There are around 94 000 000 obese people in the US alone, where 30% of the population is classified as obese.1 In industrialised countries, cardio-vascular diseases, associated with obesity and lack of physical activity, are the leading causes of death.Many millions of people affected by obesity expose themselves to stroke, heart attack, atherosclerosis, type-2 diabetes, osteoarthritis and other joint problems, sleeping problems , cancer, and psychological illnesses such as depression.While both in the United States and in the (...) United …. (shrink)

People with mental illnesses have higher prevalence and mortality rates with regard to common somatic diseases and causes of death, such as cardio-vascular conditions or cancer. One factor contributing to this excess morbidity and mortality is the sub-standard level of physical healthcare offered to the mentally ill. In particular, they are often subject to diagnostic overshadowing: a tendency to attribute physical symptoms to a pre-existing diagnosis of mental illness. This might be seen as an unfortunate instance of (...) epistemic bad luck, where particular features of a group of patients make a timely and correct diagnosis unlikely. While this can explain some cases of diagnostic overshadowing, I argue that in other cases, epistemic injustice is involved. Analyzing the case of diagnostic overshadowing, I distinguish two kinds of testimonial injustice. For one, there are classic cases of transactional testimonial injustice resulting from prejudices against the mentally ill. In addition, there are cases of structural testimonial injustice resulting from features of health care systems. To overcome diagnostic overshadowing, remedies on the individual as well as structural level are thus needed. (shrink)

(1941). A survey of the growth of knowledge about certain parts of the foetal cardio-vascular apparatus, and about the foetal circulation, in Man and some other mammals. Part I: Galen to Harvey. Annals of Science: Vol. 5, No. 1, pp. 57-89.

Despite optimistic reports about the results of amputation for advanced vascular disease, the patient’s assessment of advantages and disadvantages is seldom acknowledged. A detailed social study of 67 amputees has revealed considerable disparity between the patient’s views and those of the medical staff. About a third of the patients are forced to retire from active work by the amputation; about three-quarters report a serious decline in their social activities; only about half are really independent with prostheses in the long (...) term; a quarter report severe and intractable symptoms related to their amputation stumps; only about a quarter feel that the amputation was definitely beneficial; and only about one in five feel that the medical staff have provided adequate support during their hospital stay. Amputees face physical and financial disability, isolation, and discomfort. Every effort must be made to explain the implications of amputation honestly and realistically and to ensure continuing patient assessment and support. (shrink)

Until recently, cardiotoxicity in the setting of a malignant disease was attributed solely to the detrimental effects of chemo‐ and/or radio‐therapy to the heart. On this account, the focus was on the evaluation of well‐established cardiac biomarkers for the early detection of myocardial damage. Currently, this view has been revised. Cardiotoxicity is not restricted to a single organ but instead affects the endothelium as a whole. Indeed, it has come into light that not only cancer therapy but also malignant cells (...) per se can impair the cardiovascular system, through a paracrine and endocrine mode of action. Even more intriguingly, a clear interplay between molecular pathways involved in cancer and cardiovascular disease has become prevalent, suggesting a common nominator that governs the pathophysiology of these two entities. Taken together, our strategy in the quest of novel biomarkers in the emerging field of cardio‐oncology should be critically reshaped. (shrink)

Osteoporosis (OP) is a bone disease which affects a number of post‐menopausal females and puts many at risk for fractures. A large number of patients are taking bisphosphonates (BPs) to treat their OP and a rare complication is the development of atypical femoral fractures (AFF). No real explanations for the mechanisms underlying the basis for development of where AFF develop while on BPs has emerged. The present hypothesis will discuss the possibility that part of the risk for an AFF is (...) a secondary effect of BPs on a subset of vascular cells in a genetically at‐risk population, leading to localized deregulation of the endothelial cell (EC)‐bone cell‐matrix units in nutrient channels/canals of the femur and increased risk for AFF. This concept of targeting ECs is consistent with location of AFF in the femur, the bilateral risk for occurrence of AFF, and the requirement for long term exposure to the drugs. (shrink)

The development of photodynamic therapy and anti-vascular endothelial growth factor agents have revolutionized the treatment of retinal diseases, transforming the retina subspecialty by ushering in an age of pharmacological treatments for a wide range of diseases, including age-related macular degeneration.

