Robert Cyril Bollinger, Jr, M.D., M.P.H.

• Founding Director, Center for Clinical Global Health Education
• Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0004611/robert-bollinger

It contains many neurones medicine organizer order persantine no prescription, glial cells and a dense fenestrated capillary plexus and is covered by flattened ependyma medications 1040 25mg persantine with amex. It is believed to have widespread hypothalamic interconnections and to function in the regulation of fluid balance and drinking medications 7 buy persantine discount. Neurohypophysis (posterior pituitary)-The neurohypophysis is the site of termination of neurosecretory projections from the supraoptic and paraventricular nuclei of the hypothalamus medications herpes order persantine mastercard. These neurones release vasopressin and oxytocin treatment 001 best persantine 25 mg, respectively treatment xeroderma pigmentosum discount persantine 25 mg visa, into the capillary bed of the neurohypophysis, where the hormones gain access to the general circulation. Median eminence-The median eminence contains the terminations of axons of hypothalamic neurosecretory cells. Peptides released from these axons control the hormonal secretions of the anterior pituitary via the pituitary portal system of vessels. Subcommissural organ-The subcommissural organ lies ventral to and below the posterior commissure. The ependymal cells on the dorsal aspect of the cerebral aqueduct are tall, columnar and ciliated, with granular basophilic cytoplasm. Pineal gland-The pineal gland is part of the epithalamus, located beneath the splenium of the corpus callosum. Area postrema-The area postrema is a bilaterally paired structure located at the caudal limit of the floor of the fourth ventricle. It is an important chemoreceptive area that triggers vomiting in response to the presence of emetic substances in the blood. In addition, in the adult, the ependymal and subependymal glial cell layers are the source of undifferentiated stem cells (Mercier, Kitasako, and Hatton 2002), currently under intensive study for their potential neurorestorative properties. They include the vascular organ (organum vasculosum), subfornical organ, neurohypophysis, median eminence, subcommissural organ, pineal gland and area postrema. In the roofs of the third and fourth ventricles and in the medial wall of the lateral ventricle along the line of the choroid fissure, the vascular pia mater lies in close apposition to the ependymal lining of the ventricles, without any intervening brain tissue. Choroid plexuses are located in the lateral ventricles, the third ventricle and the fourth ventricle. In the lateral ventricle, the choroid plexus extends anteriorly as far as the interventricular foramen, through which it is continuous across the third ventricle with the plexus of the opposite lateral ventricle. From the interventricular foramen, the plexus passes posteriorly, in contact with the thalamus, curving around its posterior aspect to enter the inferior horn of the ventricle and reach the hippocampus. Throughout the body of the ventricle, the choroid fissure lies between the fornix superiorly and the thalamus inferiorly. From above, the tela choroidea is triangular, with a rounded apex between the interventricular foramina, often indented by the anterior columns of the fornices. At the posterior basal angles of the tela, these fringes continue and curve into the inferior horn of the ventricle; centrally, the pial layers depart from each other as described earlier. When the tela is removed, a transverse slit (the transverse fissure) is left between the splenium and the junction of the ventricular roof and the tectum. It marks the posterior limit of the extracerebral space enclosed by the posterior extensions of the corpus callosum above the third ventricle. The latter contains the roots of the choroid plexus of the third ventricle and of the lateral ventricles, enclosed between the two layers of pia mater. The choroid plexus of the third ventricle is attached to the tela choroidea, which is, in effect, the thin roof of the third ventricle as it develops during fetal life. In coronal sections of the cerebral hemispheres, the choroid plexus of the third ventricle can be seen in continuity with the choroid plexus of the lateral ventricles. The choroid plexus of the fourth ventricle is similar in structure to that of the lateral and third ventricles. She has a history of presumed viral meningoencephalitis years before but has otherwise been well. The aqueduct is not visualized, and the fourth ventricle and cisterna magna are normal. A diagnosis of aqueductal stenosis is made, and ventricular shunting results in remarkable clinical improvement. Discussion: Aqueductal stenosis may be congenital or acquired later in life, presumably as a result of viral or bacterial infection with ependymitis and subsequent occlusion of the aqueduct. It is often asymptomatic until adulthood, ultimately presenting with a non-specific syndrome of hydrocephalus involving primarily the anterior ventricular system, as visualized in this case with appropriate neuroimaging. The syndrome of so-called normal-pressure hydrocephalus is evidenced classically by progressive memory deficits and dementia; ataxia; pyramidal tract signs, especially in the legs; and urinary tract dysfunction. This disorder is most likely due to obliteration of the cerebral subarachnoid space. This thin sheet forms the tela choroidea of the fourth ventricle, lying between the cerebellum and the inferior part of the roof of the ventricle. The choroid plexus of the fourth ventricle is T-shaped, having vertical and horizontal limbs, but this form varies widely. The vertical (longitudinal) limb is double, flanks the midline and is adherent to the roof of the ventricle. The limbs fuse at the superior margin of the median aperture (foramen of Magendie) and are often prolonged on the ventral aspect of the cerebellar vermis. The horizontal limbs of the plexus project into the lateral recesses of the ventricle. Small tufts of plexus pass through the lateral apertures (foramina of Luschka) and emerge, still covered by ependyma, in the subarachnoid space of the cerebellopontine angle. The blood supply of the choroid plexus in the tela choroidea of the lateral and third ventricles is usually via a single vessel from the anterior choroidal branch of the internal carotid artery and several choroidal branches of the posterior cerebral artery. The blood supply of the fourth ventricular choroid plexus is from the inferior cerebellar arteries. When presented with an infant with progressive hydrocephalus, as in this case, other diagnoses to consider include aqueductal stenosis (either congenital atresia of the aqueduct of Sylvius or acquired secondary to chronic infection such as tuberculous meningitis with granular ependymitis); obstruction of draining cerebral veins secondary to vascular events such as infantile subarachnoid haemorrhage or preterm intracerebral haemorrhage, especially in low-birth-weight infants; and colloid cysts of the third ventricle. A 14-month-old boy exhibits progressive enlargement of the head, with bulging fontanelles, spreading of the cranial sutures and dilatation of the draining craniocerebral veins. No focal signs are observed, but he demonstrates progressive motor (and cognitive) retardation, spasticity, visual failure with optic atrophy and ataxia, along with occasional seizures. Most tumours here 88 Chapter 5 / Ventricular System and Cerebrospinal Fluid Anterior thalamic tubercle Stria terminalis Stria medullaris Superior colliculus Pulvinar Lateral geniculate Habenular commissure Habenular trigone Pineal Brachium of superior colliculus Medial geniculate body Brachium of inferior colliculus Cerebral peduncle Inferior colliculus Trochlear nerve Anterior medullary velum Median sulcus Medial eminence Superior fovea Facial colliculus Vestibular area Brachium conjunctivum (superior cerebellar peduncle) Brachium pontis (middle cerebellar peduncle) Lateral aperture of fourth ventricle Trigeminal nerve Facial nerve Vestibulocochlear nerve Glossopharyngeal nerve Vagus nerve Taenia of fourth ventricle Gracile