Entocort

By J. Einar. Boston University. 2018.

The consensus would be that synaptic activation during high-frequency stimulation triggers a series of intracellular events that lead to the expression of synaptic potentiation with the release of glutamate being the first step cheap entocort 100 mcg amex allergy symptoms of low blood pressure. This persistent increase in synaptic efficacy is thought then to be critical for memory discount entocort 100 mcg allergy testing quackery,presumably the acquisition. Much of the vast literature is based on electrophysiology,mainly in vitro,and so despite the conceptual appeal of LTP,the functional studies find it much harder to link LTP with memory. From a large clinical literature,the hippocampus appears to be a key structure in memory,and blocking glutamate receptors causes reduced memory-like behaviour in animals. Also the more recent description of activity-dependent long-term depression (LTD) could be associated with the processes of forgetting. However,this may be overly simple since LTD also occurs in the cerebellar cortex and might contribute to the motor aspects of learning in animals. LTD is reversibly blocked by NMDA receptor antagonists which suggests that postsynaptic Ca2‡ entry through the NMDA receptor channel is critical for LTD induction. Nearly all mechanistic studies of LTP have been carried out in the CA1 region of hippocampal slices,where Schaffer collateral/commissural fibres make monosynaptic contacts with the dendrites of CA1 pyramidal cells. It is generally accepted that the 220 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION Table 10. This results in the relief of the voltage-dependent block of the NMDA receptor channel by Mg2‡. Ca2‡ then enters the postsynaptic neurons or dendrite as a necessary and perhaps sufficient trigger for LTP. Although the NMDA receptor channel may be the critical entry point for the Ca2‡ involved in triggering LTP,activating voltage-dependent calcium channels during NMDA receptor blockade can also cause an increase in synaptic efficacy. Once induction of LTP has occurred,the maintenance of LTP is then non-NMDA receptor dependent,favouring the idea of intracellular mechanisms as key factors. It has also been suggested that activation of mGluRs enhances NMDA receptor- mediated LTP and there is also good evidence that switching off GABA mechanisms is also a prerequisite. One of the most controversial areas in the study of the mechanisms of LTP has been the search for a so-called retrograde messenger,a factor that is released from the postsynaptic neuron and diffuses back across the synapse to modify neurotransmitter release from the presynaptic terminal. The necessity for the existence of such a messenger was first suggested by the finding that LTP was associated with an increase in the concentration of glutamate in perfusates. Although there is data that the candidate retrograde messenger could be arachidonic acid,most recent work indicates the gas NO (nitric oxide),although there is almost as much evidence against as for this molecule (see Chapter 13). Postsynaptic NMDA receptors are involved in the induction of both LTP and both forms of plasticity appear to need retrograde messengers,and use common intracellular events Ð what occurs when these mechanisms converge will then determine whether neurons become potentiated or depressed. On the basis of the events that occur in pain and LTP,it is easy to see how the actions of glutamate relate to the excessive firing of neurons Ð as yet no NMDA receptor antagonist has been tested in human epilepsy. AP-5 is an NMDA receptor antagonist while MK-801 blocks the NMDA receptor channel (non-competitive) EXCITOTOXICITY The final issue relating to the function of the NMDA receptor is excitotoxicity. Briefly, the depolarisation may drive neurons into a state where large quantities of calcium enter the neuron. For this to occur,the release of glutamate would have to be excessive and in this context,cerebral ischaemic episodes are thought to disrupte the reuptake of glutamate into neurons and glia. The consequent influx of calcium,if excessive,can bring water into the neuron as a result of the cation entry. These osmotic changes can then lead to swelling and damage to the cell,although if the neuronal activity is reduced,then the osmotic stress is reversible. A second delayed phase of neuronal damage then occurs in that intracellular signalling is driven by the high calcium levels 222 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION leading to permanent destruction of the neuron. A number of culprits have been identified,including activation of kinases,phospholipases leading to the generation of arachidonic acid and free radicals,nitric oxide synthase and also lipases and proteases. The overactivation of glutamate receptors is therefore thought to be a key initial step in the neuronal and glial cell loss following cerebral vascular accidents. Despite this,the trials of NMDA receptor antagonists in patients with brain ischemia had so far been disappointing with poor efficacy and marked side-effects. Both factors could be improved by targeting NMDA receptor subtypes but it may be that AMPA and kainate receptors also have key roles in excitotoxicity. Another issue is that even when NMDA receptors are blocked the influx of calcium through voltage-gated calcium channels may induce neuronal damage. However,a combination of motoneuron disease,dementia and a Parkinson-like syndrome was possibly triggered by a constituent of the cyclad seed,used in Guam in times of famine for which the most likely candidate appears to be an excitatory amino- acid agonist. Certainly,there is evidence for a defect in mitochondrial energy metabolism in PD which may lead to neuronal depolarisation and an easier removal of the voltage-dependent Mg2‡ block of the NMDA receptor.

