AbstractEnvironmental heterogeneity of Belize and southern Mexico savannahs as well as their geographical location suggest that these plant communities share floristic elements, making them conducive to a phytogeographical analysis. The aim of this study was to analyse the floristic affinities of nine savannahs of Belize and southern Mexico and to explain the similarities and differences amongst them.A binary data matrix containing 915 species was built based on the authors’ own collections and on nine floristic lists already published. A second data matrix, consisting of 113 species representing trees, was also used since most literature on neotropical savannahs has focused on this life form. In addition, the ten most species-rich families as well as the characteristic species present in more than five savannahs were analysed. Floristic similarities were calculated using the Jaccard index. Dendrograms obtained in both types of analysis showed clusters with low similarity values, corresponding to geographic locations formed by the savannahs of Belize-Tabasco and the Yucatan Peninsula.Fabaceae and Poaceae mainly dominated the local floras with 121 and 116 species each; remarkably, Melastomataceae was absent in the Yucatan Peninsula and Oaxaca. Nine species occurred in five to seven savannahs, confirming that they are widespread in both Belize and southern Mexico, and the Neotropics. Geographic location and floristic affinities of the nine savannahs support, to some extent, three different biogeographic provinces.The floristic affinities of the savannahs may be explained in terms of heterogeneity in climate and physiography. The Yucatan Peninsula and Belize-Tabasco groups have differences in climate type and the amount of rainfall. In addition, the Yucatan Peninsula savannahs are established at the bottom of karstic valleys, while the Belize and Tabasco savannahs develop on extensive flatlands. The savannahs of Oaxaca have the same climate type and amount of rainfall as those of the Yucatan Peninsula but they are distributed along peaks and the slopes of shale hills. PageBreak Wendl. , Crescentiacujete L. , Byrsonimacrassifolia (L.) Kunth (craboo), Curatellaamericana L. (tachicon), Melastomataceae spp. and Quercusoleoides Schltdl. & Cham. (oak) are usually amongst the most structurally conspicuous non-herbaceous elements  and by following the classification system of the Angiosperm Phylogeny Group  showed clusters in a geographic arrangement and low similarity values amongst the nine sites Figs , 3. DendFabaceae and Poaceae mainly dominated the flora of the studied sites with 121 and 116 species each. Table Asteraceae, Euphorbiaceae, Convolvulaceae and Apocynaceae were absent in one site and remarkably, Melastomataceae was absent in five of the nine sites, four in the Yucatan Peninsula and one in Nizanda.Byrsonimacrassifolia, Mimosaalbida Humb. & Bonpl. ex Willd. recorded at seven sites; Piriquetacistoides (L.) Griseb., Setariaparviflora (Poir.) Kerguélen PageBreakrecorded at six sites; and Andropogonvirginicus L., Crescentiacujete, Paspalumplicatulum Michx., Psidiumguineense Sw. and Sidalinifolia Juss. ex Cav. recorded at five sites were the widespread species of the lowland savannahs of Belize and southern Mexico.Nine of 915 species were present in five or more sites, but none of the species was present in all sites. PageBreakphological characteristics may be the major determining variables at both continental and regional scales (Dendrograms of Belize and southern Mexico savannahs showed arrangements according to their geographical locations and suggested floristic patterns associated with heterogeneity in climate and physiography. Differences in the amount of annual rainfall and geomorl scales . The lowl scales , rainforl scales  and xerol scales .The dendrograms resulting from the two anlyses were similar in structure except by the position of Nizanda and Xpujil savannahs. Both appeared as the most distant sites in the dendrograms and this may be explained by having more single-site species. Furthermore, the similarity levels increase when only shared species are taken into account, which reinforces the Belize-Tabasco and Yucatan Peninsula groups. The similarities and differences amongst clusters can be interpreted as a response to similar environmental conditions amongst some sites. In terms of climate, the Yucatan Peninsula savannahs are close to each other and share Aw climate, with relative low annual rainfall. Although the Nizanda savannah is distant on the Pacific Coast, it also has Aw climate. The Belize and Tabasco savannahs have Am climate with higher rainfall than the other regions. In terms of physiography, the savannahs of the Yucatan Peninsula are small and established at the bottom of karstic valleys , while tPlant inventories and differences in area size did not seem to influence the cluster outcome and lack of outstanding geological barriers may facilitate the similarity. In contrast, the archipelago effect may explain the low similarity values obtained at the adjacent sites of the Yucatan Peninsula. There, heterogeneity in physiographical and hydrological dynamics may lead to variation in the floristic composition . The fouFabaceae, Poaceae, Cyperaceae, Asteraceae, Melastomataceae, Euphorbiaceae, Malvaceae, Rubiaceae, Convolvulaceae and Apocynaceae. A similar floristic pattern was found in South American savannahs by Melastomataceae family in the four savannahs of Belize (Melastomataceae has been reported for other regions of tropical America in mesic, PageBreakcool environments and on deep soils rich in nutrients, such as the Llanos of Venezuela (Individual site floras were largely dominated by species of f Belize  and Tabaf Belize  and its enezuela  and the enezuela .Byrsonimacrassifolia and Crescentiacujete. Next most common, but only found in two or three localities were Acoelorrhaphewrightii, Curatellaamericana, Pinuscaribaea and Quercusoleoides. Along with these tree species, which are widesperead in neotropical grasslands, can be added the common shrubs Mimosaalbida, and Psidiumguineense and the herbs Piriquetacistoides, Setariaparviflora, Andropogonvirginicus, Paspalumplicatulum and Sidalinifolia, which also shape the so-called basic floristic matrix present in most of neotropical savannahs (The most common species of Belize and southern Mexico savannahs were the trees avannahs . FloristGeographic location and floristic affinities of these nine savannahs support to some extent three different biogeographic provinces, proposed by Lastly, it is emphasised that the floristic variation amongst these savannahs and their unique contribution to the flora of Central America give them high conservation importance. Yet they are environmentally undervaluated and severely affected by human activities. Conserving Central American savannahs is more of an urgent task for Mexico, since the Belize conservation system cover savannah areas .


Temporal lobe epilepsy is considered to be one of the most common and severe forms of focal epilepsies. Patients often develop cognitive deficits and emotional blunting along the progression of the disease. The high incidence of resistance to antiepileptic drugs and a frequent lack of admissibility to surgery poses an unmet medical challenge. In the urgent quest of novel treatment strategies, neuropeptides are interesting candidates, however, their therapeutic potential has not yet been exploited. This review focuses on the functional role of the endogenous opioid system with respect to temporal lobe epilepsy, specifically in the hippocampus. The role of dynorphins and kappa opioid receptors (KOPr) as modulators of neuronal excitability is well understood: both the reduced release of glutamate as well of postsynaptic hyperpolarization were shown in glutamatergic neurons. In line with this, low levels of dynorphin in humans and mice increase the risk of epilepsy development. The role of enkephalins is not understood so well. On one hand, some agonists of the delta opioid receptors (DOPr) display pro-convulsant properties probably through inhibition of GABAergic interneurons. On the other hand, enkephalins play a neuro-protective role under hypoxic or anoxic conditions, most probably through positive effects on mitochondrial function. Despite the supposed absence of endorphins in the hippocampus, exogenous activation of the mu opioid receptors (MOPr) induces pro-convulsant effects. Recently-expanded knowledge of the complex ways opioid receptors ligands elicit their effects , opens up exciting new therapeutic potentials with regards to seizures and epilepsy. Potential adverse side effects of KOPr agonists may be minimized through functional selectivity. Preclinical data suggest a high potential of such compounds to control seizures, with a strong predictive validity toward human patients. The discovery of DOPr-agonists without proconvulsant potential stimulates the research on the therapeutic use of neuroprotective potential of the enkephalin/DOPr system. With a prevalence of 1–2% worldwide, epilepsy is one of the most frequent neurological diseases affecting people of all ages  or multiple brain centers or the entire brain , and are sometimes accompanied with a loss of consciousness and control of bowel or bladder functions. The cause of epilepsy is mostly unknown (ca. 60%), although several patients have a history of brain injury, stroke, brain tumor, and substance use disorders , mostly for the person's entire life. Notably, 30–50% of the patients are refractory to the presently available pharmacological treatments  is considered as one of the most frequent types of epilepsy , delta opioid receptor (DOPr), and mu opioid receptor (MOPr), are Gi/o-coupled 7-transmembrane domain proteins, and they share highly homologous protein sequences (60% amino acid sequence identity) including a common opioid receptor binding pocket within the helical transmembrane core. The extracellular domains are crucial for selectivity, however, the opioid system is fairly promiscuous and the affinities of dynorphins, endorphins, and enkephalins to KOPr, MOPr, and DOPr vary only in the range of one potency -1 receptor was also classified as an opioid receptor due to its genetic sequence homology