tubercle Hypoglossal trigone Area postrema Cuneate tubercle Accessory nerve (cranial part) Obex Posterior intermediate sulcus Posterior median fissure Accessory nerve (spinal part) Fasciculus cuneatus Fasciculus gracilis. The floor of the fourth ventricle has been exposed by cutting the cerebellar peduncles and removing the cerebellum. It is not simply an ultrafiltrate of blood but is actively secreted by the choroid plexus epithelium. Choroid plexus epithelial cells have the characteristics of transport and secretory cells. There are tight junctions at the apical ends of the epithelial cells, which are permeable to low-molecular-weight substances. Fenestrated capillaries in the stroma of the choroid plexus lie just beneath the epithelial cells. However, there is also a small contribution from the ependymal lining of the ventricles and from the extracellular fluid from brain parenchyma. The ventricles contain approximately 25 ml (almost all of which is in the lateral ventricles), and the remaining 100 ml is located in the cranial subarachnoid space. Within the brain, critical points at which obstruction may occur correspond to the narrow foramina and passages of the ventricular system. Thus, obstruction of the interventricular foramen, as with an intraventricular tumour, causes enlargement of one or both lateral ventricles. Obstruction of the cerebral aqueduct, which may be congenital, due to atresia of the aqueduct, or acquired, as in ependymitis accompanying chronic infection. Obstruction or congenital absence of the apertures of the fourth ventricle leads to enlargement of the entire ventricular system. Subfornical organ Organum vasculosum Pineal Area postrema Median eminence Neurohypophysis. The tumour is benign but is compressing the brain stem and causing secondary hydrocephalus. At the time of admission to the hospital, he exhibits a stiff neck with signs of meningeal irritation, mild facial diplegia, bilateral sixth nerve palsies and papilledema. He has a low-grade fever, and chest X-ray demonstrates several lesions in both lung fields, consistent with a diagnosis of tuberculosis. Tuberculous meningitis must be differentiated from other chronic meningitides, such as syphilitic or cryptococcal. Some viral infections, in particular herpes and mumps, may produce a similar set of changes within the spinal fluid. Metastatic leptomeningeal invasion and sarcoid must also be considered in the differential diagnosis. Describes the structure and ultrastructure of the basal laminae and subependymal layer. It has high metabolic activity due in part to the energy requirements of constant neural activity. It demands about 15% of the cardiac output and uses 25% of the total oxygen consumed by the body. The brain is supplied by two internal carotid arteries and two vertebral arteries that form a complex anastomosis (circulus arteriosus, or the circle of Willis) on the base of the brain. In general, the internal carotid arteries and the vessels arising from them supply the forebrain, with the exception of the occipital lobe of the cerebral hemisphere; the vertebral arteries and their branches supply the occipital lobe, the brain stem and the cerebellum. Acute interruption of the blood supply to the brain for more than a few minutes causes permanent neurological damage. Such ischaemic strokes along with intracranial haemorrhages are major sources of morbidity and mortality. Numerous small hypophysial branches supply the neurohypophysis and are of particular importance because they form the pituitary portal system. Internal Carotid Artery the internal carotid arteries and their major branches (sometimes referred to as the internal carotid system) essentially supply blood to the forebrain, with the exception of the occipital lobe. The petrous part of the internal carotid artery ascends in the carotid canal and curves anteromedially and then superomedially above the cartilage filling the foramen lacerum, to enter the cranial cavity. It lies at first anterior to the cochlea and tympanic cavity and is separated from the latter and the pharyngotympanic tube by a thin, bony lamella that is cribriform in the young and partly absorbed in old age. Further anteriorly it is separated from the trigeminal ganglion by the thin roof of the carotid canal, although this is often deficient. The artery is surrounded by a venous plexus and the carotid autonomic plexus, which is derived from the internal carotid branch of the superior cervical ganglion. The caroticotympanic artery is a small, occasionally double vessel that enters the tympanic cavity by a foramen in the carotid canal and anastomoses with the anterior tympanic branch of the maxillary artery and the stylomastoid artery. When present, it enters the pterygoid canal with the nerve of the same name and anastomoses with a (recurrent) branch of the greater palatine artery. The cavernous part of the internal carotid artery ascends to the posterior clinoid process. It turns anteriorly to the side of the sphenoid within the cavernous sinus and then curves up medial to the anterior clinoid process to emerge through the dural roof of the sinus. Occasionally, the two clinoid processes form a bony ring around the artery, which is also surrounded by a sympathetic plexus. Cavernous branches supply the trigeminal ganglion, the walls of the cavernous and inferior petrosal sinuses and the nerves contained therein. A minute meningeal branch passes over the lesser sphenoid wing to supply the dura mater and bone in the anterior cranial fossa and also anastomoses with a meningeal Petrous Part After piercing the dura mater, the internal carotid artery turns back below the optic nerve to run between the optic and oculomotor nerves. It reaches the anterior perforated substance at the medial end of the lateral cerebral fissure and terminates by dividing into large anterior and middle cerebral arteries. The ophthalmic artery arises from the internal carotid as it leaves the cavernous sinus, often at the point of piercing the dura, and enters the orbit through the optic canal. Small branches from its posterior half pierce the posterior perforated substance, together with branches from the posterior cerebral artery. Collectively, they supply the medial thalamic surface and walls of the third ventricle. The anterior choroidal artery leaves the internal carotid near its posterior communicating branch and passes back above the medial part of the uncus. It crosses the optic tract to reach and supply the crus cerebri of the midbrain; it then turns laterally, recrosses the optic tract and gains the lateral side of the lateral geniculate body, which it supplies with several branches. It finally enters the inferior horn of the lateral ventricle via the choroid fissure and ends in the choroid plexus. This small but important vessel also contributes to the blood supply of the globus pallidus, caudate nucleus, amygdala, hypothalamus, tuber cinereum, red nucleus, substantia nigra, posterior limb of the internal capsule, optic radiation, optic tract, hippocampus and fimbria of the fornix. The surgical nomenclature divides the vessel into three parts: A1, from the termination of the internal carotid artery to the junction with the anterior communicating artery; A2, from the junction with the anterior communicating artery to the origin of the callosomarginal artery; A3, distal to the origin of the callosomarginal artery. The anterior cerebral artery starts at the medial end of the stem of the lateral cerebral fissure and passes anteromedially above the optic nerve to the great longitudinal fissure, where it connects with its fellow by a short transverse anterior communicating artery. It gives off numerous anteromedial central branches that supply the optic chiasma, lamina terminalis, hypothalamus, para-olfactory areas, anterior columns of the fornix and cingulate gyrus. The two anterior cerebral arteries travel together in the great longitudinal fissure. Two or three orbital branches ramify on the orbital surface of the frontal lobe and supply the olfactory cortex, gyrus rectus and medial orbital gyrus. Frontal branches supply the corpus callosum, cingulate gyrus, medial frontal gyrus and paracentral lobule.

