Cardiac diseases are mainly caused by malfunction of or injuries to the hearts. Although significant advances have been made during the past decades to improve the successful rate of treatments of these diseases, they still remain the top leading cause of morbidity and mortality in the world. Currently, cardiac diseases are defined according to the traditional system- or organ-based classification and the identification of diagnostic and therapeutic biomarkers has been focused on the heart. Therefore, the “golden standard” biomarkers are mainly cardiac muscle-related. For example, the conventional troponin (cTn) has been widely utilized for the diagnosis of acute myocardial infarction in the clinics. However, multiple limitations exist with clinical applications of these types of biomarkers. The ELISA based cTn detection assay is time consuming, and the dynamics of the biomarkers are not sensitive enough to represent the development of the diseases. Clearly, there is an urgent need for identifying sensitive, specific biomarkers of different types of cardiac diseases and development of new therapies for this unmet medical need. In this special issue, we have assembled a series of articles of reviews, perspectives, and original contributions from experts in current research of novel biomarkers and treatments of cardiac diseases in both basic research and clinical practice.In the effort to develop more sensitive cardiac specific troponin-based diagnosis for heart diseases, the highly sensitive troponin T (hsTnT) was found to offer an excellent diagnostic performance due to its high sensitivity and negative predictive values compared with conventional troponin (cTn) test. In this special issue, the potential clinical use of hsTnT for diagnosing perioperative myocardial infarction (PMI) was discussed. In addition, it was discovered that hsTnT combined with advanced oxidation protein products (AOPPs) could be useful for monitoring myocardial function of cirrhotic patients with chronic hepatitis C virus infection.Other than the circulating troponins, many other proteins have been tested recently as biomarkers for cardiac diseases. For example, caveolin-1, a membrane protein, has been found in blood circulation and might serve as a novel biomarker for idiopathic pulmonary artery hypertension. Serum level of pentraxin-3, a member of pentraxin family, is a long-term independent predictor of prognosis of patients with chronic heart failure.In addition to circulating proteins, other circulating molecules have also been discovered as biomarkers in many disease settings. MicroRNAs are small RNAs with ~22 nucleotides in length that can regulate specific messenger RNAs (mRNAs). They present in both tissues and blood circulation and can be used as biomarkers of cardiac diseases . In one  Withania somnifera leaf extract, one of the most valuable herbs in the traditional Indian systems of medicine, can effectively treat isoproterenol-induced oxidative damage in rat myocardium.Some other molecules have also been investigated for the value of biomarkers in cardiac diseases. For example, alteration of preoperative and postoperative plasmatic endogenous ouabain (EO) has been linked to patients with higher risk of morbidity and mortality after cardiac surgery. The differential expressed genes (DEGs) in human epicardial adipose tissue (EAT) can serve as biomarkers as well as therapeutic targets for treatment of cardiovascular diseases. A research article in this special issue also demonstrated that activation of endocannabinoid system, as evidenced by elevation of cannabinoid receptors, infiltration of leukocytes and mononuclear cells, is associated with persistent inflammation in human aortic aneurysm. As a novel therapeutic strategy for the treatment of cardiac diseases,Taken together, the studies assembled in this special issue represent several important paradigm shifts in the area of biomarkers for the diagnosis, prognosis, and treatment of cardiac diseases. The identification of biomarkers for the diagnosis and treatment of cardiac diseases should not be limited to the organ- or tissue-specific molecules (proteins or nucleotides). The systematical nature of pathogenesis and pathophysiology of cardiac diseases requires broader vision and strategies outside the organ- or system-based box . The fas


Two reasons for the lack of success of programs or interventions are poor alignment of interventions with the causes of the problem targeted by the intervention, leading to poor efficacy (theory failure), and failure to implement interventions as designed (program failure). These failures are important for both public health programs and randomized trials. In the Sanitation Hygiene and Infant Nutrition Efficacy (SHINE) Trial, we utilize the program impact pathway (PIP) approach to track intervention implementation and behavior uptake. In this article, we present the SHINE PIP including definitions and measurements of key mediating domains, and discuss the implications of this approach for randomized trials. Operationally, the PIP can be used for monitoring and strengthening intervention delivery, facilitating course-correction at various stages of implementation. Analytically, the PIP can facilitate a richer understanding of the mediating and modifying determinants of intervention impact than would be possible from an intention-to-treat analysis alone. The emergence of implementation science over the past decade has advanced understanding of the many possible impediments to delivery and utilization that can limit the potential impacts of proven health and nutrition interventions –3. One aWithin the growing body of literature in this area –20, 2 puThe Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial is designed to test the independent and combined effects of 2 village health worker (VHW)–delivered intervention packages to improve water, sanitation, and hygiene (WASH) and infant feeding behaviors with the aim of improving length and hemoglobin concentration (or reducing stunting and anemia respectively) at 18 months of age. The design is a cluster-randomized, 2-factorial, community-based intervention trial in 2 rural districts of Zimbabwe. Whereas the factorial design allows for efficient comparison of 2 interventions with hypothesized independent and additive effects, the cluster-randomized design is necessitated by the theoretical  and practical  considerations of delivering sustained behavior change communication to rural communities . The uniThe overall approach of the SHINE Trial is to implement a health system-based project in which randomized behavior change interventions are delivered by VHWs. In SHINE, VHWs are dually supervised; (1) by Ministry of Health and Child Care nurses in carrying out their regular duties, and (2) by SHINE research staff in carrying out the additional tasks required by the trial. VHWs are trained to visit participants monthly, deliver messages in accordance with behavior change intervention modules relevant to their randomized arm, and deliver corresponding inputs such as soap, water chlorination agents, and small-quantity lipid-based nutrient supplements (LNSs). As such, the SHINE Trial is a complex intervention within a complex system –29. EvalIntention-to-treat (ITT) analysis of the main outcomes is the standard approach for statistical tests of the hypothesis of null effects of treatment in a randomized trial  and is tIn this article, we present the theory-driven process evaluation embedded within the SHINE Trial. First, we present the SHINE program impact pathway (PIP), which details how we hypothesize the interventions will achieve their desired effects. Second, we describe how we are measuring the key mediating domains at each step in the PIP. Third, we describe how we use the PIP operationally. Finally, we discuss its application in 2 broad analytic approaches: a PIP analysis that examines the flow of the intervention impact at each step along the hypothesized pathway and per-protocol analyses that explore treatment effects among the treated at each step.actual behaviors carried out at the level of the unit of randomization (communities served by 1–4 VHWs), let alone at the individual level. Rather, SHINE randomly allocates VHWs to receive training for, offer, and deliver, 1 of the 4 treatments; and under black box [As with a CRT of any complex intervention, the SHINE Trial cannot randomize the lack box  ITT assuIn collaboration with the Ministry of Health and Child Care, SHINE staff train VHWs and provide behavior change materials, intervention hardware, and supervisory support  to effect 4 sequential intermediate processes: (1) improved VHW performance capacity, as measured by their relevant knowledge, self-efficacy, and goal-setting capacity; (2) actual VHW performance as measured by the degree to which it conforms with intervention design ; (3) improved maternal and household behavioral determinants, as measured by their relevant knowledge, message recall, and attitudes toward recommended behaviors; and (4) improved trial and maintenance of WASH and/or infant feeding behaviors by the study participants, as measured by the evidence of recommended behaviors being practiced. These improved behaviors represent proximate outcomes to stunting and anemia that directly precede the biologic processes described in Prendergast et al .Recognizing that effect heterogeneity is inevitable in the program pathway of a complex intervention , the PIPOne way in which we operationalize the PIP is by monitoring fidelity of implementation . In SHINE, FOI is operationalized to include the delivery process , the quality of delivery (how well they do it), and participant responsiveness (how households respond) .Ensuring high treatment fidelity in a randomized trial of a complex intervention is important for ethical, as well as statistical, reasons. It is crucial for ensuring internal validity  and generalizability of results . InternaAre VHWs receiving regular (monthly) and systematic  on-the-job support and feedback from their supervisors?Are VHWs delivering the required number of behavior change messages at the required times with the required material inputs and correct education techniques?Are