An understanding of underlying mechanisms involved in the activation of HIF‐1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF‐1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, (...) resulting in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF‐1α, a key component of HIF‐1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF‐1α. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF‐1α to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies. BioEssays 26:262–269, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

An understanding of underlying mechanisms involved in the activation of HIF‐1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF‐1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, (...) resulting in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF‐1α, a key component of HIF‐1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF‐1α. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF‐1α to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies. BioEssays 26:262–269, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The metabolic organization of both normal and malignant prostate cellular phenotypes involves some unusual and surprising features. In particular, both conditions exhibit ratios of NADH/NAD+ and NADPH/NADP+ charactersitic of high oxidative states despite a chronic shortage of O2 in both conditions. In this paper, we observe that, in prostate cancer cells, the oxidizing power of the fatty acid synthesis (FAS) pathway is so large that redox is stabilized more favorably (more oxidized) than in normal prostate cells. This FAS‐facilitated redox improvement (...) occurs despite the fact that malignant cells are more O2 limited and therefore express more hypoxia inducible factor 1 (HIF1) and express hypoxia‐regulated genes more robustly. This unusual metabolic situation clearly separates direct regulatory effects of redox balance from secondary effects of hypoxia per se. The physiological significance of the FAS pathway is thus the harnessing of its oxidizing power for improving redox balance despite conditions of more extreme hypoxia. Similar hypoxia defense strategies are found in animal species that are unusually tolerant to oxygen lack. Our hypothesis is that the metabolic organization in the “low zinc, low citrate” phenotype reflects an hypoxia‐defense adaptation geared toward redox balance, with prostate cancer cells being relatively more oxidized, even if more hypoxic, than normal prostate cells. Recognition and understanding of these redox balancing and hypoxia defense functions may lead to new intervention strategies by developing new intracellular targets for prostate cancer therapy. BioEssays 24:749–757, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Included in the acute response of lowlanders exposed to reduced oxygen availability is an elevated red blood cell count due to increased erythropoietin (Epo) synthesis. According to current thinking, hypoxia is “sensed” by hydroxylases that permit Hypoxia Inducible Factor 1α (HIF‐1α) to complex with HIF‐1β to form a transcriptional activator (HIF‐1) that drives expression of hypoxia‐sensitive genes (such as EPO) under hypoxic conditions. In altitude‐adapted Andean natives, the Epo hypoxic response may be blunted; however, our data indicate (...) that the DNA sequences of the genes encoding Epo (including the 3′ regulatory region) and HIF‐1α appear to be conserved. Hence, adaptive changes in the Andean hypoxic response are not a consequence of changes in the primary sequence of these proteins or of known transcriptional regulatory domains of EPO. These results suggest that the altered erthropoietic response in Andean natives reflects adaptations in hypoxia sensing, rather than hypoxia response, mechanisms. BioEssays 25:515–519, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

A broad pattern of correlations between mechanisms of brain function impairment and self-transcendence is shown. The pattern includes such mechanisms as cerebral hypoxia, physiological stress, transcranial magnetic stimulation, trance-induced physiological effects, the action of psychoactive substances and even physical trauma to the brain. In all these cases, subjects report self-transcending experiences o en described as ‘mystical’ and ‘awareness-expanding,’ as well as self-transcending skills o en described as ‘savant.’ The idea that these correlations could be rather trivially accounted for on (...) the basis of disruptions to inhibitory neural processes is reviewed and shown to be implausible. Instead, this paper suggests that an as-of-yet unrecognized causal principle underlying the entire pattern might be at work, whose further elucidation through systematic research could hold great promise. (shrink)

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and (...) is a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. (shrink)

At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen species, improved (...) mitochondrial efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

Hypoxia hampers ATP production and threatens cell survival. Since cellular energetics tightly controls cell responses and fate, ATP levels and dynamics are of utmost importance. An integrated mathematical model of ATP synthesis by the mitochondrial oxidative phosphorylation/electron transfer chain system has been recently published :e36, 2005). This model was validated under static conditions. To evaluate its performance under dynamical situations, we implemented and simulated it . Inner membrane potential and [NADH] were used as indicators of mitochondrial function. Root mean (...) squared error was used to compare simulations and experiments :39155–39165, 2003). Steady-state experimental data were reproduced within 2–6%. Model dynamics were evaluated under: baseline, activation of NADH production, addition of ADP, addition of inorganic phosphate, oxygen exhaustion. In all phases, except the last one, ΔΨ and [NADH] as well as oxygen consumption, were reproduced . Under anoxia, simulated ΔΨ markedly depolarized . In conclusion, the model reproduces dynamic data as long as oxygen is present. Anticipated improvement by the inclusion of ATP consumption and explicit Krebs cycle are under evaluation. (shrink)