First-pass hepatic effect is when drugs are absorbed from the gastrointestinal tract and enter the portal venous blood and thus pass through the liver before entering the systemic circulation for delivery to tissue receptors treatment plans for substance abuse purchase 100 mg persantine with visa. For drugs that undergo extensive hepatic extraction and metabolism (propranolol symptoms ms buy persantine in india, lidocaine) treatment quotes images order persantine once a day, it is the reason for large differences in the pharmacologic effect between oral and intravenous doses symptoms umbilical hernia discount persantine online american express. The sublingual or buccal route of administration permits a rapid onset of drug effect because this blood bypasses the liver and thus prevents the first-pass hepatic effect on the initial plasma concentration of drug medications kidney damage generic persantine 25 mg with amex. Transdermal administration of drugs provides sustained therapeutic plasma concentrations of the drug and decreases the likelihood of loss of therapeutic efficacy due to peaks and valleys associated with conventional intermittent drug injections medicine list buy generic persantine online. A consideration of the derivation of these models allows consideration of their representative parts. Individual consumption of oxygen and production of carbon dioxide occur at a constant rate. The subscripts on rate constants indicate the direction of flow, noted as kfrom to . For anesthetic drugs, the model resemble several buckets connected by pipes (two or three compartment models). The clearance leaving the central compartment for the outside is the "systemic" clearance, and the clearances between the central compartment and the peripheral compartments are the "intercompartmental" clearances. Other than clearance, none of the parameters of compartment models readily translates into any anatomic structure or physiologic process. When drugs are given intravenously, every molecule reaches the systemic circulation (when given by other routes, the drug must first reach the systemic circulation). This curve has the characteristics common to most drugs when given by intravenous bolus (concentrations continuously decrease over time and the rate of decline is initially steep but becomes less steep over time). There is a "rapid distribution" phase that begins immediately after bolus injection. Very rapid movement of the drug from the plasma to the rapidly equilibrating tissues characterizes this phase. Often, there is a second "slow distribution" phase that is characterized by movement of drug into more slowly equilibrating tissues and return of drug to the plasma from the most rapidly equilibrating tissues. There is a time lag between plasma drug concentration and effect-site drug concentration. Conventional approaches to calculate a bolus dose are designed to produce a specific plasma concentration. By knowing the ke0 (the rate constant for elimination of drug from the effect site) of an intravenous anesthetic, one can design a dosing regimen that yields the desired concentration at the site of drug effect (avoids an overdose) (Table 2-2). With target-controlled drug delivery, the user sets the desired plasma or effect-site concentration. Context-sensitive half-time is the time for the plasma concentration to decrease by 50% from an infusion that maintains a constant concentration. The context-sensitive half-time increases with longer infusion durations because it takes longer for the concentrations to fall if drug has accumulated in peripheral tissues. Context-sensitive half-time and effect-site decrement times are more useful than elimination halftime in characterizing the clinical responses to drugs. Pharmacodynamics is the study of the intrinsic sensitivity or responsiveness of the body to a drug and the mechanisms by which these effects occur (what the drug does to the body). The intrinsic sensitivity is determined by measuring plasma concentrations of a drug required to evoke specific pharmacologic responses. The intrinsic sensitivity to drugs varies among patients and within patients over time with aging. As a result, at similar plasma concentrations of a drug, some patients show a therapeutic response, others show no response, and, in others, toxicity develops. The most fundamental relationship in pharmacology is the concentration (or dose) versus response curve. From a pharmacologic perspective, potency is more logically described in terms of the concentration versus response relationship (a drug with a leftshifted concentration vs. To be precise, potency should be defined in terms of a specific drug effect (50% of maximal effect of a full agonist). Efficacy refers to the position of the concentration versus response curve in the y-axis, whereas potency refers to relative drug concentration for a particular response on the y-axis. When there is substantial plasma effect-site disequilibrium, the effect-site decrement time will provide a better estimate of the time required for recover than the contextsensitive half-time. Opioids potently reduce the minimum alveolar concentration of inhaled anesthetics required to suppress movement to noxious stimulation. The interaction between pairs of intravenous drugs and intravenous drugs and inhaled anesthetics is typically synergistic. Enantiomers (substances of opposite shape) are pairs of molecules existing in two forms that are mirror images of one another (right and left hand) but cannot be superimposed. A pair of enantiomers is distinguished by the direction in which, when dissolved in solution, they rotate polarized light, either clockwise (dextrorotatory, d []) or counterclockwise (levorotatory, l []). These observed signs of rotation, d and l, are often confused with the designations D and L used in protein and carbohydrate chemistry. The characteristic of rotation of polarized light is the origin of the term optical isomers. The most applicable and unambiguous convention for designating isomers is the sinister (S) and rectus (R) classification that specifies the absolute configuration in the name of the compound. Molecular interactions that are the mechanistic foundation of pharmacokinetics and pharmacodynamics are stereoselective (relative difference between enantiomers) or stereospecific (absolute difference between enantiomers). The "lock and key" hypothesis of enzyme substrate activity emphasizes that biologic systems are inherently stereospecific. The pharmacologic extension of this concept is that drugs can be expected to interact with other biologic components in a geometrically specific way. The administration of a racemic drug mixture may in fact represent pharmacologically two different drugs with distinct pharmacokinetic and pharmacodynamic properties. Although only one enantiomer is therapeutically active, it is possible that the other enantiomer contributes to side effects. The therapeutically inactive isomer in a racemic mixture should be regarded as an impurity. Studies on racemic mixtures may be scientifically flawed if the enantiomers have different pharmacokinetics or pharmacodynamics. An estimated one-third of drugs in clinical use are administered as racemic mixtures. Most evidence suggests that enantiomerselective effects for volatile anesthetics are relatively weak in contrast to much stronger evidence for specific drug-receptor interactions for intravenous anesthetics. Local anesthetics, including mepivacaine, prilocaine, and bupivacaine, have a center of molecular asymmetry. In