinical trial that used a multidimensional approach to capture the complexity of TBI health states. In addition to methodological innovations, the presentation emphasized the importance of fostering neurorecovery as an endogenous continuous brain defense response that is anti-correlated with neuroprotection .Are we really able to influence impairment?”. Despite research in the field having proven that spontaneous recovery after stroke and TBI is usually 70%, the real challenge is to find advanced and integrated care interventions in order to increase this mark (Professor Volker Homberg (Germany), Chairman of the AMN Scientific Program Committee, Secretary-General of EFNR, and WFNR, further invited the audience to reflect on a difficult conundrum for clinical research and practice: “his mark .To date, the following major strategies showed results to help decrease impairment in the subacute stages: forced use or constraint-induced movement therapy, pharmacological agents , neuromodulatory techniques – peripheral neuromuscular and/or sensory stimulation  and non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS).After discussing therapeutic options in neurotraumatology, recent advancements in the field were presented from the patients’ perspective. Professor Nicole von Steinbüchel (Germany), AMN Past President, brought to light a model for patient-reported and performance-based outcomes after TBI from CENTER-TBI, a large, prospective, observational European study that includes a pragmatic data collection of all patients after traumatic brain injury (TBI) . The necWhy, where and how to operate?” – a combination of interaction, precision, and vision. His lecture was followed by Professor Heinrich Binder’s exposition of prolonged disturbances of consciousness after brain injury.Further on, Professor Christian Matula from Austria revealed the current challenges of neurosurgery – “Education in Neurotraumatology. It was continued by Professor Ştefan Florian’s speech on cranioplasty and Professor Alexandru Ciurea’s research on TBI as a trigger or aggravating factor in Alzheimer’s disease.The third session began with a topic addressed to young neurosurgeons and neurologists by dr. Martin Rakusa from Slovenia: In the last session of the day, Professor Yuri Alekseenko from Belarus discussed the diagnosis and initial management of mild traumatic brain injury, Professor Gelu Onose from Romania presented a synthetic up-to-date literature review on the main traumatic spinal cord injury current issues, while Professor Mihaela Băciuţ (Romania) discussed the situation of the 12% of the patients presenting in emergency departments with the coexistence of maxillofacial trauma and TBI. Dr. Dana Boering closed the fourth scientific session with an exciting talk on the early rehabilitation of severe brain injury.The second day started with a round table discussion on the global burden of TBI, centered on the status-quo assessment of the public health problem. Delegates from Austria, Egypt, Philippines, South Korea, Poland, Russia, Ukraine, Uzbekistan, and Romania provided rich insight and national-level information. The conclusion of the discussion revolved around the potential of using AMN expertise to bridge geographical differences in the treatment and human resource availability in TBI through multidisciplinary, cross-country collaboration.Professor Jongmin Lee from South Korea sensitized the audience about the profound impacts of severe acquired brain injury on alertness and cognition, with devastating effects on the quality of life of patients. He also reminded the emotional and financial consequences of their families and caregivers. Afterward, he presented the differential diagnostic of disorders of consciousness ranging from a comatose state or vegetative state to a minimally conscious state and different pharmacological or nonpharmacological treatments that could be used for consciousness recovery: amantadine and zolpidem, apomorphine, levodopa and methylphenidate, deep brain stimulation, transcranial direct current stimulation, and multimodal sensory stimulation. Professor Lee particularly spoke about the combined therapy of cerebrolysin and amantadine as a promising treatment option in these cases.The next presentation, held by Dr. Lynne Lourdes Lucena from the Philippines, was a multi-center, retrospective cohort study about the efficacy of neurotrophic factors in severe traumatic brain injury.The extensive research concluded that neurotrophic factors are beneficial for severe TBI patients with non-operative lesions: a greater improvement in the Glasgow Coma Scale (GCS) and Glasgow Outcome Score (GOS) and shorter length of hospital stay was evidenced in comparison to standard treatment alone.The outcome prediction in TBI was discussed by Professor Peter Lackner (Austria). He explained that after the trauma, many factors are influencing the further course of the disease. Hence not only the initial clinical presentation, secondary brain injury, or systemic complications during the acute phase of TBI but also timing and intensity of neurorehabilitation are known determinants of the outcome. Due to patient heterogeneity, large cohorts are needed to identify solid