bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenomedullin: Is There Physiological Relevance in the Pathology and Pharmacology?
Authors: Samson Willis K. , Resch Zachary T. , Murphy Tonya C. , Vargas Trini T. , Schell Debra A.
Published: December 2017

The adrenomedullin gene encodes two potent hypotensive peptides, adrenomedullin and proadrenomedullin NH2-terminal 20 peptide. As with other vasoactive peptides, the most difficult challenge is to prove the physiological relevance of their recognized pathological and pharmacological actions and to establish, against that physiological background, their therapeutic potential.
CFTR Chloride Channels: Binding Partners and Regulatory Networks
Authors: Naren Anjaparavanda P. , Kirk Kevin L.
Published: December 2017

The cystic fibrosis gene encodes a chloride channel (CFTR) that regulates transepithelial salt and water transport. Two classes of CFTR-binding proteins appear to link the opposing cytoplasmic tails of this channel to distinct regulatory networks. Such interactions may constitute new paradigms for modulating CFTR activity in health and disease.
The Beauty and the Beast: Aspects of the Autonomic Nervous System
Authors: Corti Roberto , Binggeli Christian , Sudano Isabella , Spieker Lukas E. , Wenzel René R. , Lüscher Thomas F. , Noll Georg
Published: December 2017

Sympathetic nerve activity is altered and is a prognostic factor for many cardiovascular diseases such as hypertension, coronary syndromes, and congestive heart failure. Therefore, the selection of vasoactive drugs for the treatment of these diseases should also take into consideration their effects on the sympathetic nervous system.
Inflammatory Cytokines in Nonpathological States
Authors: Cannon Joseph G.
Published: December 2017

During infection, inflammatory cytokines induce regulated changes in the host's internal milieu that create a hostile environment to an invading pathogen. Recent evidence indicates that these cytokines are constitutively produced, their production is increased by environmental stressors other than microbes, and they modulate “normal” physiological processes.
Excitatory Synaptic Transmission in Neonatal Dorsal Horn: NMDA and ATP Receptors
Authors: Bardoni Rita
Published: December 2017

Postnatal development sees a strong synaptogenesis in rat superficial dorsal horn. My studies show that synapses mediated by two excitatory neurotransmitters, glutamate and ATP, are functional since the very first postnatal days. Using an electrophysiological approach, the functional properties of two receptors activated by these neurotransmitters, glutamatergic NMDA and ATP ionotropic receptors, are described.
The Intrarenal Endothelin System and Hypertension
Authors: Abassi Zaid A. , Ellahham Samer , Winaver Joseph , Hoffman Aaron
Published: December 2017

The kidney is both a source of endothelin (ET) generation and an important target organ of this peptide. The highest concentrations of ET-1 in the body exist in the renal medulla, where it mediates natriuretic and diuretic effects through the ETB receptor subtype. It is proposed that aberrations in the renal ET system may lead to sodium and water retention and subsequently to the development of hypertension.
Molecular Recognition by Induced Fit: How Fit is the Concept?
Authors: Bosshard Hans Rudolf
Published: December 2017

Induced fit explains why biomolecules can bind together even if they are not optimized for binding. However, induced fit can lead to a kinetic bottleneck and does not describe every interaction in the absence of prior complementarity. Preselection of a fitting conformer is an alternative to induced fit.
Astrocytes Function in Matching Blood Flow to Metabolic Activity
Authors: Harder David R. , Zhang Chenyang , Gebremedhin Debebe
Published: December 2017

The brain possesses an intrinsic regulatory mechanism to maintain an adequate supply of O2 and nutrition despite local increases in neuronal activity. Brain astrocytes function as an intermediary cell type by responding to glutamate released from activated neurons, and they couple cerebral blood flow by producing cytochrome P-450-derived epoxyeicosatrienoic acids that induce vasodilation and increase capillary density.
The Physiologist's Ethical Dilemmas
Authors: Weibel Ewald R.
Published: December 2017

Physiologists are bound to test their scientific theories in experiments on living matter and, ultimately, on living organisms—animals or humans. This confronts the physiologist with ethical dilemmas: can we engage in physiological eperiments in the face of possibly harming the interests of living beings, or should we refrain from such studies, thus preventing the good that can be derived from scientific progress?
THE INSENSIBLE LOSS OF WATER
Authors: Newburgh L. H. , Johnston Margaret Woodwell
Published: December 2017

