Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging  and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival. Maximal safe resection represents the gold standard for surgery of malignant brain tumors: gross total resection of the tumor while preserving the surrounding functional brain tissue is the main goal, since it is associated with longer survival and better patient quality of life . This isConcerning gross total resection, accurate localization and precise delineation of the tumor margins are required in order to avoid devastating lesions on nervous structures . Frame-bSeveral surgical techniques and technological innovations have been recently introduced to help the surgeon achieve the maximal safe resection of the tumor while reducing the odds of post-operative complications ,7. Some Some of these innovations, such as the IOMR, are expensive and not available in every neurosurgical centre. Therefore, in the last few years, great attention has been paid to the possible intraoperative use of ultrasound (IOUS) guidance for brain tumor surgery. IOUS is not a new technology, but it is accurate in distinguishing tumor from normal parenchyma, and allows a real-time intraoperative visualization. IOUS is cheap, easily repeatable, safe for the patient, potentially available in all neurosurgical centres. As early as in the 1970s, B-mode ultrasound (US) was introduced into the operating room. However, it was the development and application of real-time grey-scale US imaging technology that really provided an impetus to IOUS. The use of ultrasound to achieve maximally safe resection of brain tumors has been implemented since the 1980s . The NorAfter the craniotomy is performed, the utility of ultrasound is evident in different phases of surgery. IOUS help to plan the opening of the dura and to centre the corticectomy. In the following phases, IOUS allows identification of the tumor margins, thus helping for a maximally radical resection. The main advantage of IOUS consists of obtaining a real-time scan: this can be repeated as many times as necessary, in order to overcome the errors produced by brain shift . It alsoIts main limitations are spatial resolution, width and orientation of the field of view , and scan quality, which are operator dependent. Even if US are widely adopted to evaluate cerebral blood flow through transcranial Doppler , NeurosuMoreover, the greatest limitation of US is their limited ability to penetrate the skull; therefore, the most important application of IOUS in brain tumor surgery occurs after performing the craniotomy.Since IOUS has gained great popularity in recent years, the purpose of this study is to review the current literature to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy.We performed a literature research through the Pubmed database by selecting each article focused on the use of IOUS in brain tumor surgery, and in particular, in glioma surgery, published in the last 15 years (from 2003 to 2018). We performed a query using the following combinations of the Medical Subject Headings (MESH) terms: ultrasound, intraoperative ultrasound, intraoperative image guidance, glioma surgery, brain tumors surgery, high-grade glioma surgery, low-grade glioma surgery, alternating all these terms in various combinations. We included all the studies with information on the diagnosis, the extent of the resection, and the postoperative evaluation of the degree of resection by neuroimaging. We excluded all papers written in languages other than English and all studies with incomplete data.After the identification of all articles that met the inclusion criteria, and after removing duplicates, we selected 39 papers dealing with the use of IOUS in brain tumor surgery, including gliomas.Twenty-one studies were prospective and 18 were retrospectives. In particular, we focused on the usefulness of ultrasound in the surgery of cerebral gliomas. 2264 patients were included in our review: 1650 patients with a histologic diagnosis of brain glioma and 522 patients with a non-glial tumor. We did not find any information about the histological report of 94 patients . We paid special attention to the evaluation of the postoperative extent of resection (EOR), and in particular, to the achievement of gross-total resection (GTR), defined as the absence of any residual enhancement on postoperative volumetric-enhanced MRI performed within 72 h after surgical resection. Another important point was the analysis we performed of the usefulness of IOUS used with or without other neuroimaging techniques. The results of our literature review are briefly summarized in The use of IOUS seems to have significantly increased the GTR rate achieved in brain tumors/gliomas surgery.As regard intraoperative visualisation of the tumor and its residuals, the effectiveness of IOUS has been documented in a series of 192 HGG patients, in which the combination of neuronavigation and IOUS was also related to increased overall survival . ErdoganRegarding the reliability of intraoperative ultrasound images, the best 2-D ultrasound images are obtained with a linear array probe  , which is quite large and difficult to manoeuvre into a scalp window. For this reason, in a series of 13 LGG patients, Coburger et al.  comparedProceeding further, the implementation of 3-D US should overcome some limitations of the 2-D US by producing a volumetric image. 3-D US showed 71% sensitivity in detecting residual tumors during the resection of cerebellar lesions, in a series of 16 patients who underwent resection of intracerebral lesions. However, the sample was too small to be conclusive . UnsgaarSerra et al. , in a ren = 39) of patients who underwent fluorescence-guided surgery [In our department, fluorescein sodium has been used as an adjunct in glioma resection since September 2015. We recently reported a resection >95% in 83%  is a valuable tool for visualizing vascularization patterns that often correlates with lesion histology. Prada et al. , in a seThe main objective in brain tumor surgery is to obtain a radical resection with minimal morbidity, as radical removal has been demonstrated to be a main factor affecting overall survival.The advent of neuronavigation has certainly brought significant advantages in brain tumor surgery, allowing identification of the lesion and its margins during the resection, but there is the great limitation of anatomic distortion after craniotomy. Intraoperative ultrasound has allowed us to overcome this limit. Furthermore, IOUS exerts a notable attraction due to the low cost, minimal interruption of the operative flow, and lack of radiation exposure. In experienced hands, sonographic features can help differentiate low-grade gliomas, which can exhibit calcifications and mild hyperechogenicity from high-grade gliomas, which can show necrotic degeneration . Our lit


Diabetes is predominant risk factor for cardiovascular diseases such as myocardial infarction and heart failure. Recently, leukocytes, particularly neutrophils, macrophages, and lymphocytes, have become targets of investigation for their potential role in a number of chronic inflammatory diseases such as diabetes and heart failure. While leukocytes contribute significantly to the progression of diabetes and heart failure individually, understanding their participation in the pathogenesis of diabetic heart failure is much less understood. The present review summarizes the role of leukocytes in the complex interplay between diabetes and heart failure, which is critical to the discovery of new targeted therapies for diabetic cardiomyopathy. Diabetes is a metabolic syndrome that manifests a low grade of systemic inflammation, leads to an increase in all-cause mortality and contributes to the development of number of cardiovascular complications . CardiovThe mechanisms contributing to diabetic cardiac dysfunction are complex and involve a number of molecular phenotypes including insulin resistance, oxidative/nitrative stress , activatNumerous studies have shown that leukocytes and their subsets  are involved in both the initiation and progression of cardiovascular diseases . DiabetiA number of review articles have summarized the role of leukocytes in either diabetes or cardiovascular disease  subtypes based on their functionality and cytokine production  or pro-reparative (M2) descriptors, and certainly a regulated balance between the two subtypes is necessary for homeostasis of inflammation . During Distinct T-lymphocytes subtypes, including T-helper subsets (Th) and T regulatory cells (Treg), regulate inflammation and insulin resistance. Increased frequency of Th1, Th17, and Th22 subsets were shown to contribute to coronary artery disease onset in diabetic patients after adjusting for age, sex, and duration of diabetes . In anot+ Treg cells have been demonstrated effective in the control of autoimmune disease  expressed elevated levels of circulating autoantibodies that bound specifically to cardiomyocytes and were associated with progression of dilated cardiomyopathy  . FurtherAlthough scientists have explored new phenotypes and functions of leukocytes in the context of heart failure, their role in diabetic cardiomyopathy is still developing and there remain several important avenues of research for the future. First, although the role(s) of leukocytes in regulating DCM in different experimental rodent models may overlay, the predominant use of the streptozotocin-induced Type I diabetes rodent model to investigate the leukocytes in the development and progression of DCM potentially leads to limited applicability to the clinically relevant and highly prevalent type II diabetes-associated DCM . Thus, fAB and DT 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.