Cells that regularly encounter hyper- Passive exit + K tonic extracellular fluids have developed additional mecha- via nongated nisms for maintaining normal volume order entocort 100 mcg overnight delivery allergy shots make you feel worse. These cells can syn- channel Active transport by thesize specific organic solutes generic 100mcg entocort visa allergy forecast alabama, enabling them to increase + + Na /K -ATPase intracellular osmolality for a long time and avoiding alter- + ATP + ing the concentrations of ions they must maintain within a K 2K narrow range of values. The organic solutes are usually + small molecules that do not interfere with normal cell func- Na tion when they accumulate inside the cell. For example, cells of the medulla of the mammalian kidney can increase ++ 3 Na3 Na the level of the enzyme aldose reductase when subjected to elevated extracellular osmolality. This enzyme converts ADP glucose to an osmotically active solute, sorbitol. Synthesis of sorbitol and inositol represents different answers to the problem of in- creasing the total intracellular osmolality, allowing normal Passive entry + cell volume to be maintained in the presence of hypertonic via nongated Na extracellular fluid. The rate of Na en- try is matched by the rate of active transport of Na out of the Oral administration of rehydration solutions has dramati- cell via the Na /K -ATPase. The intracellular concentration of cally reduced the mortality resulting from cholera and Na remains low and constant. Similarly, the rate of passive K other diseases that involve excessive losses of water and exit through nongated K channels is matched by the rate of ac- solutes from the gastrointestinal tract. The intracellular ents of rehydration solutions are glucose, NaCl, and water. During each cycle The glucose and Na ions are reabsorbed by SGLT and of the ATPase, two K are exchanged for three Na and one other transporters in the epithelial cells lining the lumen of molecule of ATP is hydrolyzed to ADP. Deposition of these type indicate high and low ion concentrations, respectively. Ion Movement Is Driven by the Absorption of glucose increases the absorption of NaCl Electrochemical Potential and water and helps to compensate for excessive diarrheal losses of salt and water. If there are no differences in temperature or hydrostatic pressure between the two sides of a plasma membrane, two forces drive the movement of ions and other solutes across the membrane. One force results from the difference in the THE RESTING MEMBRANE POTENTIAL concentration of a substance between the inside and the The different passive and active transport systems are coor- outside of the cell and the tendency of every substance to dinated in a living cell to maintain intracellular ions and move from areas of high concentration to areas of low con- other solutes at concentrations compatible with life. The other force results from the difference in sequently, the cell does not equilibrate with the extracellu- electrical potential between the two sides of the membrane, lar fluid, but rather exists in a steady state with the extra- and it applies only to ions and other electrically charged cellular solution. When a difference in electrical potential exists, concentration (10 mmol/L in a muscle cell) is much lower positive ions tend to move toward the negative side, while than extracellular Na concentration (140 mmol/L), so negative ions tend to move toward the positive side. Na enters the cell by passive transport through nongated The sum of these two driving forces is called the gradi- Na channels. The rate of Na entry is matched, however, ent (or difference) of electrochemical potential across the by the rate of active transport of Na out of the cell via the membrane for a specific solute. The expression of this intracellular Na is maintained constant and at a low level, force is given by: C even though Na continually enters and leaves the cell. The where represents the electrochemical potential ( is passive exit of K through nongated K channels is the difference in electrochemical potential between two matched by active entry via the pump (see Fig. Main- sides of the membrane); Ci and Co are the concentrations tenance of this steady state with ion concentrations inside of the solute inside and outside the cell, respectively; Ei is the cell different from those outside the cell is the basis for the electrical potential inside the cell measured with re- the difference in electrical potential across the plasma spect to the electrical potential outside the cell (Eo); R is the membrane or the resting membrane potential. By inserting these units in and each of these ions contributes to the resting membrane equation 5 and simplifying, the electrochemical potential potential. By contrast, the permeability of the membrane of will be expressed in cal/mol, which are units of energy. If most cells to divalent ions is so low that it can be ignored the solute is not an ion and has no electrical charge, then z in this context. In this The Goldman equation gives the value of the mem- case, the electrochemical potential is defined only by the brane potential (in mV) when all the permeable ions are ac- different concentrations of the uncharged solute, called the counted for: chemical potential. The driving force for solute transport RT PK[K ]o PNa[Na ]o PCl[Cl ]i becomes solely the difference in chemical potential. E E ln (8) i o PK[K ]i PNa[Na ]i PCl[Cl ]o F Net Ion Movement Is Zero where PK, PNa, and PCl represent the permeability of the at the Equilibrium Potential membrane to potassium, sodium, and chloride ions, re- spectively; and brackets indicate the concentration of the Net movement of an ion into or out of a cell continues as long ion inside (i) and outside (o) the cell. Net movement stops and equilib- not permeable to one of these ions, the contribution of rium is reached only when the driving force of electrochemi- the impermeable ion to the membrane potential will be cal potential across the membrane becomes zero. If a specific cell is permeable to an ion other than tion of equilibrium for any permeable ion will be 0. The higher Ei Eo ln (6) zF Co the permeability of the membrane to one ion relative to the RT Co others, the more that ion will contribute to the membrane Ei Eo ln potential.