The authors of the paper on The Insensible Loss of Water, p. 1, volume 22, no. 1 (January 1942) desire to record the following corrections:

p. 6: The column at the right of figure 1, designated “grams,” should start at 517 and increase by 345 for each interval. In the legend of this figure the phrase “or grams of water vapor per 24 hours” should be transferred to the end of the last sentence.

p. 14: Reference (67) following “Rubner” should become (65).

p. 16: Reference (68) should be deleted.
Metabolism of the Hemin Chromoproteins
Authors: Drabkin David L.
Published: December 2017

Page 418. David L. Drabkin, “Metabolism of the Hemin Chromoproteins.” Equation 5 should read: Cytochrome c (rat, dog, man, cow)/W0.7kg. = 0.039 gm. or 3.0 μm.
Effects of sex steroids and related compounds on pregnancy and on development of the young.
Authors: Saunders F J
Published: December 2017

Extensive animal research has shown that endogenous estrogens and progestins play a vital role in controlling the course of normal pregnancy and fetal development. The balance of the 2 types of hormones must be maintained, a relative excess of deficiency of either being detrimental to the offspring. Information on this topic is presented from a review of the animal study literature. The effect of sex steroids in the following areas of pregnancy and fetal development is discussed: 1) interruption of gestation; 2) antifertility effects; 3) prolonged gestation; 4) maintenance of pregnancy; 5) fetal masculinization; 6) fetal feminization; 7) teratogenic effects; 8) postnatal effects of steroids on males and females; 9) steroid transfer through milk; and 10) female sterility induction through early postnatal administration of steroids.
Atrial receptors and renal function
Authors: Goetz K. L. , Bond G. C. , Bloxham D. D.
Published: December 2017

The hypothesis that receptors in the heart or pulmonary vasculature initiate a reflex that influences urine flow was derived from experiments designed to evaluate the effect of mechanical ventilation on renal function. These experiments indicated that urine flow usually decreases during positive-pressure breathing and usually increases during negative-pressure breathing. It was surmised that impulses from certain cardiopulmonary receptors affect the secretion of ADH, which in turn influences urine flow. A subsequent investigation appeared to localize the pertinent receptors to the left atrium, but the results of this particular investigation were influenced by several complication factors that have not been widely appreciated. The apparent localization of volume-regulating recpetors to the left atrium and the accumulating evidence that atrial receptors do respond to changes in atrial pressure or atrial volume triggered a myriad of further studies on the function of left receptors. Nearly all these studies employed indirect techniques that produced changes in systemic and pulmonary hemodynamics in addition to changes in left atrial pressure. Nevertheless, it often was assumed that if changes in left pressure were produced, any concomitant changes in circulating ADH or in urine flow were attributable to a reflex elicited from atrial receptors. Mush of the data obtained were interpreted as being compatible with the elft atrial volume-receptor hypothesis, but very liggle of the data pertained to left atrial receptors specifically.
Organization of lumbar spinal outflow to distal colon and pelvic organs
Authors: Janig W. , McLachlan E. M.
Published: December 2017

The lumbar sympathetic outflow projects through the lumbar splanchnic, lumbar colonic, and hypogastric nerves (and to a lesser degree through the sacral sympathetic chain and pelvic nerves). It is thought to be involved in the regulation of the storage and evacuation functions of the following three organ systems: lower urinary tract, hindgut, and reproductive organs. In addition, it controls vascular resistance and capacitance. Thus the target tissues of the postganglionic neurons are vascular smooth muscle, visceral smooth muscles, probably secretory epithelia, and also neurons in the enteric nervous system and the pelvic ganglia. The preganglionic neurons are situated in the caudal part of the spinal representation, neurons associated with the colon being located rostral to those associated with the pelvic organs. Most lie medial to the classical intermediolateral cell column that may contain mainly vasoconstrictor neurons. Most (if not all) preganglionic neurons are cholinergic; some also contain an identified peptide. Most of the postganglionic neurons are situated in the inferior mesenteric ganglion (or equivalent structures); again, those projecting to the colon lie rostral to those projecting to the pelvic organs. Others lie in intercalated prevertebral ganglia, in the pelvic plexus, and in sacral paravertebral ganglia. The majority is noradrenergic, and most also contain one or several peptides, the topographical distribution of which appears to characterize functional subgroups of neurons. The terminations of noradrenergic axons in many pelvic organs probably make close contact with both vascular and nonvascular effectors. In the colon, most endings are located in the enteric plexuses. The responses of these organs to electrical stimulation of visceral nerves, and their reflex responses (together with those observed in the efferent axons of visceral nerve trunks) to electrical and natural stimulation of afferent fibers, lead to the general conclusion that several distinct classes of pre- and postganglionic neurons exist. 1) Vasoconstrictor neurons demonstrate ongoing activity with cardiac rhythm and appropriate reflexes to stimulation of cardiovascular afferent receptors and respond only weakly to natural stimulation of visceral receptors. 2) MR neurons respond to visceral stimuli but are not influenced from arterial baro- and chemoreceptors. These show at least two different response patterns consistent with their separate involvement in the reciprocal behavior of the colon and bladder. 3) Other neurons are silent in anesthetized animals and do not respond to any stimuli used thus far.(ABSTRACT TRUNCATED AT 400 WORDS)
Functional specialization of different hepatocyte populations
Authors: Jungermann K. , Katz N.
Published: December 2017