to other opioid receptors. It displays, however, distinct pharmacological properties, and therefore, is not considered to be a classical opioid receptor. Although ORL-1 and its endogenous ligand nociceptin might be involved in seizures and epilepsy  BigDyn = Dyn B = Dyn B 1-29 = α-neo-endorphin > (10–20 times) Dyn A 1-8 = β-neo-endorphin  gene known in mammals, different splice variants  are pentapetides encoded in the proenkephalin gene. Moreover, Met-Enk can be processed from proopiomelanocortin (POMC) and Leu-Enk from pDyn. The strongest expression of Enk is found in the basal ganglia, with comparably low expression levels in the hippocampus , which is expressed by interneurons of the dentate gyrus , which counteracts CREB by binding to the DRE (downstream regulatory element) sequence in the promoter  exert very different effects on seizure-induction, most likely due to their differential localization within the hippocampus  gene therapy. AAV-gene therapy is a promising tool to target a broad array of neurological diseases , is giving rise to new therapeutic concepts, and will drive research on new medical applications of the opioid systems. Specifically, the Dyn/KOPr system bears great potentials to target epilepsy and epileptogenesis, also for the fashioning of disease-modifying treatments, with the possibility of the elimination of side-effects through design, and the selection of relevant agonists and attractive delivery methods, such as gene therapy approaches. Pro-convulsant properties of DOPr activation can be avoided by the selection of adequate agonists with the desired functional selectivity to specifically exploit the neuroprotective potential of DOPr activation. Yet, the neuroprotective effects of DOPr activation require further investigations. Providing the identification of DORr agonists, which conserve the neuroprotective but lack proconvulsant effects, may be of great interest in the course of epilepsy therapy.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.CS has a patent application pending for the use of preprodynorphin viral vectors in gene therapy for focal epilepsy. The other author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Level of Evidence III, Systematic Review.Compressive syndromes of the radial nerve have different presentations. There is no consensus on diagnostic and therapeutic methods. The aim of this review is to summarize such methods. Eletronic searches related terms, held in databases (1980-2016): Pubmed (via Medline), Lilacs (via Scielo) and Google Scholar. Through pre-defined protocol, we identified relevant studies. We excluded case reports. Aspects of diagnosis and treatment were synthesized for analysis and tables. Quantitative analyzes were followed by their dispersion variables. Fourteen studies were included. All studies were considered as level IV evidence. Most studies consider aspects of clinical history and provocative maneuvers. There is no consensus on the use of electromyography, and methods are heterogeneous. Studies have shown that surgical treatment (muscle release and neurolysis) has variable success rate, ranging from 20 to 96.5%. Some studies applied self reported scores, though the heterogeneity of the population does not allow inferential analyzes on the subject. few complications reported. Most studies consider the diagnosis of compressive radial nerve syndromes essentially clinical. The most common treatment was combined muscle release and neurolysis, with heterogeneous results. There is a need for comparative studies Studies conducted since 01/01/1980 were included, and there were no restrictions on language or with regard to follow-up time or temporality of the study (prospective/retrospective review). The following study designs were included: case series (retrospective/prospective study), case-control, cohort studies, and randomized clinical trials. We opted to exclude case reports.The data were obtained from the Pubmed database , the Lilacs database  and Google Scholar, using an active keyword search (MesH and non-MesH): Search terms were : "radial tunnel syndrome" AND "radial neuropathy" AND "radial nerve palsy" AND "radial nerve neuritis" AND "posterior interosseous nerve neuropathy" AND "radial nerve neuropathy" AND "radial nerve palsy" and free search for the terms "radial nerve compression", "radial nerve syndrome", "Wartenberg syndrome", "radial nerve entrapment", "posterior interosseous compression". The operator OR was used for combinations of the terms in Pubmed. For Lilacs, an end-to-end study was used, and was limited to 01/01/1980. For relevant studies, we determined we would contact the study authors if there were any difficulties obtaining the data.The studies were selected by assessing the title and structured abstract after selection in duplicate by two researchers (MM and RG). When there was disagreement between the researchers, a third researcher cast the tie-breaking vote (VM).a priori and comprised the following information: description of the disease/condition, author, year of publication, journal, type of study, participants (inclusion and exclusion criteria), diagnostic criteria , intervention , results  and complications.The data were extracted using a protocol which was defined 2 was greater than 75%.After obtaining the data provided in this form, the authors gathered to summarize the data using qualitative tables  and quantitative analysis via meta-analysis (risk/relative risk ratio and/or difference between the means). We chose to use REVMAN version 5.0 software for the quantitative analysis; the quantitative data were followed by their 95% confidence intervals. We chose to use a 5% alpha in the inferential analyses. The heterogeneity among the studies was assessed using l², and heterogeneity was considered high if l-We found 14 studies addressing the topic of this review.The demographic characteristics and the bibliometrics of the studies are presented in In most studies, the clinical criteria were standardized, and some studies included eletroneuromyographic criteria. The majority included semiological aspects  and semio-technical aspects .The results of the treatment, which for the most part are displayed qualitatively without focus on qualitative variables, showed high heterogeneity among the studies, with a discrepancy varying from 39 to 100% good results.,,,,,The proportions and confidence intervals, calculated for the purpose of this review, are shown in In the absence of conclusive and well-delineated studies, the systematic reviews of non-randomized studies presented the following benefits: 1) they map the status of evidence, which is often deficient; 2) they determine failures in the process of determining scientific truths about the topic; 3) they quantify the available evidence, and 4) they propose and expose opportunities for future research, affirming the mobilization of human efforts and financial resources.The results of this review demonstrated the poor quality of evidence on the subject. For the most part the studies were level IV evidence, susceptible to bias from memory and selection, and as a rule they tended to overestimate the effects of treatment and bias the sample of patients. Consequently, the results of this review are limited, but they do serve to illustrate the current state of research, ratifying and supporting new studies on the theme.The results show that there is no uniformity in diagnosis and treatment, but the clinical criteria and treatment remained constant in some studies. In this respect, studies of accuracy  are a prolific area for science. This should, however, counterbalance the difficulty of grouping cohorts on this topic, because of its relatively low frequency and low rate of diagnosis.Despite this lower frequency, the studies show a considerable rate of good results, but extrapolation of these results to practice can be subject to reference bias since the evaluator is not blinded, and there is no effective methodology for measuring outcomes, which should focus on patient-reported outcomes and measures of pain and recurrence. The literature exhibits a lack of studies reporting conservative treatment techniques, which leads us to raise the possibility that the cohorts in these studies are for the most part patients refractory to conservative methods of treatment. The small rate of complications, which could be the result of underreporting, should also be mentioned.We found that the majority of studies consider diagnosis of compressive syndromes of the radial nerve to be eminently clinical. The most common treatment consisted of a mixed technique of muscle release and external neurolysis, with heterogeneous results. There is a need for comparative studies on the subject, ideally multi-center studies which examine the effectiveness of treatment methods and pay special attention to conservative methods of treatment.


Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied Rheumatoid arthritis (RA) is a chronic autoimmune disease that mainly affects large and small joints resulting in bone and cartilage erosion but can spread to multiple body systems, including cardiovascular, pulmonary, and skeletal systems , 2. The Mesenchymal stem cells (MSCs) have been reported as a potential candidate for the treatment of RA due to their regenerative and anti-inflammatory properties that could both induce the regeneration of damaged joints and modulate the pathogenic immune responses . in vitro through plastic adherence under regular culture conditions ..β/δ on MThe immunoregulatory abilities of MSCs have been studied for several years, demonstrating the wide repertory of mechanisms used by the cells to interact with the multiple actors of immune responses. Thus, in the context of arthritis involving macrophages, DCs, NK cells, T cells, B cells, and other cell types, MSCs appeared as candidate of choice for RA treatment. However, although the immunosuppressive effects of MSCs have been shown to alter the functions of several immune cells individually, the phenotypic plasticity of MSCs governed by their environment might alter MSC therapeutic effect. Importantly, the stable priming of MSCs toward an immunoregulatory state should be considered in order to optimize MSCs-based therapy.