Recent research has shown that psychological risk factors play an important role in the pathogenesis of cardiovascular diseases. The so-called coronary prone behaviour pattern predominates, an important part of which is the Type A behaviour pattern. This is characterized by a marked ambition, a constant feeling of being under pressure, due to latent aggression and to a striving to dominate. For cerebrovascular diseases the so-called pressured pattern as a risk factor has been found to be typical which is (...) comparable to the Type A behaviour. Psychological risk factors and their components are not equally important for different vascular diseases. Besides the explanation of the question as to how far psychological processes really are involved in the development of vascular diseases, the research on psychological risk factors serves as a foundation for psychosomatic theories. (shrink)

Anti-vascular endothelial growth factor therapy has revolutionised the treatment of a variety of ophthalmic conditions and has become the first-line therapy for a range of retinal diseases. Bevacizumab, a VEGF inhibitor first approved for the treatment of colorectal cancer, has been shown to be nearly or virtually as effective and safe as other anti-VEGF therapies in the treatment of certain retinal diseases but is not approved or registered by the Food and Drug Administration or European Medicines Agency. (...) While other anti-VEGF options are approved and registered, they are generally more expensive and less accessible. Accordingly, despite its off-label status, bevacizumab is frequently used for a variety of disabling retinal diseases. Indeed, bevacizumab is included on the World Health Organization’s list of essential medicines. However, its use in some parts of the world remains restricted due to its off-label status. How, then, should healthcare authorities approach this situation? What are the ethical and societal implications of adhering to a standard and generally effective evaluation and approval system while restricting access to a potentially cost-saving therapy? In countries where its use is not restricted, how should providers approach off-label treatment with bevacizumab? By examining the evidence behind bevacizumab’s efficacy and safety and evaluating the individual and societal implications of off-label use and restriction, this paper illustrates the ethical factors providers and policy makers must consider in the off-label use of bevacizumab and ultimately argues for increased access to bevacizumab in the treatment of retinal disease. (shrink)

Hedgehog is an important morphogenic signal that directs pattern formation during embryogenesis, but its activity also remains present through adult life. It is now becoming increasingly clear that during the reproductive phase of life and beyond it continues to direct cell renewal (which is essential to combat the chronic environmental stress to which the body is constantly exposed) and counteracts vascular, osteolytic and sometimes oncological insults to the body. Conversely, down‐regulation of hedgehog signalling is associated with ageing‐related diseases (...) such as type 2 diabetes, neurodegeneration, atherosclerosis and osteoporosis. Hence, in this essay we argue that hedgehog signalling is not only important at the start of life, but also constitutes an important anti‐geriatric influence, and that enhanced understanding of its properties may contribute to developing rational strategies for healthy ageing and prevention of ageing‐related diseases.Also watch the Video Abstract. (shrink)

Anna Chavlovski,1 Greg A Knoll,1–3 Timothy Ramsay,4 Swapnil Hiremath,1–3 Deborah L Zimmerman1–31University of Ottawa, 2Ottawa Hospital, 3Kidney Research Centre, Ottawa Hospital Research Institute, 4Ottawa Methods Centre, Ottawa, ON, CanadaBackground: In patients with end-stage renal disease, use of vitamin D and calcium-based phosphate binders have been associated with progression of vascular calcification that might have an impact on renal transplant candidacy. Our objective was to examine management of mineral metabolism in patients wait-listed for renal transplant and to determine the impact (...) on cardiac perfusion imaging.Methods: Data was collected retrospectively on patients wait-listed for a renal transplant, being either active and on hold. Demographic data, medications, serum concentrations of calcium, phosphate, parathyroid hormone, and cardiac perfusion imaging studies were collected from the electronic health record. Chi-square and Student’s t-tests were used to compare active and on-hold patients as appropriate. Logistic regression was used to examine variables associated with worsening cardiac imaging studies.Results: The wait-listed patients were of mean age 56 ± 14 years and had been on dialysis for 1329 ± 867 days. On-hold patients had received a significantly greater total dose of calcium and were more likely to have developed worsening cardiovascular imaging studies. Total doses of calcium and calcitriol were associated with worsening cardiovascular imaging studies.Conclusion: Patients on hold on the renal transplant waiting list received higher total doses of calcium. A higher total dose of calcium and calcitriol was also associated with worsening cardiovascular imaging. Time on dialysis before transplant has been associated with worse post-transplant outcomes, and it is possible that the total calcium and calcitriol dose received contributed to these inferior outcomes.Keywords: dialysis, calcium, cardiac, transplantation. (shrink)

Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue structure (...) and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

