In a recent article (“The current state of the platelet supply in the US and proposed options to decrease the risk of critical shortages”) published in _Transfusion,_ Stubbs et al. have argued that platelet donors should be paid. Dodd et al. have argued against this proposal, supporting their response with survey data that shows that blood donors (and by extension platelet donors) and potential platelet donors are uninterested in receiving incentives to encourage them to donate. Instead, (...) argue Dodd et al., prospective platelet donors are motivated more by the ease of donation than the prospect of payment. This article defends Stubbs et al. from the criticisms of Dodd et al. It first argues that the preferences that persons state they have in response to survey questions might not reflect the preferences that their actions would reveal they have in actual rather than hypothetical situations. This hypothetical bias is especially likely when persons respond to surveys that ask them about the performance of morally commendable actions (such as platelet donation). This article then argues that the survey that Dodd et al. rely on exhibits serious selection bias with respect to the set of persons it considers to be potential platelet donors. (shrink)

Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α‐granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet‐derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet‐secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, (...) and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo‐angiogenesis and the growth of newly formed myofibers, and reduces post‐injury muscle force production. Platelets also contribute to the recruitment of pro‐regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease. (shrink)

Platelet‐derived growth factor (PDGF) was originally identified in platelets and in serum as a mitogen for fibroblasts, smooth muscle cells (SMC) and glia cells in culture. PDGF has since expanded to a family of dimers of at least four gene products, whose biological actions are mediated through two receptor tyrosine kinases, PDGFRs. The present review summarizes and discusses the biological functions of PDGFs and PDGFRs in developmental processes, mainly as revealed through genetic analysis in mice. Such studies have demonstrated (...) multiple critical roles of PDGFs and PDGFRs in embryonic and postnatal development. PDGFs seem to act upon specific populations of progenitor cells that give rise to several different cell types with distinct functions in a variety of developmental processes. Analogies are seen between the cell functions and the developmental processes controlled by PDGFs. This suggests that ancestral PDGF and PDGFR expression patterns and functions may have been iterated in related sets of morphogenetic processes in the course of evolution. BioEssays 23:494–507, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The use of platelet rich plasma as a novel treatment is discussed in the context of a qualitative research study comprising 38 interviews with sports medicine practitioners and other stakeholders working within the English Premier League during the 2013–16 seasons. Analysis of the data produced several overarching themes: conservatism versus experimentalism in medical attitudes; therapy perspectives divergence; conflicting versions of appropriate evidence; subcultures; community beliefs/practices; and negotiation of medical decision-making. The contested evidence base for the efficacy of PRP is (...) presented in the context of a broader professional shift towards evidence based medicine within sports medicine. Many of the participants while accepting this shift are still committed to casuistic practices where clinical judgment is flexible and does not recognize a context-free hierarchy of evidentiary standards to ethically justifiable practice. We also discuss a tendency in the data collected to consider the use of deceptive, placebo-like, practices among the clinician participants that challenge dominant understandings of informed consent in medical ethics. We conclude that the complex relation between evidence and ethics requires greater critical scrutiny for this emerging specialism within the medical community. (shrink)

In the world of elite sport, pain and suffering are inherent. In exploring return-to-play treatments and decision-making in sports medicine, two overarching areas seem to dominate the existing lite...

Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of (...) class='Hi'>platelet aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. (shrink)

Severe COVID‐19 is often accompanied by coagulopathies such as thrombocytopenia and abnormal clotting. Rarely, such complications follow SARS‐CoV‐2 vaccination. The cause of these coagulopathies is unknown. It is hypothesized that coagulopathies accompanying SARS‐CoV‐2 infections and vaccinations result from bacterial co‐infections that synergize with virus‐induced autoimmunity due to antigenic mimicry of blood proteins by both bacterial and viral antigens. Coagulopathies occur mainly in severe COVID‐19 characterized by bacterial co‐infections with Streptococci, Staphylococci, Klebsiella, Escherichia coli, and Acinetobacter baumannii. These bacteria express unusually (...) large numbers of antigens mimicking human blood antigens, as do both SARS‐CoV‐2 and adenoviruses. Bacteria mimic cardiolipin, prothrombin, albumin, and platelet factor 4 (PF4). SARS‐CoV‐2 mimics complement factors, Rh antigens, platelet phosphodiesterases, Factors IX and X, von Willebrand Factor (VWF), and VWF protease ADAMTS13. Adenoviruses mimic prothrombin and platelet factor 4. Bacterial prophylaxis, avoidance of vaccinating bacterially infected individuals, and antigen deletion for vaccines may reduce coagulopathy risk. Also see the video abstract here: https://youtu.be/zWDOsghrPg8. (shrink)

