Various cell types cooperate to create a highly organized and dynamic micro-environmental niche in the bone marrow. Over the past several years, the field has increasingly recognized the critical roles of the interplay between bone marrow environment and hematopoietic cells in normal and deranged hematopoiesis. These advances rely on several new technologies that have allowed us to characterize the identity and roles of these niches in great detail. Here, we review the progress of the last several years, list some of (...) the outstanding questions in the field and propose ways to target the diseased environment to better treat hematologic diseases. Understanding the extrinsic regulation by the niche will help boost hematopoiesis for regenerative medicine. Based on natural development of hematologic malignancies, we propose that combinatory targeting the niche and hematopoietic intrinsic mechanisms in early stages of hematopoietic malignancies may help eliminate minimal residual disease and have the highest efficacy. The bone marrow is the home for blood-forming hematopoietic stem and progenitor cells. Normal generation of blood and immune cells depends on highly regulated interactions between these stem and progenitor cells with their surrounding environment. Emerging evidence suggests that therapeutic interventions directed at these cellular interdependencies can help boost hematopoiesis and eradicate malignant hematopoietic cells. (shrink)

The PRDM family has recently spawned considerable interest as it has been implicated in fundamental aspects of cellular differentiation and exhibits expanding ties to human diseases. The PRDMs belong to the SET domain family of histone methyltransferases, however, enzymatic activity has been determined for only few PRDMs suggesting that they act by recruiting co‐factors or, more speculatively, confer methylation of non‐histone targets. Several PRDM family members are deregulated in human diseases, most prominently in hematological malignancies and solid (...) cancers, where they can act as both tumor suppressors or drivers of oncogenic processes. The molecular mechanisms have been delineated for only few PRDMs and little is known about functional redundancy within the family. Future studies should identify target genes of PRDM proteins and the protein complexes in which PRDM proteins reside to provide a more comprehensive understanding of the biological and biochemical functions of this important protein family. (shrink)

The doctor-patient relationship has evolved to respect “the autonomy and patients’ rights”. One of the cornerstones in such autonomy is the opportunity for patients to draw living wills, also known as advance directives. However, information about AD available to patients remains scarce largely due to the lack of involvement of General practitioners for several reasons. The aim of our study was to evaluate current general practitioner residents’ behavior concerning their role in informing their patients about AD. We built a French (...) nationwide survey from GPR class of 2012 to 2014. Two thousand three hundred ten residents completed our survey. 89.8% declared their willingness to offer patients the opportunity of writing AD. When asked about the usefulness of AD, 73.6% of residents responded that these are a suitable help for patients, but 19.7% considered that AD are essentially geared towards frail patients. Among residents who want to inform patients about AD, 14.7% wanted to involve all patients. Only 20.5% thought that elderly people should be systematically informed about AD. When the question involves other frail people in various disease areas, information seems relevant for 60.1% of GPR considering patient with cancer or malignant hematologic disease and for 56.2% about patients affected by neurodegenerative disease. When considering the routine use of AD, 20.5% of GPR would take them into account only if they are in agreement with the patient’s decision. The results of the survey indicate that GPR would rather choose to decide who should be informed about AD, and when to take AD into account for ethical concerns. (shrink)

With decades of research seeking to generalize sterile alpha motif (SAM) biology, many outstanding questions remain regarding this multi‐tool protein module. Recent data from structural and molecular/cell biology has begun to reveal new SAM modes of action in cell signaling cascades and biomolecular condensation. SAM‐dependent mechanisms underlie blood‐related (hematologic) diseases, including myelodysplastic syndromes and leukemias, prompting our focus on hematopoiesis for this review. With the increasing coverage of SAM‐dependent interactomes, a hypothesis emerges that SAM interaction partners and binding affinities (...) work to fine tune cell signaling cascades in developmental and disease contexts, including hematopoiesis and hematologic disease. This review discusses what is known and remains unknown about the standard mechanisms and neoplastic properties of SAM domains and what the future might hold for developing SAM‐targeted therapies. (shrink)

