Sleep is an indispensable normal physiology of the human body fundamental for healthy functioning. It has been observed that Parkinson's disease (PD) not only exhibits motor symptoms, but also non-motor symptoms such as metabolic irregularities, altered olfaction, cardiovascular dysfunction, gastrointestinal complications and especially sleep disorders which is the focus of this review. A good understanding and knowledge of the different brain structures involved and how they function in the development of sleep disorders should be well comprehended in order to treat and alleviate these symptoms and enhance quality of life for PD patients. Therefore it is vital that the normal functioning of the body in relation to sleep is well understood before proceeding on to the pathophysiology of PD correlating to its symptoms. Suitable treatment can then be administered toward enhancing the quality of life of these patients, perhaps even discovering the cause for this disease. Sleep is vital to foster adequate health and bodily function  is portrayed by a classical triad of movement disorders comprising bradykinesia, worsening resting tremors and rigidity with impaired postural reflexes  neurons of the dorsal raphe nuclei (DRN), noradrenaline or norepinephrine (NE) neurons of the locus coeruleus (LC), and dopamine (DA) neurons of the substantia nigra (SN) and ventral tegmental area (VTA). These neurons innervate the entire forebrain. The second pathway include projections from glutamate, hypocretin, and the histaminergic tuberomammillary nucleus (TMN) of the posterior hypothalamus, midline-intralaminar thalamus, and the cholinergic nucleus basalis neurons which innervate via the diencephalic and basal forebrain to the cortex Moore, .In PD, damage and cell loss occur in the dopaminergic VTA, serotonergic DRN, noradrenergic LC and vagus nerve dorsal nucleus cell, cholinergic Meynert basal nucleus, neocortex, hippocampus, Edinger Westpal and pedunculopontine nucleus (PPN), peptidergic neuropeptide Y neurons in the spinal cord, somatostatic hippocampus and cortex, substance P in the medulla, and the cholecystokinic and metenkephalic basal ganglia , and rapid eye movement sleep , promote sleep through inhibition of multiple wake-promoting brain areas and excitation of sleep-promoting cell groups , where axons make direct synaptic connection with SCN cells. This photic information is assimilated with other timing cues to generate vigorous circadian oscillations synchronized to the environment, thus acting as a mechanism that entrains the circadian sleep-wake rhythm to the light-dark cycle of the natural environment  and Cryptochrome . Two transcriptional activators, Bmal1 and Clock, form heterodimers in the cytoplasm and enter the nucleus where they bind to E-box sequences in the promoters of Per and Cry genes  to regulate independent circadian oscillators throughout the body  for arousal Moore, . This inThe SCN is intact in PD patients however it functions through innervation with the hypothalamus and brainstem-associated central autonomic network.The presence of defective pathways lead to malfunctioning effects  and monoamine oxidase B (MAO-B). MAO-A is a clock-controlled gene , and peri-LC structures, which further lead to RWA. Further degeneration of these structures, together with changes in locomotor generator structures, lead to obvious RBD. This chronological sequence of pathology explains why RBD precedes motor symptoms, cognitive decline and dementia in most patients who develop PD. In the Braak stage 2 description of PD, it is stated that further Lewy body and neurite formation in the structures involved in stage 1 appear, which are the dorsal motor nucleus of the vagus nerve, olfactory bulb and anterior olfactory nucleus complex. Lewy body and neurite formation begin to form in the SLD and precoeruleus region, the MCRF, the DRN, and LC. Once the accumulation threshold is reached, changes in mood, behavior, and sleep start to develop. Measurable changes in serotonin and noradrenaline might also be present at this stage. Degeneration in the SLD and precoeruleus region, MCRF, or both lessen the inhibitory effects on the caudal anterior horn cells, thus leading to RWA Boeve,  Figure .Based on animal studies, it is proposed that the SLD sends projections to spinal motoneurons through a direct route that causes active inhibition of skeletal muscle activity in REMS. The SLD also functions through an indirect route via the ventrolateral reticulospinal tract to reduce excitation of the MCRF, thus causing a net reduced inhibition of spinal motoneurons. Therefore lesions, degeneration and pharmacological manipulation of the SLD or MCRF can cause RWA, though not yet sufficient to cause dream enactment behavior , or a problem with airflow through breathing passages, also known as obstructive sleep apnea. As breathing becomes more difficult or ceases a decrease in blood oxygen level occurs, which in turn results in awakening to restore breathing. SAS leads to sleep disordered breathing, and is identified through a history of loud crescendo snoring and irregular snoring with snorting and gasping (Mitra and Chaudhuri, Upper airway muscle dysfunction caused by nocturnal akinesia or dyskinesia of the respiratory muscle lead to development of obstructive sleep apnea, which develops onto life-threatening nocturnal stridor caused by vocal cord abductor dysfunction (Suzuki et al., PD and its symptoms are caused by various dysfunctional structures compromising many control areas in the brain, resulting in motor and non-motor abnormalities including sleep. Good comprehension and knowledge of the various brain structures involved, their relationship, and their pathophysiology in the initiation and development of these symptoms will benefit in administering innovative treatments such as deep brain stimulation. Further studies focusing on genetics and biochemistry could also help in finding a possible cause and cure for this debilitating disease.Ms IF is the main author who wrote the manuscript in order to have a broader understanding on the pathophysiology of Parkinson's disease, especially in aspects Parkinson's disease and various brain structures in relation to sleep. KM was the author who supervised and helped in the writing of this 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.


Plasmodium falciparum, and is currently in late-stage Phase III clinical trials at multiple sites across Africa. Modeling and simulation have been used to predict the public health impact (PHI) of RTS,S but previous exercises had access to limited trial data and did not provide country-specific results. PHI is sensitive to many assumptions including vaccine profile and underlying country specific inputs.RTS,S is a malaria vaccine directed at the pre-erythrocytic stage of We simulated the numbers of cases and deaths averted by RTS,S if rolled out in each of 43 malaria endemic countries in sub-Saharan Africa. Predictions were made for different transmission profiles, different levels of access to care for malaria cases, and four different immunisation schedules, with varying initial efficacies and decay rates of vaccine efficacy. Country-specific predictions were made via weighted averages over the database of predictions, with weights estimated from country-specific data. These included prevalence data from the Malaria Atlas Project, access to care from Demographic and Health Surveys, country level estimates of patient adherence and system compliance, immunization coverage from UN/WHO, and demographic projections from the UN. Sensitivity analysis was carried out to determine the robustness of the predictions of average impact and main drivers of uncertainty in these.A pre-erythrocytic vaccine is unlikely to completely protect vaccinated individuals against malaria disease but overall PHI will probably compare favourably with that of other vaccines in routine programs. Currently only short follow up of RTS,S Phase III trial data is available and thus uncertainty in overall PHI remains mainly driven by uncertainty in the vaccine profile, especially in the rate of decay of the protective effects. There will be considerable variation between countries in PHI, with the main driver of this variation being the underlying levels of transmission and disease burden.