Abstract: Tomatoes are part of the major crops in food security. Tomatoes are plants grown in temperate and hot regions of South American origin from Peru, and then spread to most countries of the world. Tomatoes contain a lot of vitamin C and mineral salts, and are recommended for people with constipation, diabetes and patients with heart and body diseases. Studies and scientific studies have proven the importance of eating tomato juice in reducing the activity of platelets in diabetics, which (...) helps in protecting them from developing deadly blood clots. A tomato classification approach is presented with a data set containing approximately 5,266 images with 7 species belonging to tomatoes. The Neural Network Algorithms (CNN), a deep learning technique applied widely in image recognition, is used for this task. (shrink)

A general hypothesis of atom size effects for G.P. zone formation is discussed in this paper and results are presented of precipitation in the systems Fe-Au and Fe-Mo. Techniques used are resistivity measurements and electron microscopy. In the Fe-Mo system it is shown that after initial cluster formation during the early stages of ageing after the quench, further growth ceases and vacancies anneal out into dislocation loops. The activation energy for the initial clustering was 1·3 ev whilst the excess vacancy (...) concentration estimated from the loop area gave a vacancy formation energy of ∼1·5 ev. These results confirm recent quenching results on pure iron. The refusal of Mo zones to grow confirms the general hypothesis of size effects.In the Fe-Au system precipitation of gold platelets after quenching is shown to be associated with the high density of dislocations formed during quenching through the phase transformation of the iron matrix. The effect of the dislocations is shown by the low value of ∼0·5 for the Johnson—Mehl kinetic parameter and by the activation energy for growth which is ∼0·8 of the equilibrium diffusion energy for Au in Fe. As the size-effect hypothesis does not apply to precipitation on dislocations the growth of zones in Fe—Au does not affect its validity. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:What Now?Mike AbellThe cry broke the church’s uncomfortable silence. It actually was more of a moan than a cry. It was deeper, coming from her core. I’d heard it only once before and knew it as a sound caused by a loss that will never be recovered. No one in the church had to turn to discover its source. We all knew the mother had entered to say goodbye (...) to her 19–month–old son.We watched as the now composed mother, along side her husband, followed the small casket—a family rendered incomplete. As they passed our pew, my wife clutched my arm and we wept tears of sympathy, guilt and fear.Just 15 months earlier our now, 2–and ½–year–old son, Jun, had been diagnosed with a brain tumor not dissimilar from the child in the casket. The tumor has a different name, but it’s equally complicated, and comparably rare and aggressive.Over nine months, Jun endured two craniotomies, three rounds of induction chemo, three rounds of high dose chemo with stem cell rescue, 28 days of proton radiation, a sub–dural shunt placement, a port placed and removed, a broviac placed and removed and many, many blood and [End Page 16] platelet transfusions. As of his last scan, there was no evidence of tumor.Jun has now been out of treatment for six months. His hair has grown back. He’s stronger. The meals have stopped arriving. And we no longer are the recipients of sad eyes at playgrounds and restaurants.In many ways we have returned to a somewhat normal life. If you didn’t know Jun was in remission for a brain tumor, you wouldn’t know. Despite all this, cancer still strangles us with fear.Brain tumors often come back. Too often. We’ve heard a few different numbers on the likelihood. And while we’ve never paid too much attention to statistics, they are too scary to ignore. Especially knowing that should it recur, there is no cure. This is our day–to–day reality.A lot of our time is spent analyzing, over analyzing and obsessing. We watch him closely. Every time he stumbles, coughs, or sleeps fifteen minutes longer than normal, we wonder if it’s something more. I’ve called our oncologist about a 99–degree temperature. Something I wouldn’t have done during treatment (I usually waited to 100). I’ve questioned whether hiccups are a sign of recurrence. Admittedly, I’ve even Googled that last one just to be sure.All the anxiety builds the closer you get to an MRI date. My son has scans every three months so I’m beginning to recognize the cycle. It starts a couple weeks out. Normally it begins as a twinge the moment the date is set. But each day it grows, occupying more and more of my mind. This is not to say, I don’t think about it everyday. I do. But the thoughts become more paranoid and frequent. Worst–case scenarios play out. It’s different from the time during treatment. We always had the comfort of knowing that there is still more treatment.By the time we reach MRI day, bring Jun back to the machine room, watch the anesthesiologist put him under, and leave him to be scanned for the next two and half hours, I feel close to nauseas. In my mind, at this point, someone knows. I know they may be a technician and are not necessarily trained to read an MRI. But they know. They’ve seen it before.There usually is a waiting period between the time of the scan and the time you can meet with your oncologist or someone else qualified to read and interpret the scan. I do whatever I can to make that window as narrow as possible. I leave radiology with a disc in hand and head directly to the clinic to pass it off. I’ve heard of people waiting days for an appointment. That’s not an option for me. There would be no eating, no sleeping, and no resting heart rate without knowing. Fortunately, our oncologist is... (shrink)