BackgroundA child’s death is the most stressful event and the most complex grief that families face. The process of psychological adaptation to the illness and death of a child is difficult due to a variety of emotional reactions. Parental grief had received the attention of researchers only in recent years when it became clear that this reality differs substantially from the general grief process.ObjectiveThis work aims to highlight the needs of bereaved parents; increase the specificity and effectiveness of the therapeutic (...) approach to prevent complications in the process of loss-making; and find the recurrent thematic nuclei in the development of bereavement present in a therapeutic group of parents who have lost their child to an onco-hematological disease.MethodBetween 2011 and 2016, five therapeutic groups for the grief elaboration were made. The sample included a total of 50 parents of children who died from cancer between the ages of 0 and 21 years.Content analysis was carried out as a qualitative analysis method. The SAS® Text Miner software was used to read, interpret, classify and integrate the data from numerous sources.ResultsThe development and consecutive interpretation of the 5 clusters have been carried out to analyze the related topics using the node “Topic Analysis” and requesting the subdivision into five topics. Four topics have been well defined. Clear topics are reducible to categories of emotional relief, tools, legacy, and unfinished business. The topic analysis provides interesting indications about the different interpretive journeys of the bereavement situation and offers ideas regarding the different types of social responses.ConclusionsAfter reviewing the existing bibliography, we have confirmed the lack of specific literature on the problem of grief in parents whose children have died from cancer. Much research has shown that parents who lose a child to cancer want support, and there are still few studies on the most effective interventions for this group. (shrink)

A major challenge for The Cancer Genome Atlas (TCGA) Project is solving the high level of genetic and epigenetic heterogeneity of cancer. For the majority of solid tumors, evolution patterns are stochastic and the end products are unpredictable, in contrast to the relatively predictable stepwise patterns classically described in many hematological cancers. Further, it is genome aberrations, rather than gene mutations, that are the dominant factor in generating abnormal levels of system heterogeneity in cancers. These features of cancer could (...) significantly reduce the impact of the sequencing approach, as it is only when mutated genes are the main cause of cancer that directly sequencing them is justified. Many biological factors (genetic and epigenetic variations, metabolic processes) and environmental influences can increase the probability of cancer formation, depending on the given circumstances. The common link between these factors is the stochastic genome variations that provide the driving force behind the cancer evolutionary process within multiple levels of a biological system. This analysis suggests that cancer is a disease of probability and the most‐challenging issue to the TCGA project, as well as the development of general strategies for fighting cancer, lie at the conceptual level. BioEssays 29:783–794, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

BackgroundThis study aimed to determine the elements and the extent of information that child participants and their parents would like to read in an informed assent form /informed consent form of a pediatric drug trial.MethodsA descriptive survey was conducted to determine the perceived importance of each element of the ICF content from child participants and their parents who underwent informed assent/consent of a multi-center pediatric drug trial. The respondents were asked to indicate the level of importance of each item in (...) a questionnaire, by giving a rating scale from 1 to 5.ResultsA total of 22 families, 17 child participants with the diagnosis of hematology or oncology diseases and 27 parents, were enrolled. Among 30 items, risk–benefit aspects were perceived to be of most concerning items from both child participants’ and parents’ viewpoint. None of the items were considered ‘slightly important’ or lower by more than 20% of the respondents.ConclusionsFor pediatric drug trials, risk–benefit information should be made a salient feature of an IAF/icf. This empirical data could help related stakeholders arrange essential information in order of importance and tailor an IAF/icf to better suit child participants’ and parents’ needs, particularly for pediatric drug trials involving children with the diagnosis of hematology or oncology diseases. (shrink)