Hepatocytes from the periportal (afferent) and perivenous (efferent) zones of the liver parenchyma differ in their enzyme content and subcellular structures and thus have different metabolic capacities. Therefore the model of metabolic zonation proposes a functional specialization for the two zones: 1) oxidative energy metabolism with beta-oxidation, amino acid catabolism, ureagenesis, gluconeogenesis for the synthesis of both glucose and glycogen, cholesterol synthesis, bile formation, and protective metabolism are predominantly located in the periportal zone; 2) glycolysis, glycogen synthesis from glucose, liponeogenesis, ketogenesis, glutamine formation, and xenobiotic metabolism are preferentially situated in the perivenous zone. The input of humoral and nervous signals into the two zones is different. During passage of blood through the liver acinus, concentration gradients of oxygen, substrates, and hormones are established; the nerve densities in the two zones seem to be different. The different expression of the genome in upstream and downstream hepatocytes can be caused among other factors by the zonal gradients in oxygen and hormone concentrations. The functional specialization of the different hepatocyte populations is especially well documented for carbohydrate, amino acid, ammonia, and xenobiotic metabolism as well as for bile formation by a number of different approaches. Zonal flux differences were calculated from enzyme and metabolite distributions measured in vivo. They were observed in periportal- and perivenous-like hepatocytes in cell culture and in hepatocyte populations enriched in periportal and perivenous cells. They were detected also during ortho-and retrograde liver perfusion and finally by noninvasive techniques, using surface micro-light guides and miniature oxygen electrodes. The peculiar zonal hepatotoxicity of many xenobiotics can be explained at least in part by the enzymatic and fine-structural hepatocellular heterogeneity.
Spectrin-Based Membrane Skeleton: A Multipotential Adaptor Between Plasma Membrane and Cytoplasm
Authors: Bennett Vann
Published: December 2017

Pages 1029–1065: Vann Bennett. “Spectrin-Based Membrane Skeleton: A Multipotential Adaptor Between Plasma Membrane and Cytoplasm.” Page 1056: Ref. 36 should read BENNETT, H., and J. CONDEELIS. Isolation of an immunoreactive analogue of brain fodrin that is associated with the cell cortex of Dictyostelium amoebae. Cell Motil. Cytoskeleton 11: 303–317, 1988.
Nonsteroidal signals originating in the gonads
Authors: Ackland J. F. , Schwartz N. B. , Mayo K. E. , Dodson R. E.
Published: December 2017

The discovery of the various peptide factors in the gonads followed different paths. A number of factors were specifically searched for because of physiological experiments that predicted that an activity from the gonads was necessary to explain phenomena. Such was the case for gonadal steroids and for such peptide factors as inhibin, MIS, OMI, FRP, seminal plasma inhibin, relaxin, PA factor and other proteases, and ABP. In the process other factors such as activin and follistatin were serendipitously discovered. A second group of factors was discovered because in vitro experiments of various combinations of gonadal cell types failed to replicate in vivo findings, suggesting missing signals. Such substances are the panoply of growth factors aiding in differentiation and growth promotion and inhibition: LS and LI, P-Mod-S, clusterin, and various components of the ECM. Finally, and most recently, another set of peptides has been identified because immunological or molecular probes have been used to search gonadal tissue for factors originally discovered elsewhere; these include POMC, GnRH-like peptide, oxytocin, AVP, angiotensin, ANF, CRF, neural peptides, and c-mos. Our understanding of the relationship of most of these peptides to the local signals necessary for gonadal function is still very elementary. Clearly some like relaxin and inhibin function as important hormones, and ABP, for example, probably functions importantly in transporting testosterone down the tubule. Most local paracrine or autocrine peptide signals appear to act in relationship to gonadotropin levels probably in local differentiation in the process of gamete maturation, but this is only conjecture at this point. No experimental verification that any of these factors is involved in follicle selection for recruitment or for atresia is yet available. For many of the factors local receptors have not yet been identified. The richness of the variety of peptides in the gonads suggests that microanalysis of cell-cell signaling would be rewarding, but at the time of this writing such investigations are not yet possible.
Cellular Defenses Against Damage From Reactive Oxygen Species
Authors: Yu B. P.
Published: December 2017