addition to pharmacokinetic differences, the cardiac toxicity of bupivacaine is thought to be predominantly due to the R-bupivacaine isomer. Ropivacaine is the S-enantiomer of a bupivacaine homolog that has decreased cardiac toxicity. The S enantiomer of ketamine is more potent than the R form and is also less likely to produce emergence delirium. After administration of identical doses, some patients may have clinically significant adverse effects, whereas others may exhibit no therapeutic response. Some of this diversity of response can be ascribed to differences in the rate of drug metabolism, particularly by the cytochrome P-450 family of enzymes (Table 2-3). It is common practice in anesthesia to administer drugs in proportion to body weight, although pharmacokinetic and pharmacodynamic principles may not support this practice. In attempts to minimize interindividual variability, computerized infusion systems (target-controlled infusion systems) have been developed to deliver intravenous drugs. In elderly patients, variations in drug response most likely reflect (a) decreased cardiac output, (b) increased fat content, (c) decreased protein binding, and (d) decreased renal function. Alterations in enzyme activity as reflected by enzyme induction may be responsible for variations in drug responses among individuals. Variations in drug responses among individuals are due, in part, to genetic differences that may also affect receptor sensitivity. Examples of diseases that are unmasked by drugs include (a) atypical cholinesterase enzyme revealed by prolonged neuromuscular blockade after administration of succinylcholine or mivacurium and (b) malignant hyperthermia triggered by succinylcholine or volatile anesthetics. Drug interactions may reflect alterations in pharmacokinetics (increased metabolism of neuromuscular blocking drugs in patients receiving anticonvulsants chronically) or pharmacodynamics (decrease in volatile anesthetic requirements produced by opioids). The net result of a drug interaction may be enhanced or diminished effects of one or both drugs, leading to desired or undesired effects. The potential for drug interactions in the perioperative period is great considering the large number of drugs from different chemical classes that are likely to be part of anesthesia management. Recent advances in neurophysiology are providing insight into how drugs interact with receptors throughout the nervous system to mediate anesthesia and analgesia. A neuron consists of a cell body, also called the soma, dendrites, and the nerve fiber, also called the axon. Afferent nerve fibers are classified as A, B, and C on the basis of fiber diameter and velocity of conduction of nerve impulses (Table 3-1). The myelin sheath is interrupted approximately every 1 to 2 mm by the nodes of Ranvier. This successive excitation of nodes of Ranvier by an action potential that jumps between successive nodes is termed saltatory conduction. Saltatory conduction allows for a 10-fold increase in the velocity of nerve transmission. The signal arrives at the axon terminal, where it causes the release of neurotransmitters into the synapse. Electromyographic testing is helpful in determining the etiology of neurologic dysfunction that may occur after surgery. Electrical potentials exist across nearly all cell membranes, reflecting principally the difference in transmembrane concentrations of sodium and potassium ions. The resulting voltage difference across the cell membrane is called the resting membrane potential. The cytoplasm is electrically negative (typically 60 to 80 mV) relative to the extracellular fluid. The transmembrane potential and duration of the action potential varies with the tissue site. The membrane resting potential is restored by the closing of the sodium channels and the opening of potassium channels (repolarization) after the action potential has passed. Propagation of action potentials along the entire length of a nerve axon is the basis of rapid signal transmission along nerve cells. A deficiency of calcium ions in the extracellular fluid (hypocalcemia) prevents the sodium channels from closing between action potentials (tetany). Neurotransmitters are chemical mediators that are released into the synaptic cleft in response to the arrival of an action potential at the nerve ending. Neurotransmitters may be excitatory or inhibitory, depending on the ion selectivity of the protein receptor (Table 3-2). It is likely that volatile anesthetics interact with multiple neurotransmitter systems by a variety of mechanisms. The recognition site faces the exterior of the cell membrane to facilitate access of water-soluble endogenous ligands and exogenous drugs, whereas the catalytic site faces the interior of the cell. G proteins can either be stimulatory, promoting a specific enzymatic reaction within the cell, or inhibitory, depressing a specific enzymatic reaction. Dopamine is important to the reward centers of the brain and plays a key role in addiction and drugs. Norepinephrine is present in large amounts in the reticular activating system and the hypothalamus, where it plays a key role in natural sleep and analgesia. Substance P is an excitatory neurotransmitter coreleased by terminals of pain fibers that synapse in the substantia gelatinosa of the spinal cord. Endorphins are endogenous opioid peptide agonists (act through the opioid receptor, the same receptor responsible for the effects of administered opioids). There are three basic types of ion channels: (a) ligand-gated ion channels ionotropic receptors, (b) voltage-sensitive ion channels, and (c) ion channels that respond to other types of gating. Ligand-gated ion channels are complexes of protein subunits that act as switchable portals for ions (involved principally with fast synaptic transmission between excitable cells). Excitatory ligand-gated ion channels cause the inside of the cell to become less negative typically by facilitating the influx of cations into the cell (acetylcholine, glutamate, serotonin). Inhibitory ligand-gated ion channels cause the inside of the cell to become less negative, typically by facilitating the flux of chloride into the cell. Voltage-gated sodium channels are the site of local anesthetic action (local anesthetics block neural conduction by blocking passage of sodium through the voltage-gated sodium channel). Excess circulating concentrations of ligand often results in a decrease in the density of the target receptors in cell membranes (excessive circulating norepinephrine in patients with pheochromocytoma leads to downregulation of -adrenergic receptors). The synapse functions as a diode that transmits an action potential from the presynaptic membrane to the postsynaptic membrane across the synaptic cleft. Calcium triggers the fusion of the vesicle to the cell membrane and the release of the neurotransmitter into the synaptic cleft through exocytosis, resulting in the extrusion of the contents of the synaptic vesicles. Synaptic delay reflects the time for release of the neurotransmitter from the synaptic varicosity, diffusion of the neurotransmitter to the postsynaptic receptor, and the subsequent change in permeability of the postsynaptic membrane to various ions. Synaptic fatigue is a decrease in the number of discharges by the postsynaptic membrane when excitatory synapses are repetitively and rapidly stimulated (decreases excessive excitability of the brain as may accompany a seizure, thus acting as a protective mechanism against excessive neuronal activity).

