Allen Ray Sing Chen, M.D., M.H.S., Ph.D.
https://www.hopkinsmedicine.org/profiles/results/directory/profile/0008071/allen-chen
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Thus medications in checked baggage accupril 10mg overnight delivery, glucose (or the acetyl CoA or other compounds produced from glucose metabolism) must be metabolized in neurons to a considerable extent Major cell types and their subcellular structures have different energetic requirements and metabolic capabilities the brain contains two major classes of cells: neurons and glia. Neurons have many phenotypes that reflect different neurotransmitters and structural and functional properties; glia include astrocytes, oligodendroglia and microglia, each of which has specific and quite different functions. The proportion of energy used by the major cell types is unclear, but major white matter tracts that contain oligodendrocytes have much lower metabolic rates than neuropil that contains astrocytes and neurons; also, neuronal cell bodies have lower rates of glucose utilization than the synapse-rich regions that contain pre- and post-synaptic neuronal processes and astrocytes (Clarke & Sokoloff, 1999). Some processes with high energy costs, such as phospholipid turnover and maintenance of phospholipid polarization in membranes, are likely to be higher in glia than in neurons due to the large surface area of fine filopodial processes of astrocytes and of the myelin of oligodendrocytes. Most pathways of energy metabolism in brain are similar to those in other tissues, but compartmentation of metabolism in brain due to the highly specialized cellular and subcellular functions and the corresponding localization of transporters, enzymes, and metabolic pathways makes brain cells uniquely interdependent. Metabolic compartmentation is defined as the presence in cells or tissue of more than one distinct pool of a given metabolite. These separate pools of a metabolite are not in rapid equilibrium with each other but maintain their own integrity and turnover rates (Berl et al. However, the effects of chronic hyperglycemia and diabetes mellitus on glucose transport are conflicting; some studies report decreased glucose uptake while others find no difference (Pelligrino et al. Cerebral oxygen consumption is low at birth, rises rapidly during the period of cerebral growth and development I. During the suckling period the brain is highly dependent on the use of ketone bodies for energy and as carbon source for synthesis of lipids, amino acids and protein (Cremer, 1982; Nehlig, 2004) and hence, the activities of the enzymes for utilization of these substrates are high, whereas activities of pyruvate dehydrogenase and of some oxidative enzymes are lower (Patel et al. The first two enzymes in the pathway of ketone utilization are D-hydroxybutyrate dehydrogenase and aceto-acetyl-succinyl-CoA transferase. These exhibit a postnatal pattern of development that is well adapted to the nutritional demands of the brain (Patel et al. At birth, the activities of these enzymes in brain are low; activities rise rapidly with the ketosis that develops at the onset of suckling. The activities reach their peaks just before weaning and then gradually decline after weaning to normal adult rates of approximately one-third to one-fourth the maximal rates attained at the earlier stages (Patel et al. When weaned onto the normal, relatively high-carbohydrate diet, high circulating levels of ketones disappear and cerebral ketone utilization decreases considerably. The reports of ketoacidosis and developmental delay in infants with impaired ability to utilize ketone bodies underscore the importance of these substrates during the suckling period (Tildon & Cornblath, 1972). After birth, the activities of enzymes for glycolytic and oxidative use of glucose progressively increase with maturation to reach adult levels shortly after weaning (McKenna et al. This may also be true for neonatal human brain since local increases in the glucose metabolic rate reflect the functional maturation of specific brain regions (Takahashi et al.