Cardiophenomenology aims at refining the neuro-phenomenological approach created by F. Varela as a new paradigm, jointly based on Husserl’s a priori dynamics of the living present and an experiment on anticipatory time-dynamics of visual motor perception. In order to do so, we will situate the paradigm of neurophenomenology at the cardio-vascular level, focusing on the emotional dynamics of lived experience and thus refining the dialogue, more precisely, the generative mutual constraints between first- and third-person analysis. In this article (...) we present the theoretical hypothesis of cardiophenomenology, which places the bodily-emotional heartsystem at its core, as an intrinsic part of the cognitive system. The latter therefore needs to be enlarged in order to include an enactive embodied cardiac-affective dimension. Here we present five main arguments for the necessary inclusion of the bodily-emotional heartsystem in the cognitive system: first, two pragmatic operational arguments, then three theoretical ones. A direct methodological-pragmatic consequence is the actual operativity of the generative mutual constraints based on an experiential -experimental continuity of the embodied cardiac-affective fold inherent in the subject. (shrink)

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase (...) the likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging. (shrink)

Plasminogen activator inhibitor‐1 (PAI‐1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI‐1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI‐1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the “PAI‐1 paradox”. Many factors are responsible for the upregulation of PAI‐1 in the tumor microenvironment. We hypothesize that there is a breast cancer (...) predisposition to a more aggressive stage when PAI‐1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the “PAI‐1 cycle”. Sustained by MetS, adipocytokines alter PAI‐1 expression to promote angiogenesis, tumor‐cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI‐1 synthesis. All of these factors culminate in a chemotherapy‐resistant breast tumor microenvironment. The PAI‐1 cycle may partly explain the PAI‐1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI‐1 and how an increased level of PAI‐1 can be linked to a poor prognosis. BioEssays 29:1029–1038, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Chronic pain affects a large part of the population causing functional disability, being often associated with coexisting psychological disorders, such as depression and anxiety, besides cognitive deficits, and sleep disturbance. The world elderly population has been growing over the last decades and the negative consequences of chronic pain for these individuals represent a current clinical challenge. The main painful complaints in the elderly are related to neurodegenerative and musculoskeletal conditions, peripheral vascular diseases, arthritis, and osteoarthritis, contributing toward poorly (...) life quality, social isolation, impaired physical activity, and dependence to carry out daily activities. Organ dysfunction and other existing diseases can significantly affect the perception and responses to chronic pain in this group. It has been proposed that elderly people have an altered pain experience, with changes in pain processing mechanisms, which might be associated with the degeneration of circuits that modulate the descending inhibitory pathways of pain. Aging has also been linked to an increase in the pain threshold, a decline of painful sensations, and a decrease in pain tolerance. Still, elderly patients with chronic pain show an increased risk for dementia and cognitive impairment. The present review article is aimed to provide the state-of-art of pre-clinical and clinical research about chronic pain in elderly, emphasizing the altered mechanisms, comorbidities, challenges, and potential therapeutic alternatives. (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)

Vascular calcifications are the consequence of several pathological conditions such as atherosclerosis, diabetes, hypercholesterolemia and chronic renal insufficiency. They are associated with risks of amputation, ischemic heart disease, stroke and increased mortality. A growing body of evidence indicates that vascular smooth muscle cells (VSMCs) undergo chondrogenic commitment eventually leading to vascular calcification, by mechanisms similar to those governing ossification in the cartilage growth plate. Our knowledge of the formation of cartilage growth plate can therefore help us to (...) understand why and how arteries calcify and, consequently, develop new therapeutic strategies. Reciprocally, thorough consideration of the events leading to ectopic chondrocyte differentiation appears crucial to further increase our understanding of growth plate formation. In this context, we will review the effects of known or suspected factors that promote chondrogenic differentiation in growth plate and arteries. BioEssays 27:708–716, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). (...) Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models. (shrink)

Human cerebral organoids (HCOs) are three-dimensional in vitro cell cultures that mimic the developmental process and organization of the developing human brain. In just a few years this technique has produced brain models that are already being used to study diseases of the nervous system and to test treatments and drugs. Currently, HCOs consist of tens of millions of cells and have a size of a few millimeters. The greatest limitation to further development is due to their lack of (...) vascularization. However, recent research has shown that human cerebral organoids can manifest the same electrical activity and connections between brain neurons and EEG patterns as those recorded in preterm babies. All this suggests that, in the future, HCOs may manifest an ability to experience basic sensations such as pain, therefore manifesting sentience, or even rudimentary forms of consciousness. This calls for consideration of whether cerebral organoids should be given a moral status and what limitations should be introduced to regulate research. In this article I focus particularly on the study of the emergence and mechanisms of human consciousness, i.e. one of the most complex scientific problems there are, by means of experiments on HCOs. This type of experiment raises relevant ethical issues and, as I will argue, should probably not be considered morally acceptable. (shrink)