“Exercise starts and ends in the brain”: this was the title of a review article authored by Dr. Bengt Kayser back in 2003. In this piece of work, the author highlights that pioneer studies have primarily focused on the cardiorespiratory-muscle axis to set the human limits to whole-body exercise tolerance. In some circumstances, however, exercise cessation may not be solely attributable to these players: the central nervous system is thought to hold a relevant role as the ultimate site of exercise (...) termination. In fact, there has been a growing interest relative to the “brain” response to exercise in chronic cardiorespiratory diseases, and its potential implication in limiting the tolerance to physical exertion in patients. To reach these overarching goals, non-invasive techniques, such as near-infrared spectroscopy and transcranial magnetic stimulation, have been successfully applied to get insights into the underlying mechanisms of exercise limitation in clinical populations. This review provides an up-to-date outline of the rationale for the “brain” as the organ limiting the tolerance to physical exertion in patients with cardiorespiratory diseases. We first outline some key methodological aspects of neuromuscular function and cerebral hemodynamics assessment in response to different exercise paradigms. We then review the most prominent studies, which explored the influence of major cardiorespiratory diseases on these outcomes. After a balanced summary of existing evidence, we finalize by detailing the rationale for investigating the “brain” contribution to exercise limitation in hitherto unexplored cardiorespiratory diseases, an endeavor that might lead to innovative lines of applied physiological research. (shrink)

Acidity, generated in hypoxia or hypermetabolic states, perturbs homeostasis and is a feature of solid tumors. That acid peripherally disperses lysosomes is a three‐decade‐old observation, yet one little understood or appreciated. However, recent work has recognized the inhibitory impact this spatial redistribution has on mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of metabolism. This finding argues for a paradigm shift in localization of mTORC1 activator Ras homolog enriched in brain (RHEB), a conclusion several others have now (...) independently reached. Thus, mTORC1, known to sense amino acids, mitogens, and energy to restrict biosynthesis to times of adequate resources, also senses pH and, via dampened mTOR‐governed synthesis of clock proteins, regulates the circadian clock to achieve concerted responses to metabolic stress. While this may allow cancer to endure metabolic deprivation, immune cell mTOR signaling likewise exhibits pH sensitivity, suggesting that suppression of antitumor immune function by solid tumor acidity may additionally fuel cancers, an obstacle potentially reversible through therapeutic pH manipulation. (shrink)

In many forms of severe acute brain injury there is an early phase when prognosis is uncertain, followed later by physiological recovery and the possibility of more certain predictions of future impairment. There may be a window of opportunity for withdrawal of life support early, but if decisions are delayed there is the risk that the patient will survive with severe impairment. In this paper I focus on the example of neonatal encephalopathy and the question of the timing of prognostic (...) tests and decisions to continue or to withdraw life-sustaining treatment. Should testing be performed early or later; and how should parents decide what to do given the conflicting values at stake? I apply decision theory to the problem, using sensitivity analysis to assess how different features of the tests or different values would affect a decision to perform early or late prognostic testing. I draw some general conclusions from this model for decisions about the timing of testing in neonatal encephalopathy. Finally I consider possible solutions to the problem posed by the window of opportunity. Decision theory highlights the costs of uncertainty. This may prompt further research into improving prognostic tests. But it may also prompt us to reconsider our current attitudes towards the palliative care of newborn infants predicted to be severely impaired. (shrink)

Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre‐clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress‐induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation of oxygen and nutrients. The (...) resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors. (shrink)

The reprogramming of metabolism has been identified as one of the hallmarks of cancer. It is becoming more and more frequent to connect other diseases with metabolic reprogramming. This article aims to argue that metabolic reprogramming is not driven by disease but instead is the main hallmark of metabolism, based on its dynamic behavior that allows it to continuously adapt to changes in the internal and external conditions.

The Supreme Court has ruled in the case of Y that there is no requirement to seek the approval of the Court of Protection in decisions to withdraw clinically assisted nutrition and hydration from patients in a prolonged disorder of consciousness.1 Mr Y was 52-year-old man who suffered a cardiac arrest after a myocardial infarction as a result of coronary artery disease. It was not possible to resuscitate him for well over 10 min, resulting in severe cerebral hypoxia which (...) caused extensive brain damage. Mr Y’s family and the NHS Trust treating him agreed that Mr Y would not want to be kept alive through the provision of CANH given his poor prognosis. They sought a declaration that it was not mandatory for applications of withdrawal of CANH to come before the court, which was granted by Mrs Justice O’Farrell in the first instance.2 Permission was granted for the appeal to ‘leapfrog’ the Court of Appeal and to proceed to the Supreme Court for consideration. In the interim, Mr Y died after contracting acute respiratory sepsis, but the Supreme Court determined that the appeal should go ahead in light of the general importance of the issues raised. In delivering the opinion of the Supreme Court on 30 July 2018, Lady Justice Black rejected the historical distinction that had been drawn between patients in PDOC and non-PDOC patients, in a way that had justified judicial involvement for patients in PDOC but not for others.3 She was clear that the correct approach to all cases involving CANH was to make a decision based on what was in the best interests of the patient. She further outlined that: > The documentation supplied to us shows that the difficulty that there is in assessing the patient and in …. (shrink)