outcome predictors. The international initiative for traumatic brain injury research supports the further development of common data elements for TBI as a method for international comparative effectiveness research (CER). low- and middle-income countries face regarding TBI patient treatment. Delegates identified the following items of importance: incorrect assessment of the TBI, insufficient number of neurosurgeons, treatment availability, competencies for acute, post-acute and long-term staff, and precarious curriculum of the medical specialization. The requirement of the rapid transport from the place of accident to the emergency hospital and the need for acute units of neurorehabilitation integrated into acute hospitals were highlighted as key care standards. The future perspectives were intensively debated in five workshops focused on different topics. Group workshops were essential highlights of the conference, bringing together top-tier specialists on five key topics. First, an international panel of participants tackled the critical problems that Concerning acute neurorehabilitation, there are currently no criteria for prognostic evaluation, guidelines for treatment techniques, goal-assessment, and orientation of patients in the pathway of patients with central and peripheral neurological lesions and post neurotrauma. In some countries, post-acute neurorehabilitation is defined, but not by standards . quality improvement program for medical care in TBI, to describe potential tools and to elaborate attainable milestones for 2025. The group presented a 5-step plan: (1) decreasing time to decision making, (2) early rehabilitation , (3) TBI registries, (4) development of a unique and multidisciplinary TBI guideline and (5) definition of a clinical decision algorithm. For the TBI code, decreasing “door to decision making” and improving communication process  the proposed solutions consisted in the development of multidisciplinary workshops, TBI simulations, pre-hospital notification for patients with moderate/severe TBI – protocol for ambulance , training for paramedics/nurses .One workshop group faced the challenging topic of designing a medical and therapeutic competence required to improve the acute, post-acute, and long-term care of TBI patients. The lack of neurosurgeons and pediatric surgeons in rural areas, the hospitalization of traumatic patients in the Internal Medicine or Neurology Ward in small hospitals, the overcrowding of the Emergency Room and the Neurosurgery Department in university centers, the poverty of specific imagistic methods, are some of the alarm signals that were triggered. Other evoked problems were: the poor collaboration between neurosurgeon – anaesthesiologist – neurologist, the deficit of neuropsychologists, long-term psychotherapists, and specialists in neurorehabilitation. In poorly developed countries, there are not enough paramedics for patient triage and not sufficient equipment in the operating units.Another topic focused on the Potential solutions to overcome these problems would be to adopt the European and international guidelines adapted to the conditions of each country or center , to develop TBI registries, to create neurotraumatology centers with multidisciplinary teams and appropriate devices, to deliver proper training of paramedics and ambulance personnel in order to recognize the severe cases and transport the patients to specialized medical services in the shortest time. The long-term strategies in order to fulfill this purpose involve cooperation in a multidisciplinary team and governmental involvement in raising funds.neurologists (with expertise in TBI and neurorehabilitation), neuropsychologists, physical therapists, and respiratory physiotherapists, nurses specialized in neurorehabilitation and social workers.The workshops also tackled the importance of multidisciplinary treatment concepts becoming the gold standard for optimal medical TBI patients’ care, discussing on how these may be achieved and with what priorities. After the debate, the group presented an optimal structure of a multidisciplinary team: What should the AMN do to support countries in their mission to improve TBI care? Representatives asserted the need to establish a communication line and feedback cycle across all the parties involved in the patient treatment course in order to promote long-term follow-up and using novel technological solutions, such as an online TBI registry and a communication platform. This online initiative could aid in the dissemination of treatment guidelines (“What to do? When? By whom?”), patient pathways , and neurorehabilitation guidelines. An official AMN statement on the necessity of a multidisciplinary framework across the whole course of patient treatment and follow-up was elaborated.In closing, the last topic challenged the role of the hosts: By the value of the debates, the quality of workshops, and prominent speakers that took part at the event, the 17th Congress of the Academy for Multidisciplinary Neurotraumatology distinguished itself as a unique opportunity to refresh one’s knowledge and to network with the world’s finest professionals in the challenging and complex field of neurotraumatology.