VHWs motivated and satisfied with their remuneration, supervision, and provision of tools of the trade? Do they feel adequately equipped to do their work, and do they feel valued, respected, and well supervised?Process evaluation is the principal approach for identifying discrepancies between the program as intended and the program as implemented . The SHIAnswers to these questions represent actionable information that can be used to address implementation problems on an ongoing basis. For example, reported dissatisfaction with monetary allowances identified during the baseline round of VHW interviews informed the formulation of a performance-based incentive package begun in December 2013 to improve VHW motivation and job performance outcomes .We collect process evaluation data through record reviews, structured observations, interviews with VHWs and interviews with study participants at outcome measurement time points . All enuVHWs maintain a module-delivery schedule for each mother they recruit into SHINE. These schedules specify which module should be delivered when, as well as allowable and acceptable windows around the target date. VHWs record when the module was delivered. VHWs also maintain registers in which they record their activities, such as prospective pregnancy surveillance. Supervisors routinely inspect this documentation and collect these data from each VHW during their scheduled monthly supervisory contacts. These data will be used to characterize supportive supervision (frequency of VHW-supervisor contacts) and VHW performance.VHW supervisors conduct structured observations of all VHWs to assess and document VHW interactions with study participants and adherence to behavior change intervention protocols. For each VHW, these observations are conducted during the first delivery of each new behavior change intervention module and quarterly thereafter. The assessment tools consist of Likert-type, multiple-choice, dichotomous, and subjective qualitative items that are used to assess specific behaviors of VHWs. Measures of VHW performance, such as lesson delivery scores, will be derived from these data.Research staff (part-time enumerators) administer a questionnaire to each VHW (following their informed consent as a research subject) 3 times, at baseline, midline, and endline. Data on sociodemographic, supervisory and motivational characteristics , curricuResearch nurses administer questionnaires to participating women during 2 antenatal and 5 postnatal visits between recruitment at approximately 14 weeks of gestation and 18 months postpartum. Data collected include sociodemographic information, exposure to behavior change interventions, curriculum knowledge, maternal capabilities for caregiving , and WASSupplementary Appendix Table 1.A summary of the data collected, data sources, the indicators derived, and timing of data collection is presented in The full PIP, from randomized treatment allocation to reduced childhood stunting and anemia, elucidates several intermediate steps, a number of potential modifiers at each step, and different potential measures to characterize each step (including of FOI at delivery/receipt steps such as between the VHW and caregiver or between the caregiver and infant). Above and elsewhere , we descMore specifically, we will conduct analyses of intermediate outcomes at each step along the PIP: 1) VHW performance capacity; (2) VHW performance; (3) maternal behavioral determinants/capacity; and (4) maternal behavior/performance. We will employ 2 analytical approaches in these analyses: (1) ITT based on the original randomized design and examining each intermediate outcome separately as an endpoint; and (2) per-protocol analyses linking together intermediate steps and conditional on specific prior outcomes or achievements in an earlier step, such as high FOI. For both approaches we will, via interactions, explore the role of pre-specified modifiers. Examples and potential hypotheses to be explored are presented in Table  VHW perfThe ITT analyses will examine the impact of the randomized interventions on an intermediate outcome, one at a time, treating that outcome as an endpoint , 20, 22,The per-protocol analyses go beyond these intermediate outcome ITT estimates to examine movement along the PIP—that is, the linkages from earlier to later steps in the chain including, in particular, the final outcomes. For example, linking VHW performance capacity to actual VHW performance. Per-protocol analyses will also explore the linkages from earlier steps in the chain to the final outcomes, such as linking FOI of VHW delivery and stunting and anemia (to ascertain the effects among those who received the treatment as intended), and linking FOI of maternal/caregiver delivery to stunting and anemia (effects among those who tried and maintained the treatment behaviors). Conditional on having delivered/received the intervention relevant to the participant's treatment arm (as defined by indicators for FOI), we will examine the association between the intervention and the outcome in a later step of the PIP, as well as with the final outcomes of the trial. As with the first set of ITT analyses, potential modifiers at each stage can be assessed using interactions.Depending on the starting point, the per-protocol analyses will be based on our categorization of FOI into 2 types—VHW and caregiver. In the first of these, FOI of VHW delivery, we classify participants who had at least 10 of the 15 VHW SHINE scheduled visits, starting at 24 weeks of gestation as having high/adequate fidelity. We standardized the number of VHW visits (15 module delivery contacts) across treatments to ensure that the content, rather than the number of contacts, is what differentiates the treatment groups. A visit is therefore defined by having contact at a scheduled behavior change intervention delivery visit. For FOI of caregiver delivery, we will develop separate and combined compliance indices for the WASH and infant feeding behaviors and apply a similar condition of at least two-thirds of the behaviors implemented.In contrast to the ITT, for these analyses the estimation sample is limited to those following protocol, and for whom effects are hypothesized to be larger. A limitation to this approach is that it no longer fully exploits the randomized design and therefore weakens causal inference. A benefit to this approach, however, is that it allows us to explore more directly the links between improved WASH and infant feeding practices themselves and the final outcomes.In particular, evidence on the linkages along the intermediate stages of the PIP, as well as any dose-response associations in the relationships between VHW delivery of interventions and the final outcomes, can provide additional plausibility to any observed ITT effects. Furthermore, identifying the drivers of effect heterogeneity can elucidate the circumstances, persons, and contexts in which any such effects are likely to be greatest.There are numerous examples in the literature of large-scale interventions that had disappointing health outcomes , 46. In Supplementary materials are available at Clinical Infectious Diseases online . Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.


Cardiac surgery patients are now more risky in terms of age, comorbidities, and the need for complex procedures. It brings about reperfusion injury, which leads to dysfunction and/or loss of part of the myocardium. These groups of patients have a higher incidence of postoperative complications and mortality. One way of augmenting intraoperative myocardial protection is the phenomenon of myocardial conditioning, elicited with brief nonlethal episodes of ischaemia-reperfusion. In addition, drugs are being tested that mimic ischaemic conditioning. Such cardioprotective techniques are mainly focused on reperfusion injury, a complex response of the organism to the restoration of coronary blood flow in ischaemic tissue, which can lead to cell death. Extensive research over the last three decades has revealed the basic mechanisms of reperfusion injury and myocardial conditioning, suggesting its therapeutic potential. But despite the enormous efforts that have been expended in preclinical studies, almost all cardioprotective therapies have failed in the third phase of clinical trials. One reason is that evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. Ischaemic conditioning, which is among these, is also limited by this. At present, the prevailing belief is that such options of treatment exist, but their full employment will not occur until subquestions and methodological issues with the transfer into clinical practice have been resolved. The spectrum of cardiac patients has recently shifted to groups exposed to a higher risk level in terms of age and comorbidities, as well as the type of treatments needed. This increases the need for emergency surgery in acute coronary syndromes with complications including acute heart failure . AnotherThe current gold standard of cardioplegia is a depolarisation myocardial arrest through perfusion of the coronary arteries using a hyperkalaemic solution. The time of reversible ischaemia that it provides is satisfactory for the surgery (up to 4 hours); plus, there is the restoration of function (a number of days) and low systemic toxicity . MyocardMyocardial RI is a complex response of the organism to the restoration of coronary blood flow in the ischaemic tissue and is an important component of ischaemia-reperfusion injury , 15. TheAlthough the no-reflow phenomenon was described as early as 1966, the aetiology is still unclear. There are a number of other events involved, including embolisation of debris from the site of the occlusion, the release of vasoconstrictor and thrombogenic factors, and inflammatory substances; plus there are considerations in respect of the structural collapse of the capillary bed . WhetherOxygen is the main factor of damage, that is, its acute lack in the phase of ischaemia and toxicity in the reperfusion phase. This paradox can be explained by the evolution of the relationship between organisms and oxygen on Earth. After the increase in concentration of oxygen in the atmosphere 2.4 billion years ago that nearly wiped out life on Earth (the great oxygenation event), aerobic organisms entered the path of adaptation, eventually ending up on oxygen, an electron acceptor for their energy mechanisms. Multicellular organisms thus gained the opportunity of explosive development at the cost of shortening the lifespan of individuals. Although widespread, the evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. To this day, eukaryotic cells are dealing with a difficult logistical task, that is, to bring enough oxygen to the cell for respiration whilst eliminating the pernicious consequences of its presence. The start of reperfusion is the moment at which cells are most vulnerable, and as for antioxidant enzymes to regenerate, available energy is needed , 32.