The vitality of the pulp is fundamental to the functional life of the tooth. For this aim, active and living biomaterials are required to avoid the current drastic treatment, which is the removal of all the cellular and molecular content regardless of its regenerative potential. The regeneration of the pulp tissue is the dream of many generations of dental surgeons and will revolutionize clinical practices. Recently, the potential of the regenerative medicine field suggests that it would be possible to achieve such complex regeneration. Indeed, three crucial steps are needed: the control of infection and inflammation and the regeneration of lost pulp tissues. For regenerative medicine, in particular for dental pulp regeneration, the use of nano-structured biomaterials becomes decisive. Nano-designed materials allow the concentration of many different functions in a small volume, the increase in the quality of targeting, as well as the control of cost and delivery of active molecules. Nanomaterials based on extracellular mimetic nanostructure and functionalized with multi-active therapeutics appear essential to reverse infection and inflammation and concomitantly to orchestrate pulp cell colonization and differentiation. This novel generation of nanomaterials seems very promising to meet the challenge of the complex dental pulp regeneration. The dental pulp located in the heart of the tooth (endodontic area) allows its vitality. The main endodontic tissue is a soft connective tissue that is well innervated and vascularized, and composed of collagen fibers, fibroblasts and dental stem cells. In its periphery, layers of odontoblasts are differentiated cells producing dentin. The whole pulp can sense the slightest mechanical, chemical and thermal stimuli and pulp cells can defend against various oral aggressions and microorganisms.After a significant aggression, as any other connective tissue, the pulp responds with an inflammation process in order to eliminate pathogens and to allow repair. Due to its confinement in a hard chamber and its unique blood irrigation and lymphatic circulation, pulp inflammation (pulpitis) is a complex and painful process that is difficult to control and dissipate. Generally, it results in pulp necrosis .Pulpitis is often so painful and clinically irreversible that the surgical removal of the whole pulp from the tooth is required. All the cellular and molecular content is removed, whatever its regenerative potential, to be replaced by an inert polymer material , leaving the tooth without defenses.This inflammation is considered to be clinically irreversible because to date there are not enough suitable biomaterials to properly control its different features.The vitality of the pulp is so fundamental to the functional life of the tooth that new and smart biomaterials are required to avoid this current drastic treatment and to regenerate the lost endodontic tissues. Biomaterials functionalized through different nanotechnologies could be absolutely strategic .Regeneration of the pulp tissue is the dream of many generations of dental surgeons and will revolutionize clinical practice. The potential of regenerative medicine suggests that it would be possible to meet the challenge of this complex regeneration.There are three crucial steps for this regeneration: (i) damaged tissues must be safely disinfected and all microorganisms must be eliminated by well-targeted antimicrobials ; (ii) thThe strategies of regeneration depend on the state of the dental pulp: the stage of inflammation and volume of damaged and infected tissues. For less important lesions, it is possible to perform an indirect or direct capping on the pulp with the biomaterials . For morFor dental pulp regeneration, a very promising procedure is root revascularization. After disinfection by local triple antibiotics, a broach is inserted into the root canal beyond its length in order to make the blood arise from the vessels of the surrounding bone to the root. Thus, by this procedure, teeth can recover vitality and apexification or apexogenesis can be obtained ,7. This In order to carry the dental pulp regeneration, different kinds of postnatal stem cells have been isolated and studied from different tissues, including brain, skin, hair follicles, skeletal muscle, bone marrow and dental tissue ,11. Threin vivo into endothelial cells may contribute to pulp vascularization [in vivo in root canals [The DPSC and the SHED are able to regenerate dental pulp ,20. The rization . The SCAt canals ,22,23.Procurement and multiplication of these dental stem cells is more complicated than for BMSC (bone marrow stem cells). When there is whole pulp necrosis, a lot of exogenous competent cells are needed ,7,24. ThAfter a root revascularization of immature teeth, the SCAP may be responsible for the root edification and the more fragile DPSC remaining may contribute to pulp regeneration and differentiation into odontoblasts-like cells . These cSome authors showed than SFD-1  and bFGF (basic fibroblast growth factor) are good molecules to induce this "cell homing" of DPSC . PDGF  is increased during terminal differentiation of odontoblasts and that BMP-7 promotes the formation of reparative dentin mineralization in vivo ,29,30. Bin vivo . The groin vivo ,32,33,34in vivo . Bone siin vivo .Enough nutriments and oxygen is critical for sustaining the activity of regenerative cells. To enhance neovascularization is a challenge for pulp regeneration considering the anatomical characteristics of endodontic confinement. Adding to the revascularization technique ,7, diffeWhatever the competent cells selected, a biodegradable colorless scaffold is necessary to control their colonization and their regenerative activity. Some aberrant pulp mineralization was observed after endodontic injection of stem cells without scaffold. The probability of producing a new functional tissue pulp by exclusively injecting stem cells without matrix or signaling molecules is very low ,39,40.The most suitable for dental pulp regeneration are three-dimensional (3D) implantable or injectable scaffolds ,19. PulpSeveral scaffolds have been studied ,41. HydrThe quantity and the size of pores inside the hydrogels, crucial for diffusion of nutriments, active biomolecules, and cellular waste transport, are determined by the quantity and the size of the particles than can be incorporated . The minNanomaterials for dental pulp regeneration can be used alone, or with growth factors, drugs or stem cells. To build biomaterials at the nanoscale level is very crucial for dental pulp regeneration. It allows the concentration of many different functions in a small volume and presents the advantage of increasing the quality of targeting while controlling the cost and delivery of the active molecules.These endodontic nanomaterials can be reservoirs of antibacterial and anti-inflammatory molecules and they deliver growth factors guiding the migration, proliferation, and differentiation of the different pulp cells: fibroblasts, vascular and nervous cells, and odontoblasts.Nano-assemblies targeting the first step of dental pulp regeneration have been built with two polymers carrying an anti-inflammatory hormone: Poly-L-Lysine Dendrigraft (DGL), Poly-Glutamic Acid (PGA) and α-Melanocyte Stimulating Hormone . PGA-alpha-MSH induces the reduction of inflammation of pulp connective tissue, acting on fibroblasts, monocytes and macrophages. DGLG4-PGA-α-MSH nano-assemblies promote the initiation of the regeneration of pulp connective tissue, providing adhesion and multiplication of pulp fibroblasts . In endoNanotechnologies also allow the construction of biomimetic scaffolds. Scaffolds of natural nanofibers are known to support endodontic regeneration. The root revascularization can be optimized by the use of type I collagen scaffolds . CollageNanofibrous and microporous membranes are very promising to promote dental pulp regeneration as a mimetic extracellular matrix . By elecThe functionalization by active molecules incorporated in scaffolds is the best drug delivery system. Different strategies of functionalization of electrospun nanofibers are possible: by plasma or wet chemical treatment, by surface graft polymerization, and by incorporation into the polymer solution to electrospin . This lain vivo [The strategy of functionalization of nanofibers by nanoreservoirs of BMP-2 or BMP-7 shows a great efficiency for bone regeneration and increases the differentiation of MSC , accelerating the tissue regeneration in vivo ,66,67.Different nanofibrous microporous scaffolds provide an excellent environment for dentin regeneration. Electrospun PCL/gelatin scaffolds with nano-hydroxyapatite enhance the differentiation of DPSC towards an odontoblast-like phenotype . NanofibThe mineralization of electrospun PCL scaffolds is particularly attractive for dentin tissue engineering by promoting the growth and odontogenic differentiation of HDPC  . The incNanofibrous PCL membranes are also suitable scaffolds for the regeneration of the bone-tooth unit. These nanomaterials functionalized with BMP-4 and Noggin increase bone tissue regeneration and favorably control the root development after an immature tooth implantation in a mice model . Thus, tin vivo, which is a particularly strategic point for dental pulp regeneration [The functionalization of nanofibrous PCL membranes by NGF  promotes innervation ascending from the root to the coronal part of the pulp neration .These electrospun nanofibrous scaffolds can also optimize the disinfection by local antibiotics. Electrospun nanofibrous scaffolds of polydioxanone containing two antibiotics of the revascularization technique (metronidazole and ciprofloxacin) ,7 show tNanotechnologies optimize the distribution of active molecules and the extracellular mimetic structure of scaffolds. Thus, they appear essential to control/inhibit infection and inflammation and to orchestrate pulp cell colonization and differentiation. In the future, nanotechnologies would be able to build temporally and spatially controlled drug delivery systems of several crucial bioactive molecules. These multi-functionalized nanomaterials would help to meet the challenge of complex dental pulp regeneration.