With time (initially medicine grapefruit interaction purchase persantine amex, the fat compartment is almost invisible because fat blood flow is low) treatment tennis elbow discount persantine, the fat gradually absorbs more and more drug medicine x boston buy persantine with a visa, sequestering it away from the highly perfused tissues medicine 4h2 pill buy generic persantine on line. This redistribution of drug from the highly perfused tissue to the fat accounts for a substantial part of the offset of drug effect following a bolus of an intravenous anesthetic or fat-soluble opioid (fentanyl) treatment hepatitis c buy persantine master card. Most drugs are bound to some extent to plasma proteins medications 3605 discount persantine 25mg, primarily albumin (acidic drugs) and 1-acid glycoprotein and lipoproteins (basic drugs). Protein binding effects both the distribution of drugs (only the free or unbound fraction is readily cross cell membranes) and the apparent potency of drugs (it is the free fraction that determines the concentration of bound drug on the receptor). For intravenous anesthetic drugs, the number of available protein binding sites in the plasma vastly exceeds the number of sites actually bound. Alterations in protein binding are important only for drugs that are highly protein bound (90%). For such drugs, the free fraction changes inversely proportionally with a change in protein concentration. If the free fraction is 2% in the normal state, then in a patient with 50% decrease in plasma proteins, the free fraction will increase to 4%, a 100% increase. Theoretically, an increase in free fraction of a drug may increase the pharmacologic effect of the drug, but in practice, it is far from certain that there will be any change in pharmacologic effect at all. Metabolism converts pharmacologically active, lipid-soluble drugs into water-soluble and usually inactive metabolites; exceptions are metabolism to active compounds as for diazepam and opioids (morphine-6-glucuronide is more potent than morphine; codeine is a prodrug metabolized to morphine). The four basic pathways of metabolism are (a) oxidation, (b) reduction, (c) hydrolysis, and (d) conjugation. Hepatic microsomal enzymes (hepatic smooth endoplasmic reticulum but also present in kidneys and gastrointestinal tract) are responsible for the metabolism of most drugs. Phase I enzymes responsible for phase I reactions include cytochrome P-450 enzymes (predominantly hepatic microsomal enzymes), noncytochrome P-450 enzymes, and flavin-containing monooxygenase enzymes. Drugs can alter the activity of these enzymes through induction and inhibition (phenobarbital induces microsomal enzymes and thus can render drugs less effective through increased metabolism). Examples of oxidative metabolism of drugs catalyzed by cytochrome P-450 enzymes include hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation. Under conditions of low oxygen partial pressures, cytochrome P-450 enzymes transfer electrons directly to a substrate such as halothane rather than to oxygen. The resulting water-soluble glucuronide conjugates are then excreted in bile and urine. Enzymes responsible for hydrolysis of drugs, usually at an ester bond, do not involve the cytochrome P-450 enzyme system. Although the metabolic capacity of the body is large, it is not possible that metabolism is always proportional to drug concentration, because the liver does not have infinite metabolic capacity. The rate at which drug flows out of the liver must be the rate at which drug flows into the liver, minus the rate at which the liver metabolizes drug. To understand hepatic clearance, one must understand the relationship between hepatic metabolism and drug concentration. This is a common approach to analyzing metabolism or tissue uptake across an organ in mass-balance pharmacokinetic studies. Renal excretion of drugs involves (a) glomerular filtration, (b) active tubular secretion, and (c) passive tubular reabsorption (most prominent for lipid-soluble drugs). A highly lipid-soluble drug, such as thiopental, is almost completely reabsorbed such that little or no unchanged drug is excreted in the urine. Conversely, production of less lipid-soluble metabolites limits renal tubule reabsorption and facilitates excretion in the urine. Most drugs are weak acids or bases that are present in solutions in ionized and nonionized form (Table 2-1). A high degree of ionization thus impairs absorption of drug from the gastrointestinal tract, limits access to drug-metabolizing enzymes in the hepatocytes, and facilitates excretion of unchanged drug because reabsorption across the renal tubular epithelium is unlikely. The degree of drug ionization is a function of its dissociation constant (pK) and the pH of the surrounding fluid. Small changes in pH can result in large changes in the extent of ionization, especially if the pH and pK values are similar. Basic drugs, such as opioids and local anesthetics, are highly ionized at an acid pH. Because it is the nonionized drug that equilibrates across lipid membranes, a concentration difference of total drug can develop on two sides of a membrane that separates fluids with different pH. Systemic administration of a weak base, such as an opioid, can result in accumulation of ionized drug (ion trapping) in the acid environment of the stomach. A similar phenomenon occurs in the transfer of basic drugs, such as local anesthetics, across the placenta from mother to fetus because the fetal pH is lower than maternal pH. The ionized fraction in the fetus cannot easily cross the placenta to the maternal circulation and thus is effectively trapped in the fetus. The systemic absorption rate of a drug determines the magnitude of the drug effect and duration of action. Changes in the systemic absorption rate may necessitate an adjustment in the dose or time interval between repeated drug doses. Disadvantages of the oral route include (a) emesis caused by irritation of the gastrointestinal mucosa by the drug, (b) destruction of the drug by digestive enzymes or acidic gastric fluid, (c) irregularities in absorption in the presence of food or other drugs, and (d) metabolism in the gastrointestinal tract before absorption can occur. The principal site of drug absorption after oral administration is the small intestine due to the large surface area of this portion of the gastrointestinal tract. Axons typically have many synapses, not just the single synapse implied by the conventional typical rendition below. The presynaptic membrane encloses the synaptic vesicles that contain the neurotransmitters, the reuptake pump that removes the neurotransmitter following synaptic transmission, and the voltage-gated calcium channel that responds to the incoming action potential. The postsynaptic density contains multiple proteins and receptors and appears responsible for organizing the structure of the receptors on the synapse. Synaptic fatigue is unmasked at the neuromuscular junction in myasthenia gravis when the enormous reserve for neuromuscular transmission is limited by either pre- or postsynaptic autoimmune damage. Neurons are highly sensitive to changes in the pH of the surrounding interstitial fluids (alkalosis enhances neuron excitability and acidosis depresses neuron excitability). The two cerebral hemispheres, known as the cerebral cortex, constitute the largest division of the human brain. Frontal, temporal, parietal, and occipital designate anatomic positions of the cerebral cortex. The area of the cerebral cortex to which the peripheral sensory signals are projected from the thalamus is designated the somesthetic