+ gradient on myocyte membranes. Activation of the Na/H pump follows, as well as the rapid entry of sodium into myocytes. This causes a passive reverse running of the membrane Na/Ca exchanger, the exchange of sodium for calcium causing the second intracellular calcium peak. The result of the rapid pH adjustment and calcium overload comprises an abolition of protease disinhibition , opening of mitochondrial transport channels (mPTP) and hypercontracture of the myofibrils  . Not onlIntracellular signal transmission takes place via at least three parallel channels: the first is activated by receptors coupled with G protein (GPCR) and proceeds via a nitric oxide (NO), cGMP, and PKG (protein kinase G). The second channel, also activated by GPCR and termed RISK , contains a number of kinases including PKB (protein kinase B), ERK (extracellular regulated kinase) and key GSK 3beta (glucose synthase kinase). The third channel is SAFE , which is activated by TNF-alpha and includes JAK  and STAT3 .Mitochondria are considered key effectors of cardioprotection, with mPTP  being the primary end point. They are nonspecific channels in the inner mitochondrial membrane, their physiological role being not known in detail . IschaemThe mechanisms of the acute and late stages of cardioprotection have many things in common. Some mediators of the intracellular signal transduction, however, induce gene transcription and synthesis of defensive proteins within 12–24 hours after the ischaemic stimulus . These iAnother modality which can reduce the size of myocardial infarction involves the application of several ischaemia-reperfusion stimuli immediately (within the first minute) after the restoration of perfusion in the ischaemic region . The redRemote ischaemic conditioning is a form of cardioprotection induced by short cycles of ischaemia and reperfusion, which are applied to a distant tissue and/or organ. The phenomenon was originally observed intraorganally and it is interesting that it was predicted using a mathematical model . In the The mechanism of RIPC at the myocardial level is largely the same as in the basic application, but the transfer of the protective signal from a remote organ to the myocardium is not fully explained. Three channels of communication were designed and partially tested: the humoral blood channel, neuronal stimulation, and communication of immunity cells. The humoral mechanism was tested by a perfusate and dialysate from the ischaemic organ, which induced cardioprotection after being applied to the isolated myocardium . The ideIts noninvasiveness and ease of application determined RIPC to be the most tested modality in clinical research. In terms of orders, dozens of “proof of concept” clinical studies have tested remote conditioning by an application of ischaemia/reperfusion on the upper/lower limb using a pressure cuff in elective operations in cardiac surgery and invasive cardiology –71. NoneThe basic type, ischaemic preconditioning (IPC), was first used in clinical testing on a small set of CABG patients in 1993, the stimulus comprising repeated aortic clamping and declamping prior to the cardioplegic arrest itself. The IPC group was observed to have an increased level of ATP in biopsy samples and lower levels of serum troponin I , 76. MetRemote ischaemic conditioning (RIC) has regained interest in clinical testing. The first clinical trial was performed on a group of 37 children undergoing surgery for congenital heart defect. RIC stimulus comprised three five-minute inflations/deflations using a pressure cuff (200 mmHg) on the lower limb before connecting to extracorporeal circulation. Children randomized in the RIC group had a lower consumption of inotropes, lower inspiratory pressures, and lower serum troponin I concentrations for 24 hours after the surgery . A serieIschaemic postconditioning (IPostC) has been successfully tested in paediatric cardiac surgery. The IPostC stimulus comprised repeated 30-second aortic declamping and clamping before the definite myocardial reperfusion. Children randomized in the IPostC group had lower serum levels of CKMB and troponin T for two hours after the surgery . Use in Compared to the previous modalities, the late phase of ischaemic preconditioning was clinically tested only in two studies. Our research group conducted a study based on some negative studies in CABG patients. At the start of surgery or, more specifically, prior to the cardioplegic cardiac arrest itself, there are stress stimuli that may also activate the phenomenon of the early stage of ischaemic preconditioning  and the IC stimulus applied, local or remote, already comes as an extra event . In addiNCT01502774, which is now underway [NCT01374321, EMBRACE: NCT01572909) [NCT01438086) [NCT00966563) [NCT00640094) [NCT01398384) [NCT01388504) [NCT01584453) [NCT00378352) [NCT01311700) [Revelation of the principles of ischaemia-reperfusion myocardial injury, on the one hand, and congenital defence mechanisms, on the other hand, offers the possibility of pharmacological intervention. Cardioprotective agents may be applied before application of the aortic clamp, added to the cardioplegic solution, or used in the reperfusion stage, or a combination of these may be an option. Just as with STEMI patients, drug administration may be considered during the acute myocardial ischaemia or in the reperfusion stage. The experiment successfully tested many substances and processes, clinical testing reducing the number of positive ones, and the most promising are now being tested in large sets of patients in multicenter studies. Recently, drugs are being tested (and attracting great attention) that mimic ischaemic conditioning (IC), at all of the three hierarchical levels, adenosine being amongst the first of such pharmaceuticals, the substance ranking among the IC triggers. For CABG patients, the administration of adenosine (intravenously or as part of cardioplegia) was associated with less myocardial injury and faster postoperative recovery , 91; othunderway . Other m1572909) , 106. Fu1438086) , mangafo0966563) , melaton0640094) , inhaled1398384) , IV sodi1388504) , intraco1584453) , thymosi0378352) , and met1311700) . Those o1311700) , 116, ac1311700) , while i1311700) , enipori1311700) , delcase1311700) , atorvas1311700) , and als1311700)  and gluc1311700) . Accordi1311700) . Moreove1311700) , 126. FX1311700) .The above studies represent only a small part of the efforts and resources that have been expended in this field. In the US alone, it is estimated that over the last 40 years, hundreds of millions of dollars were spent in preclinical studies for so-called infarction life-saving therapies. This gave rise to hundreds of treatments that were identified as controlling myocardial infarction. Nonetheless, these enormous resources have failed to lead to clinical application due to a number of methodological shortcomings.Mechanisms of cellular defensive response to ischaemic stress and pharmacological interventions were investigated using animal, tissue, and subcellular models, particularly in mice, rats, and rabbits, and, to the lesser extent, large animals. Thus, they cannot easily be transferred to human research, where differences may exist. In addition, little is known about the spatial and temporal organisation of these defence mechanisms. This may be one of the reasons for pharmacological cardioprotection failing in clinical trials . Pharmacμg/kg/minute versus placebo. SPECT (single photon emission CT) revealed the smallest infarction in higher concentrations: 11%, 23% versus 27% for placebo [In 2003, a workshop took place in the US, initiated by NHLBI , the event's title, “Transfer of Therapies to Protect the Myocardium from Ischemia,” was self-explanatory and its main recommendations included continuation of the clinical testing of adenosine . The AMI placebo . However placebo . Challen placebo . Optimis placebo .The fundamental discovery of cardioplegic myocardial protection in cardiac surgery in the 1970s and 1980s enabled effective surgical treatment bringing prolonged and better-quality life to the patient. Also, early reperfusion in STEMI patients remains the only effective treatment in cardiology. Both therapeutic strategies, however, are accompanied by reperfusion injury of the myocardium, which leads to dysfunction and/or loss of part of the myocardium. During the same period, another fundamental discovery was made: termed ischaemic preconditioning, it activates protection from ischaemia-reperfusion myocardial injury. The extensive research on this phenomenon in the past three decades has revealed basic mechanisms and suggested methods of use. Thus, the question is whether activation or augmentation of the defence mechanism may enhance myocardial protection in cardiac surgery or rescue another portion of the jeopardised myocardium after reperfusion therapy in STEMI patients. Although widespread, the evolutionary young cellular mechanisms of protection against oxygen handling are not very robust. Ischaemic conditioning, which is among them, is also thus limited and for myocardium, the organ with the highest oxygen turnover, it is of undeniable importance. At present, the prevailing belief is that such options of treatment exist for reperfusion myocardial injury, but the time for their full employment has not yet come, due to unresolved subquestions and methodological issues with the transfer into clinical practice.