The formation of particles of elemental tin in association with the nucleation of the precipitate phase θ′ in an Al–1.7 at.% Cu–0.01 at.% Sn alloy has been investigated by high resolution transmission electron microscopy. Analysis of lattice images has demonstrated that these tin particles associated with θ′ platelets formed during short-term ageing (typically 3 min at 200 degrees Celcius) exhibit a crystallographic form that is distinctly different from that previously reported in such ternary alloys and also from that observed in (...) the binary alloy Al–0.01 at.% Sn. Those tin particles that could be clearly identified as β-Sn phase shared a crystallographic relationship of the form (001)Sn‖(001)Al‖(001)θ′, [110]Sn‖[100]Al‖[100]θ′ with the α-Al and θ′ phases with which they were simultaneously in contact. The observations imply that, while tin may assist nucleation of platelets of θ′, the formation of θ′ equally influences the crystallography of β--Sn that forms in association with θ′. Following prolonged ageing (typically 50 h at 200°C), the β-Sn particles in contact with θ′ plates had coarsened and diminished in number, and most now exhibited an orientation relationship with α-Al matrix similar to that observed in the binary alloy Al–0.01 at.% Sn (i.e. (100)Sn‖(111)Al, [010]Sn‖[112]Al) and to that previously observed in the later stages of ageing of the ternary alloy Al–1.7 at.% Cu–0.01 at.% Sn. (shrink)

Protein‐carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate‐binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L‐, E‐ and P‐selectins, have domains homologous to other Ca2+‐dependent (C‐type) lectins. L‐selectin is expressed constitutively on lymphocytes, E‐selectin is expressed by activated endothelial cells, and P‐selectin is expressed by activated platelets and endothelial cells. Here, we review (...) the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L‐selectin on leukocyte surfaces. In contrast, E‐ and P‐selectins recognize specific carbohydrate determinants related to sialyl Lex antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitemient among glycoconjugate researchers that other carbohydrate‐binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions. (shrink)

Multicellular organisms develop on a predictable schedule that depends on both cell‐intrinsic timers and sequential cell‐cell interactions mediated by extracellular signals. The interplay between intracellular timers and extracellular signals is well illustrated by the development of oligodendrocytes, the cells that make the myelin in the vertebrate central nervous system. An intrinsic timing mechanism operates in each oligodendrocyte precursor cell to limit the length of time the cell divides before terminally differentiating. This mechanism consists of two components, a timing component, which (...) depends on the mitogen platelet‐derived growth factor (PDGF) and measures elapsed time, and an effector component, which depends on thyroid hormone and stops cell division and initiates differentiation at the appropriate time. The cell‐cycle inhibitor p27/Kip1 accumulates in the precursor cells as they proliferate and is part of both components of the timer. It seems likely that similar timing mechanisms operate in other cell lineages. BioEssays 22:64–71, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear—while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, (...) we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands such (...) as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