High blood pressure is an important component of pre-eclampsia. The underlying mechanism of development of hypertension in pre-eclampsia is complicated and still remains obscure. Several theories have been advanced including endothelial dysfunction, uteroplacental insufficiency leading to generalized vasoconstriction, increased cardiac output, and sympathetic hyperactivity. Increased blood flow and pressure are thought to lead to capillary dilatation, which damages end-organ sites, leading to hypertension, proteinuria and edema. Additional theories have been put forward based on epidemiological research, implicating immunological and genetic factors. (...) None of these theories have been substantiated. Based on a review of literature this paper postulates that the initiating event for the development of preeclampsia is intermittent hypoxia associated with irregular breathing during sleep, hypoapnea, apnea,inadequate respiratory excursions during the waking hours and inadequate cardiopulmonary synchronization (abnormal sympatho-vagal balance). (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Bibliography of Resources by and about André E. Hellegers*Compiled by Doris Mueller Goldstein (bio)This bibliography is derived from the holdings of the National Reference Center for Bioethics Literature and the BIOETHICSLINE© database (both of which are at the Kennedy Institute of Ethics and supported by the National Library of Medicine); the archives of Lauinger Library, Georgetown University; the Medline databases of the National Library of Medicine; the WorldCat database (...) of OCLC, Dublin, Ohio, and selected Internet sites.Primarily comprised of writings by Dr. Hellegers, the list also includes interviews and media programs in which he participated, as well as writings about him that were written following his death. The arrangement within each section is by date. The 231 authored pieces reflect the transition from Dr. Hellegers’s early career as a researcher in fetal physiology at Johns Hopkins Medical School, where he published his first research report at the age of 29, to the early years of the Kennedy Institute, where he produced so many provocative columns on bioethical issues that influenced the growth of the field.Due to the diversity of sources and the 40-year time span covered, there are some variations in bibliographic style. Time and availability constraints precluded verifying all of the citations with the original documents. Any additions or corrections should be submitted to the compiler.Works Authored by André E. HellegersNo Date Ethical Issues in Sterilization of the Retarded. Unpublished paper.1956Vitamin B12 Serum Level and Pregnancy. American Journal of Clinical Nutrition 4: 440+, 1956. [With Bacon F. Chow and Kunio Okuda] [End Page 89]1957Vitamin B12 Absorption in Pregnancy and in the Newborn. American Journal of Clinical Nutrition 5: 327+, 1957. [With Bacon F. Chow, Robert E. L. Nesbitt, Kunio Okuda, and David W. Smith]1958The Effects of Acute Hypoxia on the Osmotic Pressure of the Plasma. Quarterly Journal of Experimental Physiology 43: 197+, 1958. [With Donald H. Barron, Frederick C. Battaglia, and Giacomo Meschia]Studies on the Absorption of Vitamin B12 in Human Pregnancy with Especial Reference to the Effect of D-Sorbitol. American Journal of Obstetrics and Gynecology 76: 91+, 1958. [With Bacon F. Chow, Harry Prystowsky, and Vernon Wong]1959The Alveolar PCO2 and PO2 in Pregnant and Nonpregnant Women at Altitude. Proceedings of the Society for Clinical Investigation 38: 1010+, 1959. [With Donald Barron, William Huckabee, Giacomo Meschia, James Metcalfe, and Harry Prystowsky]A Comparison of the Oxygen Dissociation Curves of the Bloods of Maternal and Fetal Goats at Various pHs. Quarterly Journal of Experimental Physiology 44: 215–21, July 1959. [With Donald Barron, Giacomo Meschia, Harry Prystowsky, and A. Stark Wolkoff]Fetal Blood Studies. XII. On the Relationship Between the Position of the Oxygen Dissociation Curve of Human Fetal Blood and Adult Fetal Hemoglobin. American Journal of Obstetrics and Gynecology 77: 585+, 1959. [With Paul D. Bruns, Julian Cotter, and Harry Prystowsky]Fetal Blood Studies. XIV. A Comparative Study of the Oxygen Dissociation Curve of Nonpregnant, Pregnant and Fetal Human Blood. American Journal of Obstetrics and Gynecology 78: 489–93, September 1959. [With Paul D. Bruns and Harry Prystowsky]Fetal Blood Studies. XVI. On the Changes in Total Osmotic Pressure and Sodium and Potassium Concentration of Amniotic Fluid During the Course of Human Gestation. Surgery, Gynecology and Obstetrics 109: 509–12, October 1959. [With Frederick Battaglia, Paul D. Bruns, Harry Prystowsky, and Clayton Smisson]Further Observations on the Metabolism of Vitamin B12 in Human Pregnancy. American Journal of Obstetrics and Gynecology 77: 1+, 1959. [With Bacon F. Chow, Harry Prystowsky, Bruno Ranke, and Elma Ranke]The Oxygen Dissociation Curves of the Bloods of Adult and Fetal Llamas. Federation Proceedings 18, 1959. [With Donald Barron, William Huckabee, Giacomo Meschia, James Metcalfe, and Harry Prystowsky] [End Page 90]Transfer of Oxygen Across the Sheep Placenta at High Altitude. Federation Proceedings 18, 1959. [With Donald Barron, William Huckabee, Giacomo Meschia, and Harry Prystowsky]Uterine Blood Flow and Metabolism in Pregnant Sheep at High Altitude. Federation Proceedings 18, 1959. [With Donald Barron, William Huckabee, Giacomo Meschia, James Metcalfe, and Harry Prystowsky]Uterine Blood Flow and Metabolism in Unanesthetized Pregnant Sheep. Federation Proceedings 18, 1959. [With Donald Barron, William Huckabee, Giacomo... (shrink)