Pachydermodactyly (PDD) is a rare and benign acquired form of digital fibromatosis, characterized by asymptomatic fusiform soft tissue hypertrophy of the lateral aspect of the proximal interphalangeal (PIP) joints of the fingers. The etiology of PDD remains unknown, but it usually affects healthy males around the age of puberty. It can be misdiagnosed as inflammatory rheumatic diseases, especially as juvenile chronic arthritis. Here, we report a case of PDD in an 18-year-old man who had progressive fusiform swelling of the PIP joint on his left middle finger. Although he had no pain or functional limitation of movement, he chose to undergo surgical resection of the lesion to obtain a conclusive diagnosis and to rectify the deformity's appearance. Histologically, the lesion was characterized by coarse fibrosis in the adipose tissue, peripheral nerve fibers, and eccrine glands; this is compatible with a diagnosis of PDD. Pachydermodactyly (PDD), from the Greek words pachy (thick), dermo (skin), and dactylos (finger), was first reported by Bazex et al. in 1973 . The diaAn 18-year-old man presented at our hospital with asymptomatic, gradually increasing fusiform swelling of the PIP joint in his left middle finger. He was right-handed. Over the past 5 years, he had undergone examinations by various specialists without a convincing diagnosis being made. On physical examination, there was diffuse thickening, predominantly, of the radial and ulnar aspects of the PIP joint, without any skin pigmentation or neurological deficits . He had PDD has been recognized as a distinct clinical entity because of its typical presentation of asymptomatic thickening of the soft tissues that overlie the radial and ulnar aspects of the PIP joints without any fundamental damage to the joint structures . The dis


We aimed to summarize the efficacy of simulation-based education in cardiopulmonary resuscitation and airway management .We searched the MEDLINE, Scopus and EMBASE databases for all peer-reviewed articles enrolling physicians/medical students in a simulation of either cardiopulmonary resuscitation or airway management protocols compared with no intervention or traditional teaching methods. We categorized the outcomes of the studies into four groups: task success, process skill, time skill, knowledge. Task success was defined as evaluation of successful completion of the task, process skill as evaluation of the procedure, time skill as the time required to complete the task, and knowledge as the objective assessment of conceptual understanding. When studies investigated more than one outcome, we considered the primary outcome, the overall measure or the most clinically relevant outcome.From 8,528 articles, we selected 24 studies  involving 1,149 participants. Compared with no intervention or traditional teaching methods, simulation was associated with a significant improvement from mild to moderate of all outcomes (Figure Simulation is an effective educational method to improve performance of physicians/medical students in the application of protocols for cardiopulmonary resuscitation and airway management.


The quadrate of reptiles and most other tetrapods plays an important morphofunctional role by allowing the articulation of the mandible with the cranium. In Theropoda, the morphology of the quadrate is particularly complex and varies importantly among different clades of non-avian theropods, therefore conferring a strong taxonomic potential. Inconsistencies in the notation and terminology used in discussions of the theropod quadrate anatomy have been noticed, including at least one instance when no less than eight different terms were given to the same structure. A standardized list of terms and notations for each quadrate anatomical entity is proposed here, with the goal of facilitating future descriptions of this important cranial bone. In addition, an overview of the literature on quadrate function and pneumaticity in non-avian theropods is presented, along with a discussion of the inferences that could be made from this research. Specifically, the quadrate of the large majority of non-avian theropods is akinetic but the diagonally oriented intercondylar sulcus of the mandibular articulation allowed both rami of the mandible to move laterally when opening the mouth in many of theropods. Pneumaticity of the quadrate is also present in most averostran clades and the pneumatic chamber—invaded by the quadrate diverticulum of the mandibular arch pneumatic system—was connected to one or several pneumatic foramina on the medial, lateral, posterior, anterior or ventral sides of the quadrate. The terms for each quadrate sub-units were selected by their relevance, significance and importance in the non-avian theropod literature. The non-standardized traditional Romerian directional and anatomical terms  were, thPart of the quadrate that includes the quadrate shaft, the quadrate ridge, the lateral contact , and the lateral process, and excludes the quadrate head, mandibular articulation, and pterygoid flange  and 2A. Part of the quadrate body that excludes the lateral process and all articulating surfaces  of Shallow and well-delimited pneumatic recess on the posterior surface of the quadrate body, at mid-height of the bone and medial to the quadrate foramen .Shallow and poorly-delimited pneumatic recess on the ventral portion of the lateral surface of the quadrate, directly dorsal to the ectocondyle .To establish comparisons between taxa with a widely disparate quadrate morphology, a homology concept of the feature in question is required. Here, we will give a general account of the variability within different anatomical sub-units of the quadrate by following the criteria summarized in Dilophosaurus wetherilli  but the demarcation of this structure may be only subtly developed, as in Noasaurus leali (PVL 4061), Majungasaurus crenatissimus  but also forms a thin crest as in Tyrannosauridae  or flatten at the mid-height of the quadrate such as in Albertosaurus sarcophagus (Allosaurus fragilis (AMNH 600) and Allosaurus europaeus (ML 415). The quadrate ridge can also flare at the second dorsal third of the quadrate, and reappears slightly more dorsally, as observed in some derived Spinosauridae .The quadrate ridge is easily distinguishable in many theropod taxa such as therilli ; Fig. 3Ctherilli , Allosausauridae . LikewisHerrerasaurus ischigualastensis . In anterior view, the pterygoid flange can be straight and only projected anteriorly, as in the carcharodontosaurid Shaochilong maortuensis  and Allosaurus fragilis , pneumatized  or at mid-height of it and directly dorsal to a large pneumatic recess like in Mapusaurus roseae (MCF PVPH-108.102).The medial fossa of the quadrate , mfq is Mapusaurus; MCF PVPH-108.102), or in the middle of the quadrate shaft and between the quadrate ridge and the lateral limit of the quadrate shaft , Tsaagan (Majungasaurus (Acrocanthosaurus (NCSM 14345), or form an oval concavity lateromedially wide  or ventrally  inside the fossa.The posterior fossa of the quadrate , pfq can Tsaagan , Majungagasaurus ; Fig. 3ICarnotaurus, Torvosaurus, Eustreptospondylus; Syntarsus’; Bambiraptor; Sinraptor; Dromaeosaurus). Finally, in a few theropods, the foramen can be completely enclosed in the quadrate . If the quadrate foramen is absent or fully enclosed by the quadrate, the lateral quadratojugal contact typically forms an elongated line of variable width along the lateral margin of the quadrate. Where separated by the quadrate foramen, the ventral and dorsal contacts can display a wide variety of surface and outlines. Both quadratojugal contacts may face laterally, anteriorly or posteriorly, and their articulating surface can be smooth, irregular or deeply grooved by several radiating ridges, as in Allosaurus fragilis , Sinraptor dongi , or lateromedially elongated and subtriangular in posterolateral view  and Torvosaurus (BYUVP 9246), and allosauroids such as Aerosteon  and Shaochilong (IVPP V2885.3), or subquadrangular in some Spinosaurinae such as Irritator (SMNS 58022). While the dorsal surface of the quadrate head is either convex or flattened in posterior view in most non-avian theropods, the quadrate head of some allosaurids , or narrow, deep and strongly lateromedially-oriented as in some derived spinosaurids .The intercondylar sulcus , ics varCitipati osmolskae (Tsaagan mangas (IGM 100/1015). In Tsaagan, the convex outline of the mandibular articulation in posterior view results from a poor delimitation of the ecto- and entocondyle and the separation of these two condyles by a shallow intercondylar sulcus; yet this morphology might be due to the bad preservation of the mandibular condyle. A posterior intercondylar notch (Allosaurus (Suchomimus tenerensis (MNN GAD 502) whereas an anterior intercondylar notch .In posterior view, the shape of the mandibular articulation , mar cansmolskae : Fig. 6 ar notch , pin wasar notch , ain is Mapusaurus roseae , instead of being firmly sutured to the quadrate as in other non-avian theropods, would have contacted the lateral surface of the quadrate through a movable joint  was noticed by ey items .Allosaurus, the enlargement of the mandibular condyles associated with the posteroventral inclination of the ventral part of the quadrate, and the intercondylar notch, were interpreted by Carnotaurus sastrei (MACN-CH 894) and Majungasaurus crenatissimus (FMNH PR 2100), and the spinosaurid Suchomimus tenerensis (MNN GAD 502), perhaps implying similar jaw mechanics of the mandibular articulation as in Allosaurus. Yet, In Sinraptor dongi , the basal oviraptorosaur Incisivorosaurus gauthieri , in the homologous position of that of the posterior fossa of other ornithomimosaurs . It is, therefore, surprising that this fossa was apneumatic, as implied by Sinraptor dongi in which the quadrate, though apneumatic, includes a well-delimited pneumatic fossa between the quadrate foramen and quadrate ridge . This lateral movement of the rami was due to a helicoidal and diagonally oriented intercondylar sulcus of the mandibular articulation. The presence of an intercondylar notch in allosaurids is interpreted as a joint-stabilization zone that would improve the stability of the mandibular articulation when the mouth was widely opened. However, this assumption needs further investigation from modern functional morphology techniques.The quadrate of the large majority of non-avian theropods is akinetic, and it is unlikely that a streptostylic quadrate is present in the derived alvarezsauroids A pneumatic quadrate is present in members of most non-avian avetheropod clades, in which a pneumatic foramen is seen in the ventral part of the pterygoid flange and in the medial and lateral fossae. Pneumatic foramina invading the quadrate seem to be independently acquired by allosauroids, tyrannosauroids, compsognathids, and ornithomimosaurs throughout their evolution. The presence of pneumatic foramina in the quadrate of basalmost members of therizinosaurs, oviraptorosaurs, troodontids and dromaeosaurids suggests that quadrate pneumaticity is a synapomorphy of the clade Therizinosauria + Pennaraptora. Although the pneumatic recess invaded by the quadrate diverticulum of the mandibular arch pneumatic system is linked to a single pneumatic foramen in most avetheropods, the presence of several pneumatic openings perforating different sides of the quadrate has been recorded in Carcharodontosauridae and Tyrannosauridae.10.7717/peerj.1245/supp-1Supplemental Information 1Lourinhanosaurus autunesi and Shuvuuia deserti.Function of quadrate sub-entities, quadrate sub-units terminology, and quadrate ontogeny in Click here for additional data file.