cortex. The two hemispheres of the cerebral cortex, with the exception of the anterior portions of the temporal lobes, are connected by fibers in the corpus callosum. The corpus callosum and anterior commissure make information processed or stored in one hemisphere available to the other hemisphere. Language function and interpretation is typically localized in the dominant cerebral hemisphere, whereas spatiotemporal relationships (ability to recognize faces) are localized in the nondominant hemisphere. The cerebral cortex, especially the temporal lobes, serves as a storage site for information that is often characterized as memory. The favored explanation for short-term memory is posttetanic potentiation (tetanic stimulation of a synapse for a few seconds causes increased excitability of the synapse that lasts for seconds to hours). Long-term memory depends on stable synaptic changes that are induced by experience. The stability of this system is evidenced by total inactivation of the brain by hypothermia or anesthesia without detectable significant loss of long-term memory. Long-term memory is thought to rely on long term synaptic potentiation mediated by structural changes. The incidence of awareness with recall (conscious memory) following general anesthesia has been estimated at between 1 and 5 in 1,000 general anesthetics, depending on the risk group. Although the incidence of conscious recall of intraoperative events is rare and the development of posttraumatic stress disorder is even more uncommon, the fact that approximately 20 million general anesthetics are administered annually in the United States would correspond to 26,000 cases of awareness (0. The use of neuromuscular blockade is a risk factor for awareness under general anesthesia, particularly, awareness that is associated with memories of pain and complicated by posttraumatic stress disorder. Many cases of conscious awareness during surgery can be attributed to intentionally or unintentionally low concentrations of administered anesthetic. Indicators of awareness (heart rate, blood pressure, and skeletal muscle movement) are often masked by anesthetic and adjuvant drugs (-adrenergic blockers) and/or neuromuscular-blocking drugs. Homeostatic life-sustaining processes are controlled subconsciously in the brainstem (control of systemic blood pressure and breathing in the medulla). Behavior associated with emotions is primarily a function of structures known as the limbic system (hippocampus, basal ganglia) located in the basal regions of the brain. The balance between agonist and antagonist skeletal muscle contractions is an important role of the basal ganglia. Whenever destruction of the basal ganglia occurs, there is associated skeletal muscle rigidity. Reticular activating system is a polysynaptic pathway (excitatory and inhibitory) that is intimately concerned with electrical activity of the cerebral cortex. During slow-wave sleep, sympathetic nervous system activity decreases, parasympathetic nervous system activity increases, and skeletal muscle tone is greatly decreased. Cerebellum operates subconsciously to monitor and elicit corrective responses in motor activity caused by stimulation of other parts of the brain and spinal cord. The cerebellum is important in the maintenance of equilibrium and postural adjustments. In the absence of cerebellar function, a person cannot predict prospectively how far movements will go (results in overshoot of the intended mark referred to as past pointing). In the presence of cerebellar disease, a person is unable to activate antagonist skeletal muscles that prevent a certain portion of the body from moving unexpectedly in an unwanted direction. Spinal cord extends from the medulla oblongata to the lower border of the first and, occasionally, the second lumbar vertebra. Below the spinal cord, the vertebral canal is filled by the roots of the lumbar and sacral nerves, which are collectively known as the cauda equina. Gray matter of the spinal cord functions as the initial processor of incoming sensory signals from peripheral somatic receptors and as a relay station to send these signals to the brain. Anatomically, the gray matter of the spinal cord is divided into anterior, lateral, and dorsal horns consisting of nine separate laminae that are H-shaped when viewed in cross-section. White matter of the spinal cord is formed by the axons that make up their respective ascending and descending tracts. This area of the spinal cord is divided into dorsal, lateral, and ventral columns. A major pathway for transmission of motor signals from the cerebral cortex to the anterior motor neurons of the spinal cord is through the pyramidal (corticospinal) tracts. Spinal nerves are made up of fibers of the ventral (anterior) and dorsal (posterior) roots. Each spinal nerve innervates a segmental area of skin designated as dermatome and an area of skeletal muscle known as a myotome. Spinal shock is a manifestation of the abrupt loss of spinal cord reflexes that immediately follows transection of the spinal cord. Within a few days to weeks, spinal cord neurons gradually regain their intrinsic excitability (bladder and colon evacuation). Paco2 and Pao2 influence cerebral blood flow, whereas sympathetic and parasympathetic nerves play little or no role in the regulation of cerebral blood flow. Cerebral blood flow is closely autoregulated between a mean arterial pressure of about 60 and 140 mm Hg. Autoregulation of cerebral blood flow is attenuated or abolished by hypercapnia, arterial hypoxemia, volatile anesthetics, and the area surrounding an acute cerebral infarction. There is a direct relationship between the degree of cerebral activity and the frequency of brain waves. Brain waves are classified as alpha, beta, theta, and delta waves, depending on their frequency and amplitude. The waveforms resulting from sensory stimulation reflect transmission of impulses through specific sensory pathways. The resulting evoked potentials reflect the integrity of sensory neural pathways from the peripheral nerve to the somatosensory cortex. Visual evoked potentials may be useful to monitor the visual pathways during -transsphenoidal or anterior fossa neurosurgical procedures. The eye is optically equivalent to a photographic camera in that it contains a lens system, a variable aperture system (pupil), and light sensitive surface (retina). Ophthalmoscopic examination of the eyes with retinal artery occlusion shows a pale edematous retina. Nausea is the conscious recognition of excitation of an area in the medulla that is associated with the vomiting (emetic) center. The medullary vomiting center is located close to the fourth cerebral ventricle and receives afferents from the (a) chemoreceptor trigger zone, (b) cerebral cortex, (c) labyrinthovestibular center, and (d) neurovegetative system. The chemoreceptor trigger zone includes receptors for serotonin, dopamine, histamine, and opioids. Stimulation of the chemoreceptor trigger zone located on the floor of the fourth cerebral ventricle initiates vomiting independent of the vomiting center. The peripheral nerves extend from the dendrite in the periphery to the dorsal root ganglion, where the cell body is located, and from there to the spinal cord by way of the dorsal root. Anterior motor neurons in the anterior horns of the spinal cord gray matter give rise to A- fibers that leave the spinal cord by way of anterior nerve roots and innervate skeletal muscles. Transection of the brainstem at the level of the pons (isolates the spinal cord from the rest of the brain) results in spasticity known as decerebrate rigidity.