This study identified the influences of maternal socio-demographic and antenatal factors on stillbirths and neonatal deaths in New South Wales, Australia. Bivariate and multivariate analyses were used to explore the association of selected antenatal and maternal characteristics with stillbirths and neonatal deaths. The findings of this study showed that stillbirths and neonatal deaths significantly varied by infant sex, maternal age, Aboriginality, maternal country of birth, socioeconomic status, parity, maternal smoking behaviour during pregnancy, maternal diabetes mellitus, maternal hypertension, antenatal care, plurality (...) of birth, low birth weight, place of birth, delivery type, maternal deaths and small gestational age. First-born infants, twins and infants born to teenage mothers, Aboriginal mothers, those who smoked during the pregnancy and those of lower socioeconomic status were at increased risk of stillbirths and neonatal deaths. The most common causes of stillbirths were conditions originating in the perinatal period: intrauterine hypoxia and asphyxia. Congenital malformations, including deformities and chromosomal abnormalities, and disorders related to slow fetal growth, short gestation and low birth weight were the most common causes of neonatal deaths. The findings indicate that very low birth weight (less than 2000 g) contributed 75·6% of the population-attributable risks to stillbirths and 59·4% to neonatal deaths. Low gestational age (less than 32 weeks) accounted for 77·7% of stillbirths and 87·9% of neonatal deaths. The findings of this study suggest that in order to reduce stillbirths and neonatal deaths, it is essential to include strategies to predict and prevent prematurity and low birth weight, and that there is a need to focus on anti-smoking campaigns during pregnancy, optimizing antenatal care and other healthcare programmes targeted at the socially disadvantaged populations identified in this study. (shrink)

The mechanism by which the mammalian kidney creates the osmotic gradient necessary for urine concentration remains an open question. We present a brief survey of the give-and-take between theory and experiment on this question over the last half century. We start with the introduction of the countercurrent multiplier paradigm in 1951. We finish with a description of a recent suggestion that the explanation for the enigmatic inner medullary osmotic gradient may reside in the very metabolism of the inner medullary cells, (...) which are required by the region's hypoxia to obtain their ATP largely from anaerobic glycolysis and which thus, by the same token, furnish net osmoles to the medullary interstitium by convering glucose to lactate. (shrink)

The role of the microenvironment in cancer development is being increasingly appreciated. This paper will review data that highlight an emerging distinction between two different entities: the microenvironment that altered/preneoplastic/neoplastic cells find in the tissue where they reside, and the peculiar microenvironment inside the focal lesion (tumor) that these cells contribute to create. While alteration in the tissue environment can contribute to the selective clonal expansion of altered cells to form focal proliferative lesions, the atypical, non‐integrated growth pattern that defines (...) such focal lesions leads to the appearance of what is correctly referred to as the tumor microenvironment. The latter represents a new and unique biological milieu, characterized by hypoxia, acidosis and other biochemical and metabolic alterations, including genetic instability, that can set the stage for tumor progression to occur. Thus, the two microenvironments act in sequence and play complementary roles in the development of overt neoplasia. This distinction has important implications for the understanding of disease pathogenesis and for the management of preneoplastic/neoplastic lesions at various stages of cancer development. BioEssays 29:738–744, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Stuttering is a disorder characterized by intermittent loss of volitional control of speech movements. This hypothesis and theory article focuses on the proposal that stuttering may be related to an impairment of the energy supply to neurons. Findings from electroencephalography, brain imaging, genetics, and biochemistry are reviewed: Analyses of the EEG spectra at rest have repeatedly reported reduced power in the beta band, which is compatible with indications of reduced metabolism. Studies of the absolute level of regional cerebral blood flow (...) show conflicting findings, with two studies reporting reduced rCBF in the frontal lobe, and two studies, based on a different method, reporting no group differences. This contradiction has not yet been resolved. The pattern of reduction in the studies reporting reduced rCBF corresponds to the regional pattern of the glycolytic index. High regional GI indicates high reliance on non-oxidative metabolism, i.e., glycolysis. Variants of the gene ARNT2 have been associated with stuttering. This gene is primarily expressed in the brain, with a pattern roughly corresponding to the pattern of regional GI. A central function of the ARNT2 protein is to act as one part of a sensor system indicating low levels of oxygen in brain tissue and to activate appropriate responses, including activation of glycolysis. It has been established that genes related to the functions of the lysosomes are implicated in some cases of stuttering. It is possible that these gene variants result in a reduced peak rate of energy supply to neurons. Lastly, there are indications of interactions between the metabolic system and the dopamine system: for example, it is known that acute hypoxia results in an elevated tonic level of dopamine in the synapses. Will mild chronic limitations of energy supply also result in elevated levels of dopamine? The indications of such interaction effects suggest that the metabolic theory of stuttering should be explored in parallel with the exploration of the dopaminergic theory. (shrink)