Adult neurogenesis has been convincingly demonstrated in two regions of the mammalian brain: the sub-granular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, and the sub-ventricular zone (SVZ) of the lateral ventricles (LV). SGZ newborn neurons are destined to the granular cell layer (GCL) of the DG, while new neurons from the SVZ neurons migrate rostrally into the olfactory bulb (OB). The process of adult neurogenesis persists throughout life and is supported by a pool of neural stem cells (NSCs), which reside in a unique and specialized microenvironment known as “neurogenic niche”. Neurogenic niches are structured by a complex organization of different cell types, including the NSC-neuron lineage, glial cells and vascular cells. Thus, cell-to-cell communication plays a key role in the dynamic modulation of homeostasis and plasticity of the adult neurogenic process. Specific cell-cell contacts and extracellular signals originated locally provide the necessary support and regulate the balance between self-renewal and differentiation of NSCs. Furthermore, extracellular signals originated at distant locations, including other brain regions or systemic organs, may reach the niche through the cerebrospinal fluid (CSF) or the vasculature and influence its nature. The role of several secreted molecules, such as cytokines, growth factors, neurotransmitters, and hormones, in the biology of adult NSCs, has been systematically addressed. Interestingly, in addition to these well-recognized signals, a novel type of intercellular messengers has been identified recently: the extracellular vesicles (EVs). EVs, and particularly exosomes, are implicated in the transfer of mRNAs, microRNAs (miRNAs), proteins and lipids between cells and thus are able to modify the function of recipient cells. Exosomes appear to play a significant role in different stem cell niches such as the mesenchymal stem cell niche, cancer stem cell niche and pre-metastatic niche; however, their roles in adult neurogenic niches remain virtually unexplored. This review focuses on the current knowledge regarding the functional relationship between cellular and extracellular components of the adult SVZ and SGZ neurogenic niches, and the growing evidence that supports the potential role of exosomes in the physiology and pathology of adult neurogenesis. To date it is well known that neural stem cells (NSCs) reside in the brain of most adult mammals, including humans, and that neurogenesis does occur throughout life  intercellular contacts, and (ii) secreted molecules, such as growth factors, cytokines, hormones, etc. (paracrine or endocrine communication). However, a novel way of cell-to-cell communication mediated by extracellular vesicles (EVs) has attracted the attention of several researchers in different fields. EVs, such as exosomes, carry a specific cargo of proteins, lipids and nucleic acids and are currently consider one of the most complex and physiologically relevant messengers between cells. This review focuses on the cellular components of the adult neurogenic niches, the mechanisms involved in intercellular communication, and the potential role of exosomes as regulators of the neurogenic process, and as mediators and novel biomarkers of neuropsychiatric and neurological disorders associated with defective adult neurogenesis.In the adult mammalian brain, neurogenesis is well documented to continue throughout life in two regions: the subventricular zone (SVZ) of the lateral ventricles (LV) and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus Figure . A lineain vivo -filled ventricles and on the other by a complex arrangement of parallel blood vessels  communicate with migrating neuroblasts  and the substantia nigra  can regulate proliferation of type B NSCs in the SVZ by activating GABAThe SVZ is uniquely situated to experience the effects of the flow and the composition of the CSF. Intriguingly, the direction of migrating neuroblasts in the RMS, parallels that of CSF flow , or distantly , novel types of intercellular messengers, such as EVs, have emerged. EVs, and particularly exosomes, are considered one of the most complex ways of cell-to-cell communication, allowing the transfer of mRNAs, microRNAs (miRNAs), proteins and lipids between cells and thus, being able to modify the physiology of recipient cells. However, their precise role in adult neurogenic niches remains virtually unexplored.EVs, and particularly exosomes, are emerging as one of the major mediators of intercellular communication. It is known since the late 1960’s/early 1970’s that membrane-enclosed vesicles are present outside cells in different tissues and biological fluids  appears as a unique mechanism compared with other forms of intercellular communication. Even though the physiological and/or pathological role of locally- or distantly-generated exosomes in the adult neurogenic niches is currently virtually unknown, growing indirect evidence strongly suggest that exosomes might be one the major elements communicating and coordinating the function of the adult neurogenic niches. First, neural stem/progenitor cells and most of the cell types present in the CNS, including those cells that constitute and regulate the neurogenic niche, secrete and/or are target of exosomes and other EVs Table . FurtherDrosophila neuromuscular junction  or cancer initiating cells (CICs) are tumor cells that have properties of self-renewal, clonal tumor initiation, and metastatic potential  are extensively used in different cell therapy-based clinical trials today. It is known that functional improvement with MSCs therapies is not mainly due to cell engraftment or differentiation at the site of injury but they exert their effects through their secreted products, including exosomes  exosomes may condition the microenvironment of a particular region such as the neurogenic niche; (ii) the content of exosomes in a particular cell type may change in different physiological and pathological conditions; and (iii) that brain parenchyma-derived exosomes may have access to the CSF and the peripheral blood circulation, neurogenic niche-derived exosomes may represent not only powerful regulators of adult neurogenesis, but also attractive therapeutic targets and useful biomarkers for different CNS disorders.In neurodegenerative disorders such as Alzheimer’s disease  as well as with its pathogenic form (PrPsc) release exosomes containing prion proteins as well as a specific miRNA signature  expressing α-synuclein release exosomes that contain this protein and are capable of transporting α-synuclein to SH-SY5Y cells that do not express it  or neural cell adhesion molecule L1 (L1CAM), have been used. With this experimental strategy, the group of Kapogiannis has been able to detect plasma or serum exosomes with increased content of Aβ1–42, and of phosphorylated forms of tau and type 1 insulin receptor substrate (IRS-1) specifically associated to patients suffering Alzheimer’s Disease. Interestingly, these findings are proposed as useful predictive tools up to 10 years before the clinical onset of the disease  can vary according to the circumstances, and (ii) might reach the peripheral blood circulation, thus linking or communicating directly the physiological or pathological status of the CNS to peripheral organs or tissues. This could be relevant (1) to understand the high prevalence of co-morbidity of pathologies associated to impaired neurogenesis and peripheral disorders, such as major depression and diabetes or inflammatory diseases (Kessler et al., The contribution of specific cell- and tissue-derived exosomes on adult neurogenesis should be further investigated with the use of proper animal models in which exosomes should be labeled with the use of molecular biology techniques, and later should be validated in health and disease with the use of a panel of biomarkers able to define specific exosome populations. We envisage that, in the near future, many of this work will be addressed by a growing community of researchers interested in the role of exosomes in disease-related processes that, among others, affect the neurogenic niche in a yet unsuspected manner.All the authors have contributed substantially to the writing and revising of the manuscript. LFB and UW have participated in the conception and design of the work. LFB have designed the figures. RIM, ZDV and LFB have designed and completed the table. MAC, RIM, PVB, ZDV, CAL, P-ET have participated in writing, drafting and revising of different sections of the manuscript. All the authors have approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Our research topic on the roles and mechanisms of parasitism in aquatic microbial communities should be of broad interest, given that there are probably more parasitic species than free-living ones Windsor, , a hypotCandidatus Xenohaliotis californiensis (WS-RLO), with potential impacts to wild abalone (Lafferty and Ben-Horin, New findings in the papers include the conceptualization of viral lifestyles and the extension of their role as microbe killers, cell partners, or metabolic manipulators (Sime-Ngando, We hope the contributions to this collection bring a new focus to the aquatic sciences. Microbial interactions are clearly important and largely unknown. There are still methodological barriers to assessing prokaryotic and eukaryotic parasites of aquatic microbes (Sime-Ngando and Niquil, 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.