Physiological vascular function regulation is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the main risk factors of cardiovascular pathology, where the imbalance between the synthesis of vasodilator and vasoconstrictor molecules is common in the development of vascular disorders in systemic and placental circulation. In the placenta, an organ without autonomic innervations, the local control of vascular tone is critical for maintenance of fetal growth and mechanisms that underlie shear stress response induced by blood flow are essential during pregnancy. In this field, shear stress induced by moderate exercise is one of the most important mechanisms to improve vascular function through nitric oxide synthesis and stimulation of mechanical response of endothelial cells triggered by ion channels, caveolae, endothelial NO synthase, and vascular endothelial growth factor, among others. The demand for oxygen and nutrients by tissues and organs, especially in placentation and pregnancy, determines blood flow parameters, and physiological adaptations of vascular beds for covering metabolic requirements. In this regard, moderate exercise versus sedentarism shows potential benefits for improving vascular function associated with the enhancement of molecular mechanisms induced by shear stress. In this review, we collect evidence about molecular bases of physiological response to shear stress in order to highlight the relevance of moderate exercise-training for vascular health in adult and fetal life. The endothelium is the main regulator of vascular physiology, controlling hemodynamics and angiogenesis in postnatal and fetal life. Dysfunction of endothelial cells have several clinical implications related with alteration of physiological regulation of capillary permeability, vascular homeostasis, leukocyte trafficking, vasomotor control, angiogenesis, acquired and innate immunity, among others. Furthermore, these cells exhibit morphological and functional heterogeneity, which give them high capacity for adaptation, according to environmental conditions to maintain homeostasis in different vascular beds . In humaRelevant pathologies in developing and middle-income countries are NCDs, like CVD, metabolic syndrome, obesity and diabetes mellitus. With changes in lifestyle and quality of nutrition in western civilization, there is a sustained increase in DM2, GDM, overweightness and obesity during pregnancy . There iEndothelial dysfunction is established as one of the main risk factors for CVDs, where the imbalance between synthesis of vasodilators and vasoconstrictors is the most common factor . High syD-glucose, there is high synthesis of NO  in detriment of NO synthesis , a powerful oxidizing agent that induces DNA fragmentation and lipid oxidation , which is estimated from the values of blood flow velocity (V) and internal arterial diameter (d) according to the following equation , V is the mean velocity (cm/s), and d is the diameter of umbilical vein (mm). In this study, the mean umbilical venous blood flow velocity was between 13 and 14 cm/s and was similar in preterm and full-term infants, whereas the diameter of the umbilical vein was greater in the full-term group. In preterm pregnancies, there was a decrease of umbilical blood flow in late pregnancy correlated with both gestational age and birth weight and the umbilical blood flow per unit body weight of the fetus or per placental weight was increased in preterm group. The authors argue that the increase of umbilical blood flow in the course of gestation is dependent of umbilical vein growth and there is a physiological decrease in the ratio between umbilical blood flow and fetal body weight that could be dangerous in post-term pregnancies  and vascular tree anatomy . For insMechano-transduction induced by shear stress is widely studied, showing that there are multiple signaling pathways which are activated in response to stress in endothelial cells . These pL-NMMA; NOS inhibitor) solutions demonstrated that FMV of conduit arteries in humans is, at least in part, mediated by NO  the decrease of shear stress for 14 days did not reduce the diameter of arterial lumen and exhibit high vascular wall thickness associated with reduction in the FMV and eNOS phosphorylation in serine 1176 , potassium (K+) and chloride (Cl-) ions, which elicit a rapid response of endothelial cells to shear stress  in response to prolonged stimulation to shear stress and ischemic remodeling, decreases the diameter of capillaries and angiogenesis of low blood flow areas  associatr stress .In placental circulation, it has been determined that the VEGF/angiogenesis pathway is relevant for early placental vascularization and deficiencies in this signaling pathway could be related with placental pathologies like IUGR or preeclampsia. Is well known that plasma levels of sFlt-1 is higher in mothers with preeclampsia  which isClinical evidence shows that physical exercise applied in cardiovascular rehabilitation is effective in decreasing both hospitalization rate and mortality associated with CVDs . In this2 max) increases the endothelium-dependent vasodilatation through stimulation of NO synthesis. Nonetheless, high intensity exercise could be an oxidative stress signal  in healthy subjects and they demonstrated that exercise at 50% VO2 max induces vasodilatation through high bioavailability of NO, whereas high intensity exercise was associated with an increase in the production of ROS  in exercised-trained pregnant women. These responses are triggered, presumably, by exercise-induced shear stress  that the exercise-training decreases the proteinuria, cardiac hypertrophy, and vascular reactivity of placental vessels. Also, it was observed that PlGF was normalized in trained transgenic mice . Studiesr stress . Additior stress . Regardir stress . Additior stress . Interesr stress . In the r stress . The mair stress . These dr stress . This lar stress .Thus, mechanisms associated with benefits of exercise include: (1) VEGF-induced angiogenesis in early placentation due to short hypoxic events induced by redistribution of blood during exercise; (2) High levels of PlGF and reduction of circulating sFlt-1 and sEng in late gestation of exercised women; (3) High resistance against oxidative stress and lipid peroxidation, (4) Lower levels of endothelin-1 (vasoconstrictor) and high expression of eNOS and antioxidant enzymes, increasing the bioavailability of NO .Even though studies are still scarce and controversial, new findings show the potential role of exercise-training on placental endothelial function. It is necessary to increase and improve experimental evidence, with carefully designed protocols on time and type of interventions, exploring molecular mechanisms in isolated endothelial cells and SMC from uterine (mother), placenta, umbilical cord , and systemic resistance vessels in offspring. The combination of animal models and human trials will give new insights about the benefits of exercise to avoid deleterious effects of pre-gestational and gestational diseases that are growing in the human population.in vitro and in vivo. This allows us to provide the experimental evidence that supports the positive effects of physiological shear stress and exercise-induced shear stress in systemic and placental circulation.Evidence shows that hemodynamic stimulus plays a crucial role in modulating synthesis and bioavailability of endothelial NO both Figure 1 we postulate a potential mechanism for response to exercise of placental vasculature, considering direct evidence and results obtained from systemic circulation and in vitro umbilical vasculature.The role of eNOS and VEGF in the regulation of physiological responses to shear stress is well known, and there is increasing evidence about the benefits of physical exercise (acute or training-exercise programs) for cardiovascular health. However, evidence about the effects of physical exercise on fetal and placental circulation remains obscure, mainly because of little information based on controlled trials in human pregnant women. In The endothelium is an inexhaustible source of cardioprotective substances which can be induced by exercise. For that reason, exercise-training can be considered an effective, economical and natural protector. Furthermore, light and moderate exercise does not have adverse effects, which cannot be said for the best medication synthesized in the pharmaceutical industry. These features, and the strong evidence about the high proportion of obesity and metabolic syndrome in pregnant women, demonstrate that the relevance of obtaining better knowledge about the effect of exercise-induced shear stress in fetoplacental vasculature.The Guest Associate Editor, Dr. Carlos Alonso Escudero, declares that despite having collaborated with author Marcelo Gonzalez in the past 2 years, there has been no conflict of interest during the review and handling of this 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.


Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system. Stem cells are characterized by their continuous self-renewal ability and pluri- or multipotentiality, and could consequently give rise to a wide panel of cell types. Non-germinal stem cells are classified into different categories. Embryonic stem cells (ES) are found in the inner cell mass of the blastocyst and are pluripotent stem cells that generate any mature cell of each of the three germ layers. Somatic stem cells are tissue-specific and more restricted than ES cells in terms of fate choice and of differentiation capabilities. They can be isolated from various fetal and adult tissues, and therefore constitute an attractive supply of material for cell therapy.Stem cell niches were deeply analyzed over these last years in order to better understand and control stem cell proliferation and differentiation. Indeed, the concept of niche refers to a microenvironment harboring stem cells, which regulates both their self-renewal property and cell fate choice. During embryonic development, various factors inside the niche act on stem cells and modify gene expression to induce their proliferation or differentiation, in order to favor the development of the fetus.Within the adult human body, the main role of those niches is the maintenance of stem cell quiescence. Mammalian adult stem cell niches have been described in many tissues including the testis, the hematopoietic tissue, the skin, the intestine, or the brain. Several important factors regulate stem cell characteristics within the niche, such as adhesion molecules that mediate important cell-cell interactions between stem cells and supportive cells, neighboring differentiated cells or matrix components. In some cases of tissue injury, the surrounding environment acts on the niche and actively recruits stem cells to either self-renew or differentiate, to generate new cells and tissues. In the following paragraphs, we will more precisely focus on hematopoietic stem cell and neural stem cell niches Figure .in vitro co-culture system, while spleen cells were less efficient in insuring HSC regulation  maintenance and activity in an in vivo reconstitution of the hematopoietic niche may be achieved upon transplantation of MSCs or of a subpopulation of osteoprogenitors, which tightly interact with sinusoids and secrete growth factors   of the BM stroma are well-known cellular components of the HSC niche which regulate hematopoietic processes through the secretion of many growth factors and cytokines (see below)  structures that are not supposed to hold neural crest-derived cells, it appears that many similarities and connections between HSC and NSC niches could be revealed by the recent literature and presented in Figure As mentioned before, adult stem cell niches have been described in many different tissues. Despite significant anatomical differences, those tissues share many common features concerning the extracellular mechanisms by which the stem cell population is regulated within the niche  is a member of the chemoattractive cytokine family (chemokines), and is essential for the proper proceedings of hematopoiesis, general ontogeny, cardiovascular formation, and neurogenesis. Indeed, it has been observed that CXCR4-deficient mice (lacking the receptor for CXCL12) die around birth and present important defects in hematopoietic and nervous system, such as a reduced myelopoiesis and B-lymphopoiesis, and impaired neuronal migration in the cerebellum  involves recruitment and engraftment of circulating myeloid cells and HSCs originating from the fetal liver, which will then interact with BM endothelium in order to migrate toward endosteal or vascular niches  and HSCs are critical for regulating stem cell engraftment and quiescence, in the endosteal niche  are members of the transforming growth factor β family. Among them, BMP4 signaling regulates mesoderm cell commitment into HSC and differentiated myeloid cells during embryogenesis and hematopoietic tissue development  constitute a transient population of multipotent cells that arise at the border of the neural plate. After induction, NCCs delaminate, undergo epithelial-to-mesenchymal transition and migrate in discrete streams  toward different tissues, finally giving rise to neurons and glia of the peripheral nervous system, melanocytes, craniofacial osteocytes, chondrocytes, etc.  chemoattractant signaling is required for the proper progression and migration of cardiac neural crest cells (NCCs) toward their appropriate locations in the developing heart   and the recent findings concerning several regulatory cell components of hematopoietic niches together shed the light on the obvious similarities concerning the molecular regulation pathways of the two systems. Moreover, increasing description of the nervous regulation of hematopoietic function, together with the putative importance of the relationship between SVZ vasculature and NSCs, seems to be the dawn of an interpenetration of both systems. Likewise, recent findings demonstrating that crayfish neurons are generated from the immune system is another example of this crisscross . Indeed, in both systems, adult niches have been demonstrated to provide a sanctuary for subpopulations of leukemic, but also glioblastoma cells that escape chemotherapy- and/or-radiotherapy induced death. Indeed, xenografted glioblastoma cells were recently shown to migrate toward the SVZ upon stimulation by CXCL12, which is secreted by endothelial cells (Goffart et al., CC: Work conception and design, data collection and analysis, manuscript writing. VN: Work conception and design, data collection and analysis, manuscript writing. AG: Revision for intellectual content, final approval of the version to be published. SW: Work conception and design, revision for intellectual content, final approval of the version to be published. BR: Work conception and design, revision for intellectual content, final approval of the version to be published.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.