Beverly Beckham writes in the Boston Globe in praise of Lisa Genova’s Still Alice: “You have to get this book. … I couldn’t put it down. …” After I read Still Alice, a book of fiction about an accomplished Harvard professor with early-onset Alzheimer’s disease, I too wanted to tell everyone to get this book, but not because “I couldn’t put it down.” The first time I read it, I put it down several times to cry. It was too painful (...) to read in one stretch. Years back, my mother, Gloria Baylis,1 had been diagnosed with vascular dementia, and recently there had been findings suggestive of an atypical presentation of Alzheimer’s disease. The story of Alice Howland, the Alice of Still Alice, was both too... (shrink)

Context and AimsAlthough some exercise-based interventions have been associated with lower levels of pain and performance-related musculoskeletal disorders among musicians, the evidence is still mixed. Furthermore, little is known about musicians’ general engagement in physical activity, their knowledge of PA guidelines, or the relevant training they receive on pain prevention and the sources of such training. Similarly, little is known about the relationship between PA and PRMDs and other risk factors for PRMDs.MethodsFollowing a cross-sectional correlational study design, both standardized andad (...) hocmeasurements were used to investigate self-reported PA [International Physical Activity Questionnaire – Short Form ], knowledge of PA guidelines, and barriers to engaging in PA [Centers for Disease Control ; Determinants of Physical Activity Questionnaire ]; sedentary behavior [Sedentary Behavior Questionnaire ]; pain [36-Item Short Form Survey Instrument ] and PRMDs ; reported physical exertion ; anxiety [Hospital Anxiety and Depression Scale ]; practice behaviors ; and relevant training among conservatoire students in the United Kingdom. The entire set of questionnaires was administered both online and via hard copies between June 2017 and April 2018.ResultsDemographic information was obtained from 111 respondents, mostly undergraduate students from seven conservatoires. They reported high levels of engagement in PA, despite poor knowledge of PA guidelines. Teachers were the most frequently mentioned source of pain prevention information, and 62% agreed that they had received advice on why they should engage in cardio PA. Sedentary behavior was comparable to normative data. Levels of bodily pain and PRMDs were low, but 43% showed “abnormal” clinical anxiety and found playing their instruments “somewhat hard” on average. Bodily pain interfering with practice and performance was positively correlated with frequency and severity of PRMDs, anxiety, and RPE. Frequency and severity of PRMDs were also associated with sedentary behavior at the weekend. Anxiety was associated with RPE. No association was found between PA and PRMDs.ConclusionThe relationship between PA and PRMDs and pain remains unclear and needs further investigation. While health education needs to be improved, other pathways may need to be taken. Given the high levels of anxiety, the ideology of Western classical music itself may need to be challenged. (shrink)

Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and (...) other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors. (shrink)

Lymphangiogenesis is an important developmental process that is critical to regulation of fluid homeostasis, immune surveillance and response as well as pathogenesis of a number of diseases, among them cancer, inflammation, and heart failure. Specification, formation, and maturation of lymphatic blood vessels involves an interplay between a series of events orchestrated by various transcription factors that determine expression of key genes involved in lymphangiogenesis. These are traditionally thought to be under control of several key growth factors including vascular (...) growth factor‐C (VEGF‐C) and fibroblast growth factors (FGFs). Recent insights into VEGF and FGF signaling point to their role in control of endothelial metabolic processes such as glycolysis and fatty acid oxidation that, in turn, play a major role in regulation of lymphangiogenesis. These advances have significantly increased our understanding of lymphatic biology and opened new therapeutic vistas. Here we review our current understanding of metabolic controls in the lymphatic vasculature. (shrink)

We hypothesize that threat of dehydration provided selection pressure for the evolutionary emergence and persistence of the anterior communicating artery (ACoA – the inter‐arterial connection that completes the Circle of Willis) in early amniotes.The ACoA is a hemodynamically insignificant artery, but, as we argue in this paper, its privileged position outside the blood‐brain barrier gives it a crucial sensing function for the osmolarity of the blood against the background of the rest of the brain, which efficiently protects itself from dehydration. (...) Till now, the questions of why the ACoA evolved, and what its physiological function is, have remained unsatisfactorily answered. The traditional view—that the ACoA serves as a collateral source of vascularization in case of arterial stenosis—is anthropocentric, and not in accordance with principles of natural selection that apply more generally. Diseases underlying arterial stenosis are associated with aging and the human lifestyle, so this cannot explain why the ACoA formed hundreds of millions of years ago and persisted in amniotes to this day.The peculiar hemodynamic properties of the ACoA could be selected traits that allowed for more efficient forebrain detection of dehydration and complex behavioral responses to water loss, a major advantage in the survival of early amniotes. This hypothesis also explains insufficient hydration often seen in elderly humans. (shrink)