This study is aimed at determining the effects of midsole thickness on movement characteristic during side cutting movement. Fifteen athletes performed side-step cutting while wearing shoes with varying midsole thicknesses. Temporal-spatial and ground reaction force variables as well as foot and ankle frontal kinematics were used to describe breaking and propulsive movement characteristics and modulation strategies. Regardless of midsole thickness, temporal-spatial variables and breaking and propulsive force during side cutting were statistically unchanged. Significantly greater peaks of ankle inversion and plantarflexion with a thicker sole and greater midtarsal pronation with a thinner sole were observed. Current results demonstrated that hypotheses formed solely based on material testing were insufficient to understand the adaptations in human movement because of the redundancy of the neuromusculoskeletal system. Participants were able to maintain temporal-spatial performance during side cutting while wearing shoes with midsoles of varying thicknesses. Increased pronation for a thinner sole might help reduce the force of impact but might be associated with an increased risk of excessive stress on soft tissue. Increased peak of ankle inversion and plantarflexion for a thicker sole may be unfavorable for the stability of ankle joint. Information provided in human movement testing is crucial for understanding factors associated with movement characteristics and injury and should be considered in the future development of shoe design. Enhancement of sports performance and injury prevention possess both intrinsic and extrinsic factors. As footwear is an important extrinsic factor, researchers have examined the effect of certain footwear with specific design variables including material properties and thickness on lower limb muscle activities , proprioA challenge to determine the effect of footwear on human movement is the redundant nature of the musculoskeletal system, in which there are more joints and muscles that are necessary to accommodate the changing extrinsic conditions . AthleteMovements involving a side cutting (SC) maneuver are critical during sports activities which can limit performance or induce risks of injuries . InverteThe way that the neuromusculoskeletal system organizes the redundant degrees of freedom of the joints in order to maintain temporal-spatial performance during a side-cutting maneuver cannot be determined solely by pure material testing. Therefore, we investigated the effect of midsole thickness on temporal-spatial movement characteristics, ground reaction force (GRF) variables, and ankle and foot kinematics during lateral SC. We hypothesized the following: (a) Athletes who wear thin-soled shoes would demonstrate quicker temporal and greater spatial movement characteristics with higher propulsive force, which would enhance performance; however, high loading rate and breaking force caused by a thin sole would increase the risk of repetitive injuries. (b) Athletes who wear thick-soled shoes exhibit a greater midtarsal pronation range of motion during the early stance than do athletes who wear thin-soled shoes, which might strengthen shock absorption. In addition, athletes who wear thick-soled shoes demonstrate greater ankle inversion than do athletes who wear thin-soled shoes, which might be unfavorable for the joint position.Fifteen highly trained male badminton athletes (age: 21.37 ± 3.82 years) participated in this study. The athletes were all free from neuromusculoskeletal dysfunction, with normal or corrected vision. All participants were right-leg dominant, which was classified based on their preferred kicking leg. All athletes used their right hand to hold the badminton racket. Before data collection, written informed consent was obtained from each participant, and clearance to conduct the study was approved by the Institutional Human Research Ethics Committee.The three testing badminton shoes contained the same vamp, shoe last, and insole. The midsole hardness of each shoe was 62 C , but the midsole thicknesses represented three distinct levels produced by the manufacturer (Victor Corporation): thin, medium, and thick. The three midsole thicknesses, 5 mm, 6 mm, and 7 mm, represented the range of thicknesses commonly used in current badminton footwear produced by the manufacturer. Testing order was randomized.Passive infrared retroreflective markers were attached to the skin of body segments to determine their spatial positions, including the shank (head of the fibula (HF), tibial tuberosity (TT), and medial and lateral malleolus (MMA and LMA)), the rearfoot , most of the medial apex of the sustentaculum tali (ST), and the lateral apex of the peroneal tubercle (PT)), and the midfoot , the base of the fifth metatarsal (VMH), the dorsolateral aspect of the fifth metatarsocuboid joint (VMB), the base of the second metatarsal (SMH), and the dorsomedial aspect of the second metatarsocuneiform joint (SMB)). Motion data were measured using a motion analysis system equipped with ultra-high-resolution infrared cameras at a sampling rate of 200 Hz. To reconstruct the 3D coordinates of the markers from 2D video images, the Vicon system was calibrated using calibration objects. These objects were designed to allow the cameras to measure the motion of the markers with an accuracy within 1 mm. Calibrated force platforms  with 2000 Hz sampling rates, connected to a multichannel charge amplifier, were embedded in the floor to measure the GRF produced during side cutting, which were also used to define movement cycle.The participants were instructed to perform lateral side cutting while infrared-retroreflective markers with a diameter of 14 mm were used to track the motion of the shank and foot segments. Marker placement on shoes has previously been demonstrated to overestimate calcaneal movement during running. Therefore, shoe windows were constructed to allow placement of the markers directly on the bony landmarks of the calcaneus and midfoot . Each paThe movement task performed in this study required the participants to perform SC footwork with right-limb leading. Therefore, the leg of the racket-hand side (right limb) was defined as the leading limb, and the leg opposite to the racket-hand side (left limb) was thus a trailing limb. The SC movement required the participants to perform lateral SC footwork with the lateral step leading the right limb toward the force platform. The SC involved five phases: the leading single-limb support (SLS) phase, the floating phase, the first trailing SLS phase, the double-limb support (DLS) phase, and the second trailing SLS phase. These phases were divided by six critical events: the trailing toe off, the leading toe off, the trailing toe on, the leading toe on, the leading toe off, and the trailing toe off . The effTemporal-spatial variables, including total, breaking, and propulsive impulse duration of the leading stance phase as well as the leading step length, and step time were calculated. The total impulse duration refers to the duration of the total stance phase, the passive impulsive duration refers to the duration from the beginning of the leading stance phase to the time when the vertical GRF decreases to its lowest value, and the active impulsive duration refers to the duration from the time when the vertical GRF decreases to its lowest value to the end of the leading stance phase .x-axis pointing forward, y-axis pointing upward, and z-axis pointing to the right, was based on ISB recommendation [For dynamic analysis during each of the movement trials, the shank, rearfoot, and midfoot were modeled as a three-link system. Each link was embedded with an orthogonal coordinate system. Orientation of the axes, endation .Osha, is located at the middle point between LMA and MMA, the Xsha-axis is orthogonal to the frontal plane defined by LMA, MMA, and HF, the Zsha-axis is orthogonal to the sagittal plane defined by the Xsha-axis and TT, and the Ysha-axis is orthogonal to the XZsha plane (transverse plane). For the rearfoot local coordinate system, the origin point is at CA, the Xrear-axis direction is defined by CA and the middle point, IC, between ST and PT, the Yrear-axis is orthogonal to the transverse plane defined by the Xrear-axis and ST, and the Zrear-axis is orthogonal to the XYrear plane . For the midfoot local coordinate system, the origin point, Omid, is at the middle point between TN and VMB, the Xmid-axis direction is defined by the Omid and SMB, the Ymid-axis is orthogonal to the transverse plane defined by the Xmid-axis and TN, and the Zmid-axis is orthogonal to the XYmid plane .Ankle joint kinematic calculations were based on the virtual rearfoot referenced to the shank segment. Midtarsal joint kinematic calculations were based on the virtual midfoot referenced to the rearfoot segment, where the shank local coordinate system, the rearfoot local coordinate system, and the midfoot local coordinate system were defined as follows: For the shank local coordinate system, the origin point, z–y–x) were according to the ISB recommendation [z-axis of the proximal shank segment, the eversion/inversion is about the x-axis of the distal rearfoot segment, and the internal/external rotation is about the axis orthogonal to the z-axis of the proximal segment and the x-axis of the rearfoot segment (floating axis); also, for the midtarsal joint, the supination/pronation is about the x-axis of the distal midfoot segment [The definitions and terms for the description of the rotational movements of the joints using a Cardanic rotation sequence  and midtarsal joints (pronation). The patterns of angular displacement of the ankle and midfoot joint during the cutting movements were provided to have a clear illustration of the key concerns discussed in our study. The leading stance phase which comprised the DLS of a complete side-cutting maneuver will be taken as the time period during which key variables are analyzed. Ankle inversion at the beginning and the end of the leading stance phase (the DLS phase of the complete side cutting), the peak values of the frontal plane joint angle of the ankle (inversion) and midfoot (pronation) during the DLS, and the loading rate of impact peak and the peak of the GRFs in the medial, posterior, and vertical directions were extracted. The mean values of each calculated variable for the entire group of participants were obtained.α = 0.05.To analyze thickness effects, comparison of the calculated variables between shoes with three midsole thicknesses was performed using a nonparametric repeated-measure analysis of variance by using SPSS 19.0 . When a thickness effect was observed, a post hoc analysis was performed using a polynomial test to determine the trend (linear or quadratic). The level of significance was set at p > 0.05, p > 0.05). No significant thickness effects were discovered for the late impulsive peaks .Based on the observation of the participants performing lateral SC, no significant differences in the total stance phase, passive breaking impulsive phase, active propulsive impulsive phase duration, leading step time, or step length were observed among the various midsole thicknesses . For frontal plane midfoot kinematics, a significant thickness effect was observed for the peak midtarsal joint pronation during weight acceptance of the leading limb (p < 0.05).A significant thickness effect was observed for the frontal plane angles of the ankle joints at initial contact of the leading toe (T3) and at the leading toe off (T4) during lateral SC movement. An increase in midsole thickness exhibited linearly significant difference with ankle inversion . A signiWe investigated the effects of midsole thickness on temporal-spatial movement characteristics, GRF variables, and ankle and foot kinematics during lateral SC. We observed similar temporal-spatial performance among shoes with various midsole thicknesses, which might indicate the ability to maintain aspects of side-step agility despite the difference in midsole thickness. To maintain temporal-spatial performance, similar passive breaking impulse duration, active propulsive impulse duration, total stance duration, and leading step time  were ablMovements involving an SC maneuver placed the participants' feet into an unfavorable position for side-to-side joint stability. Previous studies have provided information about the GRF characteristics of cutting movements in healthy players and in players with ankle instability . In addiIn addition to deviated ankle mechanics during weight acceptance of lateral SC movements for the thick-midsole condition, we observed greater pronation at the midtarsal joint during lateral SC for thin-midsole shoes than for thick-midsole shoes . In theoAlthough we controlled the material properties, including hardness and elasticity, to eliminate factors other than thickness that might have affected the results, increased thickness of the same material can cause a reduction in stiffness, which might cause increased shear movement of the midsole during lateral movements; this is a potential limitation of studies that changes the geometry of one component of shoes without reporting other possible changes in physical characteristics of the shoes that are caused by the changes of the shoes' geometry. Researchers may also further examine the functional concept of the midsole in sports footwear by analyzing the kinematic strategies and joint mechanics of hip joints, knee joints, and the trunk. In addition, this study reports the effects of midsole thickness for side cutting maneuver; it remains unknown to what extent, if any, a preparatory strengthening program targeting on the stability of ankle and midtarsal joint would be incorporated while selecting shoes with midsoles of varying thicknesses.Athletes who wear thinner-soled shoes exhibit a greater midtarsal pronation than do athletes who wear thicker-soled shoes, which might strengthen shock absorption. However, repetitive functional adaptation to the thin sole revealed by the increased pronation might alter foot structure and, consequently, kinesiology, in the long term. Athletes who wear thick-soled shoes demonstrate greater ankle inversion during early weight acceptance than do athletes who wear thin-soled shoes, which might be unfavorable for ankle-joint stability. Biomechanical advantages formed based on pure material testing related to thickness of midsoles were incapable of fully accounting for adaptations in human movement. By studying human movement, researchers can better clarify how footwear influences the biomechanical factors that can possibly improve sports performance or lead to injury and understand the implications of these results for advertisement in the footwear market.