The mitogenic action of cytokines such as epidermal growth factor (EGF)d̊ or platelet dericed growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor‐induced and oncogenic activation of Ras involve the conversion of Ras from the GDP‐bound (D‐Ras) to the GTP‐bound (T‐Ras) forms. T‐Ras activates a network of protein (...) kinases including c‐Mos, c‐Raf‐1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c‐Jun, c‐Myc and c‐Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the coversion of T‐Ras to D‐Ras. A series of small NF1 fragments, which bind T‐Ras, as well as truncated forms or derivatives of c‐Raf‐1, c‐Jun and c‐Myc, are capable of blocking the T‐Ras‐activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T‐Ras‐associated tumors, which represent more than 30% of total human carcinomas. (shrink)

The role of membrane receptors is regarded as being to transduce the signal represented by ligand binding from the external cell surface across the membrane into the cell. Signals are subsequently conveyed from the cytoplasm to the nucleus through a combination of second-messenger molecules, kinase/phosphorylation cascades, and transcription factor (TF) translocation to effect changes in gene expression. Mounting evidence suggests that through direct targeting to the nucleus, polypeptide ligands and their receptors may have an important additional signaling role. Ligands such (...) as those of the platelet-derived and fibroblast growth factor classes, as well as cytokines such as interferon-γ and interleukins-1 and -5, have been found to localize in the nucleus through the action of nuclear localization sequences (NLSs). Where tested, these NLSs appear to be essential for full signaling activity and may be responsible for cotranslocating receptors to the nucleus in complexes with their ligands. The implication is that, subsequent to endocytosis at the membrane, particular polypeptide ligands or their receptors, or both, may translocate to the nucleus to participate directly in gene regulation. BioEssays 20:400–411, 1998.© 1998 John Wiley & Sons Inc. (shrink)

Although the generation of reactive oxygen species is an activity normally associated with phagocytic leucocytes, mammalian spermatozoa were, in fact, the first cell type in which this activity was described. In recent years it has become apparent that spermatozoa are not the only nonphagocytic cells to exhibit a capacity for reactive oxygen species production, because this activity has been detected in a wide variety of different cells including fibroblasts, mesangial cells, oocytes, Leyding cells endothelial cells, thryroid cells, adipocytes, tumour cell (...) and platelets. Since the capacity to generate reactive oxygen species is apparently so widespread, the risk‐benefit equation for these potentially pernicious molecules becomes a matter of intese interest. In the case of human spermatozoa, the risk of manufacturing reactive oxygen metabolites is considerable because these cells are particularly vulnerable to lipid peroxidation. Indeed, there is now good evidence to indicate that oxygen radicals are involved in the initiation of peroxidative damage to the sperm plasma membrane, seen in many cases of male infertility. This risk is off‐set by recent data suggesting that superoxide anions and hydrogen peroxide also participate in the induction of key biological events such as hyperactiavated motility and the acrosome reaction. Thus, human spermatozoa appear to use reactive oxygen species for a physiological purpose and have the difficult task of ensuring the balanced generation of these potentially harmful, but biologically important, modulators of cellular function. (shrink)