This communication among various signaling pathways facilitates our understanding of the far-reaching consequences of single gene mutations that result in malformation syndromes affecting the development of multiple organ systems medications like abilify 25mg persantine for sale, or in cancers medications 24 order persantine cheap. Hopwood N: A history of normal plates symptoms for pregnancy order persantine discount, tables and stages in vertebrate embryology treatment glaucoma buy 100mg persantine otc. Kirk E medications just for anxiety buy generic persantine on-line, Bottomley C medicine mountain scout ranch purchase persantine 100mg mastercard, Bourne T: Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location. Lewis J, Hanisch A, Holder M: Notch signaling, the segmentation clock, and the patterning of vertebrate somites. Van Mieghem T, Al-Ibrahim A, Deprest J, et al: Minimally invasive therapy for fetal sacrococcygeal teratoma: case series and systematic review of the literature. Wang Y, Steinbeisser H: Molecular basis of morphogenesis during vertebrate gastrulation. Hinrichsen K: the early development of morphology and patterns of the face in the human embryo. Jabrane-Ferrat N, Siewiera J: the up side of decidual natural killer cells: new developments in immunology of pregnancy. Svingen T, Koopman P: Building the mammalian testis: origins, differentiation, and assembly of the component cell populations. Kamedia Y: Hoxa3 and signaling molecules involved in aortic arch patterning and remodeling. Kudo K, Yamagishi H: A decade of advances in the molecular embryology and genetics underlyng congenital heart defects. Loukas M, Bilinsky C, Bilinski E, et al: the normal and abnormal anatomy of the coronary arteries. Patil S, Doni B, Kaswan S, Rahman F: Prevalence of dental anomalies in Indian population. Jia J, Geng L, Zong Y: Birth defects in assisted reproductive technology and spontaneously conceived children: a meta-analysis. Kawasaki M, Porntaveetus T, Kawasaki K, et al: R-spondins/Lgrs expression in tooth development. Papagerakis P, Mitsiadis T: Development and structure of teeth and periodontal tissues. Amakye D, Jagani Z, Dorsch M: Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Berdasco M, Esteller M: Genetic syndromes caused by mutations in epigenetic genes. Guillot C, Lecuit T: Mechanics of epithelial tissue homeostasis and morphogenesis. Gutierrez-Mazariegos J, Theodosiou M, Campo-Paysaa F, Schubert M: Vitamin A: a multifunctional tool for development. Lamouille S, Xu J, Derynck R: Molecular mechanisms of epithelialmesenchymal transition. Manoranjan B, Venugopal C, McFarlane N, et al: Medulloblastoma stem cells: where development and cancer cross pathways. Everyone,especiallythoseinthehealth-careprofessions, needs to know about conception, contraception, and how embryos and fetuses develop, both normallyandabnormally. Itisnotpossibleto detect the precise time of ovulation (discharge of ovum)oroffertilization(whendevelopmentbegins). Pregnant women do not menstruate, even though there may be some bleeding at the usual time of menstruation. Because there is no shedding of endometrium,thisbloodisnotmenstrualfluid;itis maternal blood that escaped from the intervillous spaceoftheplacenta. Often, a few sperms are expelled from the penis with the secretions of the auxiliary sex glands. The ovarian and menstrual cycles typically cease between48and55yearsofage,withtheaverageage being51years. Theresults of molecular approaches, such as pharmacologic antagonism of the P2X1-purinoceptor and 1Aadrenoceptor, may eventually provide a safe and reversiblemalecontraceptive. More likely, dispermic chimeras result from the fusion of dizygotic twin zygotes early in development. Thistechniquecouldbe made available to couples with a family history of sex-linkedgeneticdiseases. If fertilization occurs in a woman who is using an intrauterine device, the risk of ectopic pregnancy is approximately5%. The risk of severe maternal bleeding and fetal mortality is high in cases of abdominal pregnancy. Forinstance,antineoplasticagents(chemotherapyorantitumordrugs) can produce severe skeletal and neural tube defects in the embryo, such as acrania and meroencephaly (partialabsenceofbrain),ifadministeredduringthe thirdweek. Advanced maternal age is also associated with a significantly increased risk to the embryo or fetus. Women unfamiliar with this possible occurrence may interpret the bleeding as alightmenstrualflow. Insuchcases,theymaygive the physician the wrong date for their last normal menstrualperiod. Blood loss could also result from the rupture of chorionic arteries, veins, or both (see Chapter8). Drugs or other agents may cause early abortion of an embryo, but they do not cause birth defects if takenduringthefirst2weeks. It is impossible to tell by ultrasound examination whether the primordial sexualorgan(genitaltubercleat5weeksandphallus at 7 weeks) will become a penis or a clitoris. Ultrasound examinations have shown that mature embryos(8weeks)andyoungfetuses(9weeks)show spontaneous movements, such as twitching (sudden jerkingmovements)ofthetrunkandlimbs. Folic acid supplementation before conception and during early pregnancy is effective in reducing the incidenceofneuraltubedefects. However,noconsensusexiststhat vitamins are helpful in preventing these defects in mostat-riskpregnancies. Direct injury to the fetus from the needle during amniocentesis is very uncommon when ultrasound guidance is used to locate the position of the fetus and monitor needle insertion. Thiscreatespressure on the cord and prevents the fetus from receiving adequateoxygen. The results of such tests are positive for a short time (approximately 1 week) after the first missed menstrual period (after embryo implantation). The "bag of water" is a colloquial term for the amnioticsac,whichcontainsamnioticfluid(largely composedofwater). Sometimestheamniochorionic