Recent years have seen a dramatic increase in the scientific study of contemplative practices. While seated meditation practices have historically been at the center of inquiry in contemplative sciences, movement-based practices, such as yoga, t'ai chi, qigong, and others, are currently coming to the forefront of this discourse. In her introduction to the present Research Topic, Schmalzl et al.  introducIn this opinion paper, I focus on the necessity of studying intentional and experiential aspects of yoga as a MBCP, and on the role of first-person experiential reports in the neurophenomenological investigation of yoga and other MBCPs. I propose that the difference between yoga as a contemplative practice and yoga as a form of physical exercise needs to be assessed through nuanced investigation of subjective experience aimed at illuminating short- and long-term intentions and goals underlying yoga practice as well as dynamic variations within the lived experience of yoga.Theories of embodiment, such as enaction  and postures (asana), while a non-judgmental attitude and acceptance of one's current psycho-physical state can be characterized, in part, as open monitoring. Furthermore, Ashtanga yoga has been linked to the trait of self-transcendence . One phenomenological study of body-based therapeutic practices, including yoga, presented compelling evidence for the role of both long- and short-terms goals and intentions in practitioners and patients, including specific goals of coping with the present situation and general motivations for exploring qualities of embodiment through practice . The “lived body” is changed by MBCPs, and these changes can be qualitatively explored to investigate both effects of specific MBCPs and structure of embodied subjectivity in general. While investigating the therapeutic effect of yoga in various populations has been the approach of choice, studying healthy individuals involved in sustained contemplative yoga practice (Fiori et al.,  Maehle, . This an Maehle,  may contThe 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.


Executive function (EF) is one of the most rapidly expanding research fields in the developmental and cognitive sciences. The aim of this Research Topic is to present a broad sample of recent advances in understanding the development of EF. The 38 articles in this collection provide a unique, state-of-the-art tour of current, burning issues regarding executive function development, from cutting-edge research on the underpinning basic cognitive processes to the most promising applications in educational and clinical settings.FitzGibbon et al.; Unger et al.), how their effect can persist in time (Garcia and Dick), the specific executive processes  at play in a given task (Wright and Diamond) and the specific age windows during which critical changes in EF engagement occur (Lucenet and Blaye). Furthermore, they provide new evidence that EF may develop through progressive differentiation of executive processes from more basic cognitive processes  and of different forms of EF  . They further identify the brain correlates of EF development using EEG/ERP or MRI , revealing for instance that anatomical coupling between the left prefrontal cortex and other distributed brain regions predicts behavioral performance .EF involves several complex cognitive processes, including working memory, inhibitory control, and cognitive flexibility. The present papers shed new light on how these processes develop and how they are interrelated. Specifically, they clarify the conditions that modulate EF demands , referent assignment (Murakami and Hashiya), conversational pragmatics , narrative skills (Friend and Bates), prosocial behaviors , social interactions (Moriguchi), sensation seeking , emotional experience , fear , and emotional overeating (Groppe and Elsner). Impressively, these associations are often found over and above associations with IQ. Other findings highlight links between EF and motor function , source monitoring (Earhart and Roberts), and conceptual development (Houdé and Borst). These impressive findings highlight the foundational role that EF plays in goal-directed behavior across a wide range of domains and situations, and they underscore that the healthy development of EF skills is critical for both social-emotional and cognitive development. Indeed, they suggest that understanding the development of EF is absolutely key to understanding child development overall.The present papers also reveal or clarify the association of EF to a host of social and emotional processes including, for instance, theory of mind . Critically, they also clarify the discriminative importance of EF processes for children's mathematical learning, showing how the role of EF may increase from preschool to kindergarten  and then wane in adolescence . Such findings charting out the influence of EF on academic learning are essential to designing effective interventions that target strategic time points in development. Indeed, extant evidence suggests that such training programs can effectively enhance academic achievement , although socio-environmental factors, such as housing conditions, may moderate the effects of cognitive interventions in children .One of the most important foci in research on EF is the relation of EF development to school readiness and academic achievement. The studies included in this Research Topic provide further evidence of the predictive value of EF in academic learning, and in particular reading , whereas others, such as time spent in non-structured activities, may promote it during childhood . Meanwhile, the influence of other factors that have long been assumed to affect EF, in particular bilingualism, may have been overestimated in the past . All these thought-provoking findings have important implications on societal choices and for policy makers.Given the importance of EF for child development and academic achievement, several studies examined experiential influences that may affect its development. The findings suggest that some activities, such as regular energy drink consumption during adolescence, may Lahat et al.), Chromosome 22q11.2 Deletion Syndrome , and severe speech and motor impairments .Just as EF appears to play an essential role in typical development, difficulties in EF are central features of several developmental disorders. The studies in this Research Topic contribute to clarifying the role of EF in ADHD symptoms  and showing how physiological measures, such as pupil dilation and phasic heart rate variability (HRV), can bring further insight on children's EF .Finally, advances in research on EF development rely critically on designing effective, valid, and reliable instruments and methodologies. The present papers greatly contribute to this effort by developing new EF tasks (The articles in this Research Topic demonstrate how considerations of both basic cognitive/biological processes and applied/clinical settings help to unify and extend our understanding of EF during childhood. They illustrate the large range of questions and debates that animate this particularly dynamic field. We hope that this Research Topic will be helpful to both novices and experts of EF development by providing an overview of the field and highlighting the most recent advances.All authors drafted the manuscript, and provided critical revisions. All authors approved the final version of the manuscript for submission.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.