We hypothesize that threat of dehydration provided selection pressure for the evolutionary emergence and persistence of the anterior communicating artery (ACoA – the inter‐arterial connection that completes the Circle of Willis) in early amniotes.The ACoA is a hemodynamically insignificant artery, but, as we argue in this paper, its privileged position outside the blood‐brain barrier gives it a crucial sensing function for the osmolarity of the blood against the background of the rest of the brain, which efficiently protects itself from dehydration. (...) Till now, the questions of why the ACoA evolved, and what its physiological function is, have remained unsatisfactorily answered. The traditional view—that the ACoA serves as a collateral source of vascularization in case of arterial stenosis—is anthropocentric, and not in accordance with principles of natural selection that apply more generally. Diseases underlying arterial stenosis are associated with aging and the human lifestyle, so this cannot explain why the ACoA formed hundreds of millions of years ago and persisted in amniotes to this day.The peculiar hemodynamic properties of the ACoA could be selected traits that allowed for more efficient forebrain detection of dehydration and complex behavioral responses to water loss, a major advantage in the survival of early amniotes. This hypothesis also explains insufficient hydration often seen in elderly humans. (shrink)

Examining the status of cacao production, challenges, and prospects of cacao farmersin Zamboanga del Norte province were done in this study. The investigation revealed that cacaofarming was practiced by males (244 or 65.10%) and female cacao farmers (34%) who areprimarily married with secondary educational backgrounds. Most cacao farmers were theirproductive age ranging from 50-59 years old (42.93%), 40-49 years old (34.4%). However,fewer young people engaged in cacao farming aged below 40 years old (7.46%). The primaryoccupation of the respondents was farming (...) (86.13%), tilling their owned land (84.53%), andwith an average annual income below 60,000 pesos (50.40%). The average farm size was at 1-3hectares (80.00%), having a plain (40.27%) to rolling topography (47.47%) planted with UF 18(50.13%) and BR 25 (49.87%) varieties of cacao. Intercropping was observed (99.20%) withcoconut (79.20%) and banana (14.67%) planted along with cacao. Pest infestation of stem borer(59.73%) and bugs (22.67%) were observed at a low level (79.20%) and controlled usingLamdacyhalothrin (86.40%) as a chemical spray. Moreover, cacao diseases in farms were at alow incidence level (74.13%), with vascular streak dieback (53.06%) as the most commondisease among farms, and the method of controlling the spread was using chemicals (53.60%)and synthetic pesticides (100%) as a spray. Farms established 2 years from sowing (90.13%)observed farm management practices such as weeding twice a year (45.33%), fertilizerapplication 4 times a year (88.00%) using 1-3 bags per hectare (85.06%). Cacao trees produced0.50-1.50 (50.00%) of seeds per tree. Cacao products are sold in dried form (60.98%) withprices ranging from 81-100/kilogram through cooperative (100%). Farmers faced numerouschallenges, the most significant of which were the high cost of routine maintenance (such ascleaning/brushing) and shortage of laborers. The accessibility from the farm to the market roadwas also seen as a challenge among them. The province's cacao agricultural stakeholdersextended to support services to farmers such as free planting materials, credit assistance, cacaoproduction seminars, and post-harvest facilities, which were all considered valuable to farmersin addressing the challenges they faced on cacao farming and production. (shrink)