Apoptosis plays a central role in organs development and homeostasis. Impaired regulation of this process is often associated with the onset of several human diseases, such as developmental disorders and cancer. The last scientific investigations have discovered interesting connections between apoptosis, stem cells, tissue regeneration and cancer. The role of "programmed cell death" in stem cells and tissue engineering is extremely promising; in fact, it holds great potential for regenerative purposes. However, several questions still remain unsolved: do we really know all the main molecular actors able to switch ON/OFF the apoptosis? Is it possible to modulate these players, to obtain a predictable regeneration of tissues and organs? But primarily: should we reconsider the apoptosis as a strategic player in tissue regeneration? In this topical review, we have carefully examined the most recent discoveries about the role of apoptosis in stem cells and, specifically, in mesenchymal stem cells. The pivotal molecules involved in the activation and inhibition of the apoptotic pathways will be carefully described, with the aim to shed an overall light on the complex scenario of stem cell life and death, and on a novel strategy for tissue regeneration. Apoptosis plays a central role in organs development and homeostasis. Impaired regulation of this process is often associated with the onset of several human diseases, such as developmental disorders and cancer Apoptotic cells undergo segmentation of the nucleus and alteration of their membrane, with a consequent formation of the so-called "apoptotic bodies", typically phagocytized by immune or surrounding cells The scientific discussion on the role of apoptosis in tissue regeneration can be considered as a relatively novel topic; on the other hand, the role of mesenchymal stem cells (MSCs) in regenerative procedures have been widely demonstrated. MSCs have been isolated from many human tissues, and they promise useful applications in different pathological conditions. MSCs have the ability to differentiate into the three classical mesenchymal lineages: adipogenic, osteogenic and chondrogenic MSCs express the surface markers CD73, CD90, and CD105, but they lack the expression of CD34, CD45, and HLA-DR hematopoietic antigens. After their first discovering in human bone marrow, MSCs have been isolated from several other tissues, including adipose tissue, fetal structures as umbilical cord and, placenta, and the oral cavity The potential of MSCs to differentiate into osteoblasts have been exploited for bone regeneration In the last years, MSCs have been used in clinical trials targeting the regeneration of damaged tissues, as well as in the treatment of several pathologies, such as multiple sclerosis (MS), Crohn's disease, diabetes and graft-versus-host disease (GVHD). Numerous clinical trials are ongoing, to better understand the different aspects related to efficacy and safety of MSCs for clinical use In this topical review, we have carefully examined the most recent discoveries about the role of apoptosis in stem cells and, specifically, in mesenchymal stem cells. The pivotal molecules involved in the activation and inhibition of the apoptotic pathways will be carefully described, to shed an overall light on the complex scenario of stem cell life and death, and on a novel strategy for tissue regeneration.A literature searching strategy has been used to select the papers to be included in this review. The most used searching engines, such as Medline and Google Scholar has been used by searching for the following keywords: "Apoptosis AND Regeneration", "Apoptosis AND Stem Cells", "Apoptosis AND MSCs", "Apoptosis AND Disease" and "Apoptosis AND Tissue repair". The authors have carefully revised the title, the abstract, and the main text for each of the selected papers. Finally, the papers specifically correlated to our aim were included in this review.Based on the central role of apoptosis in maintaining the body homeostasis, it is not surprising that specific alterations of this process may lead to several pathological conditions. Numerous diseases are related to a massive cell death, which determines severe damages with severe consequences for patients' health. In liver failure induced by drugs or alcohol, viral infections, stroke, heart infarction, and cachexia In cancer pathogenesis, several alterations of different proteins involved in apoptotic pathways, including the Bcl-2 Family proteins, the death receptor, the apoptosome, and the aberrant caspase activity, are commonly found in neoplastic cells. The mutation of p53 gene, which is fundamental in activating programmed cell death in response to different stimuli, represents the major alteration found in the human tumors: this is indicative about the importance of apoptosis in neoplastic transformation.Degenerative disease of the brain, including Alzheimer's disease Interesting studies have pointed out the central role of apoptosis in tissue repair Experimental studies reported that apoptosis occurring within the inflammatory phase of wound healing could be mediated by specific cytokines, such as tumor necrosis factor-α and interleukin-1, released from immune cells: these mediators promote a local response that activates the programmed cell death in vitro researches propose that apoptosis of fibroblasts and vascular cells could be induced by c-myc, that promotes the interaction of fas and Fas-ligand on cell membranes Some C. Elegans; in a second stage, different biological systems, including Drosophila and mammals, allowed further investigations Numerous animal models have clarified the complex apoptotic mechanisms, including the wide range of molecular elements involved and the multitude of pathways implicated. Apoptosis was first characterized in Table .The programmed cell death has a remarkable significance in regulating the correct cell replication in damaged tissue. Worldwide labs have been increasingly involved in research programs aimed to clarify the intriguing role of apoptosis in stem cell function during tissue regeneration The importance of the apoptotic pathways is particularly interesting in the gastrointestinal tract: in fact, a limited number of stem cells cyclically undergo apoptosis because of a mechanism controlled by a p53-independent way. On the other hand, in response to genotoxic stimuli, stem cells residing in the gastrointestinal duct undergo p53-dependent apoptosis. This different regulation pathway could partially explain the lower prevalence of cancer in such tissues with high-rate cell turn-over During the MSC apoptosis, ARTS protein is activated, and it passes from the mitochondria to the cytoplasm: there, ARTS blocks XIAP, a potent apoptosis inhibitor. In recent studies, mice models deficient for ARTS expression showed significant resistance against intestinal tissue damage, and those animals showed improved tissue regeneration, mainly mediated by the blocking of XIAP Apoptosis occurring during the tissue development involves at the same time entire clusters of cells, in order to ensure proper growth of immature tissues; in this context, we can report as an example what commonly happens during the catagenic-phase of the hair follicles. The "cluster apoptosis" is regulated by a feedback mechanism, called "apoptosis-induced-apoptosis" (AIA) The tissue regeneration that occurs after any traumatic wound, typically consists of a proliferative reply by local cells, in order to replace the damaged tissue; this physiologic mechanism is called "compensatory proliferation". Apoptotic cells produce mitogenic signals able to trigger this compensatory proliferation: this pivotal biological mechanism is called "apoptosis-induced compensatory proliferation" (AIP). Apoptosis-induced proliferation is an advantageous process for the organism, as it permits the elimination of damaged cells that could develop genetic mutations or cancer. Furthermore, AIP allows replacing those atypical cells with a new progeny of healthy cells. Alterations of this compensatory process may potentially result as pathological for the body AIP has been first discovered in the study-model Drosophila melanogaster; several studies have confirmed that apoptotic cells can secrete different mitogenic signals, able to trigger the cell mitosis of neighboring cells Pro-apoptotic signals can also induce the production of reactive oxygen species (ROS), that have been demonstrated to be essentials for an effective wound healing and the local recruitment of immune cells at the site of injury In Xenopus tadpole, tail amputation induces a profuse production of ROS; these amputation-induced ROS can activate the Wnt/β-catenin and FGF signaling, and this starts an active tissue regeneration Hydra is also able to regenerate any part of its body. Following a surgically created trauma, this polyp rapidly regenerates its head, and it undoubtedly seems to be promoted by massive apoptosis. In some tissues of hydra, on the other hand, the apoptosis is very limited: consequently, the tissue regeneration is markedly slower. Forced induction of apoptosis also in the foot-related tissues fatally promotes the rapid formation of a second head. Conversely, the inhibition of the apoptosis blocks any regrowth of amputated organs. These impressive examples about the apoptosis in different animal models are strongly suggestive about the strategic role of the releasing of WNT3 signal by apoptotic cells: this is the main engine that induces tissue regeneration Oxidative stress is a well-known trigger for different pathological conditions The administration of H2O2 promotes apoptosis in MSCs, in a time- and dose-dependent manner. This treatment is able to induce the activation of p38 and JNK signaling, however, it does not affect the ERK1/2 - MAPK pathway and the death receptor signaling. To better describe these molecules: the P38 can start the mitochondrial cell death pathway and the ER-initiated (endoplasmic reticulum-initiated) cell death pathways, that lead to early apoptosis; the JNK activation, instead, is involved in the late apoptosis Current studies focused on tissue regeneration are based on the application of alternative techniques: some interesting ones are the using of Platelet-Rich Fibrin (PRF) for the management of uncommon inflammatory diseases Apoptosis-related caspases are involved in the differentiation and growing of stem cells.Deficiency of the effector caspase 3 in mice, increases the proliferation of hematopoietic stem cells and delays their differentiation; furthermore, in primarily derived neural stem cells showing a lacking of caspase 3, it reduces the physiological differentiation into neurons In embryonic stem cells, the overexpression of caspase 3 induces their differentiation by down-regulation of Nanog signaling; Nanog is a well-known target of caspase 3, and the expression of a cleavage-resistant form of Nanog has been demonstrated in self-renewal increasing of embryonic stem cells Caspase 3 is also involved in cell proliferation and the regulation of organs size.In sebaceous glands, the proliferating cells may express activated caspase 3 without any sign of apoptosis. The caspase 3 induces nuclear translocation of the central regulator protein of organ size: the Yes-associated protein; thus, caspase 3 inhibition reduces cell proliferation and sebaceous gland dimension in vivo evidence, underlines that also the in vitro induction of apoptosis, mediated by caspase 3 activation, could represent a valuable tool for the rapid down-regulation of the immune response in GVHD patients. Furthermore, several studies have supported the concept that host cytotoxic cells can induce apoptosis of injected MSCs: this allows that transplanted MSCs does not engraft into host recipient site, although they may continue to act with their immunomodulatory activity.Apoptosis is also involved in the MSC-mediated immunomodulation in transplants. In a mouse model of graft-versus-host disease (GVHD), the infusion of apoptotic MSCs activates phagocytic cells that produce the immunosuppressive mediator indoleamine 2,3-dioxygenase, after