Both Notch and NFκB signaling pathways are well‐known for regulating proliferation, differentiation and apoptosis. Recent studies have presented several lines of evidence supporting an integration of the Notch and NFκB signaling pathways in differentiation/maturation of a diverse range of cell types. It is notable that Notch and NFκB signaling pathways share many common features: (i) both are activated by common stimuli such as TNF‐α and hypoxia, (ii) activated Notch (NICD) and NFκB mediate transcription by regulating corepressors such as SMRT/N‐COR, (...) and (iii) both regulate similar target genes such as Hes‐1 and IκBα. This review expands on how the collaboration between these pathways may play an important role in the CNS. We will speculate on the mechanisms by which Notch and NFκB signaling may collaborate to regulate stem cell renewal and differentiation during brain development and function. BioEssays 29:1039–1047, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Timers and sensors are common devices that make our daily life safer, more convenient, and more efficient. In a cellular context, they arguably play an even more crucial role as they ensure the survival of cells in the presence of various extrinsic and intrinsic stresses. Biological timers and sensors generate distinct signaling profiles, enabling them to produce different types of cellular responses. Recent data suggest that they can work together to guarantee correct timing and responsiveness. By exploring examples of cellular (...) stress signaling from mitosis, DNA damage, and hypoxia, the authors discuss the common architecture of timer‐sensor integration, and how its added features contribute to the generation of desired signaling profiles when dealing with stresses of variable duration and strength. The authors propose timer‐sensor integration as a widespread mechanism with profound biological implications and therapeutic potential. -/- . (shrink)

Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo during cellular metabolism, most notably heme degradation. CO binds to the heme iron of most hemoproteins. Tissue hypoxia following hemoglobin saturation represents a principle cause of CO‐induced mortality in higher organisms, though cellular targets cannot be excluded. Despite extreme toxicity at high concentrations, low concentrations of CO can confer cytoprotection during ischemia/reperfusion or inflammation‐induced tissue injury. Likewise, heme oxygenase, an enzyme that produces CO, biliverdin and iron, as (...) well as a secondary increase in ferritin synthesis, from the oxidation of heme, can confer protection in vivo and in vitro. CO has been shown to affect several intracellular signaling pathways, including guanylate cyclase, which generates guanosine 3′:5′ cyclic monophosphate and the mitogen‐activated protein kinases (MAPK). Such pathways mediate, in part, the known vasoregulatory, anti‐inflammatory, anti‐apoptotic and anti‐proliferative effects of this gas. Exogenous CO delivered at low concentrations is showing therapeutic potential as an anti‐inflammatory agent and as such can modulate numerous pathophysiological states. This review will delve into the biological significance and medical applications of this gas molecule. BioEssays 26:270–280, 2004. © 2004 Wiley Periodicals, 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)