Both blood vessels and nerves are guided to their target. Vascular endothelial growth factor (VEGF)A is a key signal in the induction of vessel growth (a process termed angiogenesis). Though initial studies, now a decade ago, indicated that VEGF is an endothelial cell‐specific factor, more recent findings revealed that VEGF also has direct effects on neural cells. Genetic studies showed that mice with reduced VEGF levels develop adult‐onset motor neuron degeneration, reminiscent of the human neurodegenerative disorder amyotrophic lateral sclerosis (...) (ALS). Additional genetic studies confirmed that VEGF is a modifier of motor neuron degeneration in humans and in SOD1G93A mice—a model of ALS. Reduced VEGF levels may promote motor neuron degeneration by limiting neural tissue perfusion and VEGF‐dependent neuroprotection. VEGF also affects neuron death after acute spinal cord or cerebral ischemia, and has also been implicated in other neurological disorders such as diabetic and ischemic neuropathy, nerve regeneration, Parkinson's disease, Alzheimer's disease and multiple sclerosis. These findings have raised growing interest in assessing the therapeutic potential of VEGF for neurodegenerative disorders. BioEssays 26:943–954, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The ideal goal of a screening program for breast cancer is to detect the disease at a stage when it is still curable by a simple lumpectomy. This goal would be possible if the tumor had an early latent period before it was vascularized. However, even if there existed a harmless screening examination that was sensitive enough to discover the cancer at this stage the benefit to be gained from a screening program would be highly dependent on the time the (...) tumor spends in the latent stage as well as on the chance of false negatives at the examination. Calculations derived from a mathematical model suggest a variety of theoretically possible situations including: (1) For certain cancers screening every three years would offer almost as much benefit as screening every year; (2) A large increase in the sensitivity of a screening examination does not necessarily lead to a large increase in the benefit of a screening program; (3) For certain cancers the benefit of screening might remain low no matter how sensitive the examination used. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reifying Relevance in Mild Cognitive Impairment:An Appeal for Care and CautionJanice E. Graham (bio) and Karen Ritchie (bio)KeywordsAlzheimer’s disease, construction, dementia, market forces, mild cognitive impairmentWe thank the reviewers for their thoughtful comments that probe shadowy areas in our argument, and we welcome this opportunity to elucidate our position. First, we are not repudiating the natural and social facts of pathologic brain degeneration and the physical and cognitive impairments (...) that manifest in people affected by dementia disorders. We are, however, questioning the epistemology, politics, and persistence by some to harden the construct of mild cognitive impairment (MCI) prematurely as a "natural" precursor to dementia. We suggested insufficiencies in viewing MCI as prodromal to Alzheimer's disease (AD; Graham and Ritchie 2006, 36), and pointed to evidence for the prognostic irrelevance of some MCI subcategories (35). The commentators have read our manuscript as suggesting that AD and MCI are different kinds, and that a diagnosis of AD is more "real" than that of MCI. But AD is also fraught with classification issues, as we describe in the section of our paper that deals with consensus committees, published practice guidelines, and the determination of treatment efficacy. Like MCI, AD is a heterogeneous condition, but unlike MCI, AD is a constructed practical kind that does some "work" beyond essentialist (neural degeneration, brain atrophy) claims. Its criteria identify people with well-defined dementia symptoms and multiple cognitive and functional impairments who are in need of, and benefit from, support. Even with these criteria, however, there have been great attempts to achieve definitional accuracy in dementia diagnoses. Practical refinements to the differential diagnosis of dementia based on solid research evidence have made way for more specific recognitions of vascular dementias, dementia of the Lewy body type, and other subtypes beyond AD. So AD too has been subject to more careful, more cautious operationalization in recent years, with research supporting multiple factors and the comorbidity of several types (kinds) of dementia in any one individual.Our paper takes up concerns that are not resolved for dementia and suggests that the nascent category of MCI is still so insufficiently defined as to be ambiguous, and as such, is in danger of identifying individuals with what will be, and has [End Page 57] already been, linked to a debilitating and deeply stigmatizing and fatal disorder (AD). We are not contesting the reality that some people begin to display early signs of cognitive loss, nor are we suggesting that symptoms be ignored; as researchers, we stand behind the careful tracking of symptoms and signs in patients and research participants as an essential clinical and research practice. In a era where the public has been made wary of the potentially fatal effects of new treatments whose more careful scrutiny in specific populations would have saved lives (e.g., Fontanarosa, Rennie, and DeAngelis 2004; Psaty and Furberg 2005), and made all the more popular by what Kramer coined "diagnostic bracket creep" (1993, 15), we are questioning the drivers and value of a premature diagnostic classification whose definitional accuracy is neither sufficient nor effective for specific identification of individuals.That matters of fact are constructed does not take away from their natural fact. Some people have subjective reports or show objective evidence of cognitive decline while having preserved activities of daily living—the construction of this evidence indicates they are not normal and they are not demented. Based on such evidence, where then does the balance of probability for MCI lie? A multidisciplinary international group of experts gathered in Stockholm in 2003 to discuss MCI concepts (Winblad et al. 2004). They acknowledged that the heterogeneous etiology of MCI contributes to "some confusion concerning the specific boundaries of the condition", stating that this "not normal, not demented" condition is nonetheless "useful both clinically and as a research entity" (p. 241). Importantly, they concluded that MCI needs "better definition" (p. 246). It was at this stage that we first wrote our manuscript, and in the subsequent two years we have eagerly awaited new studies, and the recognition of flexible, practical subtypes to evolve.We state "that MCI cannot be considered to be a separate clinical entity" (Graham and... (shrink)