Dysregulation of genes that control cell‐cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post‐mitotic neurons under certain conditions. The gene for ataxia‐telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss‐of‐function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) (...) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss‐of‐function mutations in which account for about half of cases of early‐onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re‐expression sensitizes derivative cell lines to inhibitors of cell‐cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long‐held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders. BioEssays 30:719–727, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Robust ex vivo expansion of umbilical cord blood (UCB) derived hematopoietic stem and progenitor cells (HSPCs) should enable the widespread use of UCB as a source of cells to treat hematologic and immune diseases. Novel approaches for HSPC expansion have recently been developed, setting the stage for the production of blood stem cell derived products that fulfill our current best known criteria of clinical relevance. Translating these technologies into clinical use requires bioengineering strategies to overcome challenges of scale‐up, reproducibility, (...) and product quality assurance. Clinical‐scale implementation should also define criteria and targets for cost‐effective cell manufacturing. As production strategies become more effective, new opportunities in the therapeutic use of ex vivo expanded hematopoietic cell products will emerge. Herein we examine key technological milestones that need to be met in order to move ex vivo expanded HSPC therapies from the bench‐top to the bedside in a robust and reliable manner. (shrink)

An eighteen‐year‐old with sickle cell disease was admitted to the pediatric hematology service at his local children's hospital for management of an acute pain crisis, one of many such admissions. He had a good relationship with his primary hematologist and primary nurse, but with other health care providers, there was evident friction. Sometimes, he was simply rude, rolling over and pretending to sleep in response to questions about his symptoms. When frustrated or convinced that his pain was not being addressed (...) appropriately, he was prone to yelling and cursing at his nurses. After members of the health care team complained, their supervisor decided to transfer the patient to an adult general medicine service. Reasons cited for the transition included the stressful work environment created by the patient's actions, his refusal to follow directives from staff (although he was generally adherent to treatment), and the hypothetical harm to other young patients who might witness his behavior. Was this a just outcome? Is it ever permissible to deny access to pediatric care to a patient whose best interests would be served by it? Can access be withheld for “bad” behavior, and can transfer of care be wielded as a punishment? (shrink)

Robust ex vivo expansion of umbilical cord blood (UCB) derived hematopoietic stem and progenitor cells (HSPCs) should enable the widespread use of UCB as a source of cells to treat hematologic and immune diseases. Novel approaches for HSPC expansion have recently been developed, setting the stage for the production of blood stem cell derived products that fulfill our current best known criteria of clinical relevance. Translating these technologies into clinical use requires bioengineering strategies to overcome challenges of scale‐up, reproducibility, (...) and product quality assurance. Clinical‐scale implementation should also define criteria and targets for cost‐effective cell manufacturing. As production strategies become more effective, new opportunities in the therapeutic use of ex vivo expanded hematopoietic cell products will emerge. Herein we examine key technological milestones that need to be met in order to move ex vivo expanded HSPC therapies from the bench‐top to the bedside in a robust and reliable manner. (shrink)