In lieu of an abstract, here is a brief excerpt of the content:“Just Because You Can—Doesn’t Mean You Should”Mindy B. StatterAs Albert R. Jonsen stated, “The technological imperative begins to rule clinical decisions: if a technology exists, it must be applied. Patients... are moved to higher and higher levels of care, finally becoming enmeshed in a tangle of tubes that extinguish their identity and needs as persons.” In this case the conflict created by the parental demand for the utilization of (...) technology, extracorporeal support in a neonate will be explored.I was consulted in the care of a newborn with a right–sided congenital diaphragmatic hernia (CDH). In this anomaly the diaphragm, the muscular partition that separates the abdomen and the thorax, forms incompletely, and the viscera migrate up into the chest compressing the developing lung, shifting the medistinum and heart and compressing the contralateral lung. The resulting lung maldevelopment is termed pulmonary hypoplasia. The maldevelopment of the lungs in CDH is variable with the most severe forms resulting in neonatal death. This congenital anomaly is associated with 55% survivability; the poor prognosis is due to the pulmonary hypoplasia. In addition to pulmonary hypoplasia, there is the association of pulmonary hypertension with CDH. Pulmonary hypertension is a condition where the vascular resistance in the lung is high with reduced blood flow within the lung. The physiologic consequence of pulmonary hypertension is hypoxemia, oxygen deficiency in the blood, and reduced oxygen delivery to all organs. Unlike severe pulmonary hypoplasia, pulmonary hypertension is reversible. When an infant with CDH is born and deteriorates due to respiratory failure it can be difficult to determine whether the respiratory failiure is due to pulmonary hypoplasia or pulmonary hypertension. Extracorporeal membrane oxygenation (ECMO) is indicated in the management of reversible respiratory and, or cardiac failure. In the case of neonates with CDH, ECMO addressess the reversible component of the respiratory failure, the pulmonary hypertension. The respiratory failure due to severe pulmonary hypoplasia is not reversible; ECMO is not indicated. There are established criteria to guide the determination of which infant is a candidate for ECMO. Depending upon the ECMO center, the stringency can vary.In this case, the baby had significant respiratory failure with impairment in both oxygenation, hypoxia, and ventilation–the elimination of carbon dioxide, hypercapnea. The neonatologist spoke with the mother who stated that she wanted “everything done” including ECMO in the management [End Page 22] of her baby. When the neonatologist consulted me to put the baby on ECMO I expressed my concern that this infant had irreversible respiratory failure due to pulmonary hypoplasia. And simply from a technical aspect, I could not guarantee that ECMO would “work”. When an infant is “cannulated” for extracorporeal support, cannulas are inserted to allow for the drainage of blood into the ECMO circuit, the blood oxygenated and the carbon dioxide is cleared, and the blood is then returned to the infant. The majority of diaphragmatic hernias are on the left and when the CDH is on the right side, the right heart may be compressed by the viscera in the chest, and venous drainage into the ECMO circuit may be impaired. When this is encountered, the next step in the management algorithm is to fix the hernia–reduce and return the viscera within the chest to the abdomen and eliminate the visceral compression of the right heart. The neonatologist shared my concern and also reiterated that this baby’s mother wanted “everything done”. I had little uncertainty as to the etiology of the respiratory failure in this baby. In meeting the mother’s demands I then suggested that the hernia be repaired first, and if there was improvement in the hypoxia and hypercapnea, then give the baby the benefit of the doubt that there is a component of reversibility to the respiratory failure and then proceed with ECMO cannulation. The neonatologist agreed with this suggested plan.I then went to talk with the baby’s mother. I explained my concerns that based on the profound hypercapnea on the arterial blood gases that the baby’s respiratory failure was due to pulmonary hypoplasia and not reversible with extracorporeal support. She insisted that her baby be put on ECMO. I then explained the operative algorithm and... (shrink)

This commentary reviews data supporting circuitry reconstruction, replacement neurotransmitters, and trophic action as mechanisms whereby transplants promote recovery of function. Issue is taken with the thesis of Sinden et al. that adequate data exist to indicate that reconstruction of hippocampal circuitry damaged by hypoxia with CA1 transplants is a confirmed mechanism whereby these transplants produce recovery. Sinden et al.'s and Stein & Glasier's proposal that there is definitive evidence showing that all transplants produce trophic effects is also questioned.