Systemic pesticides (SPs) are usually recommended for soil treatments and as seed coating agents and are taken up from the soil by involving various plant-mediated processes, physiological, and morphological attributes of the root systems. Microscopic insights and next-generation sequencing combined with bioinformatics allow us now to identify new functions and interactions of plant-associated bacteria and perceive plants as meta-organisms. Host symbiotic, rhizo-epiphytic, endophytic microorganisms and their functions on plants have not been studied yet in accordance with uptake, tanslocation and action of pesticides. Root tips exudates mediated by rhizobacteria could modify the uptake of specific pesticides while bacterial ligands and enzymes can affect metabolism and fate of pesticide within plant. Over expression of specific proteins in cell membrane can also modify pesticide influx in roots. Moreover, proteins and other membrane compartments are usually involved in pesticide modes of action and resistance development. In this article it is discussed what is known of the physiological attributes including apoplastic, symplastic, and trans-membrane transport of SPs in accordance with the intercommunication dictated by plant–microbe, cell to cell and intracellular signaling. Prospects and challenges for uptake, translocation, storage, exudation, metabolism, and action of SPs are given through the prism of new insights of plant microbiome. Interactions of soil applied pesticides with physiological processes, plant root exudates and plant microbiome are summarized to scrutinize challenges for the next-generation pesticides. Over the last few years, considerable attention has been devoted to the concept of “plant as metaorganism.” Healthy plants host symbiotic and non-symbiotic rhizo-epiphytic and/or endophytic microorganisms that do not cause diseases but support the host nutritionally by stimulating germination and growth or help the plant to overcome biotic or abiotic stress. Therefore, plants have to be considered as metaorganisms revealing close relationships with their associated microorganisms . The plaS-methyl in corn and tomato plants, respectively . On the other hand, endophytic bacteria usually act on host cells or stimulate biological systems by using enzymatic processes or ligands (adhesins) which are also expected to interact with SPs. Metabolism, conjugation and complex formation within plant compartments are processes that affect pesticide efficacy and fate.Plant growth-promoting rhizobacteria (PGPR) and fungi (PGPF) can stimulate plant growth through the production of phytostimulators , increase the nutrients uptake , even confrere tolerance to plants against abiotic stress such as drought and salinity or by suppressing biotic stressors like plant diseases or pests . Accordiectively , 2015. Dectively . Suppresectively . The devectively . Recentlectively . While mectively . NonetheAlthough a single beneficial microorganism is already recommended for soil applications and management of plant diseases, information on plant microbiome suggests that microbial consortia or bespoke artificial root microbiome transfer can be more effective . Moreove-1 or 10–100 g ha-1) than the respective soil application rates .The first classes of pesticides marketed had only contact action. However, by the 1950s many classes of SPs, which were able to enter plants by roots, stem or leaves and be translocated to other parts of the plant have been developed. Many herbicides, insecticides and fungicides have been registered for use in soil to control weed, soil-born diseases, and protect plants from herbivore pests. The standard application methods of soil pre- or post-emergence pesticides have been to be applied in farrow during planting or spray directly to the soil. Granular or liquid formulations were commonly used in the past but have been discontinued due to resistance development, environmental concerns, regulatory and cost reasons. Seed coating with fungicides and insecticides is a well-established young plants protection method form pathogens and pests. Current seed coating technology requires much less active ingredient . Nanomaterials can cross plasma membrane, bind with cytoplasmic organelles and interfere with metabolic processes . The systemic action of most pesticides is the result of a balance between uptake and translocation and the degree of those two processes will dictate the treatment effectiveness.Kow values 1–3 , but many metabolites are biologically active and may have physiological, ecological, and toxicological significance. However, in other cases metabolism can activate propesticides  and modify their effectiveness and fate (uptake and translocation) within plants .Table 1). Biological membranes support numerous cell functions which are targeted by pesticides while simultaneously, the cell compartments affect the behavior of pesticides the most . Moreover, genetic or epigenetic modifications on target organisms, leading to biochemical and physiological differences on biological membranes, are usually involved in the development of resistance mechanisms against pesticides  and on non-target organisms (toxicity). Today, more than 100 mechanisms of pesticides action have been revealed among the approximately 900 currently commercially available pesticides . In manysticides .Figure 1). The side or collateral effects of SPs on plant “metaphysiology” and not only on their target sites is another interesting research task related to SPs. This kind of side effects are more obvious if we consider the hormone-like action of many pesticides and that membrane functions, apart from pesticides, are usually regulated by effectors, elicitors, and hormones . The appropriate structural modification of the active ingredient, the synthesis of propesticides and plant extract analogs, the development of nanopesticides and pesticide delivery systems, the introduction of new formulation for the combined application of pesticides with biocontrol agents  are the most important concepts to design modern agrochemicals. Target-specific delivery and activation of propesticides, biopesticides and biotech-pesticides exactly at the target side or only in the presence of pest or pathogen could reduce largely the application dose of pesticides and minimize the adverse effects. Moreover, structure-optimized effects on transporters, transmembrane proteins, and enzymes could be the substantial functions of the next-generation SPs , to the agroecosystem scale is the fundamental challenge for the next-generation pesticides and plant hygiene in general.ZV as sole author designed, developed, and wrote the ideas and content presented in this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


At such low pH values the ferric iron generated by their activities is soluble and serves as the chemical oxidant of sulfide minerals. One the one hand, this is highly beneficial, and is the core process in the biotechnology known generically as “biomining,” where acidophiles are used to facilitate the extraction and recovery of base  and precious metals , and also uranium. On the other hand, uncontrolled microbial metal sulfide oxidation in abandoned mines and mine spoils can generate highly noxious waste-waters (acid mine/rock drainage) which, because of their low pH, elevated concentrations of potential toxic metals and metalloids, and high osmotic potentials, pose severe threats to the environment. Recent research, however, has shown that some species of acidophilic microorganisms could also be used not only to mitigate mine water pollution but also to recover metals from acidic waste-waters via selective biomineralization.Acidophilic microorganisms thrive in extremely low pH natural and man-made environments such as acidic lakes, some hydrothermal systems, acid sulfate soils, sulfidic regoliths and ores, as well as metal and coal mine-impacted environments. The most widely studied acidophiles, prokaryotes that oxidize reduced iron and/or sulfur, are able to catalyze the oxidative dissolution of metal sulfide minerals such as pyrite  is described in the report of Nuñez et al., who investigated 580 strains of the seven recognized species of the genus  in their study. Another paper describes how bioinformatic analysis has revealed the existence of five highly conserved gene families in the core genome of the monophyletic genus Acidithiobacillus of the class Acidithiobacillia . Insights into the quorum sensing regulon of Acidithiobacillus ferrooxidans revealed by transcriptomic in the presence of an acyl homoserine lactone superagonist analog is described in the report of Mamani et al., while Wang et al. describe how transcriptional analysis has shown that the two-component system RsrS-RsrR regulates the tetrathionate intermediate pathway for thiosulfate oxidation in Acidithiobacillus caldus. A novel application of in situ spectroscopy carried out by Blake et al. has confirmed that acidophilic iron-oxidizing prokaryotes in different phyla use different electron transfer biomolecules to respire aerobically on soluble iron. Experiments on redox transformations of three transition metals  by some Acidithiobacillus spp. and two other genera of acidophilic bacteria (Leptospirillum and Acidiphilium) gave some unexpected results, including the fact that reduction of ferric iron can be mediated under aerobic conditions, and that copper, like iron, can be both oxidized and reduced by acidophiles, though via indirect mechanisms . Quantifying numbers and activities of acidophiles in natural and anthropogenic environments is becoming increasing important, and Hedrich et al. describe novel quantitative real-time PCR assays for the quantification of Acidithiobacillus, Leptospirillum, and Sulfobacillus species. When combined with other molecular PCR-based methods, total cell counts and metal sulfide oxidation activity measurements via microcalorimetry, this allows highly accurate quantitative monitoring of different microbial species during bioleaching operations.This Research Topic issue is the halotolerant species, Acidihalobacter prosperus, which is able to grow and catalyze sulfide mineral dissolution at elevated concentrations of salt (NaCl) and is potentially important for biomining in semi-arid and coastal areas, where only brackish and saline waters are available. The proteomic response of this acidophile to elevated chloride concentrations included the production of osmotic stress regulators that potentially induced production of the compatible solute, ectoine uptake protein, and increased iron oxidation resulting in heightened electron flow to drive proton export by the F0F1 ATPase. In contrast, A. ferrooxidans responded to low levels of chloride with a generalized stress response, decreased iron oxidation, and an increase in central carbon metabolism .Another extreme acidophile considered in this Research Topic issue concern contrasting species of moderately acidophilic/acid-tolerant bacteria. Metagenome analysis of strains of the relatively little-researched aerobic and acidophilic iron-oxidizing species Sideroxydans, enriched from a pilot plant for the treatment of acid mine drainage, revealed their metabolic versatility and adaptation to low pH . Lastly, sequence analysis of the draft genome of the acid-tolerant sulfur-reducer Desulfurella amilsii, and comparison to the available genome sequences of other members of the Desulfurellaceae family, is presented by Florentino et al.The two other papers in this Research Topic issue illustrate how this particular area of extreme microbiology is continuing to reveal new insights into the molecular biology and evolution of acidophiles, their biochemistries and show their potential for use in new and sustainable biotechnological applications. These fascinating prokaryotes will doubtless continue to reveal new, interesting and potentially highly useful traits as they are further researched.The manuscripts contained in this All authors listed, have made 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.