Thought Assemblies , he describes how this symbolic art interprets the neuropsychological processes of intuition and analytical reasoning. It explores numerous basic questions concerning observed interactions between artistic and scientific inquiries, conceptions, perceptions, and representations connecting mind and nature. Pointing to some key neural mechanisms responsible for forming and implementing intentions, he considers why and how we create, discover, invent, and innovate. He suggests ways of metaphorical thinking and symbolic modeling that can help integrate the neuroscience of intentional actions with the neuroscience of creativity, art and neuroaesthetics.Intentional actions cover a broad spectrum of human behaviors involving consciousness, creativity, innovative thinking, problem-solving, critical thinking, and other related cognitive processes self-evident in the arts and sciences. The author discusses the brain activity associated with action intentions, connecting this activity with the creative process. Focusing on one seminal artwork created and exhibited over a period of three decades,  Nature makes everything look simple. But nothing is as complicated as “simplicity”: from jotting down this observation to drawing things my imagination envisions that exemplify what I mean by simplicity. These intentional actions join countless others born from brain dynamics that neuroscientists grope to understand with great ingenuity in laboratory settings  exploring the nature of creativity. Posing questions about the creative process like a theoretical neuroscientist, I link putative brain processes of creativity with the actions of my unconscious and conscious intentions that I associate with the art-making process  prepares the primary motor cortex (PMC) to implement a series of commands for a voluntary movement  that was prompted by an outside world stimulus . They can describe how the pre-supplmenatry motor areas (PMAs) prepare the PMC’s implementation plans for grasping a chain of commands, which the brain generates and enacts by means of the PMC Medina, . Moreoveof science , Neuroscience of Art (left circle), and Neuroaesthetics (right circle) with Neuroscience of Intentions at the intersection; that’s where the art e Siler,  overlapsThe meanings and intentions or purposes of Neuroart involve connecting and freely interpreting the information gathered from the neuroscience of creativity, art, and neuroaesthetics—stimulating new thoughts on the creative nature of the brain. This artwork ruminates the insightful neuroscientific studies of intention . This structure represents the heart of the brain: a region where thoughts, feelings and emotions meld as they’re integrated and interpreted by the whole brain Siler,  via the Mounted on the massive cortical screen, “The Brain Theater of Mental Imagery, ” is the multipart “Thought Assemblies.” This artwork consists of 515 constituent images, each one depicting a mental image that’s been rendered on a substrate. The substrate represents the concomitant neural processes corresponding to the creation of the images. Collaged on the surface of “Thought-Assemblies” are examples of historical and everyday innovations that reveal inspired acts of creativity.“Thought Assemblies” envisions and explores the possible structure and organic unity of creative cognition. It examines the neural mechanisms that create and connect thoughts-feelings-actions . The mosaic of drawings and paintings picture the creative process as a system dynamically resembling the fusion and fission processes that form and shape the universe. I hypothesize the mergence of brain functions  at the instant of intuition and the divergence of these functions  in moments of analytical reasoning and expression. Here reasoning includes both analytic and affective reasoning in artistic and scientific expressions (representations) of knowledge, experience, etc. Virtually every form or aspect of reasoning is represented in artistic expression including sequential, feature by feature reasoning  and emotional or affective reasoning . Figure Metaphorically, this Neuroart interprets My intention was to present ideas and images towards a theory proper that emerged from a phenomenological study of insight-perception and introspective analyses, relating it to experimental studies of cerebral functions: e.g., evoked potentials Regan, , positroBrain Activity Map (BAM) requires broad cross-disciplinary creative collaborations, in order to describe the whole brain’s functional architecture and neural activity. BAM joins the Blue Brain Project (BBP), which maps the labyrinth of synaptic connections between diverse populations of neurons and how they grow. These projects and advancements in Neuroinformatics (Koslow and Subramaniam, I continue to advocate using arts-based learning methods and tools to contribute to neuroscientific discoveries and inspire innovations Siler, . Interprhttp://www.incf.org; BRAIN Initiative,The example of Neuroart highlighted here pictures intentional actions. Its contents intimate how the creative process of convergent and divergent thinking is similar in all representations of thought that comprise the interrelated History of Art, Science, Technology, Engineering, Mathematics, and other forms of explicit, implicit and tacit knowledge Polanyi, , 1967. NThe 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.


The cell wall is one of the characteristic components of plant cells. The cell wall composition differs among cell types and is modified in response to various environmental conditions. To properly generate and modify the cell wall, many proteins are transported to the plasma membrane or extracellular space through membrane trafficking, which is one of the key protein transport mechanisms in eukaryotic cells. Given the diverse composition and functions of the cell wall in plants, the transport of the cell wall components and proteins that are involved in cell wall-related events could be specialized for each cell type, i.e., the machinery for cell wall biogenesis, modification, and maintenance could be transported via different trafficking pathways. In this review, we summarize the recent progress in the current understanding of the roles and mechanisms of membrane trafficking in plant cells and focus on the biogenesis and regulation of the cell wall. Membrane trafficking is a key mechanism for transporting proteins, lipids, and polysaccharides among organelles in plant cells . The keytrans-Golgi network (TGN) and subsequently delivered to each organelle or the plasma membrane/extracellular space or traffic through the Golgi-independent trafficking pathway to the vacuole in plant cells  vesicle budding from donor organelles, frequently involving coat protein complexes, such as COPI and COPII; (2) tethering the vesicles to the target membrane through activated Rab and Rab effectors; and (3) vesicle fusion with the target organelle, mediated through SNARE molecules  are key molecules that determine the characteristics of membrane domains . InteracSome proteins at the plasma membrane are endocytosed into the cytoplasm in response to the signals associated with extracellular conditions . ClathriFunaria hygrometrica , callose synthase (CALS)/glucan synthase like (GSL), and pectin methylesterase (PME), are transported to the plasma membrane and/or extracellular compartment via membrane trafficking. The cellulose synthase complex (CSC), comprising CESA, synthesizes cellulose at the plasma membrane. Cellulose deposition is strictly regulated depending on cell types, developmental stages, and environmental changes, thus the subcellular localization of the CSC, which profoundly depends on membrane trafficking, should be tightly regulated . The CSCometrica . This evometrica . The endometrica . A recenometrica , indicatometrica .ech and trs120-4, a mutant of the predicted component of the RAB11 activation complex, exhibit a defect in general secretion, but only ech is defective in wax secretion (CALS/GSL synthesizes callose at the plasma membrane or cell plate . Polysacecretion . Wax is ecretion . Thus, wecretion , and a recretion .Arabidopsis RABA, regulates trafficking from the recycling endosome to the plasma membrane in animal cells (The delivery of cell wall components is also strictly regulated during tip growth and cell plate formation. The CSC and CALS accumulate at the tip of the pollen tube , and thial cells . Thus, eThe direction of membrane trafficking dynamically changes during cell plate formation , and botOrganelle membranes in both animal and plant cells comprise many microdomains . Recent As described above, various aspects of interaction between the plant cell wall and membrane trafficking have been reported. However, the underlying mechanisms remain unclear. In particular, the feedback mechanism of the regulation of membrane trafficking via the cell wall has essentially remained unexplored. There are also many open questions concerning the molecular mechanisms underlying the transport of cell wall components through distinct trafficking pathways. For example, how and where are cell wall components sorted for loading onto different trafficking intermediates? Further extensive research in this area is needed to obtain a precise understanding of the tight linkage between the cell wall and membrane trafficking.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Review Editor Samantha Vernhettes declares that, despite having collaborated with the author Takashi Ueda within the past two years, the review was handled objectively. The Guest Associate Editor Masaru Fujimoto declares that, despite being affiliated with the same institute as the author Kazuo Ebine, the review process was handled objectively.


The prevalence of methamphetamine (METH) use is estimated at ~35 million people worldwide, with over 10 million users in the United States. METH use elicits a myriad of social consequences and the behavioral impact of the drug is well understood. However, new information has recently emerged detailing the devastating effects of METH on host immunity, increasing the acquisition of diverse pathogens and exacerbating the severity of disease. These outcomes manifest as modifications in protective physical and chemical defenses, pro-inflammatory responses, and the induction of oxidative stress pathways. Through these processes, significant neurotoxicities arise, and, as such, chronic abusers with these conditions are at a higher risk for heightened consequences. METH use also influences the adaptive immune response, permitting the unrestrained development of opportunistic diseases. In this review, we discuss recent literature addressing the impact of METH on infection and immunity, and identify areas ripe for future investigation. The growing popularity of Methamphetamine (METH), a street drug associated with the severe neurological and physical consequences afflicting its users, has created an increasingly serious public health problem worldwide. In a 2011 United Nations survey, approximately 2.5% of Australians over the age of 14 have tried METH, a prevalence rate three to five times higher than those seen in the United States (USA), Canada, and the United Kingdom  stimulant that mimics the pharmacological effects of cocaine. The “rush” that follows METH use is associated with the release of neurotransmitters, including adrenaline, dopamine, and serotonin  enantiomer of METH ((S)-N-Methyl-1-phenyl-propan-2-amine), dextromethamphetamine, is popularly used among METH users for its potent effect on the cardiovascular system and CNS  the concentration of METH, its distribution and metabolism varied in all the organs  permeability in rodents. Moderate to high doses of METH disrupt the BBB in several regions, including the cortex, hippocampus, thalamus, hypothalamus, cerebellum, amygdala, and striatum that, in turn, are further injured by hyperthermia and, potentially, by seizures  production, thus triggering BBB breakdown  were highest in the kidneys and lungs; intermediate in the stomach, pancreas, liver, and spleen; and lower in the brain and heart , dendritic cells (DCs), monocytes, macrophages, and granulocytes, indicating complex mechanisms of immunosuppression  levels  being extremely common , injecting with unsterile equipment and contaminated drug solutions can introduce high bacterial loads  infection and HIV disease are overlapping epidemics in the USA and worldwide  , which potentially indicates a mechanism by which the drug exacerbates HIV infection (Harms et al., Histoplasma capsulatum is the most prevalent cause of fungal respiratory infections, representing 53.19% of cases of endemic mycoses in the US (Chu et al., H. capsulatum is endemic to the Midwestern USA, where METH is a critical public health issue; the fungus is an ideal model organism to study the impact of METH in a systemic disease model. METH abrogates normal macrophage function, resulting in accelerated disease in murine histoplasmosis (Martinez et al., H. capsulatum by primary macrophages. METH exposed H. capsulatum-infected mice have increased fungal burdens, increased pulmonary inflammation, and decreased survival. METH exposure results in cytokine dysregulation, aberrant processing of yeasts within macrophages, and immobilization of MAC-1 receptors on the macrophage surface. Additionally, METH inhibits T cell proliferation and alters antibody production, both important components of adaptive immunity. Hence, it is established that METH alters the immune system of a mammalian host, resulting in enhanced disease (Martinez et al., Fungal pathogens have been recently used as empirical models to understand the impact of METH use on host homeostasis and increased permissiveness to opportunistic microorganisms. Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS killing = 600,000 people worldwide (Park et al., in vitro assays, it was recently demonstrated that METH stimulates fungal adhesion, capsular polysaccharide release, and biofilm formation in pulmonary tissue (Patel et al., C. neoformans dissemination from the respiratory tract into the CNS. METH alters BBB integrity and modifies the expression of tight junction and adhesion molecules (Eugenin et al., The encapsulated fungus METH use has become increasingly prevalent in recent years, creating a severe public health epidemic and societal burden. The drug adversely changes user behavior, including putting METH users at high risk for the acquisition of diverse infectious diseases. Recent studies have identified a causal linkage between METH and immune dysfunction in mature mammals. METH immunosuppression may underlie the mechanism for the rapid development of AIDS in METH users, progressing from HIV to AIDS within only a few months CDC, . InvestiAnother important question yet to be answered is how METH disarms the adaptive immune system, further rendering the host more susceptible to opportunistic infections. We recently showed that the impairment of adaptive immunity by METH diminishes the ability of mammalian hosts to mount and maintain efficient immune responses to pathogens (Martinez et al., There is an urgent need for innovative METH treatment interventions to prevent the acquisition and transmission of infectious diseases. Through utilization of drug abuse treatment and community-based outreach programs, drug abusers can change their HIV risk behaviors (Garfein et al., At this time, cognitive behavioral and contingency management interventions are the most effective treatments for METH addiction (Rawson et al., Finally, the research described to date is likely to be only the tip of the proverbial iceberg, such that numerous other diseases, especially infectious diseases, are likely to be significantly modified by METH. The propagation of this disease, along with many other viral and bacterial contagions, demonstrates the necessity for continued studies in this area of healthcare and substance abuse. Until the use of METH is strictly curtailed, the impact of METH on our society will continue to be severe.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.