In the mouse, at least 16 genes regulate vesicle trafficking to specialized lysosome‐related organelles, including platelet dense granules and melanosomes. Fourteen of these genes have been identified by positional cloning. All 16 mouse mutants are models for the genetically heterogeneous human disease, Hermansky–Pudlak Syndrome (HPS). Five HPS genes encode known vesicle trafficking proteins. Nine genes are novel, are found only in higher eukaryotes and encode members of three protein complexes termed BLOCs (Biogenesis of Lysosome‐related Organelles Complexes). Mutations in murine (...) HPS genes, which encode protein co‐members of BLOCs, produce essentially identical phenotypes. In addition to their well‐known effects on pigmentation, platelet function and lysosome secretion, HPS genes control a wide range of physiological processes including immune recognition, neuronal functions and lung surfactant trafficking. Studies of the molecular functions of HPS proteins will reveal important details of vesicle trafficking and may lead to therapies for HPS. BioEssays 26:616–628, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:In Search of FaithKate RowlandSometimes I’m jealous of my patients’ faith. As a former happily religious person I miss the benefits I used to get from an active faith. I know that some of my patients must struggle with their faith, and I know the struggle probably affects their well–being. For those who simply believe or those who simply don’t believe, it’s easy. And for those who do believe, (...) there can be so much serenity and so much reward.As a doctor, I spend a lot of time reading science, weighing evidence, and making recommendations. Religion has been a respite from this. Faith, for me, has never been a series of decisions based on the best available evidence. I could analyze it as much as I wanted, peel its layers apart, question it, but in the end, it was just faith, not a hypothesis. It has always been something that I believe (or don’t), and practicing my faith had always been a relatively pleasant decision of figuring out what kind of community I want to share in.My faith life has been in shambles for the past several years. I feel distant from and unwelcome in the church where I was raised, and I haven’t found anywhere else to land. I cannot decide how to raise my own small children. I want them to have grounding in God, but I can’t decide how much I believe in God anymore, and I am fixated on the idea that I don’t want to be hypocritical or lie to [End Page 210] them. I don’t want them to see me worshipping in a way that is not really authentic to me.My husband is agnostic—literally—on the issue. He is open to introducing a loving, kind, forgiving God, but unsure about a God incarnate. We both worry about the identity with a particular religion usurping the actual relationship with God: I am [religion], therefore I believe [this], therefore my God does [this] or is [this].And so all of these fears and doubts have led us to live with no religion, and no outward faith. Our children attend a parochial nursery school run by a religion other than one where we were raised, and they have an apparently happy but neutral opinion of religion and God. They understand ceremonies. At age four, they have a more active faith life than I do, since they attend weekly services at school. But then, they have fewer choices than I do. They do what the teachers tell them. They would do what I told them to do, if I could ever decide what I believed in.I spend so many hours a week with my patients that they have become my main source of demonstration of active, living faith. I know that they share mostly good parts with me. I see so much of the good because I mostly see patients who get to choose how to practice their own religions; they don’t feel oppressed by religious or culturo–religious demands or expectations. It’s interesting that I see the positive sides of their faith, not the struggle, because I otherwise see a lot of the struggling parts of their lives. I see the flinty, edgy woman, the patient who has spent more time in the hospital in the past month than I have, the woman who is sick of her low platelet count that keeps her from living a normal life. And every day she has some message of faith: she tells our medical team what Bible passage is keeping her strong, she tells us how God watches over her when we tell her that her counts are better, she tells us to have a blessed day. Sometimes she curses at the hospital or her condition or at her medications, sometimes at us. So far her faith is unshaken.I take care of a woman who has burning mouth syndrome, a chronic condition that causes her lips, her tongue, and her palate to feel as though they are on fire. Eating makes it worse, drinking makes it worse, breathing makes it worse... (shrink)