Pages 139–162: Yu. “Cellular Defenses Against Damage From Reactive Oxygen Species.” Page 150: The section 2. Ceruloplasmin should appear as follows:

[See PDF]
Oxygen sensing and molecular adaptation to hypoxia
Authors: Bunn H. F. , Poyton R. O.
Published: December 2017

This review focuses on the molecular stratagems utilized by bacteria, yeast, and mammals in their adaptation to hypoxia. Among this broad range of organisms, changes in oxygen tension appear to be sensed by heme proteins, with subsequent transfer of electrons along a signal transduction pathway which may depend on reactive oxygen species. These heme-based sensors are generally two-domain proteins. Some are hemokinases, while others are flavohemoproteins [flavohemoglobins and NAD(P)H oxidases]. Hypoxia-dependent kinase activation of transcription factors in nitrogen-fixing bacteria bears a striking analogy to the phosphorylation of hypoxia inducible factor-1 (HIF-1) in mammalian cells. Moreover, redox chemistry appears to play a critical role both in the trans-activation of oxygen-responsive genes in unicellular organisms as well as in the activation of HIF-1. In yeast and bacteria, regulatory operons coordinate expression of genes responsible for adaptive responses to hypoxia and hyperoxia. Similarly, in mammals, combinatorial interactions of HIF-1 with other identified transcription factors are required for the hypoxic induction of physiologically important genes.
Mechanism of signaling by growth hormone receptor
Authors: Argetsinger L. S. , Carter-Su C.
Published: December 2017

Growth hormone (GH) has long been known to stimulate linear growth and regulate metabolism. The cellular mechanism by which GH elicits these effects has only recently begun to be understood. This review provides an overview of a current model of GH signaling. Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2. Tyrosyl phosphorylation of GH receptor and JAK2 recruits and activates signaling molecules such as Stat transcription factors, SHC, and insulin receptor substrates 1 and 2 that lead to the release of second messengers such as diacylglycerol, calcium, and nitric oxide and the activation of enzymes such as mitogen-activated protein kinase, protein kinase C, phospholipase A2, and phosphatidylinositol 3'-kinase. These pathways regulate cellular function including gene transcription, metabolite transport, and enzymatic activity that result in the ability of GH to control body growth and metabolism.
Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin
Authors: Sandvig K. , van Deurs B.
Published: December 2017

Protein toxins such as ricin and Shiga toxin with intracellular targets have to be endocytosed and translocated to the cytosol to inhibit the protein synthesis and thereby kill the cell. Ricin is internalized by both clathrin-dependent and -independent endocytic mechanisms, whereas Shiga toxin seems to be taken up exclusively from clathrin-coated pits. After endocytosis, internalized membrane and content are delivered to endosomes, where sorting for further routing in the cell takes place. Toxins that remain membrane bound at low endosomal pH can be recycled to the cell surface or transcytosed in polarized epithelia. A large proportion of internalized toxin is transported to lysosomes for degradation. Most importantly, a fraction of the internalized ricin and Shiga toxin molecules is delivered to the trans-Golgi network (TGN). Shiga toxin can, in some very sensitive cells, be transported retrogradely through the Golgi cisterns all the way back to the endoplasmic reticulum (ER), and it is possible that also ricin is transported retrogradely to the ER. In this review, a cell biological overview of these intracellular transport steps is presented, and evidence is provided that the delivery to the TGN and the subsequent retrograde transport to the ER are required for optimal intoxication. Moreover, it is argued that knowledge of this transport is important for targeted drug delivery such as the application of immunotoxins in cancer therapy.
Lactate-proton cotransport in skeletal muscle
Authors: Juel C.
Published: December 2017