In lieu of an abstract, here is a brief excerpt of the content:Ethics & the Environment 12.2 (2007) 128-130MuseSearchJournalsThis JournalContents[Access article in PDF]The Future of Environmental PhilosophyIrene J. KlaverEnvironmental philosophy is invitational: it in-vites thinking into life as well as life into thinking. Life is vita in Latin—the same vita as in vital and in vitamins. An in-vita-tion leads to new connections, or a renewal of existing relations. This affects how we understand things. As Wittgenstein says, "understanding [...] consists in (...) the very fact that we 'see connections.'"1 This is the case for philosophy in general, it makes connections, reveals relations between entities, thoughts, and events, which elucidates our understanding. Environmental philosophy has (re-)opened certain realms of relevance to philosophical inquiry by foregrounding our connections to the non-human world. It accommodates the broadest invitation: of life itself, including our relation to the conditions of life.The future of environmental philosophy lies precisely in this broad invitation. That means that it needs to occupy a profoundly interdisciplinary place, at the node of multiple institutions and practices. It deals with global issues on a local level and with the effects of local issues on a global scale. This involves science, policy, economy, law, ethics, aesthetics, religion, history, etc. An environmental philosopher is a specific generalist, someone who can connect various relations, sees the multiple angles in a particular perspective, the world in a grain of sand.The evolved environmental philosopher is a translator, translating various concerns along multiple perspectives. Translation is crucial to an understanding of the viewpoints, positions, and situations of others. Environmental philosophy enlarges the category of the "other" with many more entities. This is not a politically correct move to bring so-called repressed voices to the fore, it is to evoke different modes of knowledge and experience, to enhance cultural imagination2, a crucial component to raising awareness about environmental concerns.In her 1962 book Silent Spring3, Rachel Carson connected pesticide DDT to the decline in some predatory bird populations and sparked the rise of the environmental movement. She triggered a powerful cultural imagination by invoking a future silent spring without the singing of birds. Hegel saw the owl of Minerva as the symbol of wisdom, spreading "its wings only with the falling of the dusk."4 That is, for Hegel understanding arises after the events, philosophy can never be prescriptive. [End Page 128] Environmental philosophy, on the contrary, is engaged thinking, its understanding arises out of the practices of the everyday. The albatross around our neck is of our own shooting. Environmental ethics and environmental justice might stake out basic prescriptive rules, but these are always born from knowledge of—if not a participation in—certain practices. Environmental philosophy's bird is the spotted owl of social-political engagement, the canary in the mineshaft, but also the sparrow in the backyard. Birds that fly from dawn to dusk, seeing and reporting in the light the practical connections that reveal understanding, possible action, communication needs, and suggest a lexicon for translation. In and through practical connections rises therefore translation and understanding.Understanding is a transformative process—it changes our interpretative frameworks. When we see connections we begin to understand how the dead zone in the Gulf of Mexico is related to agriculture in the midwestern United States thousands of miles away, with watersheds within the Mississippi River Basin draining nitrogen fertilizers into the Mississippi, causing hypoxia in the Gulf.5 Environmental philosophy shows how wetlands are not just wastelands but take nitrogen and phosphorus out of the water, buffer "our" coasts, and feed the migrating birds along their long routes. By not seeing these connections, our wetlands are pumped dry; and by abusing our water, springs disappear, major rivers strand in sand, and dead zones emerge in oceans and seas. "These, too, were silent, deserted by all living things," Rachel Carson states, writing about streams.6 In the twenty first century it is no longer a "fable of tomorrow:" silent springs, silent rivers, silent seas.Environmental philosophy is empirical philosophy dealing with big issues such as global warming, biodiversity, and sustainability, but... (shrink)

B cell activation is accompanied by metabolic adaptations to meet the increased energetic demands of proliferation. The metabolic composition of the microenvironment is known to change during a germinal center response, in inflamed tissue and to vary significantly between different organs. To sustain cellular homeostasis B cells need to be able to dynamically adapt to changes in their environment. An inability to take up and process available nutrients can result in impaired B cell growth and a diminished humoral immune response. (...) Furthermore, the metabolic microenvironment can affect B cell signaling and provide a means to avoid aberrant proliferation or modulate B cell function. Thus, a better understanding of the intricate interplay between cell signaling and metabolism could provide novel insight into how B cell function is regulated and have implications for the development of vaccines or treatment of autoimmune disorders and B cell derived malignancies. Throughout their lifespan, B cells are exposed to different metabolic environments. Signaling pathways regulating cellular responses to metabolic stress not only help to maintain B cell viability and to facilitate cellular functions but may also play an important role in preventing excessive proliferation and malignant transformation. (shrink)

With the advancement of in vivo magnetic resonance imaging (MRI) technique, more detailed information about the human brain at high altitude (HA) has been revealed. The present review aimed to draw a conclusion regarding changes in the human brain in both unacclimatized and acclimatized states in a natural HA environment. Using multiple advanced analysis methods that based on MRI as well as electroencephalography, the modulations of brain gray and white matter morphology and the electrophysiological mechanisms underlying processing of cognitive activity (...) have been explored in certain extent. The visual, motor and insular cortices are brain regions seen to be consistently affected in both HA immigrants and natives. Current findings regarding cortical electrophysiological and blood dynamic signals may be related to cardiovascular and respiratory regulations, and may clarify the mechanisms underlying some behaviors at HA. In general, in the past 10 years, researches on the brain at HA have gone beyond cognitive tests. Due to the sample size is not large enough, the current findings in HA brain are not very reliable, and thus much more researches are needed. Moreover, the histological and genetic bases of brain structures at HA are also needed to be elucidated. (shrink)

With a previous paper (Niu & Wang, 1995), a general, hypothetical outline of the mechanism of carcinogenesis was proposed. With reference to the fact of starvation-induced hypermutation in micro-organisms, we propose that the hypoxia commonly seen in the cells at the centre of solid tumours might also result in hypermutation, and then p53-dependent programmed cell death. Like the apparently adaptive mutations in micro-organisms, only those genes (e.g. p53) that enable the cells to escape from apoptosis may be selected.