A 3-D phase contrast MRA (A) and an inverted video image seen in A and B purchase entocort 100mcg with amex allergy treatment natural, is usually continuous with the right transverse sinus at window (B) of the same view show major vessels and sinuses from an- the confluence of sinuses buy 100 mcg entocort overnight delivery allergy medicine for diabetics. Cerebral Angiogram, MRA, and MRV 247 PCA, Cortical branches PCA Thalamoperforating arteries SCA AICA Basilar artery (BA) Vertebral artery (VA) B Posterior cerebral artery, Cortical branches Posterior cerebral arteries (PCA) Thalamoperforating arteries (of the basilar bifurcation) Superior cerebellar artery (SCA) SCA BA AICA Anterior inferior cerebellar artery (AICA) PICA Posterior inferior cerebellar artery (PICA) VA 8-8 A vertebral artery angiogram (anterior–posterior projection, The root of the oculomotor (IIIrd) nerve, after exiting the inferior arterial phase) is shown in A; the same view, but in a different patient, aspect of the midbrain, characteristically passes through the interpe- is shown in B, using digital subtraction methods. Even though the in- duncular cistern and between the superior cerebellar and posterior jection is into the left vertebral, there is bilateral filling of the vertebral cerebral arteries en route to its exit from the skull through the supe- arteries and of branches of the basilar artery. In this position the IIIrd nerve may be damaged by arteries are important branches of P1 that generally serve rostral por- large aneurysms that impinge on the nerve root. The portion of the ACA arching on the movement of fluid in these structures. These are inverted video around the genu of the corpus callosum is the A3 segment (precallosal) images of 3-D phase contrast MRA images as viewed from the dorsal and the A4 (supracallosal) and A5 (postcallosal) segments are located to ventral (A) and from the lateral aspect (B). Compare these images with anterior cerebral artery (ACA) immediately rostral to the anterior arteries and veins as depicted in Figures 2-18 and 2-19 (page 23), 2-21 communicating artery and inferior to the rostrum of the corpus callo- (page 25), and 2-23 (page 27). Cerebral Angiogram, MRA, and MRV 249 Anterior cerebral artery: Cortical branches A1 segment A Internal carotid artery Branches of middle cerebral artery Middle cerebral artery: Branches on insula (M2) Internal carotid artery M1 segment Posterior communicating artery Cortical branches (M4) Posterior communicating Posterior cerebral artery: artery P2 segment P1 segment Posterior cerebral artery Parieto-occiptal artery Calcarine artery Anterior communicating artery B Orbit Anterior cerebral artery (A1 segment) Ophthalmic artery Middle cerebral artery Cavernosus sinus (branches on insula) (containing internal carotid artery) Petrosal segment of internal carotid artery Middle cerebral artery Superior cerebellar artery (M1 segment) Tumor (vestibular schwannoma) Posterior communicating artery Posterior cerebral artery Basilar artery Calcarine artery Posterior cerebral artery Vertebral arteries 8-10 MRA images of the vessels at the base of the brain forming much of the cerebral arterial circle (of Willis) (A, B). Note the ante- rior, middle, and posterior cerebral arteries as they extend outward from the circle. The upper image is from a normal individual, and the lower image is from a patient with a vestibular schwannoma. Descrip- tions of the segments of the anterior, middle, and posterior cerebral arteries are found on pages 25 and 242. Compare with Figures 2-13 (page 19), 2-16 (page 21), 2- seen in this lateral view (A) and in the anterior-posterior view (B). Blood Supply to the Choroid Plexi 251 A Choroid plexus (CP) in body of lateral ventricle CP in atrium of lateral ventricle CP in roof of third ventricle CP in temporal horn of lateral ventricle Anterior choroidal artery CP in fourth ventricle AICA PICA Posterior communicating artery Lateral posterior choroidal artery BA VA Medial posterior