Activation of the coagulation system is a fundamental host defense mechanism. Microorganisms that have invaded the body are trapped and disposed of in clots. Monocytes/macrophages are widely accepted as the main players in the procoagulant process; however, recent evidence suggests that neutrophils also play important roles. Tissue factor, which initiates the extrinsic coagulation cascade, is reportedly expressed on the surface of neutrophils, as well as on microparticles derived from neutrophils. Neutrophil extracellular traps (NETs) are another source of tissue factor. The components of NETs, such as DNA, histones, and granule proteins, also provide procoagulant activities. For instance, DNA initiates the intrinsic pathway, histones are a strong generator of thrombin, and granule proteins such as neutrophil elastase, cathepsin G and myeloperoxidase contribute to the suppression of the anticoagulation systems. Although understanding of the mechanisms that are involved in coagulation/fibrinolysis in sepsis has gradually progressed, the impact of neutrophils on thrombogenicity during sepsis remains to be addressed. Since the importance of the connection between coagulation and inflammation is advocated nowadays, further research on neutrophils is required. Activation of the coagulation system is a critical step in the prevention of bacterial dissemination as the coagulation system participates in host defense via fibrin deposition and thrombus formation . RecentlMonocytes and macrophages, together with platelets, have long been regarded as the leading actors in activation of the coagulation system; however, recent evidence has suggested that neutrophils also play important roles. For instance, the attenuation of thrombotic manifestations after neutrophil depletion demonstrates the significant contribution of these cells . In the Consequently, knowledge of neutrophil functions is quite important, not only for understanding how the coagulation system is activated but also for elucidating the mechanisms involved in inflammation and host defense. Although anticoagulant therapy could be the treatment of choice for patients with sepsis , concurrin vitro. TF expression has also been observed in monocytes from patients with bacteremia [TF is a trans-membrane protein that initiates the coagulation cascade and results in thrombin generation . It bindcteremia  or with cteremia . As wellcteremia .in vivo and ex vivo production of TF by neutrophils [Escherichia coli phagocytosis in the absence of inflammatory mediators was not sufficient for TF production, despite the observed upregulation of TF mRNA, and this finding is in accordance with the previously reported inability of lipopolysaccharide-treated granulocytes to produce TF [In contrast, the ability of neutrophils to express TF has been a matter of debate. Although Rapaport and Rao  reportedtrophils ,24. Maugtrophils  and Rititrophils  also reptrophils  reportedtrophils  reportedoduce TF .de novo or is acquired from other sources, we think neutrophil-derived TF plays some roles in coagulopathy during sepsis since neutrophils are recognized as a core part of thrombus formation. Indeed, it seems reasonable to consider the activity of TF produced and/or acquired by neutrophils as part of the pathogenesis of thrombotic events during sepsis [Other studies have also reported that neutrophils do not synthesize TF, but can acquire TF by binding monocyte/platelet-derived microparticles . Regardlg sepsis , since nE. coli-induced disseminated intravascular coagulation in baboons [NETs, which are composed of nuclear and granule constituents of neutrophils, were first described by Brinkmann and colleagues . They pr baboons . Thus, fNETs stimulate platelets via histones H3 and H4 to promote the thrombotic reaction . FurtherAs well as TF expression on NETs, histones are also involved in initiation of the coagulation cascade. According to a report by Xu and colleagues , histoneHistone/DNA complexes are potent activators of human platelets via Toll-like receptor-2 and -4. Histones also interact with the A1 domain of von Willebrand factor, leading to further acceleration of platelet activation . FurtherAs mentioned above, NET release is thought to play important roles in the pathophysiology of sepsis and activation of coagulation, although it remains controversial whether NETs contribute significantly to sepsis-associated coagulopathy and pathogen killing. To prove the significance of NET release during sepsis, more sophisticated imaging techniques will be needed with appropriate fluorescent dyes to delineate NETs.As discussed, it is assumed that NETs play at least some role in the development of sepsis-associated coagulopathy; however, the contribution of neutrophils to the activation of coagulation is not limited to infectious diseases. NETs also contribute to coagulopathy in non-infectious diseases such as autoimmune disease  and maliMicroparticles are released from a variety of cells by budding of the plasma membrane, a process known as ‘ectocytosis’ . These mIn addition to the aforementioned mechanism of neutrophil-transmitted activation of coagulation, protease-related systems also accelerate coagulation. Neutrophil elastase and cathepsin G are the two major proteases related to coagulation, with neutrophil elastase considered to be dominant. In mice lacking neutrophil elastase but expressing cathepsin G, a significant reduction in fibrin formation has been reported . NeutropAnother important function of neutrophil elastase is the inactivation of anticoagulants. Plasma levels of physiological anticoagulants such as antithrombin and activated protein C are known to decrease markedly because of their increased consumption, suppressed synthesis, and degradation by neutrophil proteases . Since tImmunothrombosis is a major element of the intravascular innate immune system. Neutrophils expressing TF are recruited into the circulatory system and the release of TF-bearing neutrophil-derived microparticles, NETs and their components intensifies activation of the coagulation cascade, leading to thrombus formation and the activation of other cell populations, such as platelets and endothelial cells. These cellular and molecular responses all participate in clot formation. In addition, neutrophil-derived proteases, such as neutrophil elastase and cathepsin G, further accelerate these sequential reactions. However, the magnitude of the contribution of neutrophils to the activation of coagulation still remains to be elucidated. The debate on the ability of neutrophils to produce functional TF is ongoing, and the intracellular localization of TF in neutrophils raises a concern regarding its ability to activate the coagulation system. These issues should be addressed in the future. Is the neutrophil a ‘prima donna’ or a ‘corps de ballet’ in the procoagulant process during sepsis? Further evidence is needed to answer this question.FDP: fibrin/fibrinogen degradation product; NET: neutrophil extracellular trap; PAR: protease activated receptor; TF: tissue factor; TFPI: tissue factor pathway inhibitor.The authors declare that they have no competing interests.