Nuclear hazards, linked to both U.S. weapons programs and civilian nuclear power, pose substantial environment justice issues. Nuclear power plant (NPP) reactors produce low-level ionizing radiation, high level nuclear waste, and are subject to catastrophic contamination events. Justice concerns include plant locations and the large potentially exposed populations, as well as issues in siting, nuclear safety, and barriers to public participation. Other justice issues relate to extensive contamination in the U.S. nuclear weapons complex, and the mining and processing industries that have supported it. To approach the topic, first we discuss distributional justice issues of NPP sites in the U.S. and related procedural injustices in siting, operation, and emergency preparedness. Then we discuss justice concerns involving the U.S. nuclear weapons complex and the ways that uranium mining, processing, and weapons development have affected those living downwind, including a substantial American Indian population. Next we examine the problem of high-level nuclear waste and the risk implications of the lack of secure long-term storage. The handling and deposition of toxic nuclear wastes pose new transgenerational justice issues of unprecedented duration, in comparison to any other industry. Finally, we discuss the persistent risks of nuclear technologies and renewable energy alternatives. Nuclear technologies, both from military and commercial applications, pose a complex of environmental justice issues in terms of current and future risks they pose to people and environments. These risks, as both nuclear testing and nuclear reactor accidents have shown, transcend national boundaries, can span millennia, and can have multigenerational health risks. To explore nuclear risks and environmental justice, we focus on issues only in the continental U.S. However, we recognize that the risks are expanding at a global level with accumulations of high-level nuclear waste, mining and milling waste, and unresolved serious nuclear contamination problems at military sites in North America, Europe, Africa, and Asia (see ).Weapons programs and nuclear power generation involve a complex nuclear fuel cycle, from mining and milling of the ore, to enrichment and nuclear fuel rod or warhead fabrication, leaving at the end of the cycle extremely toxic high-level nuclear waste that must be isolated from humans for hundreds of thousands of years . This coBeyond the catastrophic failures, even in routine operations, nuclear power plants (NPPs) are a source of low level ionizing radiation potentially affecting workers and those living in proximity to reactor sites, particularly children (for a review or research in the European context (see ). A growThe toxic legacies of the global nuclear weapons complex—from uranium mining and milling, to weapons production and testing—have been global in reach, from Kyrgyzstan to the Marshall Islands to the Navajo Nation and Alaska ,8. RadioTo approach the topic, our discussion is organized into four sections. First we examine distributive and procedural justice issues at commercial reactors in the U.S. Our concern here is to examine the nature of the at-risk populations living in proximity to civilian nuclear power plants in the U.S. and discuss some of the environmental risks and procedural justice issues that pertain to nuclear plant siting, license renewal decision-making, and emergency preparedness. We highlight the growing constraints by the Nuclear Regulatory Commission (NRC) in public participation in nuclear decision-making, which appear to reinforce a tradition of secrecy, denial, and misinformation that has long been part of the nuclear industrial complex ,13. The The fourth section of the paper discusses the issue of safe disposal of high-level nuclear waste from power plants and weapons production. As of this writing no geologic burial site is open and operational that can provide secure storage of nuclear waste in the U.S. Further, there is a great deal of citizen opposition to the transportation of highly radioactive waste through cities and towns to secure storage sites should they become available in the future ,16,17. WWhen discussing environmental justice issues we are concerned with three key forms of justice. The first, distributive justice, refers to how environmental burdens are sociospatially distributed, and what principles are used in allocating risks . The secWe begin by considering distributive justice issues in U.S. NPPs. In general, individuals living around nuclear power plants face potential health risks posed by complex nuclear technologies. There are two categories of risks: those stemming from day-to-day operations and those arising from catastrophic failures. In case of acute failures, large areas around the nuclear plants face potential exposure to highly toxic radioactive releases, soil and water contamination, radiation from melted fuels, and large exclusion zones of uninhabitable land (as in both Chernobyl and Fukushima). The Fukushima Daiichi nuclear disaster in 2011 is the most recent reminder that nuclear power plants are subject to catastrophic failures with the potential to produce radiation-related diseases, as well displace hundreds of thousands of people and render large areas contaminated for centuries. And while these extreme events are relatively infrequent, when they occur multiple generations will be burdened with the environmental and health costs of these disasters, as Chernobyl has amply demonstrated  Ingestion Pathway, the outer geographic limit of NRC planning for nuclear contamination events. Kyne  conducteTo examine potential exposure of an urban population to a highly toxic radioactive plume from a reactor core breach, we use the Palo Verde Nuclear Generating Station (PVNGS) near Phoenix as an example. The reactor complex lies approximately 50 miles west and upwind of central Phoenix. Using NRC software to model the dispersion of a radioactive plume, using typical early spring wind conditions, we found 700,000 residents would be exposed out of the 4 million population in the metropolitan Phoenix area  . The estEvidence suggests that individuals living near the nuclear power plants face difficult-to-avoid health risks associated with exposure to low level routine radioactive effluents emitted from plants. Given that no level of radiation exposure is considered safe, any excess exposure could have deleterious impacts on human health . The effIn addition to the 50 mile EPZ, the NRC also designates a plume exposure pathway zone within a 10-mile radius of a reactor . While tPlant siting: The Atomic Energy Commission (AEC) acted as a sole responsible authority for the site selection process in the beginning years of civilian nuclear power (1957–1975) [ power 19–1975 [5757–1975) ,57. The 57–1975) ,57. GiveThe Nuclear Regulatory Commission was created by the Energy Reorganization Act of 1974, replacing the much criticized AEC . The actEmergencypreparedness: Critical in insuring public safety in the event of a nuclear disaster is robust emergency planning and a coherent response strategy by the reactor operator and the state. As the Fukushima Daiichi disaster has recently showed, the lack of emergency preparedness by the commercial plant operator, inadequate communication pathways, and various dysfunctions among government agencies can move a nuclear disaster rapidly toward a worst case scenario [scenario . When thscenario , an extrscenario . There iscenario ). Publicparticipation: While public participation and the right to know has been a hallmark of the environmental justice (EJ) and anti-toxics movements, much of the nuclear industry has been shrouded in secrecy and public exclusion [xclusion ,63. Basexclusion . On papexclusion . Neverthxclusion , which sxclusion . According to Executive Order (E.O.) 12898, issued in 1994 , federalThe license renewal procedure touches on the issue of procedural justice specifically as it relates to public participation. In this case the license renewal process began on 15 December 2008 when the PVNGS submitted the application and it ended on 22 April 2011 when a decision was reached. While the process took about 44 months, the public had only two opportunities for involvement, once in 2009 and again in 2010. The NRC announced the public meetings in the Federal Register  30 days Nuclearenergyethics: The three ethical aspects related to nuclear power are risk, justice, and democracy [emocracy . To elabemocracy . The plaemocracy . This exemocracy . In addiemocracy . It is oThe overall evidence is that, in absence of clear indications of harm from low level radiation, the NRC ostensibly will renew licenses for existing nuclear power plants in operation. Given the absence of large scale epidemiological studies of populations within the 50-mile EPZ of U.S. reactors, there is little to stand in the way of near automatic license renewals of aging plants. Nevertheless, evidence from a series of European studies suggest that elevated childhood leukemia rates, among other diseases, are associated with proximity to reactor sites ,48,70,71While the commercial nuclear power program emerged out of the U.S. nuclear weapons program in the 1950s, the environmental health impacts of radioactive contamination in the U.S. date to the Manhattan Project, the accelerated federal program to build nuclear weapons in WWII. For the Manhattan Project and the subsequent large-scale program to build increasingly powerful and sophisticated nuclear weapons, the legacies of contamination are extensive, continuing, and difficult to remediate  In thisThe “uranium frenzy” began in the West in the 1940s as the U.S. ramped up its capacity to produce nuclear weapons providing a ready market for uranium ore . While mWhile uranium mining provided a few thousand Navajo with comparatively well-paying jobs, the health costs for those exposed in the mines, as well as thousands of others exposed by mine site, mill tailing, and groundwater contamination have been and continue to be extensive. Lung cancers began being documented among Navajo mine workers by the 1960s, the likely result of radon gas exposure in the mines although miners were never informed of the known risks. Lung cancer was virtually unheard of among Navajo and other Indian tribes prior to the advent of uranium mining but today the rates remain four times as high for miners as non-miners  in spiteThe experiences of the Navajo and other Indian tribes with uranium mining and processing as well as weapons testing exposure has clear and continuing environmental justice implications. These center on two key things: (1) the disregard of Indian communities’ health and well-being by the military and mining companies; and (2) the long delays between initial exposures and subsequent hazard mitigation and federal compensation programs for radiation victims. The federal Radiation Exposure Compensation Act (RECA) did not become law until 1990, 30–50 years after exposures from nuclear testing and mining, and after passage it has proved difficult