choroidal artery B Medial striate artery Internal carotid artery Middle cerebral artery (M1) A1 P 1 Anterior choroidal artery Anterior choroidal artery Posterior communicating artery Posterior cerebral artery (P2) Lateral posterior choroidal artery Superior cerebellar artery Medial posterior choroidal artery Basilar artery (BA) Anterior inferior cerebellar artery (AICA) AICA branch to choroid plexus at the foramen of Luschka Vertebral artery (VA) Posterior inferior cerebellar artery (PICA) PICA branch to choroid plexus in the fourth ventricle 8-12 Blood supply to the choroid plexus of the lateral, third, and rior lateral choroidal arteries serve the plexuses of the lateral and third fourth ventricles. The choroid plexus in the fourth ventricle and the clump of internal carotid artery and P2 segment of the posterior cerebral artery that choroid plexus protruding out of the foramen of Luschka are served by supply the choroid plexus are accentuated by appearing in a darker red posterior inferior and anterior inferior cerebellar arteries, respectively. In A, a representation of these vessels (origin, course, termination) B, the origins of these branches from their main arterial trunks are shown. Anterior, posterior medial, and poste- See also Figures 2-21 (page 25), 2-24 (page 27), and 2-35 (page 35). The first segment (V1) cerebral artery and middle cerebral artery, vertebrobasilar system) as seen is between the VA origin from the subclavian artery and the entrance in an MRA (anterior-posterior view). In approximately 40–45% of indi- of VA into the first transverse foramen (usually C6); the second seg- viduals the left vertebral artery is larger, as seen here, and in about 5–10% ment V2 is that part of VA ascending through the transverse foramen of individuals one or the other of the vertebral arteries may be hypoplas- of C6 to C2; the third segment (V3) is between the exit of VA from the tic as seen here on the patient’s right. The MRI in B is a detailed view of transverse foramen of the axis and the dura at the foramen magnum the vertebrobasilar system from the point where the vertebral arteries exit (this includes the loop of the VA that passes through the transverse the transverse foramen to where the basilar artery bifurcates into the pos- foramen of C1/the atlas); the fourth segment (V4) pierces the dura and terior cerebral arteries. CHAPTER 9 Q & A’s: A Sampling of Study and Review Questions, Many in the USMLE Style, All With Explained Answers D. Lancon There are two essential goals of a student studying human neu- cise, some answers may contain additional relevant informa- robiology, or, for that matter, the student of any of the medical tion to extend the educational process. The first is to gain the knowledge base and diagnostic In general, the questions are organized by individual chapters, skills to become a competent health care professional. Ref- ing the medical needs of the patient with insight, skill, and com- erence to the page (or pages) containing the correct answer are passion is paramount. The second is to successfully negotiate usually to the chapter(s) from which the question originated. However, recognizing that neuroscience is dynamic and three-di- These may be standard class examinations, Subject National mensional, some answers contain references to chapters other Board Examination (now used/required in many courses), the than that from which the question originated. Correct diagnosis of the neurologically compromised patient The questions in this chapter are prepared in two general not only requires integration of information contained in differ- styles. First, there are study or review questions that test gen- ent chapters but may also require inclusion of concepts gained in eral knowledge concerning the structure of the central ner- other basic science courses. These ques- sampling that covers a wide variety of neuroanatomical and tions have been carefully reviewed for clinical accuracy and clinically relevant points.