Neuronal transmitter release onto astrocytes elevates their [Ca2]c medications routes cheap accupril 10mg on-line, and that in turn releases gliotransmitters from the astrocyte back onto the enclosed neurons. The degree to which they do so in the intact brain is an outstanding question of vital importance, since gliotransmission would be another means of dynamically altering neuronal transmission or generating plasticity at the synapse (for review see Halassa & Haydon, 2010). In wild type mice, high-frequency stimulation of a small band of Schaffer collaterals will elicit potentiation at innervated synapses and an adenosine-mediated depression of neighboring, non-innervated ones. It was known that adenosine of unknown origin was acting on the presynaptic neuronal A1 receptor. These results strongly suggest that astrocytes can actively participate in the dynamic control of synaptic transmission. In this context we are particularly interested in the regulation of the receptor at the glycine-binding site. These results are intriguing since they may reveal the true role of d-serine as a gliotransmitter released from neighboring astrocytes. They also suggest that plasticity at the receptor might result from a highly dynamic process that changes the anatomical relationship between neurons and glia, and thereby impacts synaptic plasticity. Astrocytes have the necessary signaling cascades to produce either dilation or constriction of vessels, and these effects can be elicited by natural stimuli, synaptic inputs onto the astrocytes, or photolytic release of caged Ca2in the end-feet (Gordon et al. There are several routes by which a Ca2 signal could effect changes in the vascular tone. Present controversy aside, it is clear that astrocytes have the signaling cascades necessary for both vessel dilation and constriction, and it remains an active question as to the conditions under which an elevation in Ca2 signals either. For trauma, the therapeutic question is one of how to develop appropriate neuroprotective pharmacological cocktails to block necrosis and apoptosis. Experimental results of the last three decades suggest that it will be necessary to reexamine the simple "calcium overload hypothesis" and determine the degree to which Ca2 elevation by different routes is involved in cell death, and how associated damage from each can be minimized. Ischemic stroke interrupts the blood supply and results in oxygen and glucose deprivation to both neurons and glia (see Ch. At the core of the insult is necrosis of all cell types, and extending outward is a variable region of compromised cells. Since much of brain metabolism has been taken over by astrocytes, the glia are more likely to survive even in regions where neurons are lost. The glia are far from benign, and there is evidence in model systems that they contribute to neuronal death in the region surrounding the initial infarct. The metabolically compromised neurons are depolarized, the Mg2 block of the channel is largely absent, and the result is massive Ca2 influx. The neuronal Ca2 elevation by this pathway is the best studied, but numerous clinical approaches targeting these receptors have largely failed to be neuroprotective (Kalia et al.
Since high-resolution microscopy analysis suggests that not all GlyR1 subunit co-localizes with gephyrin treatment rosacea generic accupril 10mg visa, it is thought that other mechanisms are involved in GlyR localization, presumably at presynaptic or extrasynaptic sites (Baer et al. These data together with the anatomic data in human brain implicate glycine in basal ganglia function. Distribution of Glycine Receptors Immunocytochemical mapping specific for GlyR-subunits reveals their colocalization with [3H]strychnine Although most glycine receptors are found in a subset of retinal neurons, spinal cord and brainstem, a small but significant population is located in more rostral brain regions. The variations in the subunits for both receptors have evolved in a manner to permit intricate coordination of their functions. This coordination involves controlling temporal and spatial activation patterns for each muscle, agonists and antagonists, at each joint bilaterally (Nishimaru and Kakizaki, 2009). The first indications that this disease may be due to failure of glycinergic inhibition were derived from studies of mice in which genes related to glycinergic receptors were knocked out to study glycine transmission. These early findings led eventually to discovery in affected people of mutations in five different genes: glycine receptor subunit-1 (GlyR1), glycine receptor subunit- (GlyR), presynaptic glycine transporter (GlyT2), and the genes for the postsynaptic glycine receptor accessory proteins gephyrin and collybistin. About 70% of cases show recessive inheritance, a few percent exhibit compound heterozygote inheritance and the remainder show dominant inheritance (Harvey et al. Thus, the defect in these mutant glycine receptor proteins is in their trafficking and/or integration into the postsynaptic membranes. In contrast to effects of the recessive mutations, the dominant inheritance mutations alter ligand-gated ion channel functions including glycine binding, ion channel gating and conductance, as well as desensitization of the receptors. Molecular Genetics Elucidates Pathophysiology of Startle Disease Human startle disease, hyperekplexia, is related to genes controlling glycinergic transmission Investigations of genes whose protein products control glycinergic neurotransmission led to the elucidation of properties of the inhibitory glycinergic synaptosomal membrane organization, as well as the pathophysiology of hyperekplexia. This disease is a rare, but potentially fatal, inherited disorder characterized by markedly abnormal startle responses to sudden, unexpected stimuli, particularly auditory, but also somatic. The responses consist of exaggerated muscle stiffness, sometimes with forced eye closure and flexion of neck, trunk and limbs. The electroencephalogram does not exhibit electrical seizure activity during such episodes, so this is not considered an epileptic disease. From a physiologic viewpoint, the startle responses and stiffness are thought to be an exaggerated release from a state of Mutations in postsynaptic accessory proteins perturb glycinergic receptor localization these mutations are in the genes for gephyrin (Rees et al. It is of considerable interest to the study of refractory epilepsy and other hippocampal functions that knock-out of collybistin (Jedlicka et al. In fact, mutations have been discovered in the human gene for collybistin in a patient with symptoms of both hyperekplexia and epilepsy [35] and in a patient with epilepsy and emotional and cognitive disturbances (Kalscheuer et al. Some mutations affected glycine and Na binding to the transporter (see Harvey et al. These authors also point out the possibility that defects in the gene for or the activity of the astrocytic GlyT1 might be a cause of glycine encephalopathy in some patients in whom there is no deficiency in the glycine cleavage system (see nonketotic hyperglycinemia in Chap. Acknowledgements the editors are grateful to Heinrich Betz for his contribution to this box, excerpted from Basic Neurochemistry, Molecular, Cellular and Medical Aspects, 7th edition, 2006, pp.