the incorporation of injected apoptotic cells Apoptotic bodies are atypical extracellular vesicles produced by dying cells (ApoEVs): we previously described the ability of ApoEVs, derived from MSCs, to modulate the immune response in autoimmune conditions, in antitumor immunity and infective diseases Exogenous transplanted apoptotic bodies have been demonstrated to promote the MSCs proliferation and the osteogenic and adipogenic differentiation. The basal mechanism reported by the researchers was related to the activity of exogenous apoptotic bodies, strategically able to reuse the molecular inhibitor of Axin, finally resulting in the activation of the WNT-pathway and the self-renewal initiation In conclusion, the apoptosis of MSCs could be generally started by a severe alteration of the stem cell niche and after local damage, and the apoptosis can be enhanced by the activation of caspase 3-related pathway in vitro cell manipulation and cell expansion Nowadays, cell therapy often requires Lastly, the discovery that dying cells exert an incredible regenerative potential has increasingly stimulated scientific research to better understand the fascinating cellular and molecular mechanisms of programmed cell death and of tissue regeneration Although AIP could seem to represent a valuable tool for regenerative medicine, it may be certainly considered as a double-edged sword, because of the potential induction of tumors in in-vivo models. Radiotherapy and chemotherapy are able to eradicate tumor-related cells by triggering their death; however, such dying cells might undergo AIP, and thus they can produce mitogenic stimuli that might contribute to metastasis and relapses of primary tumors On the other hand, the complex mechanism of AIA could be, at least partially, responsible for the bystander effect, where non-irradiated cells dye, just like the tumors cells Figure .Some interesting studies have recently linked the two mechanisms AIA and AIP; in fact, they seem to be opposed pathways, but they indeed work in close correlation, thus demonstrating that apoptosis is a mechanism more complex than we are commonly used to know. It would seem that AIA works to increase the apoptotic cells and that these cells consequently produce mitogenic signals able to induce stronger cell proliferation In this review, we tried to shed light on the key molecular mechanisms that promote and/or block apoptotic pathways, describing the studies carried out on animal models that have illustrated the correlation among apoptosis and WNT, JNK p53, p38 pathways, often mediated by the recently discovered ARTS and XIAP proteins; these peptides are able to switch ON/OFF apoptosis, in order to regulate the tissue development and regeneration. The provided experimental evidence could be potentially exploited in a clinical scenario, in order to suggest a predictable regeneration of tissues and organs by manipulating of the apoptotic process.The everchanging knowledge of cell biology still remains largely obscure; however, we can take into account that an indissoluble link between cell apoptosis and tissue regeneration do exist, and it has been consistently confirmed in the last years. This extremely interesting correlation between apoptosis and regeneration seems to suggest different landscapes from the old theory about the role of apoptosis as a process only aimed at cell death, thus considering this biological process as a pivotal player for tissue regeneration and organs homeostasis.


Iraqi Kurdistan is a special hotspot for bio-cultural diversity and for investigating patterns of traditional wild food plant foraging, considering that this area was the home of the first Neolithic communities and has been, over millennia, a crossroad of different civilizations and cultures. The aim of this ethnobotanical field study was to cross-culturally compare the wild food plants traditionally gathered by Kurdish Muslims and those gathered by the ancient Kurdish Kakai (Yarsan) religious group and to possibly better understand the human ecology behind these practices.Twelve villages were visited and 123 study participants (55 Kakai and 68 Muslim Kurds) were interviewed on the specific topic of the wild food plants they currently gather and consume.The culinary use of 54 folk wild plant taxa  and two folk wild mushroom taxa were documented. While Kakais and Muslims do share a majority of the quoted food plants and also their uses, among the plant ingredients exclusively and commonly quoted by Muslims non-weedy plants are slightly preponderant. Moreover, more than half of the overall recorded wild food plants are used raw as snacks, i.e. plant parts are consumed on the spot after their gathering and only sometimes do they enter into the domestic arena. Among them, it is worth mentioning the consumption of raw wild crocus corms, also still common in Turkish Kurdistan and that of wild tulip bulbs, which was documented to be popular until the beginning of the twentieth century in the Middle East. Comparison with other ethnobotanical field studies recently conducted among surrounding populations has shown that Kurds tend to gather and consume the largest number of non-weedy wild vegetables.The collected data indicate robust traces of nomadic pastoralism in Kurdish traditional foraging. This finding confirms that studies on wild food plant gathering in the Fertile Crescent and Turco-Arabic-Iranic regions of the Middle East are crucial for understanding the possible evolution of wild food plant gathering through history within the post-Neolithic continuum between pastoralism and horticulturalism. Is Kurdistan truly an important hotspot for traditional gathering of wild vegetables in the Middle East? Are foraging patterns of different ethno-religious groups living in Kurdistan and surrounding areas similar, and if so, why? What are the possible origins of Kurdish foraging?The current field study tries to address these questions by analysing the wild food ethnobotany of a broad area of Southern Iraqi Kurdistan ranging from the biblical Nineveh Plains in the west to the semi-desert area of the Garmian Region of Kalar to the east, i.e. a bordering plain area where the Kurdish population ends at the Arabic realm.The region that we nowadays call Kurdistan, which is divided among the modern nation states of Syria, Turkey, Iraq, and Iran, and its surrounding territories are a very essential area for understanding the human ecology of food and the evolution of human nutrition patterns, as this area was home to a remarkable portion of the Neolithic Revolution. Some crucial archaeological sites in this northern and eastern part of the Fertile Crescent  have traced the transition from hunting and gathering to the first sedentary settlements, as well as the domestication of cereals, pulses, and various mammals .bio-cultural food refugium [Moreover, in the very recent ethnobotanical literature, Kurdistan seems to emerge as a remarkable refugium  for wildrefugium –13. In arefugium . The difkurd—possibly derived from the Middle Persian kwrt, meaning nomad or tent-dweller [In the present study, which we conducted at the most southern edge of the Kurdish Autonomous Region in Iraq, we considered two diverse ethno-religious Kurdish groups: the Muslim and the Kakai  communities. The term -dweller —emerged -dweller . Kurds w-dweller  while Ya-dweller .A previous study that we conducted in Hawraman, SE Iraqi Kurdistan, showed that the wild food ethnobotanies of Yarsani (Kakai) and Muslim Kurds entirely overlap . DespiteIn this study, we wanted to further verify this finding by using a broader sample which included Yarsanis still living in their original villages in the Nineveh and Garmian plains.To record the local names and specific traditional culinary uses of local wild food plants among Kurds living in different locations of Sothern Iraqi Kurdistan;To compare the data collected among the two considered religious/ethnic communities (Kakai and Muslim Kurds); andTo compare the data with all the available Middle Eastern and Mediterranean wild food ethnobotanical literature, in order to possibly trace commonalities and differences, which could be linked to historical and/or human ecological dynamics.The specific research objectives of this study were therefore:The field study was conducted in Southern Kurdistan (within the border of Iraq) in the spring of 2019, during which time we visited 12 villages Fig. . The twoThe vegetation of our study area belongs to the Armeno-Iranian Province of the Irano-Turanian Region  and, accThe villages we considered rely upon small-scale horticultural and especially pastoralist subsistence economies, with some of the younger and middle-aged population working in the public sector in the main cities.currently collected wild food plants. The data were acquired also via free-listing exercises, group walks through the natural landscape, and participant observation.Fifty-five Kakai Kurds (28 men and 27 women) and 68 Muslim Kurds (40 men and 28 women) aged between 31 and 79 years were interviewed. Respondents were selected among the middle-aged and elderly villagers who have a strong link to traditional agro-pastoral activities and still actively practise the custom of gathering wild plants. The focus of the interviews, which were conducted in Sorani Kurdish, was the local names, modalities of gathering, and detailed culinary uses of the Prior informed consent was verbally obtained before each interview, and the Code of Ethics of the International Society of Ethnobiology  was follVillages of the Nineveh Plain are still heavily affected by the consequences of the occupation of Mosul and the surrounding territory by the terrorist groups of the former Islamic State of Iraq and Syria , with several internal refugees still living in camps, after the occupiers were expelled from Mosul city and its contiguous areas. Kurdish Peshmerga (military forces of the autonomous Kurdistan Region in Iraq) did not allow the field researchers to go to all the villages that we had planned to visit in the Nineveh Plain, since their safety could not be guaranteed given that a number of ISIS affiliates may still be hiding in this area close to Mosul.Flora of Turkey and the East Aegean Islands [Flora of Iraq is still unfinished . The co volumes .Nomenclature follows the standards set by The Plant List database , while pCollected data were compared with the entire Kurdish wild food ethnobotanical literature available in English or Russian , 27, 28 Finally, the most comprehensive reviews on the wild food and medicinal plants used in Iraq  and the Table In total, 54 folk wild plant taxa and 2 folk wild fungal taxa  were recorded, while 5 plant folk taxa remained unidentified. This remarkable number of currently gathered wild food plants shows that Kurdistan still represents an extraordinary hotspot of traditional foraging in the world. This is confirmed also by all recent field studies conducted in different areas inhabited by Kurds –13, 17, sawza): both wild and cultivated greens  appear on the table and are picked up by hand, before using the flatbread to scoop up the main dish. The latter (snacks) represent plant parts which are gathered and consumed raw on the spot.Most of the quoted wild food plants are wild vegetables, and the majority of them are mainly consumed raw, both as wild greens and especially as snacks. The former refer to the Kurdish tradition of consuming raw herbs as a side-dish (Gundelia turnefortii) are dug out using a hoe  or more often nowadays simply frozen.More than 60% (36 out of 59) of the overall recorded folk plant taxa (54 identified folk taxa and 5 unidentified folk taxa) are consumed as snacks, i.e. raw on the spot. Several of these snacked plants seem to be predominately gathered by men and especially by male teenagers while they are out in nature. Some of them do enter into the domestic arena and they represent “social snacks”, i.e. they are consumed raw during family and social gatherings .Women forage instead mainly wild vegetables  that are normally further processed and cooked, or even simply consumed raw as a side-dish , still widely used