This book provides a comprehensive account of vascular biology and pathology and its significance for health and disease. It systematically and chronologically explains how we came to our current understanding of the vasculature and it's function today, and describes in an entertaining way the diverse flaws and turns in science and medicine from the past. It thereby offers a complete and well-studied history on vascular biology and medicine. The book has an easy-to-read style and is written for students as well (...) as scientists, physicians and lecturers in the field of biomedicine, human physiology, cardiology and hematology. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Advocates, Not Problem ParentsAnonymous TwoNothing could have prepared us for the shock of hearing that our son had a brain tumor.Rob* was 13½, an active, healthy eighth grader, when he developed a headache so bad he couldn’t get out of bed in the morning. We saw the pediatrician three times over the next ten days. On the third visit, after ruling out problems at home, stress at school, strep (...) throat and mono, he sent us for an MRI. When the radiology tech handed me the films and told us to drive back to the pediatrician’s office, I knew we were in trouble. Sure enough, after all the other patients had left, our long–time doctor called us into his tiny office, shut the door and fumbled with the films as he pointed to a white spot that he said was a brain tumor.So began the experience that would change the course of our lives. We remember the diagnosis in detail and relive it in slow motion. We recall packing suitcases, driving to the hospital, waiting to be seen in the emergency room, and walking through doors marked “Pediatric Hematology/Oncology” for the first time.We date everything “BC” (Before Cancer) or “AD” (After Diagnosis). We are grateful every day that [End Page 13] our son is alive, but we know he is forever changed. We are changed: Our nuclear family, our extended family, everyone who knew us and supported us at the time was affected. A pediatric cancer diagnosis is a bomb that shatters your world without warning. If you’re lucky, you can pick up a lot of the pieces, maybe even most of them, but the world you re–enter is never the one you inhabited before.Our doctor delivered the diagnosis to Rob and me at the same time. I’ve thought about this many times and perhaps one day will ask him: Why did he choose to do it that way? Was it a conscious decision or just happenstance? Was it kinder, in the long run—like pulling off a band–aid quickly—or terribly risky? What if I had collapsed at the news? I asked to step into the hall to use the phone. In a state of numbness, I called my husband. He knew we had had an MRI a few hours earlier. “Come quickly,” I said. “There’s a mass.”We chose to go to a top-ranked major medical center and were admitted that evening. A couple of days later, the discovery of tumor markers in Rob’s cerebrospinal fluid and blood confirmed a central nervous system mixed germ cell tumor. We were told he would require six cycles of chemotherapy, followed by six weeks of radiation, and possibly second–look surgery and high-dose chemo with stem cell rescue on top of that. We were given a consent form listing a catalogue of short–and long–term side effects, among them the likelihood of infertility. We were urged to start treatment as soon as possible.By sheer coincidence I had just completed a project for a small, nonprofit organization that existed to inform young adult cancer patients about their fertility rights and options. I knew that infertility concerns were usually pushed aside at diagnosis to make way for other priorities, namely the urgency of starting treatment. And that’s exactly the kind of pressure we were facing.But my husband and I were not ready to sign away our son’s fertility in what felt like a no–confidence vote, a capitulation. We needed to believe that he would survive and put this horror behind him, that he would look forward to marriage and starting a family. We were willing to cede nothing to the disease at this early stage of the game. Was this rational, naive or selfish on our part? I don’t know.The medical team seemed surprised when we asked for a delay in treatment in order to collect sperm samples. They warned that our son’s condition could decline suddenly—and that postponing treatment by even several days might be dangerous. However, at our insistence, they agreed to the delay... (shrink)

A new analysis of the Best Interests Standard is given and applied to the controversy about testing children for untreatable, severe late-onset genetic diseases, such as Huntington's disease or Alzheimer's disease. A professional consensus recommends against such predictive testing, because it is not in children's best interest. Critics disagree. The Best Interests Standard can be a powerful way to resolve such disputes. This paper begins by analyzing its meaning into three necessary and jointly sufficient conditions showing it: is an (...) "umbrella" standard, used differently in different contexts, has objective and subjective features, is more than people's intuitions about how to rank potential benefits and risks in deciding for others but also includes evidence, established rights, duties and thresholds of acceptable care, and can have different professional, medical, moral and legal uses, as in this dispute. Using this standard, support is given for the professional consensus based on concerns about discrimination, analogies to adult choices, consistency with clinical judgments for adults, and desires to preserve of an open future for children. Support is also given for parents' legal authority to decide what genetic tests to do. (shrink)

Pandemic plans recommend phases of response to an emergent infectious disease outbreak, and are primarily aimed at preventing and mitigating human-to-human transmission. These plans carry presumptive weight and are increasingly being operationalized at the national, regional and international level with the support of the World Health Organization. The conventional focus of pandemic preparedness for EIDs of zoonotic origin has been on public health and human welfare. However, this focus on human populations has resulted in strategically important disciplinary silos. As the (...) risks of zoonotic diseases have implications that reach across many domains outside traditional public health, including anthropological, environmental, and veterinary fora, a more inclusive ecological perspective is paramount for an effective response to future outbreaks. (shrink)