Skeletal muscle and most other tissues possess a membrane transport system mediating a coupled lactate and H+ translocation. Muscle possesses several lactate-proton transporter isoforms of which two have been cloned; however, the main isoform remains to be identified. The isoforms may have different properties and functional roles, but these have not been specifically characterized. The distribution of lactate-proton transport capacity in skeletal muscle is fiber type dependent, with a higher capacity in slow-twitch fibers compared with fast-twitch fibers. During intense muscle activity and in the recovery period, the lactate and H+ effluxes are mainly mediated by the lactate-proton transporter, which reduces the accumulation of lactate in muscle as well as the drop in internal pH suggested to be involved in muscle fatigue. Thus the lactate-proton transporter is of functional importance for pH regulation in association with muscle activity. This carrier is also important for lactate uptake into resting muscle and other tissues; therefore, the carrier distribution is important for the fate of lactate in the body. In addition, the capacity of the lactate-proton transporter can be increased by intense training and is reduced by inactivity; thus the lactate-proton transporter can undergo adaptive changes.
Regulation of Sexual Dimorphism in Mammals
Authors: HAQQ CHRISTOPHER M. , DONAHOE PATRICIA K.
Published: December 2017

Haqq, Christopher M., and Patricia K. Donahoe. Regulation of Sexual Dimorphism in Mammals. Physiol. Rev. 78: 1–33, 1998. — Sexual dimorphism in humans has been the subject of wonder for centuries. In 355 BC, Aristotle postulated that sexual dimorphism arose from differences in the heat of semen at the time of copulation. In his scheme, hot semen generated males, whereas cold semen made females (Jacquart, D., and C. Thomasset. Sexuality and Medicine in the Middle Ages, 1988). In medieval times, there was great controversy about the existence of a female pope, who may have in fact had an intersex phenotype (New, M. I., and E. S. Kitzinger. J. Clin. Endocrinol. Metab. 76: 3–13, 1993.). Recent years have seen a resurgence of interest in mechanisms controlling sexual differentiation in mammals. Sex differentiation relies on establishment of chromosomal sex at fertilization, followed by the differentiation of gonads, and ultimately the establishment of phenotypic sex in its final form at puberty. Each event in sex determination depends on the preceding event, and normally, chromosomal, gonadal, and somatic sex all agree. There are, however, instances where chromosomal, gonadal, or somatic sex do not agree, and sexual differentiation is ambiguous, with male and female characteristics combined in a single individual. In humans, well-characterized patients are 46, XY women who have the syndrome of pure gonadal dysgenesis, and a subset of true hermaphrodites are phenotypic men with a 46, XX karyotype. Analysis of such individuals has permitted identification of some of the molecules involved in sex determination, including SRY (sex-determining region Y gene), which is a Y chromosomal gene fulfilling the genetic and conceptual requirements of a testis-determining factor. The purpose of this review is to summarize the molecular basis for syndromes of sexual ambiguity seen in human patients and to identify areas where further research is needed. Understanding how sex-specific gene activity is orchestrated may provide insight into the molecular basis of other cell fate decisions during development which, in turn, may lead to an understanding of aberrant cell fate decisions made in patients with birth defects and during neoplastic change.
The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling
Authors: JANMEY PAUL A.
Published: December 2017

Janmey, Paul A. The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling. Physiol. Rev. 78: 763–781, 1998. — The three-dimensional intracellular network formed by the filamentous polymers comprising the cytoskeletal affects the way cells sense their extracellular environment and respond to stimuli. Because the cytoskeleton is viscoelastic, it provides a continuous mechanical coupling throughout the cell that changes as the cytoskeleton remodels. Such mechanical effects, based on network formation, can influence ion channel activity at the plasma membrane of cells and may conduct mechanical stresses from the cell membrane to internal organelles. As a result, both rapid responses such as changes in intracellular Ca2+and slower responses such as gene transcription or the onset of apoptosis can be elicited or modulated by mechanical perturbations. In addition to mechanical features, the cytoskeleton also provides a large negatively charged surface on which many signaling molecules including protein and lipid kinases, phospholipases, and GTPases localize in response to activation of specific transmembrane receptors. The resulting spatial localization and concomitant change in enzymatic activity can alter the magnitude and limit the range of intracellular signaling events.
Intracellular CFTR: Localization and Function
Authors: BRADBURY NEIL A.
Published: December 2017