in the Arabic, Israeli, and Kurdish cuisine [Although these limitations make a robust comparison with other ethnobotanical studies very difficult, we formulate here the hypothesis that snacks may have emerged during the development of mobile pastoralism. Personal observations and other ongoing field studies conducted within our research group confirm that in areas where pastoralism has been predominant in the past centuries (i.e. Sardinia), edible thorny Asteraceae, which were traditionally peeled and consumed on the spot while bringing herds to pasture, play a crucial role in the local folk diet. It is worth mentioning here that foraging pastoralist practices were possibly the origin of two currently very popular vegetables in the Mediterranean and the Near East: artichoke, which was domesticated in the central Mediterranean area a couple of thousand years ago , and wil cuisine , 39, 43.Allium, Bunium, Chaerophyllum, Crocus, Geranium, and Tulipa spp.Among the most uncommon wild plant snacks we recorded, it is important to highlight the variety of underground food items, such as those of All the recorded plant snacks present a particular sensory characteristic Table : they arAmong the recorded plant snacks, it is interesting to underline the current consumption of wild crocus corms and tulip bulbs. The gathering of raw crocus corms Fig.  in our sTulipa montana) were instead reported to be consumed in Iraqi Kurdistan in the past century [Tulipa armena bulbs have recently been reported to be (very rarely) consumed raw in Turkish Kurdistan [Fritillaria imperialis instead represents the most desired bulbous ornamental plant.Bulbs of wild mountain tulips  are repFigure No remarkable differences could be found among the two communities in terms of overall gathered plant taxa and their wild vegetable snacks Fig. a. HoweveThe available ethnographic literature may confirm this finding, since the traditional subsistence economy of Yarsanis/Kakais, which emerged in Iran during medieval times, was mainly based upon small-scale horticulturalism and handicrafts (weaving) , whereasIn other studies that we have conducted in recent years in the Balkans and the Middle East, we have demonstrated that religious groups living in the same environment may sometimes show different ethnobotanies, possibly because endogamic patterns play an important role in influencing vertical and, to less extent, also oblique transmission of folk plant knowledge , 51–54.In the current study, however, we did not observe remarkable differences between the two studied communities. One possible reason can perhaps be found in the large utilization of wild plant snacks: we observed that these are mainly gathered in the study area by young male community members, and therefore, horizontal (peer-to-peer) transmission of plant knowledge may have been predominant in our sample.Tulipa, Lilium, Crocus, Dracunculus, Johrenia, and Bongardia. Among the most uncommon customs linked to plants, we recorded the tradition of gathering the famous “Kurdish manna” (Fig. Comparison of the current data with some of the most recent wild food ethnobotanical literature on the Middle East shows that a few wild plants have only rarely been recorded as being consumed: this is the case for the botanical genera na” Fig. , well knna” Fig. .Fig. 9KMoreover, we analysed the data in terms of possible human ecological origin, i.e. calculating the proportion of weeds among the quoted wild vegetables as a proxy for analysing possible horticultural/sedentism-driven foraging patterns.Table This data suggests the idea that Kurds may have shaped their foraging habits upon their nomadic pastoralist subsistence economy, while the sedentism and horticulturalism of the Fertile Crescent have left heavy traces in the foraging patterns of Assyrians  and lateThe overall gathered data not only show a remarkable resilience of foraging traditions in Southern Kurdistan, but also document the food consumption of several wild plant ingredients as raw snacks, i.e. crocus corms and tulip bulbs. While no very significant divergences were found among the two studied religious communities of Muslim and Kaki Kurds, among the Muslim Kurds, non-weedy plants were clearly more prevalent among the most commonly quoted wild vegetables, as Kakai Kurds have historically been more horticulture oriented. At the same time, the large prevalence of snacks, especially among Muslim Kurds, confirms robust traces of pastoralism in the Kurdish foraging of wild foods.Our study calls for further field surveys in surrounding regions of the Middle East, Caucasus, and Eastern Mediterranean aimed at analysing how TEK concerning wild plants change across time and space and for a better understanding of the diachronic trajectories of the use of wild plant foods before and after the development of agriculture until today.Finally, the recorded Kurdish bio-cultural food heritage could find concrete applications in rural development projects aimed at promoting small-scale food products and eco-tourism, considering the very difficult times this area has gone through and is still partially going through.


The actions of BDNF (Brain-derived Neurotrophic Factor) in regulating neuronal development and modulating synaptic activity have been extensively studied and well established. Equally important roles for this growth factor have been uncovered in the cardiovascular system, through the examination of gene targeted animals to define critical actions in development, and to the unexpected roles of BDNF in modulating the response of the heart and vasculature to injury. Here we review the compartmentally distinct realm of cardiac myocytes, vascular smooth muscle cells, endothelial cells, and hematopoietic cells, focusing upon the actions of BDNF to modulate contractility, migration, neoangiogenesis, apoptosis and survival. These studies indicate that BDNF is an important growth factor which directs the response of the cardiovascular system to acute and chronic injury. The preponderance of research on the biology of BDNF has focused on its actions upon central and peripheral neurons. Brain-derived neurotrophic factor (BDNF) was first isolated in the 1980s, several decades after the identification of the related factor, nerve growth factor (NGF) . BDNF plThe effects of BDNF on cardiac development were first identified through the study of BDNF null mutant mice, which exhibit early postnatal lethality . In addiSeveral more recent studies have refined our understanding of BDNF/TrkB in the developing heart through the study of TrkB gene targeted mice. Similar to the deficits noted in the BDNF null animals, embryos lacking TrkB expression demonstrate a reduction in subepicardial vessels in late gestation . The mectrkB locus generates multiple trkB isoforms which encode the same extracellular domain, but express different intracellular domains, including a truncated product which lacks tyrosine kinase activity (TrkBT1)  transduces the inotropic effects of BDNF, which will require additional study.While numerous studies have investigated the roles of BDNF on cardiac development, much less is known about the effects of BDNF on adult cardiac function and cardiomyocyte contractility. Although initially described as a receptor tyrosine kinase, the (TrkBT1) . TrkBTI (TrkBT1) , whereas(TrkBT1)  and thisA concurrent study evaluated the potential impact of the BDNF-mediated activation of the kinase active isoform of TrkB in the adult heart, by genetically deleting this isoform in cardiac myocytes . Using tThese studies are highly relevant as the field considers the use of BDNF-mimetics to enhance TrkB activation in central neurons for the treatment of mood disorders, regulation of food intake, and neurodegenerative conditions. Novel BDNF mimetics will need to be evaluated for potential effects on the function of the adult cardiovascular system, which could include increased systolic blood pressure. Indeed, delivery of a TrkB agonist antibody to mice induced moderate systolic and diastolic hypertension, an effect which was dose-dependent, and reversible Many studies have evaluated plasma or serum levels of BDNF, in an attempt to correlate circulating blood levels with those available to tissues, such as the brain, myocardium or vessel wall. However, the physiochemical properties of BDNF suggest that following secretion from cells, it acts locally, over short distances. Specifically, BDNF is a highly charged molecule (pKi of ∼9), with a short half-life in the circulation following exogenous delivery, and poor tissue penetration . While nIn situ hybridization studies demonstrate that vascular smooth muscle cells in the great vessels and coronary arteries express several neurotrophins, including BDNF, during development. This expression pattern was interpreted as providing trophic support to mediate the outgrowth of developing sympathetic, parasympathetic and cranial nerves , age of animals, or mode and dose of BDNF protein delivered. For example, studies by Several laboratories have utilized gene targeted mice to elucidate possible functions of BDNF in the setting of acute myocardial injury. Studies comparing BDNF haploinsufficient vs. wild type mice  noted imIn humans, but not other species, a single nucleotide polymorphism (SNP) in the prodomain region of BDNF Val66Met is observed in approximately 20% of Caucasians, with higher allele frequencies in Asian populations. This polymorphism results in a reduction in the level of mature BDNF which is secreted by cells . The secIn situ analysis of mRNA expression has revealed that several neurotrophins are expressed in the heart and great vessels of developing and adult rodents, including ngf and nt-3, in addition to bdnf ( to bdnf . Using g to bdnf  with sub to bdnf  and card to bdnf . NT-3 an to bdnf , and dir to bdnf .ngf mRNA increases in the ischemic region, with elevated levels in pericytes in the border zone (ngf mRNA levels remain elevated for ∼5 days. Using adenoviral mediated delivery of NGF to the peri-infarct area, increased capillary density and improved blood flow were observed in mice (Nerve growth factor has been well studied for its role in modulating cardiac function, particularly in the setting of injury. Cardiac myocytes express NGF, which functions to establish cardiac sympathetic innervation during development; indeed, the classic experiments of Levi-Montalcini documented the dependence stellate ganglion sympathetic neurons on NGF . In the der zone . Interes in mice , and oth in mice . In cont in mice . ProNGF  in mice . ProNGF  in mice . These sThese studies reveal unexpected, and important roles for BDNF, and other neurotrophic factors in the regulation of the development of the heart and great vessels, in the maintenance of adult cardiac function, and complex actions following vascular injury. A key feature of this research is that BDNF plays important roles in this organ system, and that strategies to manipulate BDNF levels in the central nervous system may have unintended consequences in cardiovascular function. The protective role of BDNF in maintaining endothelial, pericyte and cardiac myocyte function and survival provide potential therapeutic strategies to promote neoangiogenesis and stabilization of damaged myocardium following ischemic injury. However, preclinical studies reveal that BDNF can induce the recruitment of multiple hematopoietic cell types to regions of ischemic cardiac injury, and further extensive investigation will be required for the optimal design and delivery of BDNF or mimetics to promote neoangiogenesis. Concurrently, additional studies of the role of BDNF isoforms on acute and chronic vascular injury is warranted, to better understand the interplay of BDNF with other growth factors in atherogenesis.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The author BH declares that she received funding from UCB Pharma for unrelated studies. The funder played no role in the study design, the collection, analysis or interpretation of data, the writing of this paper or the decision to submit it for publication. All authors declare no conflict of interest.