Background: Arthritis is very common but is not well understood. Actually, “arthritis” is not a single disease; it is an informal way of referring to joint pain or joint disease. There are more than 100 different types of arthritis and related conditions. People of all ages, sexes and races can and do have arthritis, and it is the leading cause of disability in America. More than 50 million adults and 300,000 children have some type of arthritis. It is most common (...) among women and occurs more frequently as people get older. Common arthritis joint symptoms include swelling, pain, stiffness and decreased range of motion. Symptoms may come and go. They can be mild, moderate or severe. They may stay about the same for years, but may progress or get worse over time. Severe arthritis can result in chronic pain, inability to do daily activities and make it difficult to walk or climb stairs. Arthritis can cause permanent joint changes. These changes may be visible, such as knobby finger joints, but often the damage can only be seen on X-ray. Some types of arthritis also affect the heart, eyes, lungs, kidneys and skin as well as the joints. Objectives: The main goal of this expert system is to get the appropriate diagnosis of disease and the correct treatment and give the appropriate method of treatment through several tips that concern the disease and how to treat it and we will see it through the application on the expert system. Methods: in this paper the design of the proposed Expert System which was produced to help Orthopedist in diagnosing Arthritis disease through its symptoms such as: pain on pressure in a joint , Inflammation indicated by joint swelling, Stiffness especially in the morning , Loss of flexibility of joint, Limited, joint movement, Deformity of the joints , Weight loss and fatigue , Non-specific fever and Crepitus. The proposed expert system presents an overview about Arthritis disease is given, the cause of diseases is outlined and the treatment of disease whenever possible is given out. SL5 Object Expert System language was used for designing and implementing the proposed expert system. Results: The proposed Arthritis disease diagnosis expert system was evaluated by Orthopedics students and they were satisfied with its performance. Conclusions: The Proposed expert system is very useful for Orthopedist, patients with arthritis and newly graduated Orthopedics students. (shrink)

Purposeful infection of healthy volunteers with a microbial pathogen seems at odds with acceptable ethical standards, but is an important contemporary research avenue used to study infectious diseases and their treatments. Generally termed ‘controlled human infection studies’, this research is particularly useful for fast tracking the development of candidate vaccines and may provide unique insight into disease pathogenesis otherwise unavailable. However, scarce bioethical literature is currently available to assist researchers and research ethics committees in negotiating the distinct issues raised (...) by research involving purposefully infecting healthy volunteers. In this article, we present two separate challenge studies and highlight the ethical issues of human challenge studies as seen through a well-constructed framework. Beyond the same stringent ethical standards seen in other areas of medical research, we conclude that human challenge studies should also include: independent expert reviews, including systematic reviews; a publicly available rationale for the research; implementation of measures to protect the public from spread of infection beyond the research setting; and a new system for compensation for harm. We hope these additions may encourage safer and more ethical research practice and help to safeguard public confidence in this vital research alternative in years to come. (shrink)

Neurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

Central African highland farmers' perceptions of common bean disease were investigated using both phytopathology and anthropological techniques. Farmers rarely mentioned diseases as production constraints in formal questionnaires. More participatory research showed farmers often related disease symptoms to the effects of rain and soil depletion for fungal diseases, or to varietal traits for bean common mosaic virus. Rain or moisture is divided into numerous forms through which it can damage plants, both physically and through putrefaction. Most conditions associated with (...) putrefaction appear to be linked to pathogens. Farmers have an understanding of plant health closely related to their concept of human health. In plants, this understanding is based on the prior state of plant health. Conceptually, local disease management strategies are based on prevention by managing the conditions that promote good plant health rather than by treating disease symptoms. Intervention strategies that build on local knowledge are encouraged. (shrink)

While Quine’s linguistic behaviorism is well-known, his Kant Lectures contain one of his most detailed discussions of behaviorism in psychology and the philosophy of mind. Quine clarifies the nature of his psychological commitments by arguing for a modest view that is against ‘excessively restrictive’ variants of behaviorism while maintaining ‘a good measure of behaviorist discipline…to keep [our mental] terms under control’. In this paper, I use Quine’s Kant Lectures to reconstruct his position. I distinguish three types of behaviorism in psychology (...) and the philosophy of mind: ontological behaviorism, logical behaviorism, and epistemological behaviorism. I then consider Quine’s perspective on each of these views and argue that he does not fully accept any of them. By combining these perspectives we arrive at Quine’s surprisingly subtle view about behaviorism in psychology. (shrink)

Many experts have warned that environmental degradation is increasing the likelihood of future pandemics like COVID-19, as habitat loss and poaching increase close contact between wildlife and people. This fact has been framed as a reason to increase wildlife conservation efforts. We have many good reasons to step up conservation efforts, but arguments for doing so on the basis of pandemic prevention are rhetorically, ethically, and empricially flawed.