The respiration of oxygen, while essential to aerobic organisms for the generation of energy, leads to the formation of reactive oxygen intermediates (ROIs) as harmful byproducts. ROIs damage nucleic acids, lipids and proteins. Therefore, protective mechanisms against elevated intracellular ROI levels, referred to as oxidative stress, have evolved. These include the activation of transcription factors which elevate the expression of protective enzymes. Eukaryotic cells have also evolved the ability to specifically generate ROIs are used as second messengers to activate gene (...) expression. Here we will discuss both prokaryotic and eukaryotic transcription factors that respond to ROIs. In addition, transcription factors will be described that are activated by either exposure to antioxidants, which reduce the intracellular ROI concentration, or by hypoxia, the absence of oxygen. (shrink)

Inflammatory immune cells, when activated, display much the same metabolic profile as a glycolytic tumor cell. This involves a shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis, a phenomenon known as the Warburg effect. The result of this change in macrophages is to rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins. In addition, a rise in certain tricarboxylic acid cycle intermediates occurs notably in citrate for lipid biosynthesis, and succinate, which activates the (...) transcription factor Hypoxia‐inducible factor. In this review we take a look at the emerging evidence for a role for the Warburg effect in the immune and inflammatory responses. The reprogramming of metabolic pathways in macrophages, dendritic cells, and T cells could have relevance in the pathogenesis of inflammatory and metabolic diseases and might provide novel therapeutic strategies. (shrink)

Erythropoietin (EPO), long appreciated as the chief endocrine regulator of red blood cell formation, is now recognized to exert many additional functions outside the bone marrow. Thus, the quest is on to define the full range of EPO functions in the physiology and pathology of non‐hematopoietic tissues. Two recent studies in man and mice have highlighted the importance of the mammalian skin as one peripheral tissue with a previously unsuspected role in EPO biology; both, as a target and as a (...) source of EPO. In addition, the skin has been proposed to function as an oxygen sensor. The present hypothesis essay critically reviews the currently available evidence for this and provides a unifying theoretical scenario for intracutaneous EPO functions and for a potential role of the skin in the control of EPO production. Mainly, we propose that the skin itself directly contributes to the up‐regulation of EPO plasma levels in response to hypoxia. (shrink)

Recent studies challenge the classical view that the origin of animal life was primarily controlled by atmospheric oxygen levels. For example, some modern sponges, representing early‐branching animals, can live under 200 times less oxygen than currently present in the atmosphere – levels commonly thought to have been maintained prior to their origination. Furthermore, it is increasingly argued that the earliest animals, which likely lived in low oxygen environments, played an active role in constructing the well‐oxygenated conditions typical of the modern (...) oceans. Therefore, while oxygen is still relevant to understanding early animal evolution, the relationships between the two might be less straightforward than previously thought. (shrink)

Oxygen is a key regulator of both development and homeostasis and a promising candidate to bridge the influence of the environment and the evolution of new traits. To clarify the various ways in which oxygen may modulate embryogenesis, its effects are reviewed at distinct organizational levels. First, the role of pathways that sense dioxygen levels and reactive oxygen species are reviewed. Then, the effects of microenvironmental oxygen on metabolism, stemness, and differentiation throughout embryogenesis are discussed. Last, the interplay between ecology (...) and development are reexamined with a focus on the evolution of tetrapods, including during the emergence of a novel mechanism that shapes amniote limbs—interdigital cell death. Both genetic and environmental components work together during the formation of organisms, highlighting the importance of a multidisciplinary approach for understanding the evolution of new traits. (shrink)

The origin and early evolution of animals marks an important event in life's history. This event is historically associated with an important variable in Earth history – oxygen. One view has it that an increase in oceanic oxygen levels at the end of the Neoproterozoic Era (roughly 600 million years ago) allowed animals to become large and leave fossils. How important was oxygen for the process of early animal evolution? New data show that some modern sponges can survive for several (...) weeks at low oxygen levels. Many groups of animals have mechanisms to cope with low oxygen or anoxia, and very often, mitochondria – organelles usually associated with oxygen – are involved in anaerobic energy metabolism in animals. It is a good time to refresh our memory about the anaerobic capacities of mitochondria in modern animals and how that might relate to the ecology of early metazoans. (shrink)

Celebrated for disproving the traditional view that lack of oxygen at birth (perinatal asphyxia) contributes significantly to cerebral palsy, a 1986 New England Journal of Medicine article by Karin Nelson and Jonas Ellenberg engineered a new consensus in the medical community: that lack of oxygen at birth rarely causes cerebral palsy. We demonstrate that the article's central argument relies on straightforwardly fallacious statistical reasoning, and we discuss significant implications -- e.g. how carefully fetuses are monitored during labor and delivery, expert (...) testimony in malpractice cases, and public policy decisions. (shrink)