Research Topic: Pre-clinical Models of PTSD that includes 16 publications: 11 original research articles, 2 reviews, 2 mini-reviews, and a perspective that all integrate rodent models of posttraumatic stress disorder (PTSD) in the conceptual framework of the publications. By using rodent models of traumatic stress exposure and/or measuring PTSD-specific physiologic characteristic and PTSD-like behaviors, the articles explore both established and novel brain mechanisms implicated in PTSD. The manuscripts span neurochemical and anatomical levels, sex-dependent differences, relationships to comorbid conditions, and new rodent models of PTSD-like effects.This editorial outlines the Research Topic contains manuscripts that continue this exploration, including studies that focus on brain catecholamine signaling in well-characterized and novel neurocircuitry implicated in PTSD. Papers by Chaby et al., Deslauriers et al., and Liu et al. examine aspects of catecholamine signaling as a key system relevant to the expression of PTSD-like behaviors with potential relevance to PTSD treatment. Manuscripts by Piggott et al. and Miles and Maren, and others investigate specific brain regions that likely play an important role in PTSD, including prefrontal cortex and amygdala, as well as brain regions, that have been less studied in this context, namely the striatum and bed nucleus of the stria terminalis. This subgroup of papers that explore involvement of brain mechanisms, often linked with reward, provides conceptual bridge for the understanding of the highly prevalent association of PTSD with substance use disorders, a comorbidity that is reviewed by Gisquet-Verrier and Le Dorze.Similarly to other brain based pathologies, pre-clinical models of PTSD are critical for the ability to mechanistically explore the effects that trauma have on brain structure and function, yielding considerable insight into the neurobiological processes that likely underlie PTSD phenotypes. This Research Topic includes a number of studies on the mitigating role of sex and developmental factors in expression of PTSD following trauma. For example, Asok et al. show that fear generalization is sex-dependent, Colom-Lapetina et al. illustrate a sex-dependent diversity in behavioral response to trauma, and Nahvi et al. provide evidence that females show anxiety- and depression-like behaviors akin to males, but have a unique neuro-mechanism underlying these behaviors. Interestingly, Chen et al. using two animal models of PTSD report that while fear extinction learning deficits manifest when trauma occurs in adulthood, adolescent animals might be resilient to similar trauma. Together these studies contribute to the growing body of work addressing the need to understand factors, such as sex and age that contribute to PTSD, highlighting the need to use multiple models of PTSD to define specific aspects or uncover unique characteristics associated with traumatic stress exposure.Beyond direct mechanistic studies, PTSD-related animal models provide a means to study additional risk and protective factors that can modify the development of psychopathology following exposure to traumatic stress. This Pre-clinical Models of PTSD Research Topic embraces several manuscripts that involve new models and/or investigate new mechanisms potentially relevant to PTSD. For instance, Paredes and Morilak review the use of extinction learning as a model of exposure therapy in rodents, Conoscenti and Fanselow discuss key aspects that differentiate animal models in the stress literature, and Pinna uses a novel social-isolation model to determine if a biomarker, allopregnanolone in this case, can be identified for PTSD. Furthermore, this Research Topic delves into novel mechanisms, such as those explored by Moshfegh et al. involving inflammatory response to stress, or the effects of fear extinction learning on conditioned cardiovascular response by Swiercz et al. It also includes papers that investigate neurotherapeutics for PTSD, such as a study by Shallcross et al. that studied cannabidiol and a mGlu5 positive allosteric modulator as potentially useful agents with unique effects on stress and fear-related behaviors. These novel models and mechanisms continue to expand our understanding of PTSD and emphasizing the importance of scientific and conceptual diversity in PTSD research.Historical evidence shows that with new models new candidate mechanisms come into the investigative focus. The Pre-clinical Models of PTSD focus on the use of animal models to advance understanding of PTSD-related pathophysiology, including mechanisms targeting aspects of the brain, the body, and individual behavior. Moreover, factors affecting vulnerability and resilience, comorbidities, and treatment outcomes are considered in this Research Topic. Finally, while recognizing that PTSD is a uniquely human disorder, the use of appropriate animal models of PTSD and traumatic stress exposure and measurement of defining characteristics of PTSD remain critical components of the research endeavor to understand the complex neurobiology of PTSD.The collection of manuscripts in 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.