Bradbury, Neil A. Intracellular CFTR: Localization and Function. Physiol. Rev. 79, Suppl.: S175–S191, 1999. — There is considerable evidence that CFTR can function as a chloride-selective anion channel. Moreover, this function has been localized to the apical membrane of chloride secretory epithelial cells. However, because cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane protein, it will also be present, to some degree, in a variety of other membrane compartments (including endoplasmic reticulum, Golgi stacks, endosomes, and lysosomes). An incomplete understanding of the molecular mechanisms by which alterations in an apical membrane chloride conductance could give rise to the various clinical manifestations of cystic fibrosis has prompted the suggestion that CFTR may also play a role in the normal function of certain intracellular compartments. A variety of intracellular functions have been attributed to CFTR, including regulation of membrane vesicle trafficking and fusion, acidification of organelles, and transport of small anions. This paper aims to review the evidence for localization of CFTR in intracellular organelles and the potential physiological consequences of that localization.
Structure and Function of the CFTR Chloride Channel
Authors: SHEPPARD DAVID N. , WELSH MICHAEL J.
Published: December 2017

Sheppard, David N., and Michael J. Welsh. Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79 , Suppl.: S23–S45, 1999. — The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl−channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.
Sodium/Calcium Exchange: Its Physiological Implications
Authors: Blaustein Mordecai P. , Lederer W. Jonathan
Published: December 2017

The Na+/Ca2+exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+in parallel with the PM ATP-driven Ca2+pump. As a reversible transporter, it also mediates Ca2+entry in parallel with various ion channels. The energy for net Ca2+transport by the Na+/Ca2+exchanger and its direction depend on the Na+, Ca2+, and K+gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+is transported in the same direction as Ca2+, with a coupling ratio of four Na+to one Ca2+plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+exchanger family ( NCX1, NCX2, and NCX3) and two in the Na+/Ca2+plus K+family ( NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+concentration lead to increases in Ca2+concentration mediated by the Na+/Ca2+exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+and Ca2+apparently modulate basolateral K+conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+exchanger to regulate sarco(endo)plasmic reticulum Ca2+stores and influence cellular Ca2+signaling.
Voltage-Gated Ion Channels and Hereditary Disease
Authors: Lehmann-Horn Frank , Jurkat-Rott Karin
Published: December 2017

By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.
Load-Regulating Mechanisms in Gait and Posture: Comparative Aspects
Authors: Duysens J. , Clarac F. , Cruse H.
Published: December 2017

How is load sensed by receptors, and how is this sensory information used to guide locomotion? Many insights in this domain have evolved from comparative studies since it has been realized that basic principles concerning load sensing and regulation can be found in a wide variety of animals, both vertebrate and invertebrate. Feedback about load is not only derived from specific load receptors but also from other types of receptors that previously were thought to have other functions. In the central nervous system of many species, a convergence is found between specific and nonspecific load receptors. Furthermore, feedback from load receptors onto central circuits involved in the generation of rhythmic locomotor output is commonly found. During the stance phase, afferent activity from various load detectors can activate the extensor part in such circuits, thereby providing reinforcing force feedback. At the same time, the flexion is suppressed. The functional role of this arrangement is that activity in antigravity muscles is promoted while the onset of the next flexion is delayed as long as the limb is loaded. This type of reinforcing force feedback is present during gait but absent in the immoble resting animal.
Synaptic Control of Motoneuronal Excitability
Authors: Rekling Jens C. , Funk Gregory D. , Bayliss Douglas A. , Dong Xiao-Wei , Feldman Jack L.
Published: December 2017

Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions, signal transduction, and functional role. Glutamate is the main excitatory, and GABA and glycine are the main inhibitory transmitters acting through ionotropic receptors. These amino acids signal the principal motor commands from peripheral, spinal, and supraspinal structures. Amines, such as serotonin and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre- and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K+current, cationic inward current, hyperpolarization-activated inward current, Ca2+channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior.
Extracellular Calcium Sensing and Extracellular Calcium Signaling
Authors: Brown Edward M. , MacLeod R. John
Published: December 2017

The cloning of a G protein-coupled extracellular Ca2+(Cao2+)-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Cao2+on tissues that maintain systemic Cao2+homeostasis, especially parathyroid chief cells and several cells in the kidney. The availability of the cloned CaR enabled the development of DNA and antibody probes for identifying the CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from inactivating or activating mutations of the CaR gene and the subsequent generation of mice with targeted disruption of the CaR gene. The characteristic alterations in parathyroid and renal function in these patients and in the mice with “knockout” of the CaR gene have provided valuable information on the CaR's physiological roles in these tissues participating in mineral ion homeostasis. Nevertheless, relatively little is known about how the CaR regulates other tissues involved in systemic Cao2+homeostasis, particularly bone and intestine. Moreover, there is evidence that additional Cao2+sensors may exist in bone cells that mediate some or even all of the known effects of Cao2+on these cells. Even more remains to be learned about the CaR's function in the rapidly growing list of cells that express it but are uninvolved in systemic Cao2+metabolism. Available data suggest that the receptor serves numerous roles outside of systemic mineral ion homeostasis, ranging from the regulation of hormonal secretion and the activities of various ion channels to the longer term control of gene expression, programmed cell death (apoptosis), and cellular proliferation. In some cases, the CaR on these “nonhomeostatic” cells responds to local changes in Cao2+taking place within compartments of the extracellular fluid (ECF) that communicate with the outside environment (e.g., the gastrointestinal tract). In others, localized changes in Cao2+within the ECF can originate from several mechanisms, including fluxes of calcium ions into or out of cellular or extracellular stores or across epithelium that absorb or secrete Ca2+. In any event, the CaR and other receptors/sensors for Cao2+and probably for other extracellular ions represent versatile regulators of numerous cellular functions and may serve as important therapeutic targets.
Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation
Authors: Kyriakis John M. , Avruch Joseph
Published: December 2017