Models constructed from Protein Data Base coordinates 1eul and 1iwo using DeepView 3 symptoms exhaustion accupril 10 mg order with mastercard. The three -subunit isoforms are about 40 kDa and have about 45% sequence identity. The particular subunit isoform paired with an subunit has little effect on pump parameters. However, the different isoforms may influence the ultimate cellular and subcellular localizations of the Na pumps (Peng et al. The Na pump has associated subunits these are within a family of 15 kDa single-span membrane proteins that are associated with sodium pump I. These proteins modify Na and K affinities but are not necessary for pump activity, nor are they expressed in all cells. The kidney expresses almost exclusively Na,K-pumps with 1 subunits throughout the functionally diverse segments of the nephron, but different subunits with differing regulatory effects are expressed in different segments. From this it is inferred that different subunits optimize the sodium pump for operation under the varying ionic environments along the nephron. The subunits regulate kinetic properties of the sodium pump specifically appropriate for different functions such as muscle contractility, neuronal excitability and solute reabsorption in nephrons (Bibert et al. A major fraction of cerebral energy production is consumed by the Na,K pump Most of this is required to compensate for extrusion of intracellular Na that enters through channels during electrical activity and through Na-dependent secondary transporters during neurotransmitter recovery. Assuming typical values for Na and K concentration gradients, that is, [Na]e/ [Na]i 12 and [K]i/[K]e 50, then G is about 3. Glial cell cultures from one-dayold rat brain express progressively increasing amounts of 1-, 2-, 1- and 2-isoforms as a function of increasing triiodothyronine exposure (Banerjee & Chaudhury, 2001). The distributions of -subunit isoforms provide clues to their different physiological functions While having 85% identity, the most substantial sequence differences among the -isoforms occur in their N-terminal regions and in an 11-residue sequence of the large cytoplasmic loop. When assayed in cell cultures, the isoforms differ in their apparent affinities for intracellular Na (1 2 3) (Arystarkhova et al. The 2-, 3- and 4-isoforms are unique conformers that specify their cellular and subcellular localization. These interactions bring the transporters and their regulatory proteins together to form cell-specific signaling complexes that allow spatial and temporal regulation of signal transduction and coordination with transmembrane transport. Moreover, these interactions are important for establishing stable membrane structures such as lipid rafts (Cai et al. These pumps probably do not carry out bulk movements of Ca2 but, having a high affinity, are most effective in maintaining very low concentrations of cytosolic Ca2 in resting cells. The isoforms are activated also by acid phospholipids, protein kinases and other factors.
The discussion in the following section is limited to regulation of the intestinal Pi transport symptoms after flu shot accupril 10 mg buy on-line. For regulation of renal Pi handling, the reader is referred to several recently published review articles. Indeed, increased phosphate uptake is observed in younger animals and is related to an increase in the active uptake of phosphate and an increase in the passive permeability to phosphate. Based on studies with basolateral membranes prepared from rat small intestine,287 phosphate transport was saturable, electroneutral, Na-dependent, and exhibited Michaelis-Menten kinetics. Tracer-exchange experiments and counter-transport studies confirmed the presence of a Na-dependent Pi carrier at the basolateral membrane of rat enterocytes, an observation also confirmed in human intestinal epithelial cells. This effect suggests that intestinal adaptation to a chronic low-Pi diet is mediated by vitamin D. When rats were acutely switched from a lowto a high-phosphate diet, a different adaptive response was observed. In a recent study in pigs fed a diet that was moderately Pi-deficient (43% lower than control group), jejunal Na-dependent Pi uptake increased 46%. These findings not only confirmed the susceptibility of young animals to the detrimental effects of exogenous steroids, but also raised the possibility that endogenous glucocorticoids may be involved in the post-weaning decrease in intestinal Pi absorption. However, systemic Pi levels are not significantly altered in metabolic acidosis, and this effect that has been attributed to the acid-stimulated release of Pi from the bone. The contribution of intestinal Pi transport to this phenomenon was also investigated with conflicting results. In weanling rats, metabolic acidosis suppressed intestinal Na-dependent Pi absorption. These latter results suggested that the stimulation of intestinal Pi absorption during metabolic acidosis may contribute to the buffering of acid equivalents by providing phosphate and may also help to prevent excessive liberation of phosphate from bone. It remains unclear whether the reported differences in the effects of metabolic acidosis on intestinal Pi absorption are due to the age or species of the experimental animals, or to the measured transport mechanisms (total vs. Several recent reviews have been published on their role in regulating mineral homeostasis. Chapter 70 Molecular Mechanisms of Intestinal Transport of Calcium, Phosphate, and Magnesium 1903 70. However, serum Mg2 concentration is a poor indicator of its systemic status, and it is common that patients with Mg2 deficiency have normal serum levels. Magnesium is also considered essential in maintaining calcium and potassium homeostasis. Interestingly, blood magnesium is often lower in patients with gastrointestinal diseases. Mg2 deficiency can result from three distinct mechanisms: reduced intestinal Mg2 absorption. Chronic Mg2 deficiency has been implicated in many diseases, ranging from hypertension, migraines, and asthma to osteoporosis and other bone disorders.