Major efforts are underway to improve access to mental health care in low- and middle-income countries (LMIC) including systematic training of non-specialized health professionals and other care providers to identify and help individuals with mental disorders. In many LMIC, this effort is guided by the mental health Gap Action Programme (mhGAP) established by the World Health Organization, and commonly centres around one tool in this program: the mhGAP-Intervention Guide.To identify cultural and contextual challenges in mhGAP training and implementation and potential strategies for mitigation.An informal consultative approach was used to analyze the authors’ combined field experience in the practice of mhGAP implementation and training. We employed iterative thematic analysis to consolidate and refine lessons, challenges and recommendations through multiple drafts. Findings were organized into categories according to specific challenges, lessons learned and recommendations for future practice. We aimed to identify cross-cutting and recurrent issues.Based on intensive fieldwork experience with a focus on capacity building, we identify six major sets of challenges: (i) cultural differences in explanations of and attitudes toward mental disorder; (ii) the structure of the local health-care system; (iii) the level of supervision and support available post-training; (iv) the level of previous education, knowledge and skills of trainees; (v) the process of recruitment of trainees; and (vi) the larger socio-political context. Approaches to addressing these problems include: (1) cultural and contextual adaptation of training activities, (2) meaningful stakeholder and community engagement, and (3) processes that provide support to trainees, such as ongoing supervision and Communities of Practice.Contextual and cultural factors present major barriers to mhGAP implementation and sustainability of improved services. To enable trainees to effectively apply their local cultural knowledge, mhGAP training needs to: (1) address assumptions, biases and stigma associated with mental health symptoms and problems; (2) provide an explicit framework to guide the integration of cultural knowledge into assessment, treatment negotiation, and delivery; and (3) address the specific kinds of problems, modes of clinical presentations and social predicaments seen in the local population. Continued research is needed to assess the effectiveness these strategies. Despite increasing recognition of the high global burden of mental, neurological and substance use disorders , 2 and tIn an effort to respond to this priority, the World Health Organization (WHO) has developed a set of tools, including the mhGAP Intervention Guide (mhGAP-IG) , 17 alonIn this article, we draw from our field experience to discuss challenges encountered in the process of mhGAP training and implementation and provide recommendations for future work. The fieldwork informing our reflections include the authors’ individual experiences leading, organizing, delivering, and evaluating mhGAP implementation projects in multiple countries and settings including Chad, Ethiopia, Nigeria, Guinea, and Haiti, over a period of 6 years. We have consolidated, organized, compared, and critically analyzed these experiences in order to inform future dialogue, research and practice. Our approach to the analysis discussed in more detail in “Our experience suggests that successful mhGAP implementation and capacity building requires not merely didactic and practical training but also broader implementation of support systems and interventions that are responsive to local needs and cultural contexts. The lessons learned about mhGAP implementation can inform future research and practice and assist those involved with mhGAP program implementation at the levels of health policy, training, community and health clinic.The mhGAP training tools are designed for use with non-specialized health service providers from a wide variety of backgrounds. In practice, the participants in training may include physicians, nurses, midwives, health technicians, community health workers (CHW) and, in rare instances, traditional healers. Although CHW and traditional healers are not the intended audience of mhGAP training they are sometimes included in training programs , 32–34. The mhGAP program emphasizes clinical decision-making algorithms and stepped-care treatment protocols to assess and manage a set of priority mental disorders. These manuals have been adapted for multiple settings including refugee and humanitarian crises in the mhGAP-Humanitarian Intervention Guide (mhGAP-HIG) . The mhGThroughout this text we use the term mhGAP to refer to the process of mhGAP-IG and mhGAP-HIG training and the implementation of mhGAP program. We use the term trainee to refer to any learner attending mhGAP-IG or mhGAP-HIG training.A key concern of mhGAP implementation is how trainees apply their knowledge in practice. Ensuring that mhGAP training results in improved services depends in part on understanding the structural and systemic factors that influence service provision post-training. Implementation requires effective leadership, ongoing training in early implementation phases, and ensuring retention of trained providers . There aThe mhGAP program is based on a biomedical model with particular assumptions about the nature of mental health problems. The program is agnostic to health-care providers’ own ethnocultural backgrounds and interpretations. However, it implicitly endorses the framework of biomedical psychiatric and individualistic psychology in its approach to mental health and illness in terms of discrete problems located within the individual –42. TherThis article presents systematic reflections and post hoc analysis of the authors’ informal observations during diverse field experiences in mhGAP-related projects at different sites. The projects were carried out in multiple areas in six countries  and included distance training. We did not collect or use any participant or personal data and hence no ethical approval for the project was needed. All references to data related to these projects are based on published articles and cited when relevant. Findings were organized into categories according to specific challenges, lessons learned and recommendations for future practice. We aimed to identify cross-cutting and recurrent issues. Given this goal, and to maintain confidentiality, we do not identify specific sources.We used an informal consultative approach to the analysis of our combined field experience in the practice of mhGAP implementation and training. The accumulated expertise were based on individual work and familiarity with project reports and memos, stories of experiences, participant observation, field-notes, ongoing conversations with key stakeholders and peers, academic presentations where critical reflections were provided, as well as written exchanges between the authors during and after fieldwork. We also included material drawn from inquiries and requests for consultation addressed to subject-matter experts regarding issues encountered in the field, the sharing of evaluative data collected in the field as part of auxiliary programs. All of this information was organized into categories according to challenges, lessons learned and recommendations for future practice.We employed iterative thematic analysis to consolidate and refine lessons, challenges and recommendations through multiple drafts. We generated key themes and grouped each challenge and recommendation with its corresponding theme. The challenges items and the recommendations were tabulated against the themes. Microsoft Excel was used to recode items and corresponding themes from string to categorical indicator variables. These codes were used to produce an alluvial diagram using the open source Web application RawGraphs see Fig. .Fig. 1CoWe identified six sets of cultural/contextual issues that require consideration in mhGAP implementation: (i) cultural differences in explanations of and attitudes toward mental disorders; (ii) the structure of the local health-care system; (iii) the level of supervision and support available post-training; (iv) the level of previous education, knowledge and skills of trainees; (v) the process of recruitment of trainees; and (vi) the larger socio-political context of the region.Cultural knowledge, attitudes and practices exert strong effects on help-seeking, treatment referral, adherence, and response to interventions. Although trainees with local cultural knowledge are an essential resource in mental health service delivery, they present specific challenges to standardized mhGAP training: (1) trainees may share cultural beliefs, and assumptions with others in their local culture that lead to biases and stigma toward mental illness; (2) trainees may be unclear how to apply their cultural knowledge to the specific tasks of mhGAP; and (3) the local context may include particular types of clinical problems, presentations, and social predicaments not explicitly addressed in mhGAP.Cultural attitudes toward mental disorders are important factors in service provision. Stigmatizing cultural beliefs, explanatory models and attitudes shared by both patients and mental health workers  will shape service delivery. Lack of attention to cultural context on the part of providers and decision-makers can lead to mistrust of mental health information and services and reduce motivation to engage with mental healthcare or adhere to treatment , 44. In Of course, the impact of cultural beliefs is not confined to mental conditions. Given that physical illnesses often provide signs that point to the presence of known biological agents, biomedical services may be more likely to be sought for physical conditions, but cultural meanings and implications of affliction remain a critical ingredient in the negotiation of care . In the Cultural and contextual factors also influence the types of mental health problems that practitioners face. This may pose challenges to the applicability of mhGAP materials. For example, in the Ugandan studies, practitioners found the guidelines did not provide adequate tools for the treatment of comorbid disorders and did not address the types of psychosocial problems seen in the population including war-related and residual post-conflict difficulties of Ugandan population and the psychosocial difficulties particular to refugee populations, including, for example, those related to domestic violence and disputes over land .In our field work, trainees in other regions have expressed similar concerns. Examples included reported difficulty in managing cases of severe trauma, sexual violence, and child-marriages. Trainees working with refugee populations frequently expressed the need for specific training in inter-ethnic and conjugal conflict resolution. Trainees gave examples of instances they were called on to intervene in cases related to clashes among refugees, and inter-ethnic clashes between refugees and members of their host community; the latter often due to the perception that refugees were responsible for the use and depletion of common community resources such as water and fuel wood. Less common but equally challenging concerns were related to negative attitudes toward refugees held by some trainees themselves.A large body of work demonstrates that cultural variations in illness experience and behavior influence the diagnosis and treatment of mental health problems , 49. CulWhen mhGAP training is carried out in humanitarian settings, it is common for trainers and trainees to come from different cultures. In Chad, for example, mental health training has been provided by trainers from Canada, Democratic Republic of Congo, India, Belgium and the US. The trainees are French-speaking Chadian health-providers who treat Zaghawa-speaking Darfur refugees. In these settings, the historical, geopolitical, and social contexts play important roles in communication that may affect training. Local trainees may have much relevant knowledge about idioms and explanatory models but lack ways to integrate this into mhGAP delivery.As discussed earlier, mhGAP training is based on a biomedical model and aims to be agnostic to health-care providers’ own ethnocultural backgrounds and assumptions . The bioTo be useful mhGAP training must fit the structure of the local health care system and the contexts of practice. Some studies have highlighted the importance of such structural factors in mhGAP implementation. For example, an evaluation of implementing mhGAP guidelines in Uganda  cited thIn our work, we have observed structural challenges related to the logistics of service provision of two types: those related to tangible resources and those