for downwind and mining victims to receive benefits for their illnesses . The contaminated federal research centers at Los Alamos, NM and Hanford, WA , Y-12 at Oak Ridge (TN), Rocky Flats (CO)—now closed but with significant contamination issues remaining—Fernald nuclear materials site (OH), and Lawrence Livermore Lab (CA)). All are active, difficult-to-remediate superfund sites and are further examples of the environmental and health risks that have been created in the process of producing nuclear weapons for the U.S. arsenal. Unlike tribal lands, these federal sites and numerous others are part of the national security state. As such they have lacked public oversight and have been cloaked in secrecy for much of their history . Los Alamos National Laboratory (LANL) has a storied history as the center of the Manhattan Project and the production of the first nuclear weapons to be used in war. Established in 1943, it has a longer history of nuclear research and radioactive contamination than any other site in the world. Located in northern New Mexico on the Pajarito Plateau, it occupies the former homeland of the San Ildefonso Pueblo, gifted to the Manhattan Project, with the understanding that the lands would be returned at the end of WWII . LANL siAs typical of other federal nuclear research labs, LANL today has multiple sites of contamination from radiologic and chemical substances. Also typical of other nuclear labs, it has a history of intentional nuclear materials releases that have affected downwind communities . While wAmong the legacies of 70 years of nuclear weapons research, testing, and production at LANL is an expanding nuclear dump site directly upstream/upwind of the San Ildefonso Pueblo and other communities. So-called Area G is a significant focus of concern both for Indian and Hispano communities in the area, and for anti-nuclear activists in New Mexico given the extensive store of highly radioactive materials and ongoing containment issues at LANL . Clean-uEnvironmental health and justice concerns relate to the effects of possible exposure of downstream and downwind communities from leaks and airborne contamination at the site. Currently a tritium- and chromium-contaminated plume of groundwater is moving towards the San Ildefonso Pueblo from Area G, threatening to enter an aquifer that the Pueblo and other communities depend on for drinking water as well as for irrigation . These rAnother key site of the Manhattan Project, and one that poses perhaps even greater environmental safety and long-term health concerns for both surrounding communities and site workers, is the Hanford, WA site. The Hanford site covers 580 square miles of SE Washington, adjacent to a number of farming communities as well as 10 Indian reservations and is currently undergoing a very large scale site remediation process, estimated to ultimately cost $150 billion. Site clean-up has included removal of 20 tons of plutonium, debris from hundreds of irradiated structures, 2300 tons of spent nuclear fuel rods, thousands of tons of contaminated soil, and millions of gallons of highly contaminated waste water . HanfordEven while the plant was operating it had a dubious record of safety, with planned and unplanned releases of radioactive materials, accidents, worker exposures and radiation-related illnesses, as well as on-site dumping of radioactive liquids directly on the ground  creating numerous toxic groundwater plumes . EvidencHanford and AEC personnel monitored thousands of school children near the site in the 1960s to assess radionuclide body burdens on residents, as well as to assess levels of radioactive contamination of farmlands and crops. This was not out of concern for residents’ health but for better understanding the dispersal and bioaccumulation of radioactive materials in the ambient environments around Hanford  (pp. 453–455 ). The inThe most pressing problem at Hanford is 56 million gallons of highly unstable chemically- and radioactively-contaminated waste water stored in large underground tanks. At least one million gallons of waste water has leaked out of the tanks and has entered the Columbia river . Given tAccording to U.S. NRC, high-level wastes include (1) spent (used) reactor fuel and (2) waste materials remaining after spent fuel is reprocessed . The latSince taking office in 2009, the Obama administration announced that Yucca Mountain was no longer the presumed solution to the nation’s radioactive waste problem and stopped funding the program , althougIn an effort to keep Yucca Mountain alive in May 2016 U.S. NRC completed and issued an Environmental Impact Statement supplement. While completion of adjudicatory hearing is necessary before making a decision on licensing, the site still remains suspended . In JanuThese new plans notwithstanding, in the absence of a permanent site, highly radioactive spent fuel rods accumulate at commercial reactor sites, now estimated at around 70,000 tons . On-siteThe second nuclear waste geologic burial site, the Waste Isolation Pilot Project (WIPP) was opened in the 1990s and accepted military/research lab nuclear waste (transuranic waste), much of it coming from LANL’s Area G.  The WIPP site was one of several sites evaluated in the 1970s that used hollowed out salt domes to store nuclear waste (other than fuel rods) underground. Concerns over water ingress and other issues delayed the opening of WIPP for more than two decades . The WIPThe primary concern of activists, tribes, and communities opposing these two sites is the sheer volume of nuclear waste that will traverse highways and railways through population centers in transit from nuclear reactors and nuclear weapons sites . New DOEThis study has argued that nuclear power plants, uranium mining, and waste disposal raise a suite of justice issues including distributive, procedural, recognition and intergenerational justice issues. Moreover, these issues are transnational in scope and scale. In U.S., there are substantial uncertainties regarding the health effects of NPPs on the more than 87 million people residing within a 50-mile radius of a commercial reactor. These concerns are further complicated by the history of secrecy and the suppression of public participation in any nuclear decision-making by the NRC and DOE. Further, what participation is available is circumscribed by strict and self-serving procedural rules. Given the culture of the DOE and the NRC, and before it the AEC, there would appear a strong tendency of the promoters of nuclear energy to deny any potential health and environmental risks. Indeed, as discussed above, the lack of public discussion of emergency preparedness at NPPs illustrates this culture of minimizing risk and not raising public concerns or worries over the potential for accidents. The NRC has withheld nuclear power plant emergency plan documents systematically due to security concerns and has ignored comments by the public to improve plans. This same logic characterized the exposure of civilian populations to nuclear testing fallout: people were not informed of risks so as to not worry them . Once raFurther procedural and recognition justice issues are associated with the nuclear weapons program and the sheer volumes of hazardous and poorly documented waste six decades of weapons production has produced at sites like LANL and Hanford. As weapons production is part of the national security state, it is highly secretive and public disclosures of risk typically come decades after exposures of civilian populations, if they come at all . While fThe continuing proliferation and operation of nuclear power plants globally and the waste they generate, constitutes substantial justice concerns for those living in proximity to nuclear sites and transportation corridors used for moving fuel and nuclear waste. China, for example, is on a crash course to build 40 new reactors in the next five years, a significant concern given their history of devastating industrial accidents . Given tBeyond the health risks of nuclear weapons production and NPPs, are the justice implications of the sheer costs of nuclear technologies particularly when the costs of waste disposal, contamination remediation at federal sites, and the decommissioning and entombment of NNPs at the end of their service life are calculated. That the radioactive components of a reactor as well as the spent fuel rods have to be securely stored for tens of thousands of years with limited risk to future generations, is on orders of magnitude different than any other industrial technologies. Given those cradle-to-grave environmental, health, and safety costs of nuclear power, renewable wind and solar technologies would appear to have major advantages both from a cost per kilowatt and for the lack of long-term health and safety risks to those in proximity and to future generations. That radioactive wastes and nuclear weapons and reactor technologies are potentially mutagenic, teratogenic, and carcinogenic, the potential multigenerational health risks are substantial. Subsequent generations will have to deal with highly radioactive wastes with technologies that currently don’t exist, revealing how nuclear technologies shift health, environmental, and financial burdens into the future, hiding their real costs and masking the procedural and recognition justice implications.While there is periodic talk of a “nuclear renaissance” with smaller, cleaner, and safer reactors, the diseconomics of nuclear energy with the proliferation of low cost natural gas has utilities in the U.S. and Europe closing down expensive to operate reactors and switching to gas fired plants and a portfolio of renewable sources . Indeed,What steps could be taken to begin to resolve some of the above discussed justice issues? To overcome all types of environmental justice issues, it is imperative for all key stakeholders including nuclear regulatory agency to take accountability and responsibility in carrying out activities in risk evaluation, risk decision-making, and risk management regarding nuclear power and radiation . This re


Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and  The SRC family of non-receptor protein tyrosine kinases (SFK) consists of 9 members, and can be divided into two groups according to the expression pattern of the individual kinases in the adult. Accordingly, SRC, YES and FYN are ubiquitously expressed, while expression of LCK, FGR, BLK, LYN, YRK and HCK is limited to certain types of cells and tissues. HCK expression is confined to cells of the myeloid and B-lymphocyte lineages and the protein exists as two isoforms. In humans, they comprise the p61HCK and p59HCK isoforms consisting of 525 and 504 amino acids, respectively, while in mice HCK exists as p59HCK (503 amino acids) and p56HCK (482 amino acids). In either species the two isoforms are generated by alternative initiation of protein translation from two in-frame initiation codons found within a single mRNA pyrimidine derivatives to identify candidates, which bind to the ATP binding site of HCK [Lastly, new strategies for the design of more conformation specific SFK inhibitors are required, since drugs with high specificity and potency are more effective and exhibit fewer side effects and toxicity. In particular, proteomic tools that interrogate kinase active sites provide a powerful approach for studying protein regulation and for performing screens for highly selective inhibitors for components of complex proteomes . One suce of HCK . These ne of HCK . Other ee of HCK , which be of HCK , which pKO mice on the other hand, HCK may be a promising target for cancer treatment. In particular, therapeutic-targeting strategies aimed at inhibiting HCK within the tumor stroma may be part of a paradigm-shifting approach to treating human cancers in the future. Given the role of stromal cells as key enablers and enhancers of many of the hallmarks of cancer, we predict that the inhibition of HCK in tumor-associated innate immune cells will reduce their ability to promote angiogenesis, inflammation, migration and invasion. This will be aided by the emergence of new strategies to identify novel HCK inhibitors with greater specificity and potency, which will not only provide additional insights into the mechanistic by which HCK promotes the progression of tumors, but facilitate translational outcomes for cancer patients in the clinic.An oncogenic role of HCK has been implicated in human cancers, including leukemia and solid tumors of the breast, colon and stomach. Given the high frequency of excessive HCK activation in these cancers and its correlation with a poor prognosis on one hand, and the relatively mild phenotype displayed by HCK


The analysis of these stochastic chemical kinetics is important for understanding cell-to-cell variability and its functional implications, but it is also challenging. A multitude of exact and approximate descriptions of stochastic chemical kinetics have been developed, however, tools to automatically generate the descriptions and compare their accuracy and computational efficiency are missing. In this manuscript we introduced CERENA, a toolbox for the analysis of stochastic chemical kinetics using Approximations of the Chemical Master Equation solution statistics. CERENA implements stochastic simulation algorithms and the finite state projection for microscopic descriptions of processes, the system size expansion and moment equations for meso- and macroscopic descriptions, as well as the novel conditional moment equations for a hybrid description. This unique collection of descriptions in a single toolbox facilitates the selection of appropriate modeling approaches. Unlike other software packages, the implementation of CERENA is completely general and allows, e.g., for time-dependent propensities and non-mass action kinetics. By providing SBML import, symbolic model generation and simulation using MEX-files, CERENA is user-friendly and computationally efficient. The availability of forward and adjoint sensitivity analyses allows for further studies such as parameter estimation and uncertainty analysis. The MATLAB code implementing CERENA is freely available from  Biological processes, including chemical reaction networks, are dynamical systems with inherently stochastic dynamics due to the discrete nature of matter . The kinUsing well-mixed and thermal equilibrium assumptions, the dynamics of chemical reaction networks is exactly described by the Chemical Master Equation (CME) . The solTo reduce computational complexity, a multitude of approaches have been introduced that, instead of approximating the full probability distribution, focus on the statistical moments of it. Various orders of the method of moments (MM)  and the Beyond fast numerical simulation, moment-based descriptions facilitate parameter estimation and model selection for stochastic processes , 16. ThiSeveral well-known open-source software packages are available for stochastic simulations, finite state projection, method of moments, and system size expansion , a toolbox for the analysis of stochastic chemical kinetics. CERENA includes a variety of methods for the analysis of stochastic biochemical reaction networks, focusing on mesoscopic and macroscopic descriptions, namely RRE, MM, and SSE. Also, CERENA provides the first implementation of MCM, and offers a wide range of options, amongst others variable truncation orders and different closure schemes. In addition, FSP and SSA implemented in CERENA can be used to provide microscopic descriptions of stochastic chemical kinetics. Although efficient implementations of many variants of SSA are available, e.g., in StochKit , CERENA In the following, we describe the functionality of CERENA and introduce the different approximations. CERENA is then used for a detailed quantitive comparison of different approximation methods, including various moment closures, which was not done before. In particular, the approximation accuracies and computation times are assessed, demonstrating the efficiency of the CERENA implementation.In the following, several methods for the modeling of stochastic processes and the corresponding sensitivity analysis are briefly introduced.ns chemical species and nr chemical reactions is described using a continuous-time Markov chain (CTMC) [x at time t is denoted by p(x|t). The time evolution of the probability distribution p(x|t) is governed by the CME, which is a system of ordinary differential equations (ODEs)  to provide a microscopic description. For mesoscopic and macroscopic descriptions, there exist several methods that focus on representing the solution of the CME in terms of its statistical moments. The microscopic, mesoscopic and hybrid methods implemented in CERENA are briefly introduced in the following.A chemical reaction network, comprising of n (CTMC) . The stap(x|t) is given by the frequency of sample paths that occupy state x at time t. To estimate the moments of the process, Monte-Carlo integration can be performed. While estimators for probability distribution and moments are unbiased and converge, the sample-sizes required to obtain low-variance estimates are generally large, rendering SSA-based methods computationally demanding.SSAs generate statistically representative sample paths of the CTMC . An estip(x|t), FSP [p(x|t). Growing the state-space of FSP decreases the approximation error at the cost of increased computational complexity.To enable a direct approximation of |t), FSP  reduces The RRE is the most commonly used modeling approach for biochemical reaction networks. It constitutes a system of ODEs for the time evolution of the mean of the stochastic process in the macroscopic limit. For reaction networks with constant and linear propensities, i.e. those with only zero- or monomolecular reactions, the solution of the RRE is exactly the mean of the stochastic process. For reaction networks with nonlinear propensities, the RRE prediction can be considerably different from the true mean of the process since it neglects the stochastic effects. In such cases, the solution of RRE is reflective of the true mean of the stochastic process only in the limit of large molecule numbers .For a systematic approximation of the dynamics of mesoscopic systems, the SSE has been introduced . The SSEThe method of moments (MM)  is conceThe MCM  combinesFSP, RRE, SSE, MM and MCM yield systems of differential equations. The parameters of differential equations can efficiently be inferred using gradient-based optimization methods . While gn state-variables and nθ parameters, roughly a system of n(1+nθ) differential equations is solved to compute the first-order state sensitivities with respect to all parameters. The sensitivity of measured quantities and objective functions can then be computed based on state sensitivities.Forward sensitivity equations provide the time-dependent sensitivity of the state-variables of the differential equations with respect to the parameters. Assuming that the model possesses If the sensitivity of few functions with respect to many parameters is required, computing the state sensitivities is unnecessarily demanding. In this case, the adjoint sensitivity equations  can be shttp://cerenadevelopers.github.io/CERENA/.CERENA is a MATLAB-based toolbox for the simulation of chemical reaction networks. It provides a collection of methods for the analysis of stochastic processes, focusing on SSE, MM and MCM of various orders. In addition, FSP and SSAs are implemented in CERENA to provide microscopic descriptions of the process, and can also be used to assess the approximation errors of the aforementioned methods. The workflow of the toolbox is laid out in To use CERENA, the biochemical reaction network has to be defined in a specific format described in the Following the definition of the biochemical reaction network, a modeling approach and corresponding options, such as approximation order and moment closure technique, can be selected. In addition to the moment closure techniques implemented in CERENA see , user-deode15s.The models can be exported to Data2Dynamics software  for paraForward and adjoint sensitivity equations for the selected model are derived based on the aforementioned symbolic representation. The complete symbolic representation can then be used to compile simulation files. CERENA uses CVODES and IDAS solvers of the SUNDIALS package  which arThe solvers based on differential equations are complemented by SSAs, e.g. to provide reference solutions. In the case of SSAs, realizations of the stochastic process are simulated. CERENA implements next-reaction methods for constant  and timeTo facilitate the interpretation of the numerical simulation results, CERENA offers various visualization routines. Time courses for stochastic realizations, as well as mean and higher-order moments of species, can be plotted. Moreover, the full and marginal probabilities can be visualized for SSA, FSP and MCM. To illustrate the interaction between different network components and propagation of stochasticity, correlation and partial correlation maps, including movies of these maps over time, are provided.In this Section, we present two biological models to demonstrate different features of CERENA, including the improved computational complexity. Furthermore, we exploit the comprehensiveness of CERENA to compare different approximative descriptions.As the first example, we consider the generalized three-stage model of gene expression  depictedThe accuracy of various approximative descriptions is problem-specific, and therefore, comparisons of different descriptions for a process of interest is interesting in different applications. As demonstrated for this model, CERENA offers an easy-to-use framework for such a comprehensive comparison, thanks to its broad collection of simulation methods.This process was implemented and simulated in CERENA for the parameter values given in As mRNA is only transcribed if the promotor is in the on-state, the conditional distributions of mRNA and protein counts in the on- and off-states differ. These differences are captured by the