The demand for orthodontic treatment in adults has been increasing. However, these patients often require a multidisciplinary approach, due to the lack of posterior teeth, requiring additional anchorage. The skeletal anchorage by endosseous implants is an option, since they may be used later for prosthetic rehabilitation. The application of immediate load on these appliances for orthodontic movement may reduce the costs and total treatment time. This paper discusses the utilization of endosseous dental implants with immediate load for absolute anchorage for orthodontic movement, with later utilization for prosthetic rehabilitation. For that purpose, the utilization of orthodontic mini-implants, inserted specifically during orthodontic treatment and removed thereafter, has been widely diffused.--However, in patients presenting tooth losses that will be rehabilitated with prostheses supported by endosseous implants concomitantly to orthodontic treatment, the utilization of these implants with immediate occlusal load allows prosthetic rehabilitation early at treatment onset, while also providing the necessary anchorage to move the adjacent teeth,,Dental implants are reliable accessories for oral rehabilitation, and their utilization as anchorage units has been reported as successful in several clinical situations.,It should be highlighted that the utilization of endosseous implant first as anchorage and later as prosthetic abutment requires an integrated and careful multiprofessional treatment planning between Orthodontics, Surgery, Periodontology and Prosthodontics, considering the prosthetic space, need of tooth movement, shape, position and contour of the future prosthetic crown.The decision on the ideal timing for load application is a clinical parameter that should be adjusted for each patient. Huang et al,Marins et alThis paper discusses the utilization of endosseous dental implants with immediate load as absolute anchorage for orthodontic movement, presenting a case report with multiple losses of posterior teeth and need of anchorage reinforcement, in which one endosseous dental implant was inserted with application of immediate load for orthodontic and prosthetic purposes.Female Caucasoid patient, aged 47 years and 9 months, searched for orthodontic treatment with complaint about the smile esthetics. The anamnesis revealed that the patient presented blood hypertension controlled by continuous intake of antihypertensive drugs, without additional alterations in general health.The facial examination revealed slightly convex profile with deficient chin and mandibular retrusion. The nasolabial angle was diagnosed as straight, and the mentolabial angle, as obtuse. The intraoral clinical examination revealed loss of teeth #37, #46 and #47, due to dental caries. The third molars were present, mesially inclined, and tooth #16 was extruded. The oral hygiene was satisfactory, yet with history of high caries incidence. The patient presented Class II division 1 left subdivision malocclusion, with overjet of 8 mm and good overbite of upper and lower incisors (2 mm). There was also severe upper (-10 mm) and lower (-5 mm) crowding at the anterior region, with upper midline deviation of 3 mm to the right side in relation to the facial midline, besides occlusal interferences in lateral and protrusive movements .o), with well-positioned maxilla in relation to the cranial base (SNA = 82o) and mandibular retrognathism (SNB = 76o). The patient presented dolichofacial pattern (Y-axis = 63o and SN.GoGn = 39o) and buccally tipped upper and lower incisors   .The treatment goals were to achieve space for alignment of the upper and lower incisors, coincide the dental midline with the facial midline, correct the overjet and achieve Class I canine relationship bilaterally, besides prosthetic rehabilitation of edentulous spaces, in interaction with specialties of Surgery, Implantology and Prosthodontics.The multidisciplinary treatment planning comprised extraction of teeth #15 and #26, which were endodontically compromised, to achieve space for upper alignment and leveling and reduce the overjet. The plan also included placement of miniscrews as anchorage reinforcement for intrusion of tooth #16, besides insertion of endosseous implant at the region of tooth #46 to upright the tooth #48 for later prosthetic rehabilitation.The upper arch received placement of 1.6 mm x 6 mm miniscrews  on the buccal and palatal aspects, between teeth #16 and #17, used as anchorage for intrusion of tooth #16, with chain elastics on the occlusal surface . The lower arch received an endosseous implant at the region of tooth #46 , submitted to immediate load by a bracket bonded to the provisional crown, providing anchorage for uprighting and posterior mesialization of tooth #48, achieved during treatment by utilization of a power arm fabricated with 0.019 x 0.025-in stainless steel archwire. On the lower left side, the plan comprised uprighting and mesialization of tooth #38, closing the space related to absence of tooth #37. For that purpose, 0.019 x 0.025-in finalization archwires with boot-loops at the terminal end were used for uprighting of lower third molars and control of anterior and posterior torque.After finalization of orthodontic therapy, the results were evaluated at two moments: immediately after appliance removal and on the 3-year follow-up. The results achieved at treatment completion can be observed on o to 4o), with Class II dental compensation by retroclination of upper incisors and projection of lower incisors. These effects were expected, since the exclusively orthodontic treatment was indicated. The cephalometric tracings superimpositions revealed maintenance of palatal and mandibular planes, with exclusively dental movement, represented by projection of lower incisors and retroclination of upper anterior teeth (The cephalometric analysis  evidenceor teeth .The final panoramic radiograph  evidenceThe results remained stable after 3-year follow-up, and can be seen in The biggest challenge in the treatment of patients with loss of multiple posterior teeth is the difficulty to achieve effective orthodontic anchorage during treatmentIn the treatment of this patient presenting loss of multiple posterior teeth in the lower arch, tooth malpositioning and lack of posterior anchorage, the therapeutic option of choice was uprighting and subsequent