Thrombospondin (TSP‐1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP‐1, the following observations suggest that TSP‐1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP‐1 and inhibited by anti‐TSP‐1 antibodies. (2) TSP‐1 promotes tumor cell adhesion, migration and invasion. (3) TSP‐1 promotes angiogenesis in the rat aorta model. (4) TSP‐1 up‐regulates the plasminogen activator system through a mechanism (...) involving the activation of TGF‐β1. (5) Human tumors express increased levels of the CSVTCG‐specific TSP‐1 receptor. (6) Tumor stroma is enriched in TSP‐1. (7) Cancer patients have high blood levels of TSP‐1. (8) Poor patient survival correlates with a higher expression of the CSVTCG‐specific TSP‐1 receptor on tumor cells. In this paper we discuss the evidence that TSP‐1 promotes tumor progression and present a hypothetical scheme for its mechanism of action. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Clinicians’ “Folk” Taxonomies and the DSM: Pick Your PoisonG. Scott Waterman (bio)Keywordsnosology, classification, diagnosis, psychopathologyWith attention turning to the process of formulating the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V; e.g., Kendler et al. 2008), the study by Flanagan and Blashfield (2007) of the similarities and differences between clinicians’ “folk” taxonomies and psychiatry’s official one is timely, and its lessons are in need of (...) analysis. In this commentary I first address questions raised by the existence of multiple de facto taxonomies, and by the characteristics of those taxonomies themselves, before focusing attention on the DSM diagnostic system and its attributes that make acceptance by its constituencies far less than complete. Although the aim of Flanagan’s and Blashfield’s study is explicitly descriptive rather than normative, it provides an important opportunity to examine the extent to which our taxonomies serve the purposes for which they were constructed—whether by experts or by clinicians.There are certainly reasons to expect significant deviations between clinicians’ everyday taxonomies and the official one. Perhaps the most glaring reason is the fact that—even if it were desirable—no one can be familiar with the enormous number of categories codified by the DSM. On the other hand, the remarkable hegemony of the DSM—in the education and training of physicians and clinical psychologists, in clinical communication, and in the ubiquitous administrative functions of billing and coding—makes such deviations at least somewhat surprising and in need of scrutiny and explanation. The first question, however, is whether one should be concerned by the existence (surprising or otherwise) of multiple taxonomies. Flanagan and Blashfield make the compelling case that, given the high rate at which Americans seek clinical attention for psychiatric problems, the stakes are commensurately high for our efforts at categorizing those problems in valid and useful ways. And the extent to which a gulf exists between the way psychiatry and clinical psychology are written about and taught on the one hand, and conceptualized and practiced by clinicians on the other, invites a multitude of problems—among which cynicism about our disciplines may be one of the most pernicious.At least as important as their finding of only moderate correlations between clinicians’ taxonomies [End Page 271] and that of the DSM are the characteristics of clinicians’ diagnostic systems themselves. One potentially major artifact of their methodology, however, must be borne in mind: the instruction to the clinicians in their study to “[p]ut together the diagnoses that have similar treatments…” (emphasis mine). Although they cite previous work (Flanagan and Blashfield 2006) in defense of the proposition that such instruction did not unduly influence their findings, it was certainly an avoidable potential problem, which itself likely reflects the history of our clinical disciplines in which the treatment cart frequently pulled the diagnosis horse. It is, therefore, not unlikely that clinicians’ taxonomies might emphasize treatment considerations even if they had not been directed to do so. The fallacious reasoning behind such intuitively appealing practice, however, must be exposed. The implicit assumption that treatment response is a proxy for other important characteristics of illnesses is predicated on the false proposition that our treatments exert their effects via similar mechanisms across the various indications for their uses, thus allowing us to infer from such responses that what was awry in the first place among the conditions for which a given treatment is effective must be closely related. Categorizing mania and trigeminal neuralgia together by virtue of their shared responses to anticonvulsant therapy, or considering autoimmune platelet deficiencies to be closely related to abdominal trauma due to the fact that each sometimes requires splenectomy, are examples of the potential results of acting on that false premise.Another parameter on which the clinicians in the current study based their nosologies—most explicitly by the “dimensional experts”—is the “environmental” versus “biological” one. Given that a coherent dichotomy would either distinguish environmental from genetic etiological factors, or would contrast psychological (i.e., subjective or first-person) from biological (i.e., objective or third-person) manifestations of illness, a taxonomy one of whose axes purports to represent an environmental/biological continuum cannot... (shrink)