related to information resources. Both of these were frequently reported by trainees as obstacles to the integration of mhGAP training in their routine practice across settings including refugee camps, rural and urban health-care centers. Problems related to tangible resources included the availability of an adequate supply of psychiatric medications, and the availability of appropriate physical spaces for mental health consultations. Trainees working in very low resource settings were particularly concerned that the adoption of mhGAP could further burden the over-extended system without providing support or incentives for the increased workload.Information resource challenges were associated with problems in communication and access. After training, most trainees received no feedback about the integration of mhGAP in the larger health care system or the specific impact of their work. Trainees frequently voiced concerns about a lack of information on how to access supervisory resources and referral pathways.As previously mentioned, two essential components of mhGAP implementation are task shifting and the stepped care approach. These both depend on the structure of the health care system. The stepped-care approach depends on having appropriate referral pathways. Even if referral pathways are formally present, they may be infrequently used and function poorly in practice. Related to this, due to lack of a broader vision and strategy for mental health service systems in most LMIC, efforts to integrate mental health may be confined to Primary Health Centers (PHC). For example, in Ethiopia, health-care providers in local and regional hospitals were not given the requisite training to enable them to supervise PHC workers or handle patients who come through the referral system. An exclusive focus on one sector like primary care can contribute to fragmentation in the health-care system, with mental health-care sequestered in PHC and specialty mental health-care facilities found only in the larger cities, with little or no attention given to health-care providers in between, making it difficult to implement the stepped-care component of the mhGAP.Other structural challenges that can impede efforts to implement mhGAP are related to the lack of mental health policy and planning. About half of the countries in Africa do not have mental health policy, and among those that do, nearly 40% have not updated or modified their policies since 1990 . For exaIn our field experience, mhGAP training without follow-up supervision generally has been insufficient to ensure the integration of mental health knowledge into practice. Many difficulties in the application of mhGAP are related to errors in differential diagnosis leading to inappropriate care. In most cases, pre-post tests indicate increases in mental health knowledge with mhGAP training and, in some instances, post-training evaluations indicated that most trainees had high levels of confidence in their ability to administer mental health-care services. However, there is some indication from the same study that high levels of confidence may not correlate with post-training knowledge test scores . In traiIn addition to the challenges of misdiagnosis, with over- or under-recognition of specific conditions, lack of supervision can also affect the kind and quality of interventions practitioners provide. In our experience in Ethiopia (mhGAP training 2015–2016), in the absence of adequate supervision, primary health-care physicians may be reluctant to prescribe medications in adequate doses because of concern about side effects. Diagnostic assessment and treatment approaches are mutually reinforcing. In the absence of supervision, health workers may attempt to fit symptoms they observe into the few broad categories of mental disorder they have learned about in the mhGAP program. This may result in over-diagnosis of some illnesses and potential over-prescription, thereby exposing patients at least to unnecessary expense and medication side-effects . Under-dAs discussed above, mhGAP aims to narrow the service gap by task shifting . Mental health training of healthcare providers varies considerably across countries and regions . There iDelivery of mhGAP training includes pre- and post-tests of mental health knowledge. These tests are used in almost all mhGAP training courses including refresher and train-the-trainer initiatives. Ideally these tests could provide important feedback on the success of training. However, to our knowledge, the test questions have not gone through an evidence-based process of item construction and the pre- and post-tests are not standardized measurement instruments. Their cross-cultural validity has not been established. We have observed trainees with different educational professional backgrounds and skill-levels have difficulty with some of the assessment questions. While there is an overall trend toward improvement at post-test , some trMuch preparation is needed prior to implementation of mhGAP training. A key logistical element that is not always considered systematically involves choosing and inviting trainees to enroll in the mhGAP training program. The process of selecting trainees is crucial to the ultimate success of mhGAP training. In our experience, relegating the task of trainee selection to beneficiary organizations or the state, may not lead to the best choice of candidates for mental health training, or the best outcomes in terms of accessible mental health-care for the underserved populations.At the level of the clinic, we have observed that mhGAP trainees may be selected based on status and standing in their respective organizations. In some instances, this may even result in health administrators being recruited to the exclusion of clinical staff. While health administrators can certainly benefit from mhGAP training and can play a role in future training and supervision of clinical staff, their increased competence may not translate into better patient care because administrators are usually released from clinical duties. Status-based selection is also often tied to gender and cultural defined norms. Thus, female nurses, midwives, and birth attendants may be overlooked in the selection process in localities where women have lower standing in the work place or the community.At the grassroots level, CHWs are recruited and trained as peer-support workers, sometimes without clear criteria for inclusion. This group represents an important human resource in LMIC, but recruitment strategies may ignore existing help-seeking pathways, traditional healers, and other sources of care that can hinder or promote mental health interventions. The most effective CHWs may be those who exert the most influence in their communities, who are respected opinion leaders, and who are centrally positioned in the community and able to provide information and assistance to as large a group of people as possible.The political context, both historical and current, of the community, region, and nation where mhGAP training is undertaken influences local health systems and the population’s willingness to adopt new health practices. In West Africa, for example, histories of political conflict and violence eroded trust in government institutions, including health care, with devastating effects on the response to the Ebola epidemic , 68. PubAlthough these were extraordinary circumstances, issues of trust and engagement with government or NGO programs are common in LMIC with histories of colonization, political instability and violence. There has been little discussion of this type of historically rooted challenge in the literature on public health efforts and mhGAP program implementation. However, these contextual factors play an important and largely implicit role in the adoption of programs such as mhGAP, both in the response to training, and in its integration in service provision. Strategies are needed to explore and address historically rooted political issues that may impede program implementation.The kinds of challenges we have outlined will vary widely across contexts with local culture, health care system structure and politics. Hence, generic strategies to address or mitigate these challenges will be context-dependent and must be locally adapted. The following broad recommendations are derived from our experiences with the challenges discussed in this paper. Each strategy requires careful consideration to determine its potential suitability and fit in a specific context or setting.Given that mhGAP trainees are embedded in local cultures and health infrastructures, they are well positioned to carry out cultural and contextual adaptation. To do this, they need appropriate guidance to utilize their knowledge of local contexts and culture in the conceptualization and application of their knowledge to adaptation of the mhGAP tools. There are existing guidelines for tailoring clinical assessments to local contexts and methods for cultural adaptation , 75. MetWhile mhGAP training materials emphasize inclusion of cultural beliefs, practices, language, and social norms, in practice this step may be carried out only partially or hastily, and the collected information may not always inform practice . ResearcLocal cultural and contextual adaptation should be one of the core principles of mhGAP training and implementation, rather than an afterthought. This can be facilitated by establishing ways to gather feedback from health-care providers , patientAlthough mhGAP holds great promise to narrow the Global Mental Health service gap, there is a critical need to determine if and when it leads to lasting changes in practitioner competencies and whether these competencies are translated into actual service delivery. There is also a need to develop educational and supervisory approaches to ensure that the trainees receive adequate support post-training. A study conducted in Nigeria with mhGAP trainees found that although diagnosis and referral improved greatly immediately following training, performance declined at 9-month follow-up . This anStrategy of the Communities of Practice (CoP) may offer a viable approach to providing post-training educational and supervisory support to ensure that the trainees can apply their knowledge and skills. A CoP is a learning community that organizes itself around a shared interest with the objective of facilitating peer-interaction and reciprocated support in problem-solving and collaborative learning , 90. MemCommunity and stakeholder engagement have long been identified as key components of public health program implementation and sustainability , 94. TheThe recommendations pertaining to specific challenges are summarized in Table Factors that can facilitate or impede mental health program implementation vary across contexts and cultures and must be examined and addressed prior to, during, and after the process of implementation. Mental health training alone cannot guarantee desired impacts on health systems and population health. Global Mental Health practice needs to remain open to new strategies and innovation in policy development, training and implementation that respect culture and context, including methods of leveraging existing resources for effective service provision, and processes that can ensure sustainability. Understanding local contexts and cultures and how they shape help-seeking and service provision requires the participation of many stakeholders, recognition of their ideas, needs, and concerns, and integration of local strategies in program adaptation, training and implementation. Incorporating culture and context and ongoing supervision and support are essential for program acceptability, effectiveness and sustainability.To enable trainees to effectively apply their local cultural knowledge, mhGAP training needs to: (1) address any unwarranted assumptions, biases and stigma associated with mental health symptoms and problems; (2) provide an explicit framework for how to integrate cultural knowledge into assessment, treatment negotiation, and delivery; and (3) address the specific kinds of problems, modes of clinical presentations and social predicaments seen in the local population.In sum, approaches that include deliberate cultural adaptation, contextual adaptation of training activities, meaningful stakeholder and community engagement, and processes that support the trainees such as supervision and CoPs are likely to be among the most feasible and effective methods of improving mental health integration at the primary care level in LMIC. Many of the challenges to mhGAP implementation and potential mitigation strategies discussed in this paper need further study with mixed-methods to guide the best use of resources for impact and sustainability.