Interstitial cells of cajal and inflammation-induced motor dysfunction in the mouse small intestine conventional medicine accupril 10 mg purchase fast delivery. Expression of cytokines in the longitudinal muscle myenteric plexus of the inflamed intestine of rat. Changes in enteric neural regulation of smooth muscle in a rabbit model of small intestinal inflammation. Effects of the inflammatory mediator prostaglandin E2 on myenteric neurons in guinea pig ileum. Inflammation enhances mu-opioid receptor transcription and expression in mice intestine. Experimental colitis alters myenteric nerve function at inflamed and noninflamed sites in the rat. Intestinal inflammation modulates expression of the synaptic vesicle protein neuronal calcium sensor-1. Role of sensory afferents in the myoelectric response to acute enteric inflammation in the rabbit. Increased levels of substance P in the myenteric plexus of Trichinella-infected rats. Calcitonin gene-related peptide in inflammatory bowel disease and experimentally induced colitis. Receptors for sensory neuropeptides in human inflammatory diseases: implications for the effector role of sensory neurons. De Giorgio R, Barbara G, Blennerhassett P, Wang L, Stanghellini V, Corinaldesi R, et al. Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat. Role of enteric glia in intestinal physiology: effects of the gliotoxin fluorocitrate on motor and secretory function. Neurotransmitters modulate cytokine-stimulated interleukin 6 secretion in rat intestinal smooth muscle cells. Interleukins 1 beta and 6 induce functional alteration of rat colonic motility: an in vitro study. Altered ion channel activity in murine colonic smooth muscle myocytes in an experimental colitis model. Chapter 79 Recruitment of Inflammatory and Immune Cells in the Gut: Physiology and Pathophysiology D. These adhesive interactions are regulated by a variety of molecules that are expressed on. These events normally govern the homeostatic functions of cells; however, these molecules are of great importance during pathological conditions. Of the many diverse groups of cell adhesion molecules, proteins from the selectin, integrin, cadherin, immunoglobulin, occludin, and claudin family of proteins have all been implicated in inflammatory diseases.
The in-series arrangement accounts for activation of the sensors by muscle contraction or distension medicine used to stop contractions buy accupril 10mg line. Mechanosensitive information is transmitted along spinal afferents to the spinal cord by way of dorsal root ganglia and along vagal sensory afferents to the brain stem by way of the nodose ganglia. Vagal and spinal afferent fibers are predominantly unmyelinated C-fibers or thinly myelinated A-fibers, which transmit different modalities of sensory information at low conduction velocity. In general, vagal afferents transmit physiological information on the nature and composition of the luminal contents, the presence or absence of motility, and on contractile tension in the musculature, while spinal afferents transmit pathophysiological information related to potentially noxious mechanical or chemical stimuli arising through tissue injury, ischemia, or inflammation. Sensations of pain and discomfort of digestive tract origin reflect transmission in spinal afferents and information processing in the spinal cord and brain. Sensory information transmitted by the vagus nerves appears not to reach the level of conscious sensation, because patients with high spinal cord transections and intact vagal pathways experience little or no sensations of digestive tract origin. On the other hand, the persistence of conscious perception of sensations from the digestive tract following a surgical vagotomy. Low-threshold afferents respond to weak changes in wall tension and are thought to transmit the minute-to-minute information required for functional autonomic negative-feedback control. High-threshold afferents require stronger changes in wall tension, which might be produced by distension of the lumen or strong contraction of the musculature, for activation. The high-threshold afferents are postulated to be responsible for the range of sensations from mild to severe pain that are associated with excessive distension or exceptionally strong muscle contraction. Stimulation of the receptors by paracrine mediators changes the responsiveness of the sensory receptor. Findings that a reduced threshold for painful responses to balloon distension in the large bowel is associated with degranulation of mast cells in animal models supports this possibility. On the other hand, there might be cases where normally functioning mechanosensors transmit accurate information, which is misinterpreted in processing circuits in the spinal cord and/or brain to evoke conscious perceptions of abnormal sensations from the gut. A pathway in the dorsal spinal columns was revealed recently to be a transmission conduit for visceral pain information to higher processing centers in the brain. From the dorsal column nuclei, the pain signals are transmitted