Most choles- terol comes from low-density lipoprotein (LDL) particles in the blood discount 100mcg entocort overnight delivery allergy treatment sample, which bind to receptors in the plasma membrane and are The formation of pregnenolone from cho- taken up by endocytosis generic 100 mcg entocort fast delivery allergy treatment providers. The hydrogen atoms on the car- acyltransferase; HMG, 3-hydroxy-3-methylglutaryl. The endo- of cholesterol esters, single molecules of cholesterol ester- cytic vesicle containing the LDL particles fuses with a lyso- ified to single fatty acid molecules. The cholesterol esters in used in steroid biosynthesis is generated from these choles- the core of the particle are hydrolyzed to free cholesterol terol esters by the action of cholesterol esterase (choles- and fatty acid by the action of CEH. The free cholesterol generated by that cleavage en- verted again to cholesterol esters by the action of the en- ters mitochondria located in close proximity to the lipid zyme acyl-CoA:cholesterol acyltransferase (ACAT). The process of remodeling the cholesterol mole- esters are then stored in the lipid droplets of the cell to be cule into steroid hormones is then initiated. The cholesterol that has been removed from the lipid When steroid biosynthesis is proceeding at a high rate, droplets for steroid hormone biosynthesis is replenished in cholesterol delivered to the adrenal cell may be diverted di- two ways (Fig. Most of the cholesterol converted to rectly to mitochondria for steroid production rather than steroid hormones by the human adrenal gland comes from reesterified and stored. Accumulating evidence suggests cholesterol esters contained in low-density lipoprotein that high-density lipoprotein (HDL) cholesterol may also (LDL) particles circulating in the blood. A 400-kDa protein mol- from acetate by the adrenal glands is a significant but minor ecule called apoprotein B100 is also present on the surface source of cholesterol for steroid hormone formation. The of the LDL particle; it is recognized by LDL receptors lo- rate-limiting step in this process is catalyzed by the enzyme calized to coated pits on the plasma membrane of adrenal 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA cortical cells (see Fig. The newly synthesized cholesterol is then in- LDL receptor, and both the LDL particle and the receptor corporated into cellular structures, such as membranes, or CHAPTER 34 The Adrenal Gland 611 converted to cholesterol esters through the action of In cells of the zona fasciculata and zona reticularis, most ACAT and stored in lipid droplets (see Fig. The CYPs are a large family of oxidative en- lates pregnenolone at carbon 17. The product formed by zymes with a 450 nm absorbance maximum when com- this reaction is 17 -hydroxypregnenolone (see Fig. The tion that becomes important at this step in the steroido- adrenal CYPs are more commonly known by their trivial genic process. Once the enzyme has hydroxylated carbon names, which denote their function in steroid biosynthe- 17 of pregnenolone to form 17 -hydroxypregnenolone, sis (see Table 34. Some molecules of 17 - gins with the formation of free cholesterol from the cho- hydroxypregnenolone undergo this reaction and are con- lesterol esters stored in intracellular lipid droplets. This action of cholesterol molecules enter the mitochondria, which are 17 -hydroxylase is essential for the formation of andro- located close to the lipid droplets, by a mechanism that is gens (19 carbon steroids) and estrogens (18 carbon not well understood. Evidence indicates that free choles- steroids), which lack the carbon 20–21 side chain. There- terol associates with a small protein called sterol carrier fore, this lyase activity of 17 -hydroxylase is important in protein 2, which facilitates its entry into the mitochon- the gonads, where androgens and estrogens are primarily drion in some manner. The appearance of significant adrenal an- cules bind to the cholesterol side-chain cleavage enzyme drogen secretion in children of both sexes is termed (CYP11A1), embedded in the inner mitochondrial mem- adrenarche. This enzyme catalyzes the first and rate-limiting re- it normally occurs before the activation of the hypothala- action in steroidogenesis, which remodels the cholesterol mic-pituitary-gonad axis, which initiates puberty. The ad- molecule into a 21-carbon steroid intermediate called preg- renal androgens produced as a result of adrenarche are a nenolone. The reaction occurs in three steps, as shown in stimulus for the growth of pubic and axillary hair. The first two steps consist of the hydroxylation Those molecules of 17 -hydroxypregnenolone that dis- of carbons 20 and 22 by cholesterol side-chain cleavage en- sociate as such from 17 -hydroxylase bind next to another zyme. Then the enzyme cleaves the side chain of choles- ER enzyme, 3 -hydroxysteroid dehydrogenase (3 -HSD terol between carbons 20 and 22, yielding pregnenolone II). This enzyme acts on 17 -hydroxypregnenolone to iso- and isocaproic acid. The cholesterol side-chain cleavage enzyme, leave the mito- product formed is 17 -hydroxyprogesterone (see Fig. This mecha- This intermediate then binds to another enzyme, 21-hy- nism is not understood. At this point, the further remodel- droxylase (CYP21A2), which hydroxylates it at carbon 21. The product formed is 11- ciculata and zona reticularis or the zona glomerulosa. These biosynthetic events are summarized in must be transferred back into the mitochondrion to be Figure 34.