Dysbiosis has been associated with the onset of several chronic autoimmune or inflammatory pathologies , because of its primary role in the establishment of a chronic inflammatory process leading to tissue damage. Inflammatory bowel diseases can even involve areas far away from the gut, such as the extraintestinal manifestations involving the oral cavity with the onset of aphthous-like ulcers (ALU). Studies carried out on animal models have shown that intestinal dysbiosis may be related to the development of autoimmune diseases, even if the mechanisms involved are not yet well known. The aim of this paper is to verify the hypothesis that in inflammatory bowel diseases patients, aphthous-like ulcers are the result of the concomitance of intestinal dysbiosis and other events, e.g., the microtraumas, occurring in the oral mucosa, and that  Several roles, related to the regulation of the host’s physiology, have been attributed to gut microbiota, including stimulation of the immune system, control of pathogenic bacterial proliferation, production of short-chain fatty acids, and fermentation of amino acids and saccharides [The human gut contains a high concentration of bacteria, collectively called microbiota. There are at least 1000 bacterial species (of which 150 to 500 only in the colon) with a density of 9 × 10charides .A disequilibrium of the intestinal microbiota is called dysbiosis, and it causes an alteration of the intercellular tight junctions, allowing access of pathogens  and stimulation of the mucosa-associated lymphatic tissue (MALT) with activation of the inflammatory cascade , establishment of a chronic inflammation process  and, conFor this reason, dysbiosis has been implicated in the onset of several chronic autoimmune or inflammatory pathologies, including IBD  and Crohn’s disease (CD)), metabolic diseases , autoimmune diseases , and other disorders  ,3; to da+ T cells into Th17, which act at the epithelial level to improve the integrity of the intestinal mucosal barrier. This suggests that a disruption at this level can cause changes in the intestinal barrier and the onset of various pathologies [The onset of extra-intestinal pathologies linked with dysbiosis is due to bacterial signals that affect the innate and adaptive immune system. These signals also involve type 3 innate lymphoid cells, which contribute to the differentiation of T and B cells and induce the production of Th17 cells through secretion of IL-22. Moreover, it has been shown that the intestinal microbiota influences the accumulation of IgA-producing cells in the lumen, and that IgA diversity in the intestine is related to changes in microbiota composition. The intestinal microbiota also promotes the differentiation of naive CD4Apart from the main symptoms related to the gastrointestinal involvement typical of IBD, these patients may present a broad spectrum of non-intestinal signs and symptoms known as extraintestinal manifestations (EIMs): joints, skin, eyes, the biliary tract and the oral mucosa are the most common sites involved .It is estimated that approximately one third of IBD patients may develop EIMs ; in partThe etiopathogenesis, classification, and natural history of muco-cutaneous disorders related to IBD have not yet been well defined: in general, oral lesions are found more often in patients with CD compared to UC, in children compared to adults and in males compared to females . Differences may be found in the presentation of oral lesions between CD and UC: CD is characterized by both specific and nonspecific oral lesions, while only nonspecific ones are found in UC. In CD, oral lesions are defined as specific if the histopathologic data shows evidence of granulomas ; these are less common than nonspecific lesions , since aphtae are considered a secondary manifestation and the different clinical courses of the two conditions require different management strategies . ALU areDeficiencies caused by diet or poor absorption of an essential nutrient can cause anaemia and mineral and vitamin deficiency; in particular, vitamins B1, B2, B6, B12, iron, serum ferritin and folic acid deficiencies have been reported in the pathogenesis of oral ulcers, implicating their role in weakening the immune system . AnaemiaRegarding IBD therapy, all of the currently used drug classes have been linked to alterations in the oral cavity due to their direct toxic effect on tissues and their indirect immunosuppressive effects .All the organs of the alimentary canal have a common origin in the primitive digestive gut. The oral mucosa, that covers the entire oral cavity, consists of two layers: a stratified squamous epithelium and an underlying connective tissue (lamina propria) that includes blood and lymphatic vessels, as well as nerves and immune cells. However, the oral mucosa varies in structure, function and appearance in different regions of the cavity, and it is divided into lining, masticatory and specialized (gustative) mucosa ,23, as dThe wall of the small and large bowel is canonically divided into four layers: mucosa, submucosa, muscularis propria and serosa or adventitia. The mucosa is composed of epithelium, lamina propria and muscularis mucosae. A simple columnar epithelium covers the small and large bowel , althougThe similarities between the oral and the intestinal mucosa include: (1) the presence of tight junctions between epithelial cells; and (2) the presence of a basement membrane between the epithelium and the lamina propria.The equilibrium between the epithelium and the lamina propria is very important for mucosal homeostasis, and both alterations in tight junctions and changes in basement membrane may result in dysfunction of the mucosal barrier, as seen in inflammatory bowel disease .As stated before, the wall of the bowel is canonically divided into four layers by morphologists through the observation of histological sections after processing them with reagents, including alcohols that remove mucus and other alcohol-soluble substances. However, in living subjects, the mucosal layer is characterized by the presence of a mix of symbiotic and pathogenic bacteria embedded in the mucus, produced by the epithelial cells. In this mucous matrix, apart from bacteria, are present a number of soluble substances and nanovesicles , produced by both human cells and bacteria, that actively participate in the regulation of the homeostasis of the intestinal mucosa and, consequently, through lymphatic and hematic circulation, of virtually all of the organs ,29,30. TThe persistence of dysbiosis causes a state of chronic inflammation linked to the activation of MALT and the release of inflammation mediators. This causes an onset of pathologies even in areas that are physically far away from the gut ,2,3.Intestinal epithelial cells represent the main communication barrier between the host environment and the microbiota, and also regulate the impact of the microbiota on the host immune function . For example, a healthy intestinal microbial flora promotes regulatory B (Breg) cell differentiation and IL-1b and IL-6 production, and controls inflammatory processes through Breg cells and IL-10 secretion. Gut microbiota influences not only local, but also systemic immunity by bacterial metabolites (such as ligands of aryl hydrocarbon receptor and polyamines) and bacterial components, such as polysaccharide A, that exhibit immunomodulatory action ; moreove-Alteration of Treg/Th17 due to dysregulated TLRs on antigen-presenting cells ;-Resistance to colonization, i.e., ability of the gut microbiota to limit the proliferation of external pathogens. It has been observed that in patients with autoimmune disorders , resistance to colonization was lower than in healthy controls;-Superantigens, derived from bacteria and viruses that have the ability to activate immune cells by simultaneously binding to the major proteins of the class II histocompatibility complex (MHC II) present in the antigen-presenting cells and to specific receptors present in activated T cells ;-Alteration of host antigens and overproduction of autoantigens; in particular, microbiota induces modification of host proteins and creation of neoantigens ,33;-Mucosal responses to microbiota, i.e., inflammatory cytokines that activate nearby autoreactive cells ;-Molecular mimicry, i.e., cross-reactive antibody that recognizes shared epitopes of microbial and host tissue proteins, and activation of autoreactive T and B cells ,34,35.Mechanisms with which intestinal dysbiosis could generate autoimmune activation are not yet well understood. It is thought that they may be related to: Thus, the hypothesis we formulate is that ALU is the result of the concomitance of intestinal dysbiosis (and consequent activation of the immune system) and other events, e.g., the microtraumas occurring (frequently and for various causes) in the oral mucosa. Microtraumas can be considered as a stress factor for oral mucosa that induce overexpression, trafficking and surface mislocalization of intracellular proteins that may work, pathogenetically, as autoantigens. Heat shock proteins are an example of intracellular proteins that—after cell stress—may be mislocalized to cell surface by post-translational modifications that trigger unusual intracellular trafficking pathways; in addition, bacterial Hsp60 homologous, i.e., GroEL, can induce the formation of antibodies against it that can also cross-react against surface-exposed Hsp60, generating an autoimmune response by a molecular mimicry mechanism ,37,38,39ex adiuvantibus therapy with probiotics could be able to modify the natural course of ALU . It was also showed that the dysbiosis is strongly associated with elevated inflammatory response of several cytokines with depleted lysozyme in the saliva of IBD patients [-Co-aggregation and growth inhibition;-Bacteriocin and hydrogen peroxide production;-Competitive exclusion through antagonistic activities on adhesion and nutrition;-Immunomodulation.We cannot yet precisely answer the question “how do probiotics work?” but some theories can be formulated. There are strong functional similarities between the gut and oral biofilms: it is reasonable to speculate that corresponding health-promoting events may occur in the oral cavity to those already reported in the gut. The oral cavity is a large reservoir of bacteria of >700 species and it is closely related to host health and disease ,41. In apatients . In the patients . There apatients :-Co-aggrThere is an increasing body of evidence suggesting that perturbations of mucosal microbiota can modulate innate and adaptive immune responses, with inflammation arising upon reduction of the number of symbiont microorganisms and/or increase in the number of pathobiont microorganisms  .Several immune mechanisms, implicated in the remission of ALU, by symbiont bacteria have been hypothesized, including induction of IL-10, suppression of TNF-α and IL-8, and modulation of Toll-like receptors .Lactobacillus casei increased the serum levels of IL-10 anti-inflammatory cytokine and decreased the levels of proinflammatory cytokines such as TNF-alpha, IL-6 and IL-12 [This hypothesis has been reinforced by some studies that correlate the administration of probiotics to the improvement of autoimmune diseases. For example, it has been observed that in patients with rheumatoid arthritis, the administration of nd IL-12 .Lactobacillus salivarius, Bifidobacterium lactis, Lactobacillus Plantarum and Lactobacillus fermentum [Intestinal dysbiosis causes a chronic inflammatory state and activation of the MALT in the gut, which leads to the onset of extraintestinal pathologies ,2,3. We ermentum ,49. In aermentum .Therefore, we proposed the use of probiotics as direct therapy for intestinal dysbiosis and as an indirect one for ALU. In particular, preliminary observations lead us to suggest that the therapy with probiotics should be started when the patient first starts to experience the ALU symptoms. Our hypothesis is that this therapy can reduce the duration of the disease by up to three days, through limiting the development of the lesion and favouring the re-epithelization of the lesioned oral cavity mucosa thanks to the molecular mechanisms discussed above .Experimental and clinical evidence on the use of probiotics for the treatment of oral aphthae are currently very limited, and the etiology and pathogenesis of ALU is currently unknown. So, we think that it would be opportune to carry out in depth studies of this phenomenon, taking into account that host genetics, nutritional deficiencies, and a number of systemic conditions have been recognized as systemic modulating factors of ALU ,51. Furt