Congenital heart disease (CHD) is one of the major global health problems with the highest birth prevalence in low- and middle-income countries. In these populous countries, basic health services for the children with CHD, including surgery, are lacking. Even though surgery is performed, outcome after cardiac surgery is influenced by the quality of the postoperative management with a reported high morbidity and mortality. Henceforth, there is an urgent need for comprehensive interventions to provide high quality cardiac intensive care programs to improve the quality of pediatric cardiac surgery services in order to address high morbidity and mortality after cardiac surgery. The development and training of the health workers in the field of pediatric cardiac intensive care program is required. It is imperative to conduct this training prior to actual implementation of the program in limited resources settings. Congenital heart disease (CHD) is the most common cause of major congenital anomalies representing a major global health problem. The number of children with CHD is increasing worldwide. The increase might be caused by changes in diagnostic approaches and screening methods rather than representative of a true increase. The highest birth prevalence of CHD was reported from Asia. Although, this may be skewed by data from high-income countries in the region exclusively reporting the highest CHD prevalence, while no data were available from low-income countries in the region .Approximately 1/100 babies worldwide are born with CHD, of which one fourth are critical CHD . MortaliFactors related to morbidity and mortality after cardiac surgery and cardiac intensive care include high proportions of late presenters, major comorbidities, and severe complications of CHD. Accessibility to echocardiograms has highlighted the global inequalities of access to care. In high-income countries prenatal diagnosis has led to early detection of CHD before birth resulting in early diagnosis of lesions that could result in early referral and treatment long before the onset of irreversible sequel. This is not the case in low- and middle-income countries, where only a few children with CHD are even detected after birth. The proportions of children with missed diagnoses differ among centers, are considered to be much higher in low- and middle-income countries compared to high-income countries. A general lack of awareness and recognition among health care workers, lack of resources, and low numbers of properly trained healthcare workers could be considered as the underlying reasons for the delays. Majority of pediatricians receive little or no training in pediatric cardiology because there are very few pediatric cardiac programs in low- and middle-income countries . FurtherCardiac critical care issues may affect a low resource setting in many ways. The use of cardiopulmonary bypass in children undergoing cardiac surgery may impact organ systems including altered vasomotor tone, fluid shifts, reduced pulmonary function, acute kidney injury, gastrointestinal, neurologic, hematologic endocrine dysfunction, and infection . ChildreAmong those who present with the late diagnosis of CHD, fewer options of beneficial surgical procedures are available due to complications at the time of diagnosis. Some of the most common complications among those who present with delayed diagnosis of CHD include congestive heart failure, severe pulmonary hypertension, severe malnutrition, chronic infection, severe polycythemia, chronic hypoxia, and stroke , 14.For many children correctable surgeries are not performed in low-income countries because of the absence of trained congenital heart surgeons, limitations of human resources, inadequate facilities for cardiac surgery, and severe condition at the onset of diagnosis. On the other hand, if correctable surgery is performed the perioperative period is more hazardous because of complications related to delayed surgery and postoperative care. Management of these sequelae due to the late presentation are challenging and requires a comprehensive and multidisciplinary approach focusing on the complexity of CHD, therapeutic options, surgical complexity and postoperative management. Most patients require nutritional rehabilitation, control of heart failure management of pulmonary hypertension, prevention of hypoxic spell, treatment of infective endocarditis, and correction of anemia , 14. TheThe first step is recognition of some of the contributing factors as outlined above. There is a dire need for comprehensive interventions to provide high quality cardiac intensive care programs and to improve the quality of pediatric cardiac surgery services in order to address morbidity and mortality after cardiac surgery. Problems related to pediatric cardiac surgery and cardiac intensive care program in low- and middle-income countries are multifactorial and include competing priorities, poor structural organizations, lack of financial resources, lack of trained human resources, insufficient training, and educational infrastructure . In addiHowever, to achieve these ideals in the setting of limited resources is challenging but is not impossible. These require an effective policy response, adequate financial investment to increase the numbers of cardiac intensive care programs and thereby improve the quality of pediatric cardiac surgery in low-and middle-income countries.Pediatric cardiac critical care (PCCC) training programs are very few in low- and middle-income countries . HencefoIn high-income countries, several published studies evaluating the impact of a dedicated pediatric cardiac intensive care unit on the outcome among children undergoing cardiac surgery for CHD has demonstrated better outcomes in lowering bloodstream infections, preventing prolonged use of mechanical ventilation, and reducing length of ICU stay –21. A syHenceforth, the development and training of the health workers in the field of pediatric cardiac intensive care is required and if possible should be put in place prior to actual implementation of a program in limited resources settings.Challenges occur during the development, implementation, and maintenance phases of a PCCC training program. The challenges consist of the availability and maintenance of equipment in pediatric cardiac intensive care unit, including invasive monitoring, life saving intervention, renal replacement therapy, and hemodynamic monitoring. The possible solutions that are relevant to limited resource settings include reducing costs; in addition availability of medical equipment should be appropriate to available resources and needs .Due to limited infrastructure, funding, and human resources in low- and middle-income countries, a dedicated pediatric cardiac intensive care is not widely available as compared to high-income countries. The cardiac services are provided by a multidisciplinary team including pediatric cardiologists, pediatric cardiac surgeons, intensivists, anesthesiologists, critical care nurses, respiratory therapists, and other allied health workers who are available to care for children after cardiac surgery , 24, 25.The team leader of the pediatric cardiac intensive care unit could be a pediatric cardiologist who has an experience or training in intensive care, a pediatric intensivist who has training or knowledge on hemodynamics of CHD and management of children after cardiac surgery, anesthesiologist, or adult intensivist with adequate knowledge in caring for neonates, infants, or children who have frequently been involved in pediatric cardiac surgery , 18. PedThere are considerable gaps in providing an ideal environment to care for children after cardiac surgery in low- and middle-income countries. Henceforth, emphasis should be placed on the need for a comprehensive and multidisciplinary approach to the management of pediatric cardiac patients regardless of their location. The cost of providing care in a dedicated pediatric cardiac intensive care may be prohibitive when resources are limited. However, collaborations with well-established programs in high resource settings has led to an evolution in developing pediatric cardiac intensive care units in low- and middle-income countries . The parThere are challenges to training and building a sustainable PCCC program in resource limited settings. Education and training are very important to create physician and nursing competency in the care of children with critical cardiac conditions. There are wide ranges of training experience on postoperative patients that are provided in high-income countries. Sub-specialization from high-income countries has evolved over time. In recent years majority who practiced this specialty have additional and formal training , 27. ThiTraining in PCCC in low- and middle-income countries has evolved over the time which is variable depending on the country and the visiting teams. Teams from well-established PCCC program in high-income countries have been important drivers in teaching and building the host teams confidence and experience . CardiacRetention of the trained staff working in limited resource settings is a key to the sustainability of a developing program. Factors that have led to the migration of staff can be prevailed. This might be prevailed by hiring the right candidates at the beginning or providing a decent salary. Creating or sustaining a structured program with committed personnel to surround new personnel might help to ensure an ongoing staff development .Indonesia just like other developing countries still struggles with high mortality rate, even with its many significant achievements on societal, political, and economic development. Referral in neonatal and pediatric emergencies is crucial due to the unpredictability of the complications and their potential to progress rapidly to become severe and life threatening. Deaths could be prevented if referral systems were in place and functional to allow them to reach appropriate health services to prevent complications. The healthcare system must be adequate to respond to referral patients in a timely manner and with quality care in order to save the lives of those referred.These would be very challenging for Indonesia, a country with a population of over 250 million and has long distances between each other islands, only has six institutions with comprehensive facilities to take care of the children with CHD. The substantial improvement in the number of high quality comprehensive cardiac services is needed.In order to maintain the sustainability of the program, a Steering Committee should be established prior to the commencement of the training program to seek their support and endorsement of the intervention. This includes all the stakeholders, hospital director, the head of departments, nursing, cardiac surgeon, pediatric cardiologist, intensivist, anesthesiologist, nutritionist, physiotherapist, pharmacist and other clinical, and allied health staff. The proposed program should be presented to seek their support and endorsement of the program. The Steering Committee should be asked to review and provide feedback about the available information on the development and maintenance phases that will be used during the training program. Further, all the healthcare personnel who are caring for patients after cardiac surgery should be asked to participate in a quality improvement initiative.Published studies on the pediatric cardiac intensive care program and its effectiveness in limited resource settings are very few. With increased demand of proper management for CHD in such settings, the need of PCCC training program is unavoidable and should be prioritized to improve outcome. In addition, impact of this training program should be evaluated to determine the performance and outcomes of children with heart disease in low- and middle-income countries.IM and NM determined the review question. IM wrote the first drafts of the paper. IM and NM contributed to the reviewing and interpretation of results, writing of the paper, had input and approved the final version.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.