The molecular details of mammalian stress-activated signal transduction pathways have only begun to be dissected. This, despite the fact that the impact of these pathways on the pathology of chronic inflammation, heart disease, stroke, the debilitating effects of diabetes mellitus, and the side effects of cancer therapy, not to mention embryonic development, innate and acquired immunity, is profound. Cardiovascular disease and diabetes alone represent the most significant health care problems in the developed world. Thus it is not surprising that understanding these pathways has attracted wide interest, and in the past 10 years, dramatic progress has been made. Accordingly, it is now becoming possible to envisage the transition of these findings to the development of novel treatment strategies. This review focuses on the biochemical components and regulation of mammalian stress-regulated mitogen-activated protein kinase (MAPK) pathways. The nuclear factor-κB pathway, a second stress signaling paradigm, has been the subject of several excellent recent reviews (258, 260).
Physiological Roles and Regulation of Mammalian Sulfate Transporters
Authors: Markovich Daniel
Published: December 2017

All cells require inorganic sulfate for normal function. Sulfate is among the most important macronutrients in cells and is the fourth most abundant anion in human plasma (300 μM). Sulfate is the major sulfur source in many organisms, and because it is a hydrophilic anion that cannot passively cross the lipid bilayer of cell membranes, all cells require a mechanism for sulfate influx and efflux to ensure an optimal supply of sulfate in the body. The class of proteins involved in moving sulfate into or out of cells is called sulfate transporters. To date, numerous sulfate transporters have been identified in tissues and cells from many origins. These include the renal sulfate transporters NaSi-1 and sat-1, the ubiquitously expressed diastrophic dysplasia sulfate transporter DTDST, the intestinal sulfate transporter DRA that is linked to congenital chloride diarrhea, and the erythrocyte anion exchanger AE1. These transporters have only been isolated in the last 10–15 years, and their physiological roles and contributions to body sulfate homeostasis are just now beginning to be determined. This review focuses on the structural and functional properties of mammalian sulfate transporters and highlights some of regulatory mechanisms that control their expression in vivo, under normal physiological and pathophysiological states.
Calcium: Taste, Intake, and Appetite
Authors: Tordoff Michael G.
Published: December 2017

This review summarizes research on sensory and behavioral aspects of calcium homeostasis. These are fragmented fields, with essentially independent lines of research involving gustatory electrophysiology in amphibians, ethological studies in wild birds, nutritional studies in poultry, and experimental behavioral studies focused primarily on characterizing the specificity of the appetite in rats. Recently, investigators have begun to examine potential physiological mechanisms underlying calcium intake and appetite. These include changes in the taste perception of calcium, signals related to blood calcium concentrations, and actions of the primary hormones of calcium homeostasis: parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D. Other influences on calcium intake include reproductive and adrenal hormones and learning. The possibility that a calcium appetite exists in humans is discussed. The broad range of observations documenting the existence of a behavioral limb of calcium homeostasis provides a strong foundation for future genetic and physiological analyses of this behavior.
Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis
Authors: Chapman Victoria , Markides Hareklea , Sagar Devi Rani , Xu Luting , Burston James J. , Mapp Paul , Kay Alasdair , Morris Robert H. , Kehoe Oksana , El Haj Alicia J.
Published: December 2017

Background. Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods. Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 × 106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5 × 106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL), 1.5 × 106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results. Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion. Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain.
Circulating Tumor Cells Were Associated with the Number of T Lymphocyte Subsets and NK Cells in Peripheral Blood in Advanced Non-Small-Cell Lung Cancer
Authors: Ye Liang , Zhang Fang , Li Huijuan , Yang Linfei , Lv Tangfeng , Gu Wei , Song Yong
Published: December 2017