It has long been known that the red blood cell contains a membrane skeleton that stabilizes the plasma membrane, determines its shape, and regulates the lateral distribution of the membrane glyco‐proteins to which it is attached. The way in which these functions are regulated in other cells has not been understood. It has now been shown that platelets also contain a membrane skeleton. In contrast to the membrane skeleton of the red blood cell, the platelet membrane skeleton has actin‐binding (...) protein, not spectrin, as a major component. The platelet membrane skeleton regulates the same cellular functions as the red blood cell membrane skeleton. Other cells may contain a membrane skeleton that is critical to their viability and normal functioning. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:You Can't Say "No" to That!(A "Difficult Patient" Story)Ingrid BergAs a sequela of COVID-19, my rural Wisconsin hospital has been jam-packed for months with patients for whom we routinely provide care and many for whom we do not. An exodus of health care workers and other constraints have made the transfer of critically ill patients very difficult. In this disquieting "new-normal" of our work life, we routinely must call (...) bigger cities throughout our state to find beds for complex patients.So, it was not surprising when a young patient, an IV drug user in sepsis from a heart infection, was admitted to me in the middle of the night. In less disheartening times, before the pandemic, this patient would have been transferred promptly to the big-city hospital. Now, though, the possibility of finding an open bed is next to impossible. Resigned, I placed admission orders, continued antibiotics and fluids, and crossed my fingers. Then the unexpected happened: a bed opened up, and we could send her at once!The patient had a harsh heart murmur. It was likely that a "vegetation" was clinging to the valve, between the right upper and lower chambers of her heart. A vegetation is a clump of debris, such as platelets, clotting proteins, and bacteria that is a menace to the body. Her chest imaging looked like her infection had already spread to her lungs.A definitive diagnosis for endocarditis requires a special ultrasound with a probe that goes down through the esophagus, a procedure performed by cardiologists. It's a serious infection, one that requires weeks of IV antibiotics and is best monitored by infectious disease specialists. Sometimes, cardiothoracic surgeons are called upon to strip away the infection at the site, depending on how badly the valve has been slayed or the size of the vegetation. My only recommendation for a young, otherwise healthy patient in this scenario, is transfer.All of these reasons for transfer were lolling around in my tired head when the night-time [End Page 14] nursing supervisor approached me and said, "We have a problem." When the patient was updated about the transfer, she balked: "She says she is tired and refusing to go," the supervisor began. "She doesn't feel like getting into an ambulance in the middle of the night and she doesn't care if her condition is life-threatening. She knows we can't force her to go and she will only talk about it again in the morning."The cartoon version of myself at that moment had bugged-out eyes, a dropped jaw, fists tight and clenched at my sides, and steam coming out of my head. I can look past a patient's self-neglect, poor medication adherence, abysmal communication, alcohol and drug addiction, and other crimes. But saying no to a bed at a tertiary care facility? Unacceptable!I marched down the quiet hallway and into her room. She was lying on her side, facing the door, one IV in a thin arm. I was confident I could reason with her once I explained the scarcity of beds and the medical necessity of transfer. But she was having none of it. I was calm until I could no longer maintain my cool: "You can't give up this bed!""Maybe in the morning," she insisted, yawning. "But not now. I am tired and want to rest!""But there might not be a bed in the morning," I countered. "And your infection can be life-threatening." (This is true, but we both knew she wasn't dying at this very moment.)"I am not going anywhere!" She raised her voice and then closed her eyes.And she was right. I had no choice but to keep her. I could not kick her out of the hospital because she was making a poor choice, and I was frustrated for having to manage the fallout of that decision. Giving her antibiotics and fluid boluses to bolster her blood pressure was certainly within my scope of practice. And fretting. Fretting is always within my scope of practice; not that my scope of practice matters when all the big... (shrink)

Cell recognition and adhesion, being of prime importance for the formation and integrity of tissues, are mediated by cell adhesion molecules, which can be divided into several distinct protein superfamilies. The cell adhesion molecule C‐CAM (cell‐CAM 105) belongs to the immunoglobulin superfamily, and more specifically is a member of the carcinoembryonic antigen (CEA) gene family. C‐CAM can mediate adhesion between hepatocytes in vitro in a homophilic, calcium‐independent binding reaction. The molecule, which occurs in various isoforms, is expressed in liver, several (...) epithelia, vessel endothelia, platelets and granulocytes and its expression is dynamically regulated under various physiological and pathological conditions. It is proposed that C‐CAM in different cells and tissues plays different functional roles, where the common denominator is membrane‐membrane binding. (shrink)