Introduction. Patients with head and neck cancer suffer from various impairments due to the primary illness, as well as secondary consequences of the oncological treatment. This systematic review describes the effects of radiotherapy and/or chemotherapy on the functions of the upper aerodigestive tract in patients with head and neck cancer. Methods. A systematic literature search was performed by two independent reviewers using the electronic databases PubMed and Embase. All dates up to May 2016 were included. Results. Of the 947 abstracts, sixty articles met the inclusion criteria and described one or more aspects of the sequelae of radiotherapy and/or chemotherapy. Forty studies described swallowing-related problems, 24 described voice-related problems, seven described trismus, and 25 studies described general quality of life. Only 14 articles reported that speech pathologists conducted the interventions, of which only six articles described in detail what the interventions involved. Conclusion. In general, voice quality improved following intervention, whereas quality of life, dysphagia, and oral intake deteriorated during and after treatment. However, as a consequence of the diversity in treatment protocols and patient characteristics, the conclusions of most studies cannot be easily generalised. Further research on the effects of oncological interventions on the upper aerodigestive tract is needed. Head and neck oncological patients suffer from various functional, physical, and emotional impairments due to both the primary illness and the secondary consequences of the tumor treatment . The oncIn order to assist people with dysphagia to adjust to and live successfully with the sequelae of the primary condition, speech pathologists managing this caseload need to ensure posttreatment services are available  that addEvidence-based practice (EBP) is hailed to be paramount in the practice of speech pathology . The AmeSeveral reviews have been published about the outcomes after radiotherapy and/or chemotherapy in HNC patients . The searches were limited to English language publications. In PubMed the MeSH termseoplasms . Next, t larynx or hypopharynx were linked to neoplasm and radiotherapy or chemotherapy. Next, the search outcome was combined with the following terms: dysphagia, speech, speech disorder, voice, dysphonia, xerostomia, quality of life, dysarthria, or trismus . Truncation symbols and wildcards were used to search for variant forms of words or word extensions:Only articles presenting both pre- and postintervention data of the upper aerodigestive tract functions of the participants were included. Review articles and studies with a population sample of less than 20 patients were excluded, as well as experiments on animals or articles not published in English. Furthermore, studies published before 1990, case reports, expert opinions, and articles describing combinations of therapy including surgical interventions were excluded.Final decisions on inclusion were made based on the original articles by consensus between two expert reviewers in accordance with the PRISMA statement . The refUsing MeSH or thesaurus terms, 304 articles were located in PubMed and 201 in Embase. Free text word searches resulted in another 148 articles in PubMed and 397 in Embase. The combination of these searches, without overlap, yielded 947 articles. All 60 studies focused on different functions of the upper aerodigestive tract following radiotherapy and/or chemotherapy for HNC. The following constructs were evaluated across the different studies: communication (voice and speech), functions of the digestive tract , QoL, and overall survival rates.Twenty-four studies evaluated voice and/or speech function –43 with Nine studies , 42, 44 All the studies reported good to excellent outcomes for voice quality at long-term follow-up. Some studies specifically reported pre- to posttreatment improvements of voice or speech quality following radiotherapy and/or chemotherapy , 23, 28.Forty studies , 45–76 dWith regard to nutritional status, five studies , 63, 73 Follow-up times in these studies range from immediately after therapy  to 6 yeaNine studies reported impaired swallowing function following radiotherapy and/or chemotherapy , 75, 76.Five studies , 61, 66 Ackerstaff et al.  demonstrTwenty-five studies , 76–79 dAlthough three studies , 72, 77 We assessed the speech pathology interventions against the following criteria: (a) whether a detailed description of the intervention was provided; (b) whether the authors provided a description of treatment duration and intensity; and (c) what the speech pathology intervention outcomes were. The reported efficacy of 14 speech pathology intervention studies aimed at addressing problems in dysphagia, speech, voice, and trismus is summarised in Of the 60 articles included in this review, 14 studies , 73, 74 The three studies that investigated the treatment of trismus , 52, 74 Of the eight studies on swallowing disorders, only Kotz et al.  and van In total, 60 studies met the inclusion criteria. The studies described the effects of radiotherapy and/or chemotherapy on the functions of the upper aerodigestive tract in patients with HNC. The articles yielded by this systematic review vary in their findings regarding tumor characteristics and treatment modalities. As a result of this variability, no statistical pooling was possible. We also set out to investigate the involvement of speech pathologists in treating patients with HNC.When considering treatment outcomes, voice quality worsened at the start of radiotherapy and/or chemotherapy but eventually improved after therapy finished. Dysphagia can be a major side effect of HNC and its treatment. The high incidence of dysphagia in this study population can cause serious secondary consequences, such as malnutrition, dehydration, an increased risk of aspiration, and, at worst, death . As dyspThe general description of the study population in Additionally, a large range of outcome measures were used, some of which are not validated. This calls into question the reliability of results reported in some of the studies. The use of validated and standardised assessments in future research would provide more robust findings.When considering the functional outcomes of radiotherapy and/or chemotherapy, one of the most important factors is whether the patient had received voice or swallowing therapy. Interestingly, only 14 of the 60 included studies reported whether the patients received any speech therapy. Thus, in 46 articles functional results, such as voice quality, are presented with no specification of whether the patient received therapy. As some of these studies have a follow-up of >2 years, it is fair to assume that patients sought help for voice or swallowing problems. Therefore, the involvement of speech therapy may be underreported, suggesting that the presented outcomes in these studies are biased and raise questions about their reliability.When information was provided about treatment, only six articles , 73, 74 To enable the objective reporting of the effectiveness of radiation and/or chemotherapy, baseline measurements of different aspects of voice quality and swallowing are required. To manage expectations, healthcare professionals and patients need to be made aware that some aspects of both voice and swallowing commonly do not recover to the level prior to the oncological intervention . RegardiWhen describing aspects of swallowing function, both fiber optic endoscopic evaluation of swallowing and videofluoroscopy are considered to be the gold standard in dysphagia assessment . In addiAdditional research is needed to develop clinical practice guidelines to support evidence-based practice in the area of dysphagia, speech, voice, and trismus following radiotherapy and/or chemotherapy in patients with head and neck carcinoma. These practice guidelines should bring together the best available current evidence within a specific clinical area, formulating evidence-based recommendations for clinicians and present choices between different interventions that have an impact on health and use of resources . This syThe studies included in this systematic review described a wide variety of outcomes in patients with HNC following radiotherapy and/or chemotherapy. The findings about the long-term functional implications of radiotherapy and/or chemotherapy in patients with HNC are inconclusive as a result of the wide range of outcome measures used and the possible influence of underreported speech therapy.Future researchers need to consider targeting more homogeneous groups using standardised treatment protocols to improve the treatment outcomes, thereby decreasing the side effects of the oncological treatments. Findings of these studies need to inform the decision-making process in the treatment of HNC so complications can be better predicted with due consideration of the possible negative side effects to the upper aerodigestive tract. Although the main objective of most studies was to determine curing rates, the importance of the functional implications of the side effects of oncology treatments should not be overlooked, particularly their impact on QoL. Finally, more research is needed to gain a full understanding of the complexity and variety in the effects of radiotherapy and/or chemotherapy on the functions of the upper aerodigestive tract following HNC.


Epithelial to mesenchymal transition (EMT) is a physiologic process that allows morphological and genetic changes of carcinoma cells from an epithelial to a mesenchymal phenotype, which is the basis of the high metastatic potential of pancreatic cancer cells. EMT is triggered by various tumor microenvironmental factors, including cytokines, growth factors, and chemotherapeutic agents. This review summarizes the state-of-the-art knowledge on the molecular mechanisms that support pancreatic cancer EMT and the evidences that support its involvement in invasiveness/aggressiveness, and the drug resistance of pancreatic cancer cells.


Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding of fatigue, which has recently been proposed as a defense mechanism instead of a “physiological failure” in the context of prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue. Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmacological manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally, physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve physical performance. Fatigue is a feeling commonly experienced in our daily lives, for example, during periods of vigorous and/or prolonged physical activity. In the sporting context, fatigue is crucial to the performance of athletes in virtually all competitive events, although the determinant factors  for fatigue are specific to the individual events. The present review will focus on fatigue during prolonged (aerobic) exercise, thus characterizing exertion in long-distance sports athletes, including runners, cyclists and swimmers. In these conditions, the determinant factors for fatigue will depend on several aspects, such as exercise intensity and duration, environmental conditions, nutrition and the fitness level of the individual. For instance, regulation of body temperature plays an important role on fatigue during a prolonged exercise (∼60 min) at 60% of the maximal aerobic capacity in hot weather .Fatigue and exhaustion are commonly used as synonymous in the literature, including some studies cited in this review. In general, the moment at which exercise ceases is usually termed as point of exhaustion in human studies. However, the two terms may be related to different processes with distinct physiological characteristics. The feeling of fatigue appears to occur before any damage to body systems, and it is common to see the term ‘volitional fatigue’, indicating that subjects decided to stop exercising. Exhaustion can be defined as extreme fatigue, a state in which an individual may exceed his/her physiological limits and then experience a “catastrophic” failure of homeostasis . In thisThe psycho-physiological process that triggers the feeling of fatigue is complex and may result from peripheral and central factors. Peripheral fatigue is defined as the loss of force caused by processes occurring at or distal to the neuromuscular junction . In a si+ ions. However, since the early 2000s, fatigue has been understood as a mechanism that aims to maintain the physiological integrity of the body  ,13, dopaSerotonin  is a neurotransmitter synthesized from the amino acid tryptophan (TRP), which is transported through the blood-brain barrier by a specific carrier and is then hydroxylated by the action of tryptophan hydroxylase; this hydroxylation is the rate limiting step in the biosynthesis of 5-HT. Increased plasma levels of free TRP favor increases TRP concentrations in the central nervous system (CNS), and thus any condition that increases this amino acid in the plasma will induce increased concentrations in the CNS and hence the central biosynthesis of 5-HT .The bodies of serotonergic neurons are located in the CNS structures called the raphe nuclei. These nuclei are divided into caudal raphe, with descending projections to the spinal column, and rostral and medial raphe, which send ascending projections to various brain regions, such as the substantia nigra pars compacta (SNpc), thalamus, striatum, nucleus accumbens, hippocampus and hypothalamus. The release of 5-HT into the synaptic cleft leads to the binding of the neurotransmitter to one of its fifteen receptors (divided into 7 families), thus triggering physiological responses .Experiments conducted in mice have provided evidence that exercise changes the TRP levels, as brain concentrations of TRP were increased after swimming to fatigue . The firPharmacological manipulations of the activity of 5-HT in the CNS induced changes in physical performance, which supports the theory of participation of this neurotransmitter in the central fatigue mechanisms. In studies with exercising rats, administration of drugs that increase serotonergic activity (agonists of 5-HT receptors) decreased performance, while inhibitors of serotonergic activity (receptor antagonists) increased performance . Such chThe involvement of 5-HT in the fatigue process has been studied by our research group since the early 2000s and our experiments confirm the involvement of this neurotransmitter in the modulation of fatigue. Increasing the levels of central TRP by amino acid injection directly into the cerebral ventricles reduces the time to fatigue in rats subjected to moderate intensity treadmill running ,16,29,30para-chlorophenylalanine (p-CPA). Rats treated with p-CPA showed no reduction of the time to fatigue after icv administration of TRP, confirming that the ergolytic action caused by increased central TRP was a consequence of the conversion of the amino acid to 5-HT, and excluding the direct participation of this amino acid in the modulation of fatigue ..para-chl1 receptors in the CNS, which raised the concentration of 5-HT in the preoptic area, increased the heat storage rate and lowered the performance of rats  and a reduction in time to fatigue ,30. Inde of rats . On the  of rats . TogetheInterestingly, when evaluating the effects of treatment with p-CPA , we notiAll the findings reported so far have been obtained with laboratory rodents, which represent a powerful experimental model to manipulate brain neurochemistry by locally administering drugs with agonist and antagonist effects. However, methodological and ethical issues limit the understanding of the involvement of central neurotransmitters in fatigue in humans. Even modern experimental approaches, such as positron emission tomography and near-infrared spectroscopy, fail in revealing the phenotype of the activated neurons, despite the fact that these approaches allow the evaluation of active brain areas in humans under several conditions. Due to ethical issues, it is not allowed to administer drugs and amino acids directly into the brain of humans; therefore, such substances have to be given systemically, which adds a number of confounding factors in studies, including intestinal absorption of administered substances, the degradation of these substances in the vascular periphery and the ability of these substances to cross the blood-brain barrier. As a result of the many confounding factors, studies using dietary manipulations to increase the availability of central TRP in humans show conflicting results regarding physical performance, with reports of increases  or no chAs it is not possible to directly measure the activity of neurotransmitters in humans, the blood concentrations of some pituitary hormones  have been used as indicators of CNS neurotransmitter activity, as both the 5-HT and DA modulate the secretion of these hormones . ElevatiNot only higher 5-HT concentrations, but also the sensitivity of receptors stimulated by 5-HT can modulate feelings of fatigue during prolonged exercise. It has been hypothesized that aerobic training modulates sensitivity of 5-HT receptors in laboratory rodents  and humaA recent study in our laboratory investigated the influence of aerobic capacity on the relationship between the central serotonergic activity and fatigue during prolonged exercise in humans. Contradicting the results reported for subjects at rest, pharmacological stimulation of the serotonergic system decreased the time to fatigue in volunteers with higher aerobic capacity compared to the placebo condition, while stimulation of the serotonergic system did not affect the time to fatigue in the group with lower aerobic capacity  43). Th. Th43). Relying on the “central fatigue hypothesis”, several studies have tried to delay fatigue by preventing the increase of 5-HT in the CNS. One of the main strategies used for this purpose is nutritional supplementation with branched-chain amino acids (BCAA). Supplementation of these amino acids reduces entry of free TRP into the CNS, because the BCAA and TRP compete for the same transport system across the blood-brain barrier. In a recent study, supplementation with BCAA before exercise performed to fatigue tended to reduce the concentration of 5-HT in blood samples in the treated group compared to the control group . In ratsIn summary, studies in rats and humans provide evidence that central serotonergic activity is related to fatigue during prolonged exercise. However, the results obtained in human studies are still quite controversial and many issues need clarification, such as the mechanisms underlying the physiological responses modulated by 5-HT and the effects of physical training on the activity/sensitivity of the serotonergic system.Dopamine  is another neurotransmitter involved in the central fatigue mechanisms. The first evidence of the association between DA and exercise dates from the 1970s and 1980s in studies with rats. Peripheral administration of amphetamine, a DA releaser, increased the time to fatigue , whereas1-like (containing D1 and D5 receptors) and D2-like   by tyrosine hydroxylase and then, to DA by dopadecarboxylase. The conversion mediated by tyrosine hydroxylase, which is stimulated by calcium, is considered the limiting step of the synthesis of this monoamine . The maiceptors) .The augmented activity of the dopaminergic system in response to exercise initiation appears to be due to an increase in the central levels of calcium, which increases the activity of tyrosine hydroxylase through the activation of the calcium-calmodulin system . In contDuring exercise, the increase in the activity of the dopaminergic system in the preoptic area seems to influence tolerance to heat stress. In rats, both the icv administration of DA , and the1 receptor antagonist) and eticlopride (D2 receptor antagonist) prolonged hyperthermia after performing a fatiguing, incremental speed exercise, without prolonging metabolic activation . In this condition of injury and degeneration of the nigrostriatal pathway, chronic exercise induced neural protection and recovery responses in the striatum, leading to improved motor control ,75. FollSuch effects of chronic exercise on motor recovery and on the plasticity of the dopaminergic system have also been investigated in experiments with humans. Individuals with Parkinson's disease have increased grip strength and improved fine motor coordination after 12 weeks of training karate movements emphasizing the upper limbs , as wellFrom analysis and interpretation of all these studies, we conclude that the dopaminergic system influences physical performance by acting on different neural pathways, which include the control of movement, thermoregulation, perceived exertion, motivation and reward. Moreover, chronic exercise modulates the activity of this system, even in pathological conditions, such as Parkinson's disease.As previously discussed, the development of fatigue is influenced by the neurotransmitters 5-HT and DA . In gene1A receptors (at high doses) functionally inhibit nigral dopaminergic neurons    cause biIn relation to the prosencephalon, immunohistochemical studies have shown that serotonergic neurons arising in the dorsal raphe nuclei are projected via the medial forebrain bundle to the striatum and cortex . Stimula1A, an autoreceptor that inhibits the synthesis and release of 5-HT, in the raphe  conditions and internal conditions of the body, so as to prevent extreme physical exertion that may cause irreversible damage. This integration involves the action of neurotransmitters in the CNS. In general, studies with laboratory rodents and humans indicate that increased serotonergic activity and reduced dopaminergic activity are associated with accelerated fatigue. Further research should determine exactly how neurotransmitters, mainly 5-HT and DA, modulate fatigue during exercise, as well as elucidate whether physical training protocols induce plasticity of action of these neurotransmitters in order to improve physical performance.