After witnessing extraordinary scientific and regulatory efforts to speed development of and access to new COVID-19 interventions, patients facing other serious diseases have begun to ask “where’s...

ArgumentThis article analyzes for the first time the earliest western maps of diseases in China spanning fifty years from the late 1870s to the end of the 1920s. The 24 featured disease maps present a visual history of the major transformations in modern medicine from medical geography to laboratory medicine wrought on Chinese soil. These medical transformations occurred within new political formations from the Qing dynasty (1644–1911) to colonialism in East Asia (Hong Kong, Taiwan, Manchuria, Korea) and hypercolonialism within (...) China (Tianjin, Shanghai, Amoy) as well as the new Republican Chinese nation state (1912–49). As a subgenre of persuasive graphics, physicians marshaled disease maps for various rhetorical functions within these different political contexts. Disease maps in China changed from being mostly analytical tools to functioning as tools of empire, national sovereignty, and public health propaganda legitimating new medical concepts, public health interventions, and political structures governing over human and non-human populations. (shrink)

The complex sensation of vision begins with the relatively simple photoisomerization of the visual pigment chromophore 11-cis-retinal to its all-trans configuration. This event initiates a series of biochemical reactions that are collectively referred to as phototransduction, which ultimately lead to a change in the electrochemical signaling of the photoreceptor cell. To operate in a wide range of light intensities, however, the phototransduction pathway must allow for adjustments to background light. These take place through physiological adaptation processes that rely primarily on (...) Ca2+ ions. While Ca2+ may modulate some activities directly, it is more often the case that Ca2+-binding proteins mediate between transient changes in the concentration of Ca2+ and the adaptation processes that are associated with phototransduction. Recently, combined genetic, physiological, and biochemical analyses have yielded new insights about the properties and functions of many phototransduction-specific components, including some novel Ca2+-binding proteins. Understanding these Ca2+-binding proteins will provide a more complete picture of visual transduction, including the mechanisms associated with adaptation, and of related degenerative diseases. BioEssays 22:337–350, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Cytokines, also referred to as interleukins, are the major orchestrators of host defence processes, and, as such, are involved in insults, repair and restoration of tissue homeostasis. This review summarises recent findings on and emerging models of the biological roles of the double-edged sword interleukin-13 (IL-13), which have been principally obtained from studies in mice that are deficient for IL-13, or its components. IL-13-mediated functions not only contribute to the susceptible phenotype in Leishmania major infection but also seem to play (...) a protective role in chronic leishmaniasis. Moreover, IL-13 plays a key protective role in the expulsion of helminths from the gut while also actively contributing to the pathology in schistosomiasis. In allergic asthma, IL-13 has also been found to be a key factor. Therapeutic administration of an IL-13 inhibitor in mice successfully prevents both the allergic disease phenotype and schistosoma egg-induced lung pathology. If this scenario holds true in humans, we soon may have an efficient drug for treatment of IL-13-mediated diseases. BioEssays 22:646–656, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Background Knowing the opinions of patients with Progressive Neurological Diseases and their family members on end-of-life care can help initiate communication and the drawing up of a care plan. The aim of this paper is to describe the creation and psychometric properties of the newly developed APND-EoLC questionnaire. Methods Following focus group discussion, four main areas of interest were identified: patients’ and family members’ attitudes towards end-of-life care, factors influencing decisions about treatment to prolong patients’ life, concerns and fears (...) regarding dying, and opinions on the system of care. The created questions were divided into domains based on factor analysis and psychometric properties were evaluated by sample of 209 patients with PND and 118 their family members. Results The final version of the scale contains a total of 28 questions divided into six domains and five individual questions determining views of the care system with specified response options. Construct validity was verified by confirmatory factor analysis for each evaluated area individually. Appropriate psychometric properties were identified in the questionnaire. Conclusions The APND-EoLC questionnaire can be recommended for use in both research and clinical practice. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and (...) inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and (...) inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