The interconnection of scientific studies and art represented by Leonardo Da Vinci’s portraiture accentuates his role in documenting and archiving dermatologic conditions. His anatomical dissections, sketches, and paintings, including portraits, were all a means to observe, portray, and understand the nuances of the human body. In two of his most discussed portraits, Ginevra de’ Benci and Elisabetta del Giocondo, the Mona Lisa, Leonardo’s execution of the exterior anatomy is so precise that he may have illustrated manifestations of disease that allow (...) contemporary researchers to theorize diagnoses of dermatologic as well as neurologic, endocrine and vascular conditions. These include hypochromic anemia, muscular disorders, xanthelasma, thyroid disease, lipoma, and frontal fibrosing alopecia. Leonardo’s extraordinary talent in recording his observations of shades and textures of skin and his ability to capture the nuances of subtle variations in the human body have produced a historical record that allows modern dermatology practitioners to make further observations not possible in his time. Here, dermatology and art intersect serving to document and explain the human condition, permanently archived in Leonardo’s masterpieces. (shrink)

Although considerable research has been devoted to cognitive functions deteriorating due to diseases of cardiovascular system, rather less attention has been paid to their theoretical background. Progressive vascular disorders as hypertension, atherosclerosis and carotid artery stenosis generate most of all pathological changes in the white matter, that cause specific cognitive disorder: disconnection syndromes, and disturbances in the dynamic aspect of information processing. These features made neuropsychological disorders secondary to cardiovascular diseases different than the effects of cerebral cortex (...) damage, which may be interpreted modularly. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Confidentiality and Its LimitsMaude Laliberté, John D. Lantos, and Sonia GowdaMultiple sclerosis is believed to be an autoimmune disease of the central nervous system. However, according to Italian physician Paolo Zamboni, it is related to cerebrospinal vascular insufficiency. Zamboni claims that MS can be treated by remedying this condition with venous angioplasty. This surgery is offered as treatment for MS in various countries—Poland, Bulgaria, and Costa Rica, for (...) example. But the Medical Board of Quebec, Canada, does not allow its members to perform the surgery and strongly advises patients against seeking it elsewhere. This opposition is based on the lack of evidence to support the procedure and the serious risks associated with it (including venous thrombosis, stroke, and pulmonary embolism). As a result, many Canadian MS patients have traveled to other countries to receive the surgery. Quebec physicians have been reluctant to provide surgical follow-up for patients who undergo the surgery in other countries due to the lack of information regarding the procedure. No alternative treatments are effective to partially or completely cure MS, and so the treatments available in Canada aim only to manage its symptoms.Jade is a forty-year-old Canadian woman with MS. She is on long-term disability leave, complains of growing fatigue and muscle stiffness, and has painful sensations in her limbs. She has been followed by an interdisciplinary team in a specialized hospital in Quebec for the past twenty years, since she was diagnosed. At her last appointment, Jade told her physical therapist that she recently underwent the experimental Zamboni surgery in Poland, despite her physician’s strong recommendation not to. Jade fears her physician’s reaction, so she asks the physical therapist to keep this information from the rest of her medical team.Jade is shy and tends to distrust health care professionals. It took many years for her physical therapist to gain her trust and to develop a positive therapeutic relationship with her. However, the physical therapist knows that serious complications can occur in patients who have had Zamboni’s surgery. Not telling Jade’s physician about the surgery could result in harm; Jade could have complications that are not recognized. Providing the information to the rest of the team would allow them to adjust her treatment to respond to the surgery and give her information and postoperative education that she will need. Moreover, keeping this secret could threaten team cohesion and trust if they find out about it later.Jade decided to undergo a risky surgery against her doctor’s advice in the hope of improving her quality of life. This was her autonomous choice. How should the physical therapist respond?CommentaryMaude Laliberte (bio)Laws and professional codes of ethics direct clinicians to respect their patients’ autonomy through confidentiality and informed consent unless there are compelling reasons not to do so. Health professionals are deeply committed to helping patients; above all, they want to avoid harming them. Therefore, a key component of this case is the possibility that respecting Jade’s desire to conceal information from the team may put her at direct risk if any postoperative complications are not detected, and at indirect risk if Jade’s trust in her medical team is undermined to the point where she turns away from them.The physical therapist must determine if the possible physical risks to Jade are imminent and serious enough to go against her autonomous choice. One risk that can occur following Zamboni’s surgery is inflammation of a vein caused by a blood clot. This is a life-threatening situation (although it may not be a likely complication for Jade). But the physical therapist can teach Jade to recognize the physical signs that can alert her to this problem, giving her ample time to seek treatment. Thus, even though she may be in danger from a life-threatening risk, there may be ways to manage it besides violating her confidentiality.The respect for autonomous choice is a crucial aspect of our democratic values. It promotes a process of exchange in the therapeutic alliance: the professional guides and informs the patient, but the patient is a partner in care planning and treatment. An important... (shrink)