via the ipsilateral dorsal column nuclei to the contralateral ventral posterolateral nucleus of the thalamus. A midline myelotomy that severs axons in the human dorsal columns attenuates otherwise intractable visceral pain. Severing the axons of the dorsal columns in rats or monkeys reduces the neuronal responses to colorectal distension in the ventral posterolateral nucleus of the thalamus and of neurons in the dorsal column nuclei, particularly in the nucleus gracilis. Results from imaging studies suggest that unlike somatic sensation, which has a main homuncular representation in the primary somatosensory cortex, visceral sensation is mainly represented in the secondary somatosensory cortex. Gender differences are noticeable in the cortical representation of balloon distension in the rectosigmoid region in healthy subjects. The volume of evoked cortical activity in females is greater than in men for perception levels in the range from the urge to defecate to sensations of fullness, mild discomfort, and pain. The functional significance of these gender differences is unclear; nevertheless, they are reminiscent of the greater perceptual responses reported in female patients with functional gastrointestinal disorders. Perigenual, mid-cingulate, posterior, and retrosplenial are important structural and functional regions of the cingulate cortex.
This in turn activates the endothelial cells to upregulate cell adhesion molecules (see Ch symptoms 5dpiui accupril 10mg buy with mastercard. The actual effector mechanisms for myelin damage include a direct toxic effect of tumor necrosis factor-alpha or nitric oxide on oligodendrocytes or damage mediated by macrophages and microglial cells. The latter possibility can be enhanced by the presence of antibodies, which bind to myelin and provide a ligand for activated monocytes. Focal demyelination occurs when lysolecithin is administered by intracerebral injection. Therefore, both of these models are most useful for research on mechanisms of remyelination. Immunomodulatory treatments (steroids, intravenous immunoglobulin) are typically administered in addition to supportive therapy, but controlled clinical trials assessing the efficacy of these treatments are few. However, people who are immunosuppressed, because of disorders of the reticuloendothelial system, human immunodeficiency virus infection, or therapeutic immunosuppression for autoimmune diseases or organ transplants, are susceptible (Tan & Koralnick, 2010). The disease progresses rapidly, and areas of demyelination can be large and show evidence of tissue destruction. Toxins Toxins such as cuprizone and lysolecithin can induce demyelination in animals (Denic et al. Cuprizone is a copper-chelating agent that when orally administered induces demyelination. The demyelination induced by cuprizone Some human peripheral neuropathies involving demyelination are immune mediated There are three major categories of acquired peripheral neuropathies involving demyelination. Like many other diseases involving primary demyelination, secondary axonal injury and degeneration may be the critical factors in permanent disability. In addition, axonal damage may be primary in some patients with immune-mediated peripheral neuropathy. Initial descriptions were that of a monophasic polyneuropathy that frequently occurred following a bacterial or viral infection and was characterized histologically by segmental demyelination and perivascular lymphocytic infiltrates (Lazzarini, 2004; Winer, 2011) (see also Ch. Subsequent research demonstrated cross-immunoreactivity of serum antibodies with C. These antibodies elicit activation of complement with subsequent nerve injury by phagocytosis. The precise cellular localization of immune-mediated injury has not been identified, but the node of Ranvier is a likely target.
Kurt, 42 years: Dual-specificity kinases lack the phosphotyrosine-recognition subdomain and have a shallow catalytic-site cleft (6) that is accessible to all three phosphorylated hydroxyamino acids. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. This has an important regulatory influence on the resting membrane potential in many neurons.
Leif, 31 years: Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Huassociated paraneoplastic encephalomyelitis. Negligible Glc-6-phosphatase activity in brain prevents conversion of glycogen to free glucose in vitro and in vivo (Dienel et al. Increased E-selectin expression and a blunted neutrophil recruitment response following E-selectin immunoblockade have been demonstrated in the gut after I/R, but the contribution of this adhesion molecule to radiation-induced inflammation has not yet been evaluated.
Mufassa, 59 years: At the resting membrane potential, the force of the electric field would pull the positive charges inward. Analysis of lectin binding to glycolipid complexes using combinatorial glycoarrays. In animal models, phagocytic microglia have been identified with lysosomes containing myelin degradation products.
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