In June 2021, an 1856 British Guiana 1c magenta stamp sold for US$8.3m. It is the only known specimen of its kind in existence and on a gram-for-gram basis the most valuable item in the world. Clearly, in some spheres of human engagement, rarity carries a premium. Should this logic be applied in healthcare? Magalhaes thinks not.1 They explore the topic of whether pricing and reimbursement systems should give a premium to orphan drugs for rare diseases. They argue that (...) rarity is irrelevant to pharmaceutical policy on ethical grounds, and instead drug incentives should be prioritised by disease severity. At a time when incentives for orphan medicines are being revisited globally, Magalhaes is provoking an important discussion. The author seeks to disentangle the interwoven concepts of rarity, severity and unmet need that factor into decisions on orphan drug policy. They perhaps overstate the emphasis on rarity within existing regulatory and P&R frameworks. Yes, this is one of the criteria for orphan drug designation, but in payer systems rarity is seldom explicitly referenced. For example, of the five largest European countries, only the United Kingdom formally adjusts willingness-to-pay thresholds by prevalence. In contrast, concepts of severity and unmet need feature widely in global regulatory processes (eg, Breakthrough Therapy designation from …. (shrink)

In this paper, we study a stochastic epidemic model with double epidemics which includes white noise and telegraph noise modeled by Markovian switching. Sufficient conditions for the extinction and persistence of the diseases are established. In the end, some numerical simulations are presented to demonstrate our analytical results.

Microsomal glucose‐6‐phosphatase catalyses the last step in liver glucose production. Glucose‐6‐phosphatase deficiency, now termed type 1 glycogen storage disease, was first described almost 40 years ago but until recently very little was known about the molecular basis of the various type 1 glycogen storage diseases. Recently we have shown that at least six different proteins are needed for normal glucose‐6‐phosphatase activity in liver. Four of the proteins have been purified and three cloned. Study of the type 1 glycogen storage (...) diseases has stimulated investigations of the mechanisms of small molecule transport across the endoplasmic reticulum membrane and demonstrated the existence of novel endoplasmic reticulum transport proteins for glucose and phosphate. (shrink)

Anthropogenic climate change is causing temperature rise in temperate zones resulting in climate conditions more similar to subtropical zones. As a result, rising temperatures increase the range of disease-carrying insects to new areas outside of subtropical zones, and increased precipitation causes flooding that is more hospitable for vector breeding. State governments, the federal government, and governmental agencies, like the Animal and Plant Health Inspection Service of USDA and the National Notifiable Disease Surveillance System of the U.S. Centers for Disease Control (...) and Prevention, lack a coordinated plan for vector-borne disease accompanying climate change. APHIS focuses its surveillance primarily on the effect of illness on agricultural production, while NNDSS focuses on the emergence of pathogens affecting human health. This article provides an analysis of the current framework of surveillance of, and response to, vector-borne infectious diseases, the impacts of climate change on the spread of vector-borne infectious diseases, and recommends changes to federal law to address these threats. (shrink)

"The largest Ebola outbreak to date—first detected in December 2013 and still ongoing as of April 2015—has cast new light on the shortfalls of international public health systems.1 As in previous health crises, scrutiny has reemerged over the pharmaceutical industry’s ability and willingness to innovate new medicines for underserved disease areas. The public debate has intensified following revelations that promising drug candidates to treat Ebola had gone undeveloped despite compelling preclinical results.2 This lack of development is especially troubling because it (...) occurred after a recently implemented U.S. incentive scheme—the Food and Drug Administration’s (FDA) tropical disease priority review voucher program—designed to counteract exactly this problem. Taking Ebola as a case in point, it is useful to examine the short history and ongoing refinement of this voucher program, since it represents one of the most significant legislative efforts to systematically address the relative absence of com- mercial rewards for drugs targeting tropical diseases. This analysis evaluates the voucher program’s effectiveness for both stimulating private sector innovation and achieving positive health impacts among populations most severely burdened by tropical diseases. It then proposes specific recommendations for how law- makers can improve the program’s legislation to better achieve these objectives. ". (shrink)