In this study, we aim to investigate the correlation between circulating tumor cells (CTCs) and the T lymphocyte subsets and NK cells in peripheral blood in non-small-cell lung cancer (NSCLC). The peripheral blood CTCs were determined by SET-iFISH. Flow cytometry was used to determine the distribution of T lymphocyte subsets and NK cells. Forty-one (49%) patients showed positivity for CTCs. Logistic regression analysis revealed CTC number was negatively correlated with the ratio of CD3+, CD4+, CD4+/CD8+, and NK % in patients at stage IV, while in a positive correlation was noticed between CTC number and regulatory T cell (Tregs) ratio in these patients. Multivariate analysis was performed in combination with the clinical-pathological materials to identify the risk factors for CTC positivity. Differentiation, NSCLC stage, percentages of CD3+CD4+ cells, Tregs, and NK cells were the independent risk factors for CTCs. CTCs were associated with the decrease of immune surveillance in the peripheral blood in NSCLC patients. The decrease of immune surveillance contributed to the escape of CTCs from the killing effects of the immunocytes, as well as the formation of metastasized lesions in the target organs.
Innovation in training for totally implanted port insertion
Authors: Kelly Linda J , Moss Jon
Published: December 2017

This article discusses the use of fresh frozen cadavers as an innovative way to teach the procedure of totally implanted port insertion. In an attempt to increase the number of competent medical and nursing practitioners able to insert these devices, workshops have been devised and delivered at a university clinical anatomy skills centre. This method of teaching has had positive feedback from practitioners.
Get active when it's cold outside
Authors: Neville Sarah
Published: December 2017

You might feel that there are many barriers to active outdoor learning in the winter, but they can easily be overcome with thoughtful planning and just a little imagination.
This is a good career
Authors: Webb Penny
Published: December 2017

Although there has been a steady decline in the number of registered childminders over recent years, as a career it can work financially, with benefits for your work/life balance.
Science: Coming up with ideas
Authors: Sargent Marianne
Published: December 2017

This is the seventh in a series of extracts from the book, Developing Early Science Skills Outdoors, which explores ideas for providing children with opportunities to learn outside.
Complications of conscious sedation: causes and management
Authors: Halai Tina , Naqvi Ambareen , Steel Clare , Koshal Sonita
Published: December 2017

Abstract: Conscious sedation is a common treatment modality for patients with dental anxiety. In adults, intravenous sedation using Midazolam is the most common method of conscious sedation. For inhalational sedation, Nitrous Oxide and Oxygen are used frequently. Clinicians should be aware of the potential complications associated with delivery of intravenous sedation which can occur pre-, peri- and post-sedation. An awareness of the pharmacology of the drugs as well as careful patient assessment and monitoring can help clinicians to anticipate and reduce complications. This article will review the most common complications and describe prevention and management of each.

CPD/Clinical Relevance: With increasing dental anxiety amongst the population, there may be further potential demand for treatment provision for patients using conscious sedation. This article summarizes management of complications for general dental practitioners to be mindful of, which can occur pre-sedation, during sedation and post-sedation.
A step-by-step guide to performing a complete digital rectal examination
Authors: Steggall Martin , Cox Carol
Published: December 2017

This clinical skills series is designed for the nursing professional as a basic overview on key clinical skills necessary for patient care, clearly presenting common clinical procedures and their rationale, together with the essential background theory. In this second article in the series, Martin Steggall and Carol Cox describe the process associated with digital rectal examination. It focuses on a systematic approach and highlights areas in which gastrointestinal nurses may enhance their knowledge and practice.
Help is at hand for women with anal sphincter injuries
Authors: Perston Yvette
Published: December 2017

Yvette Perston, Clinical Nurse Specialist at Queen Elizabeth Hospital Birmingham, introduces a charity for faecal incontinence due to childbirth
Speaking as one
Authors: Fry Fiona , Clayton Michelle
Published: December 2017

Fiona Fry and Michelle Clayton, Chairs of the British Liver Nurses' Association (BLNA), introduce the new professional association for UK liver nurses
Research roundup
Authors: Costello John
Published: December 2017

Synopses of a selection of recently published research articles of relevance to palliative care.
Newly qualified health visitor: Why reflective practice is essential
Authors: Smith Marie Anne
Published: December 2017

The novice professional will inevitably encounter situations that may not have come up in training, which is what happened when Marie Anne Smith was assigned a newborn baby whose mother's first language was not English