MCM , which pμMCM−μFSP|/μFSP. The accuracy of different descriptions is quantified in terms of the relative errors of the mean and variance with respect to the FSP, e.g., |A key bottleneck in the analysis of stochastic chemical kinetics is the computational complexity of the numerical simulation. As the number of biochemical species or the approximation order increases, the system of differential equations to be solved becomes larger  includes two compartments, namely cytoplasm and nucleus, and (ii) involves a time-dependent propensity.We used CERENA to describe the dynamics of JAK-STAT signaling pathway for parameter values given in In previous studies, it was shown that the parameters of the JAK-STAT signaling pathway can be estimated efficiently for RRE  and EMREWe observed that, even for a small number of parameters, a gain in efficiency is achieved by using forward and adjoint sensitivity analysis methods instead of finite differences . MoreoveA multitude of studies revealed the functional role of cell-to-cell variability in cellular mechanisms . Hence, We used CERENA for detailed quantitative comparisons of different modeling approaches on models for three-stage gene expression and Epo-induced JAK-STAT signaling. These applications demonstrated that CERENA (i) offers suitable approximative methods for different biological regimes (or systems in different regimes of copy-numbers), and (ii) renders the comprehensive comparison of approximative descriptions and the subsequent selection straightforward. Also, the implementation of numerical solvers in CERENA proved to be significantly more efficient compared to other packages/implementations. For sensitivity analysis, a further acceleration was achieved by using forward and adjoint sensitivity analyses, with the latter possessing a superior scalability with respect to the number of parameters.The current version of CERENA allows for the study of population-averaged and population snapshot data by providing time-dependent moments. To that end, a useful advancement could be realized by the integration of CERENA with sophisticated parameter estimation and model selection tools, such as ODE-constrained mixture modeling . ComplemIn conclusion, we have shown that CERENA is a comprehensive toolbox for stochastic modeling which maximizes both applicability and computational efficiency. This renders further studies of biological problems of realistic sizes feasible.S1 CERENA DocumentationThis documentation includes a more detailed description of the modeling approaches implemented in CERENA, as well as elaborate instructions on using the CERENA toolbox.(PDF)Click here for additional data file.


Neuroaxonal dystrophy (NAD) is a neurodegenerative condition affecting humans and animals characterized by the widespread presence of swollen axons (spheroids).Herein, we report the pathological findings in a case of neuroaxonal dystrophy in a Dachshund-cross puppy, which was euthanized because of a proprioceptive positioning deficits and irreversible ataxia of the hind limbs. Histologically, there was a bilaterally symmetric neuroaxonal dystrophy with eosinophilic axonal spheroids exclusively localized at the level of the ventral posterior lateral nucleus of the thalamus, medial lemniscus, gracilis nucleus, medial cuneatus nucleus in the brain as well as the gracilis and cuneatus fasciculi throughout the spinal cord.To the authors’ knowledge, this is the first report of canine neuroaxonal dystrophy with this exclusive and specific localization only in the neuronal circuit implicated in the transmission of conscious proprioceptive information. Neuroaxonal dystrophy (NAD) describes a group of inherited or acquired neurodegenerative conditions affecting humans and animals characterized by the widespread presence of swollen axons (spheroids) in the central and, rarely, peripheral nervous system.Axonal spheroids in NAD affected dogs  and catsSeveral reports have suggested that NAD is an autosomal recessive disorder and some dog breeds have a recognized predisposition to NAD , 6. RottThe mechanisms by which spheroids develop in NAD are only partly known, but immunohistochemically methods have shown that NAD entails an accumulation of synapse-associated proteins, cytoskeletal proteins and other axonal markers, thus suggesting an axonal transport deficit as the underlying cause of spheroid formation .Herein, we describe a case of NAD in a Dachshund-cross breed puppy with exclusive and specific neuro-distribution throughout the neuronal circuit implicated in the transmission of conscious proprioceptive information.Two Dachshund-cross breed puppies belonging to the same litter developed progressive difficult walking since they were a few weeks old. One puppy was euthanized without post mortem examination, while the other puppy was presented at 1 year of age for clinical examination. Neurological examination reveled hypermetria, proprioceptive positioning deficits and irreversible ataxia, particularly of the hind limbs. Muscular tone, bulk and strength were normal and higher mental functions appeared integral. The dog was humanely euthanatized because of the progressive incurable nature of the disease.At necropsy, brain, spinal cord, tracts of the sciatic nerve, as well as samples from a number of forelimb muscles, liver, and kidney were collected and promptly fixed in 10 % neutral buffered formalin. Coronal sections were obtained at six different levels of the encephalon , as well as at the levels of each emergence of the nerves of the spinal cord and then routinely processed and embedded in paraffin wax. Sections were cut serially from paraffin blocks at 5 µm and stained using hematoxylin and eosin, modified Period Acid Shiff Picro Indigocarmine Morel–Maronger (PAS-M.M.), Klüver-Barrera Luxol fast Blue (KB), and Perl’s stain. Furthermore, in-depth immunohistochemical investigations were performed on selected tissue sections using specific primary antibodies for the following markers of axonal transport: neurofilaments light chain  and tau, cytoskeletal proteins; ubiquitin, a heat shock protein; synaptophysin, a synapse-associated protein; glial fibrillary acidic protein (GFAP), the specific marker of astrocytes  revealed a bilateral symmetric neuroaxonal dystrophy, which was uniquely at the level of the ventral posterior lateral nucleus of the thalamus, medial lemniscus, gracilis nucleus, and medial cuneatus nucleus in the brain. The same change in the spinal cord was found in the gracilis and cuneatus fasciculi, particularly in the thoracic tract Fig. . In the In longitudinal sections at the level of the gracilis and cuneatus fasciculi, aspects of Wallerian-like degeneration with different digestion chambers containing sporadic macrophage and axonal debris were found Fig. b. OccasiHistochemical staining revealed that some spheroids contained PAS-M.M positive material and KB staining evidenced relative preserved myelin. Perl’s stain did not highlight the presence of iron in any sections of the encephalon.In all CNS sections, spheroids showed immunoreactivity for NF-Ls, tau, synaptophysin and ubiquitin with the signal being more intense at the level of the spinal cord Fig. . In addiFinally, the immunohistochemistry for GFAP confirmed the presence of evident astrogliosis and astrocytosis in the nuclei displaying spheroids. The sections from muscles, liver, kidney and sciatic nerve were histologically normal. As in the control, the affected dog showed weak GFAP immunoreactivity with a linear pattern in the longitudinal sections of the sciatic nerve Fig. . In the On the basis of these clinical, histopathological and immunohistochemical features, a NAD disorder was diagnosed.In NAD, distribution patterns of the spheroids differ and involve numerous areas of the grey and white matters of the brain and spinal cord with the nucleus gracilis and nucleus cuneatus along with the dorsal horn of the spinal cord being constantly and predominantly affected .So far, in Papillon , Rottweitectonin beta-propeller repeat-containing protein 2 (TECPR2) gene [Previous reports of canine NAD have reveled immunopositive reaction in spheroids for several synapse-associated proteins, including synaptophysin, together with other molecules such NF-Ls, tau and ubiquitin , 17. TheR2) gene , which iIron accumulation, within and outside the spheroids, is a characteristic aspect of human cases of the Hallervorden-Spatz syndrome. However, neuronal accumulation of iron was neither found in our case nor reported in other domestic animal NAD cases  thus excThe immunohistochemical findings reported in the present NAD case are largely in agreement with those reported in dogs by other researchers; nevertheless, the distribution of the lesions in the present case remains dissimilar from most of the neuroaxonal dystrophies reported previously.This dissemination of axonal spheroids has been documented in other species as well. In cats, vacuolization and spheroids were described in the fasciculus gracilis and fasciculus cuneatus, but also the dorso-lateral funiculi and the ventro and ventro-medial funiculi of the spinal cord were mildly affected .Axonal dystrophy in NAD has until now been thought to display a wide distribution in the CNS involving different neuronal pathways and not exclusively the sensitive ones. Our case seems to be a topographically distinctive pathological entity characterized by lesions exclusively to sensory axons controlling general conscious proprioceptive information, which travels from the mechanoreceptors to the primary somatic sensory cerebral cortex throughout the fasciculus gracilis and cuneatus, gracilis and medial cuneatus nuclei, medial lemniscus, and ventral posterior lateral nucleus of the thalamus. In fact, the affected puppy’s clinical neurological symptoms mirror and are consistent with the location of these observed lesions. The dorsal column carries the majority of information of tactile discrimination and proprioception and terminates by contacting in the gracilis and medial cuneatus nuclei. Lesions of the dorsal columns of the spinal cord in primates hamper the ability to perceive the tactile stimuli and degrade the capacity to sense the position of the limbs in a given space . In our Although no proof of inheritance was determined in the present NAD case, a genetic disorder may be speculated, because of the congenital derivation and the presence of one other affected puppy in the same litter. Interestingly, our case is also the first to be described in a cross-breed dog. Finally, our report description stimulates the need for more systematic efforts to define and accurately describe all the clinical and pathologic manifestations of NAD. The literature illustrates that a wide range of pathological findings, which vary greatly among different species and breeds and from case to case, are all commonly categorized as NAD. It would be beneficial to invest in more careful and systematic post-mortem examination of the CNS in order to define NAD subtypes based on lesion location and corresponding neurological symptomatology.