mesialization of tooth #48, using an endosseous implant at the region of tooth #46 as anchorage, which was submitted to immediate load by a bracket bonded to the provisional crown.The option to mesially move the tooth #48, closing the edentulous space, was ruled out, since some investigators highlighted the difficulty of moving teeth through edentulous areas, predisposing to loss of supporting tissue and even furcation involvement, since buccolingual dimension of the tooth is often wider than the alveolar bone area.Therefore, due to the clinical condition presented by the patient, the selected treatment plan comprised placement of a fixed orthodontic appliance, associated to insertion of an endosseous implant to serve as anchorage unit during mesialization and uprighting of tooth #48 to replace tooth #47. Later, tooth #46 was prosthetically rehabilitated over the previously placed implant.In the upper arch, the difficulty involved the intrusion of tooth #16. In this context, the use of miniscrews as temporary anchorage devices provided efficiency and control in the movement, without occurrence of undesired reciprocal movement. It should be emphasized that it is important to use a bilateral force system, with insertion of miniscrews on the buccal and palatal sides, to minimize the tooth inclination and the possibility of root apex resorption.,For insertion of the endosseous implant in the edentulous space to serve as anchorage unit, a multidisciplinary orthodontic, prosthetic and esthetic planning was designed, considering the prosthetic space, need for tooth movement, position and size of future prosthetic crown.,In general, the literature indicates that immediate load can be applied to implants with primary stability whose torque during surgery reached between 35 and 60 N/cm.,The literature also points to the use of immediate load on these implants, since the orthodontic force, of small magnitude, would cause a very mild increase in stress at the bone-implant interface.Thus, it can be concluded that, if planning and primary stability obtained during surgery converge to favorable characteristics for the use of immediate load, the treatment can be performed, providing the patient with comfort, speed and lower treatment costs.In the present case, the treatment time was extended due to the mechanical complexity of closing the extraction spaces of upper posterior teeth to reduce the increased overjet, and the difficult traction of the third molar with unfavorable inclination. However, the patient benefited from the use of endosseous implant as anchorage for uprighting and mesialization movements and its later use as prosthetic abutment, with reduction in total treatment time compared to traditional anchorage. The immediate loading did not delay or prevent osseointegration, and the tooth was successfully used in the final prosthetic rehabilitation. Scientific evidence regarding its use in Orthodontics is still scarce, and further studies are necessary to correlate the anchorage in endosseous implants and the application of immediate orthodontic load.The utilization of endosseous implants with immediate load may be an effective option for orthodontic treatment in adults. The skeletal anchorage provided by these devices increased the treatment efficiency, besides allowing later prosthetic rehabilitation, consequently reducing the total time. Despite the success achieved in the case, there is still little scientific evidence on this issue, thus further studies are necessary to demonstrate its use in Orthodontics.


Calliphora spp. in a Flamingo (Phoenicopterus ruber) from East Azerbaijan Province, Iran. A 3-yr-old female Flamingo was suffering in its left wing leading to an extensive discharging wound, which was heavily infested by maggots (fly larvae). The examination of external morphological characters of the second and third-instar larvae, posterior spiracles and internal cephalopharyngeal skeleton, led to the identification of the Calliphora spp. fly genus. Treatment consisted of removal of the larvae and surgical debridement, then spray of antibiotic and toxic drug. Following removal of larvae and treatment, the symptoms completely resolved within the last hour and remained asymptomatic several weeks later. This is the first report of wound myiasis in a Flamingo (Phoenicopterus ruber) by the facultative myiasis agent Calliphora spp. in Iran and the world.Myiasis is the infestation of animals or man tissues by parasitic dipterous fly larvae. Wound myiasis is the result of fly egg deposition on decaying flesh or pus discharging wounds. This case report describes a type of wound myiasis caused by  Myiasis is the infestation of tissues of animals or man by the larvae of flies. Although, the most common site of myiasis is the skin wound, less common sites are the alimentary canal, eyes, ears, sinuses, throat, nose, and genitourinary tract . Wound mThe larvae of Calliphoridae family, also known as the blowflies, are characterized to develop in animal flesh. “Species associated with an ectoparasitic lifestyle can be divided generally into three groups based on their larval feeding habits: saprophagy, facultative ectoparasitism, and obligate parasitism” . FlamingCalliphora spp. in a Flamingo (Phoenicopterus ruber) with a wing injury history, from East Azerbaijan Province, Iran. Following removal of the larvae and surgical debridement healing progressed rapidly and within six days the wound was virtually healed.This case report describes a type of wound myiasis caused by P. ruber) with a specific wound in left wing was referred by the environmental department of East Azerbaijan Province to the private clinic of Tabriz City Environment Protection Department, in Northwest Iran in September 2016 .Calliphora spp. has the posterior spiracles     and in oal Iran) .Phoenicopterus ruber) by the facultative myiasis agent Calliphora spp. in Iran and the world.However, this report is the first report of wound myiasis in a Flamingo (The myiasis should be considered as an accidental disease among wild bird because parasitic dipterous fly larvae infestations, especially Calliphoridae family, by endangering the health of wild birds cause be their threatened life. Awareness of the wound myiasis in protected area, especially during spring and summer, leads to the more prompt diagnosis, and institution of specific therapy for the disease.