Insulin is well known for its essential role in carbohydrate metabolism: insulin deficiency results in the development of diabetes mellitus. It has been known for many years that people with diabetes mellitus are predisposed to develop thrombotic diseases including myocardial infarction. It was thought that the thrombus formation was the consequence of impaired carbohydrate metabolism. In recent years, it has become apparent that insulin is capable of ameliorating several pathophysiological events, leading to the inhibition and dissolution of the formed thrombus (...) in the system. These insulin‐induced events include inhibition of platelet aggregation by prompting the synthesis of NO in platelet and prostacyclin in endothelial cells. Furthermore, insulin upregulates prostacyclin receptors and downregulates α2 adrenergic receptor in platelets, thereby amplifying the inhibition of platelet aggregation. Insulin also releases tissue plasminogen activator, a potent thrombolytic enzyme, from the platelet membrane which dissolves the formed thrombus leading to the resumption of normal blood circulation. In effect, insulin could be an essential tool in the control of thrombotic disorders. BioEssays 26:91–98, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

Atherosclerosis is the major cause of death in the industrialised world. Though much work on the pathogenesis of atherosclerosis points to 'oxidised' low density lipoprotein (LDL) as a key aetiological feature in the generation of the atherosclerotic plaque, the nature of this 'oxidised' LDL in vivo remains an enigma. We argue here that glycated LDL shows many of the characteristics attributed to 'oxidised LDL' and may be the source of the latter in vivo. These include the increased uptake and impaired (...) degradation of glycated LDL by macrophages and the stimulation of transendothelial chemotaxis of monocytes, cytokine secretion and platelet aggregation. We hypothesise that the covalent binding of glycated LDL to the endothelial cell wall may result in the formation of the early atherosclerotic lesion of the fatty streak and that apolipoprotein E may mediate the physiological clearance of glycated moieties. The proposed role of glycation in the pathogenesis of atherosclerosis would explain its high incidence among diabetics and the contentious epidemiological and experimental correlations between dietary sugar and atherosclerosis. (shrink)

My little girl has leukemia; she has had it for over a year, and now she needs at least five pints of blood a day. Not the whole blood, just the platelets. Most of our relatives and friends have given at least a few times. But we need more. Now I have to go to strangers.So begins Roberta Silman's short story, “Giving Blood,” a story about illness and charity. When the narrator's husband solicited blood donations at his workplace, “he thought (...) everyone would help…He must have asked a hundred people. Thirty gave. His officemate…turned green and said, ‘Oh, no, anything but that. I'm scared of needles.'”. (shrink)

This computational study generates a hypothesis for the coagulation protein whose initial concentration greatly influences the course of coagulation. Many clinical malignancies of blood coagulation arise due to abnormal initial concentrations of coagulation factors. Sensitivity analysis of mechanistic models of blood coagulation is a convenient method to assess the effect of such abnormalities. Accordingly, the study presents sensitivity analysis, with respect to initial concentrations, of a recently developed mechanistic model of blood coagulation. Both the model and parameters to which model (...) sensitivity is being analyzed provide newer insights into blood coagulation: the model incorporates distinct equations for plasma-phase and platelet membrane-bound species, and sensitivity to initial concentrations is a new dimension in sensitivity analysis. The results show that model predictions are most uncertain with respect to changes in initial concentration of factor VIII, and this hypothesis is supported by results from other models developed independently. (shrink)

Polyphosphate (polyP) is a ubiquitous biomolecule thought to be present in all cells on Earth. PolyP is deceivingly simple, consisting of repeated units of inorganic phosphates polymerized in long energy‐rich chains. PolyP is involved in diverse functions in mammalian systems—from cell signaling to blood clotting. One exciting avenue of research is a new nonenzymatic post‐translational modification, termed lysine polyphosphorylation, wherein polyP chains are covalently attached to lysine residues of target proteins. While the modification was first characterized in budding yeast, recent (...) work has now identified the first human targets. There is significant promise in this area of biomedical research, but a number of technical issues and knowledge gaps present challenges to rapid progress. In this review, the current state of the field is summarized and existing roadblocks related to the study of lysine polyphosphorylation in higher eukaryotes are introduced. It is discussed how limited methods to identify targets of polyphosphorylation are further impacted by low concentration, unknown regulatory enzymes, and sequestration of polyP into compartments in mammalian systems. Furthermore, suggestions on how these obstacles could be addressed or what their physiological relevance may be within mammalian cells are presented. (shrink)