The primary health care (PHC) sector is increasingly relevant as a site for population health interventions, particularly in relation to marginalized groups, where the greatest gains in health status can be achieved. The purpose of this paper is to provide an overview of an innovative multi-component, organizational-level intervention designed to enhance the capacity of PHC clinics to provide equity-oriented care, particularly for marginalized populations. The intervention, known as EQUIP, is being implemented in Canada in four diverse PHC clinics serving populations who are impacted by structural inequities. These PHC clinics serve as case studies for the implementation and evaluation of the EQUIP intervention. We discuss the evidence and theory that provide the basis for the intervention, describe the intervention components, and discuss the methods used to evaluate the implementation and impact of the intervention in diverse contexts.Staff education: using standardized educational models and integration strategies to enhance staff knowledge, attitudes and practices related to equity-oriented care in general, and cultural safety, and trauma- and violence-informed care in particular, and;Organizational integration and tailoring: using a participatory approach, practice facilitation, and catalyst grants to foster shifts in organizational structures, practices and policies to enhance the capacity to deliver equity-oriented care, improve processes of care, and shift key client outcomes.Research and theory related to equity-oriented care, and complexity theory, are central to the design of the EQUIP intervention. The intervention aims to enhance capacity for equity-oriented care at the staff level, and at the organizational level  and is novel in its dual focus on:Using a mixed methods, multiple case-study design, we are examining the impact of the intervention in enhancing staff knowledge, attitudes and practices; improving processes of care; shifting organizational policies and structures; and improving selected client outcomes.The multiple case study design provides an ideal opportunity to study the contextual factors shaping the implementation, uptake and impact of our tailored intervention within diverse PHC settings. The EQUIP intervention illustrates the complexities involved in enhancing the PHC sector's capacity to provide equity-oriented care in real world clinical contexts. Research shows that the primary health careDespite Canada’s national health care program, health and health care inequities are increasing in the context of oppressive neoliberal health and social policies –12. HealResearch on PHC delivery at the population level highlights two persistent problems: (a) inverse care ; and (b) fragmentation and under-resourcing of care for marginalized populations, even in high income countries . There aThe purpose of this paper is to provide an overview of an innovative multi-component, organizational-level intervention designed to enhance the capacity of PHC clinics to provide equity-oriented care, particularly for marginalized populations. The intervention, known as EQUIP  is being implemented and evaluated in four diverse PHC clinics in Canada. These clinics are located in two of the most highly populated provinces in Canada (Ontario [ON] and British Columbia [BC]), and serve as case studies for the implementation and evaluation of the EQUIP intervention. The clinics provide a wide range of interdisciplinary team-based services to populations ranging from 1300 to 6000 clients per clinic. The majority of clients are significantly affected by structural inequities and many experience major challenges accessing care. Clients include, for example, people with chronic health problems, chronic mental health and/or substance use problems, those experiencing systemic racism and discrimination including Indigenous people and racialized new immigrants, and women experiencing various forms of violence.We begin the paper with an overview of the EQUIP intervention, starting with the evidence and theory that provide the basis for the inter-related intervention components, and a discussion of the expected impacts. We then describe the methods we are using to understand the process of implementing the intervention across diverse settings and to examine its effects. We conclude with a brief discussion of the integrated knowledge translation and exchange (KTE) activities designed to link the knowledge gained from this study with knowledge users and decision-makers who have the potential to influence uptake of equity-oriented care in PHC settings. Our aim is not to provide detailed protocols for implementing and measuring the impacts of the EQUIP intervention. Rather, by providing an overview of the intervention and our approach to evaluation, we hope to illustrate the complexities involved in attempting to enhance the health care sector's capacity to provide equity-oriented care in “real world” clinical contexts.The EQUIP intervention was designed to enhance the capacity of PHC organizations to be as responsive as possible to the diverse needs of populations whose health is influenced by intersecting forms of structural inequities. Using a combination of staff education and practice facilitation to support practice and policy changes at the organizational level, EQUIP provides a flexible structure in which both the general content and processes of the intervention are tailored to fit with the most salient issues and priorities at each clinic.The EQUIP intervention is both evidence based and theoretically informed. Although many bodies of knowledge have informed the development of this intervention, research and theory related to equity-oriented care and complexity theory are particularly central to the design.The content of the EQUIP intervention is based on an evolving conceptualization of equity-oriented care. Specifically, in previous research developed and conducted in partnership with PHC clinics and other organizations serving marginalized populations, we identified evidence- and theory-informed key dimensions of PHC services that position equity as an explicit goal , 18, 19.Trauma- and violence-informed care (TVIC) involves operating from the recognition that people impacted by social inequities often experience multiple forms of violence; the structural conditions of their lives often place them at greater risk of interpersonal violence, and of experiencing challenges in accessing supports to improve their physical and emotional safety. The emphasis on violence-informed care also mitigates the potential to locate ‘the problem’ of trauma primarily in the psyche of those who have experienced violence, rather than also in the acts of structural violence and the conditions that support those acts [Increasingly, the concept of trauma is used to frame the health, social, and psychological effects of interpersonal violence , 21–33. ose acts . In contose acts , 35–37.cultural safety, originally developed in New Zealand by Maori nurse-leaders, was intended to move nursing and health care practices beyond conventional cultural sensitivity training to more explicitly address inequitable power relations, institutionalized and interpersonal racism and other forms of discrimination, and the ongoing impacts of historical injustices on health and health care [The concept of lth care –41. Cultlth care –44. Overlth care –50. In Clth care .Contextually tailored care expands the notion of client-centred care to include services that are explicitly tailored to the populations served and to local contexts. This includes tailoring practices and/or organizational policies and clinical guidelines/protocols to optimally address the most pressing needs of local populations, and the social and community realities that often shift depending on local politics, epidemiological trends, etc. At the organizational level, contextually tailored care requires understanding the local community and context, along with mechanisms for developing and updating this knowledge continuously.fit between the intervention and the local cultural or social environment in which it is implemented.Complexity theory, an emerging approach in a range of disciplines including population health –55, was Staff education: using standardized educational models and integration strategies to enhance staff knowledge, attitudes and practices related to equity-oriented care in general, and cultural safety, and trauma- and violence-informed care in particular, and;Organizational integration and tailoring: using a participatory approach, practice facilitation, and catalyst grants to foster shifts in organizational structures, practices and policies to enhance the capacity to deliver equity-oriented care, improve processes of care, and shift key client outcomes.The theoretical model of the intervention is depicted in Fig. The EQUIP intervention aims to enhance capacity for equity-oriented care at the staff level , and at the organizational level . The EQUIP intervention is novel in its dual focus on: Based on a view of health care organizations as complex adaptive systems, the EQUIP intervention was developed using core concepts and strategies that can be tailored to local contexts , 54, 58.Given the focus on change at both staff and organizational levels, we designed intervention activities to be appropriate for all staff, regardless of their specific roles, by taking varied learning styles and expertise into account. Within the intervention, three inter-related standardized educational components, described below, were delivered in ways which were tailored to local contexts and specific populations served, enhancing the relevance of the intervention , 54, 58.Health professional education has only recently included concepts from a health equity and population health approach, and rarely addresses the health consequences of violence, trauma, discrimination and racism . As suchTwo-hour workshops were offered to all staff at each site to provide an overview of the key dimensions of equity-oriented PHC and 10 strategies for enhancing capacity for equity-oriented services as shown in Fig. The primary content of Component 2 was an existing online, 8-hour, self-directed program known in Canada as the Indigenous Cultural Competency (ICC) programThe third component of staff education addressed key approaches to TVIC, as defined above. Building on existing curriculum on trauma-informed practice developed in Canada , 63, theintegration); and (b) creating locally relevant structures and processes within each organization to support such change (tailoring). As described above, the process of integrating personal learning into practice was initiated during staff education and continued throughout implementation of the intervention. To facilitate the OIT process, each site received a $10,000 catalyst grant to be used within a 12-month period. These grants provided the impetus for clinics to identify and address short-term goals and strategies to further the delivery of equity-oriented care, recognizing that change is an ongoing process that will continue to evolve beyond the study’s time parameters.The EQUIP intervention