Sensorimotor synchronization, the coordination of physical actions in time with a rhythmic sequence, is a skill that is necessary not only for keeping the beat when making music, but in a wide variety of interpersonal contexts. Being able to attend to temporal regularities in the environment is a prerequisite for event prediction, which lies at the heart of many cognitive and social operations. It is therefore of value to assess and potentially stimulate SMS abilities, particularly in aging and neurocognitive disorders, (...) to understand intra-individual communication in the later stages of life, and to devise effective music-based interventions. While a bulk of research exists about SMS and movement-based interventions in Parkinson’s disease, a lot less is known about other types of neurodegenerative disorders, such as Alzheimer’s disease, vascular dementia, or frontotemporal dementia. In this review, we outline the brain and cognitive mechanisms involved in SMS with auditory stimuli, and how they might be subject to change in healthy and pathological aging. Globally, SMS with isochronous sounds is a relatively well-preserved skill in old adulthood and in patients with NCDs. At the same time, natural tapping speed decreases with age. Furthermore, especially when synchronizing to sequences at slow tempi, regularity and precision might be lower in older adults, and even more so in people with NCDs, presumably due to the fact that this process relies on attention and working memory resources that depend on the prefrontal cortex and parietal areas. Finally, we point out that the effect of the severity and etiology of NCDs on sensorimotor abilities is still unclear: More research is needed with moderate and severe NCD, comparing different etiologies, and using complex auditory signals, such as music. (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)

Patients with schizophrenia have a higher risk of cardiovascular diseases and higher mortality from them than does the general population; however, the underlying mechanism remains unclear. Impaired cerebral autoregulation is associated with cerebrovascular diseases and their mortality. Increased or decreased cerebral blood flow in different brain regions has been reported in patients with schizophrenia, which implies impaired cerebral autoregulation. This study investigated the cerebral autoregulation in 21 patients with schizophrenia and 23 age- and sex-matched healthy controls. None of (...) the participants had a history of cardiovascular diseases, hypertension, or diabetes. All participants underwent 10-min blood pressure and cerebral blood flow recording through finger plethysmography and Doppler ultrasonography, respectively. Cerebral autoregulation was assessed by analyzing two autoregulation indices: the mean blood pressure and cerebral blood flow correlation coefficient (Mx), and the phase shift between the waveforms of blood pressure and cerebral blood flow determined using transfer function analysis. Compared with the controls, the patients had a significantly higher Mx (0.257 vs. 0.399, p = 0.036) and lower phase shift (44.3° vs. 38.7° in the 0.07–0.20 Hz frequency band, p = 0.019), which indicated impaired maintenance of constant cerebral blood flow and a delayed cerebrovascular autoregulatory response. Impaired cerebral autoregulation may be caused by schizophrenia and may not be an artifact of coexisting medical conditions. The mechanism underlying impaired cerebral autoregulation in schizophrenia and its probable role in the development of cerebrovascular diseases require further investigation. (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)

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)

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)

The study of rare diseases has long been an area of challenge for medical researchers, with agonizingly slow movement towards improved understanding of pathophysiology and treatments compared with more common illnesses. The push towards evidence-based medicine (EBM), which prioritizes certain types of evidence over others, poses a particular issue when mapped onto rare diseases, which may not be feasibly investigated using the methodologies endorsed by EBM, due to a number of constraints. While other trial designs have been suggested (...) to overcome these limitations (with varying success), perhaps the most recent and enthusiastically adopted is the application of artificial intelligence to rare disease data. This paper critically examines the pitfalls of EBM (and its trial design offshoots) as it pertains to rare diseases, exploring the current landscape of AI as a potential solution to these challenges. This discussion is also taken a step further, providing philosophical commentary on the weaknesses and dangers of AI algorithms applied to rare disease research. While not proposing a singular solution, this article does provide a thoughtful reminder that no ‘one-size-fits-all’ approach exists in the complex world of rare diseases. We must balance cautious optimism with critical evaluation of new research paradigms and technology, while at the same time not neglecting the ever-important aspect of patient values and preferences, which may be challenging to incorporate into computer-driven models. (shrink)

This paper deals with the question of how to price drugs for tropical diseases. The thesis defended in the paper is: (i) there should be no legal constraints on the profits pharmaceutical companies can make on their products for tropical diseases. In essence, (i) expresses the idea that drugs for tropical diseases should be treated as any other product on the free market and that the producers of these drugs should be allowed to sell their products at (...) whatever price the market can bear. The main argument in favour of (i) is first outlined. Five common arguments against (i) are thereafter discussed, and it is argued that all of these fail in their intended purpose. (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)