is grounded in the assumption that changes in staff knowledge, attitudes and practices are unlikely to result in significant shifts in equity-oriented processes of care unless attention is directed toward: (a) supporting staff to integrate learning from each of the three components in the context of practice  their individual interactions with clients; (b) team processes and practices, including types of programs offered and/or ways of delivering specific programs ; and (c) organizational structures and policies that direct how services are delivered ;Reviewing clinic profiles prepared by the EQUIP team, including selected health and social status indicators  for their clients compared to local, regional and national population norms to identify foci for change;Selecting 3–5 priorities for organizational change based on the assessment;Developing a detailed plan for addressing each priority, specifying goals, strategies, timelines and responsibilities, and a proposed budget for the catalyst grant;Implementing and evaluating the proposed changes within a 12-month period.Within each site, the OIT processes were initiated by the clinical administrative leaders/managers in consultation with experienced clinicians and staff who engaged in the following steps:OIT activities at the four PHC clinics include, for example: adapting the waiting room environment to be more welcoming for families caring for young children; developing and integrating harm reduction strategies into clinical programming and care; developing supports to address vicarious trauma experienced by staff when responding to the needs of clients experiencing violence; and expanding the approaches used to assess and respond to clients’ experiences of chronic pain, among others. In each site, the practice consultant was available to help problem-solve issues during implementation, reinforce the principles of equity-oriented care, and assist staff to evaluate the impact of their efforts and adjust the plan as needed.Figure Given that PHC is delivered within complex adaptive systems, we argue that multiple factors shape how equity-oriented PHC is taken up within organizations. These include: (a) the characteristics of the population; (b) the characteristics of the staff; (c) the organizational milieu, including formal and informal power structures, policies, and funding; (d) the political, policy and economic contexts, particularly government directives that affect health care delivery and factors influencing the broader determinants of health; and (e) the historical and geographic context, specifically, the physical location of organizations in varied rural and urban locations, and the social conditions linked to those locations. As we discuss below, the methods we are using to evaluate the implementation and impacts of the intervention permit us to pay close attention to these contextual factors.Using a mixed methods, multiple case-study design, we are currently examining the impacts of the EQUIP intervention in enhancing staff knowledge, confidence, attitudes and practices; improving processes of care; shifting organizational policies and structures; and improving selected client outcomes. A multiple case study is a comprehensive research strategy useful in exploring, describing, explaining, and evaluating causal links in real world interventions that are too complex to be assessed by survey or experimental strategies alone , 65. ThiWithin Canada’s publicly funded health care system, PHC is a provincial responsibility, resulting in diverse models of care and funding arrangements. Given the goal of understanding how context shapes the delivery and impact of EQUIP, we purposefully selected PHC clinics that would provide variation across five dimensions of context noted in the intervention theory Fig. . AlthougQuantitative assessments of the impact of the EQUIP intervention on staff are being conducted at three points in time  using an online survey designed to assess knowledge, attitudes and confidence in enacting practices related to the three components of staff education. We are examining changes over time in staff knowledge, attitudes, confidence and practices using statistical approaches appropriate to the level of measurement.Quantitative assessments of temporal changes in processes of care and client outcomes are being conducted using data collected through a client survey at four points in time . At baseline, a sample of 120–160 clients was recruited from each site, comprising a longitudinal cohort of 567 clients followed over 2.5 years. Clients were eligible to participate based on the following inclusion criteria: at least 18 years of age, able to understand and speak English, had made at least three visits to one of the clinics in the past 12 months, and intended to continue accessing services for the two years following recruitment. Recruitment occurred by inviting all clients who met the inclusion criteria, and who came to the clinic on purposively selected days, to participate. To enhance representativeness, both clients who had scheduled appointments and those who “dropped in” were invited to participate.The structured survey is comprised of investigator-developed survey items, standardized self-report measures and open-ended questions designed to measure the main concepts in our intervention theory, namely: (a) health care experiences, particularly perceptions of equity-oriented care; (b) short-term client outcomes, such as access to health services or community resources, capacity to address their health priorities, and overall ‘fit’ of services; and (c) longer-term outcomes including health status  and quality of life. Demographic information  was also collected. To enhance retention, we maintained contact with participants on a regular basis between the waves of data collection, and offered honoraria to acknowledge the time and effort required to complete the client interviews. Our retention rate after four waves of data collection was 77 % across the four clinics.Our initial analysis will focus on characterizing any changes in the main concepts identified in the intervention theory in Fig. Qualitative research methods are ideally suited to studying both the process and impact of implementing the EQUIP intervention at each site, including how diverse contexts shape the uptake of the intervention. We are: (a) conducting in-depth, open-ended interviews with staff and administrative leaders; (b) conducting general observations of the milieu at each setting, and more detailed observations of staff meetings recorded as fieldnotes; and (c) analyzing policy and contractual funding documents to consider how they both shape and are shaped by engagement with the intervention. The in-depth interviews focus on staff members’ experiences of engaging with the EQUIP intervention, including challenges and successes, and their perceptions of any effects on their practice, team processes, approaches to care, and organizational policies and structures. These methods of data collection are essential to the multiple case study design in order to generate both a detailed understanding of each case, and a more generalized understanding of commonalities that exist across cases. Particular attention will be paid to understanding which aspects of context best explain differences in the intervention’s impacts across the sites. The qualitative findings will also be essential to contextualize the quantitative analysis of temporal changes described above.Our multiple case study design and use of complexity theory provides an ideal opportunity to study the contextual factors shaping the implementation, uptake and impact of a complex, tailored intervention within diverse PHC settings. As our analysis proceeds, findings related to the impact of the EQUIP intervention will provide evidence about the practice-level changes, and policy and funding contexts needed to enhance capacity to provide equity-oriented care for people who are most impacted by structural inequities and structural violence.de facto, the first step in an evolving intervention-specific KTE strategy. For example, identified enablers and challenges in each context are becoming ‘lessons learned’ about what works, what does not, and why. This is informing our understanding of how the intervention (or aspects of it) could be tailored in new jurisdictions. These integrated KTE activities are informing our understanding of the complex factors that may intersect to influence implementation and the possible impacts in new sites outside of this research context. Longer term, this analysis will enable thinking beyond the specific PHC sites to inform a more policy-oriented approach to equity-oriented interventions, and ultimately, equity-driven system transformations.Integrated KTE activities cut across all aspects of our intervention research, and involve clinical leaders within the sites and knowledge users in policy-making positions collaborating in planning and delivering the intervention. Describing the site-specific contextual factors and decisions regarding how to tailor and implement the intervention becomes,


Dear Editor,Near-peer teaching (NPT) is an instructional method whereby more advanced students tutor their junior classmates by temporarily assuming the role of instructor. In recent years, this collaborative, student-centered, approach has garnered widespread, international interest – mainly among medical education programs.Many applications of NPT occur in contexts that use some type of problem-based learning (PBL) and/or small group settings featuring a fairly low teacher-to-student ratio . In factAlthough the feedback from both instructors (tutors) and students involved in NPT, in our experience, tends to be quite positive, careful evaluation and monitoring of the process is crucial to promptly identify any issues that may interfere with achieving the stated learning objective(s). Furthermore, the development of such mechanisms requires detailed documentation and evaluation to ensure that resulting changes have the desired (positive) effects.In our department, we have used NPT for more than five years and have identified several problems in the implementation process; for example, during the discussion sessions of clinical cases , the intas it occurred within the session.Associated training sessions for instructors (tutors) occurred weekly, and stressed three main objectives: 1) understanding the learning objective of the session, 2) reviewing the adequacy, relevance, and approach of the thematic content, and 3) understanding the function of the instruction process. The monitor tutors were present in all discussion activities and charged with detecting and correcting any situation or anomaly The subsequent satisfaction surveys then elicited the opinions of all NPT participants  to validate the impact of the changes on program function. Finally, we use specifically developed rubrics to evaluate the participation of students in the discussion activities. In summary, although there is more to be done, a keen eye must always be kept on process to ensure that positive strides are made to continually maximize the effects of this approach.