sac ruptures before labor begins, allowing fluid to escape. Premature rupture of the membranes may complicate the birth process, or it may allow a vaginal infection to spread to the fetus. Sometimes sterile saline is infused into the uterus by way of a catheter-amnioinfusion-to alleviate fetal distress. The displaced viscera are replaced into the abdominal cavity, and the defect in the diaphragm is surgically repaired. Infants with large diaphragmatic hernias who are operatedonwithin24hoursafterbirthhavesurvival ratesof40%to70%. Some small hernias may remain asymptomatic into adulthood and may be discovered only during routine radiographic or ultrasound examination of the thorax. The risk in this case is the same as in the general population,approximately1in1000. Minor anomalies of the auricle of the external ear are common and usually they are of no serious medical or cosmetic consequence. The incidence of respiratory distress syndrome is approximately 1% ofalllivebirths,anditistheleadingcauseofdeath innewborninfants. A 22-week fetus is viable and, if born prematurely and given special care in a neonatal intensive care unit,maysurvive. Thechancesofsurvival,however, are poor for infants who weigh less than 600g because the lungs are immature and incapable of adequate alveolar-capillary gas exchange. Undoubtedly, the individual described had an ileal (Meckel) diverticulum, a finger-like outpouching of the ileum. The neural crest cells normally form neurons, so there is a deficiency of the nerve cells that innervate the muscular wall of the bowel-congenital aganglionosis. His developing kidneys probably fused during the sixth to eighth weeks as they "migrated" from the pelvis. Virilization (masculinization) of a female fetus as a result of congenital adrenal hyperplasia is the most common cause of ambiguous external genitalia. Heart murmurs are sounds transmitted to the thoracic wall from turbulence of blood in the heart or greatarteries. A ventricular septal defect or a patent oval foramen(foramenovale)mayalsoproduceamurmur. They occur in 6 to 8 in 1000 newborn infants and represent approximately 10% of all congenital anomalies. They occur more frequently in males than in females, but the reason for this is unknown. This anomaly is called transposition of the great arteries because the positions of the great vessels (aorta and pulmonary trunk) are reversed. Most infants with this severe cardiac anomaly die during the first months of life; however, corrective surgery can be performed in those who survive for several months. Later, an arterial switch operation (reversing the aorta and the pulmonary trunk)canbeperformed. The most common type of accessory rib is a lumbar rib, but it usually causes no problems. This type of craniosynostosis accounts forapproximately50%ofcasesofprematureclosure of cranial sutures and is more commonly seen in males. The features of Klippel-Feil syndrome are a short neck,alowhairline,andrestrictedneckmovements. Thissyndromeisusually associated with malformations of the urinary tract, especially the urinary bladder. In males, almost all patients have cryptorchidism (failure of one or both testes to descend into the scrotum). Thisrelativelycommoncondition-congenital torticollis (wry neck)-may occur because of injury to the muscle during birth. Ifthe woman(likelybb)marriesthebrachydactylousman (likely Bb), the risk is 50% for a brachydactylous childand50%foranormalchild. Bendectin, an antinauseant mixture of doxylamine, dicyclomine,andpyridoxine,doesnotproducelimb defects in human embryos. Several epidemiologic studies have not shown an increased risk of birth defects after exposure to Bendectin or its separate ingredients during early pregnancy. It varies from cutaneous webbing between the digits to synostosis (union of the phalanges,thebonesofthedigits). Thisanomalyoccurs when separate digital rays do not form in the fifth week or when the tissue between the developing digitsdoesnotundergoapoptosis. The most common type of clubfoot is talipes equinovarus, occurring in approximately 1 in 1000 newborn infants. In this deformity, the soles of the feet are turned medially and the feet are plantar flexed. The feet are fixed in the tiptoe position, resembling the foot of a horse (Latin equinus, horse). Mental deficiency and growth restriction are the most serious aspects of fetal alcohol syndrome. The reduced oxygen supply to the brain could affect fetal intellectual development, even though the effect may be undetectable. Spinalmeningocele is easier to correct surgically than spinal meningomyelocele,andtheprognosisisalsobetter. Wheninfection occurs at the end of the first trimester, the probability of birth defects is only slightly higher than that for an uncomplicated pregnancy. The purposeful exposure of young girls to rubella (German measles) is not recommended. Although complications resulting from such infections are uncommon, neuritis and arthritis (inflammation of thenervesandjoints,respectively)occasionallyoccur. Rubella infection is often subclinical (difficult to detect), yet children with such infections represent an exposure risk to pregnant women. This occurs early enough in pregnancy that some women might be unawarethattheyarepregnant. Several viruses in the herpesvirus family can cause fetal blindness and deafness during infancy. Methylmercuryisteratogenic(causingbirthdefects) in human embryos, especially to the developing brain.

Oligodendrocytes originate from the ventricular neuroectoderm and the subependymal layer in the fetus and continue to be generated from the subependymal plate postnatally symptoms 0f gallbladder problems order persantine. Stem cells migrate and seed into white and grey matter to form a pool of adult progenitor cells that may later differentiate to replenish lost oligodendrocytes and possibly remyelinate pathologically demyelinated regions medicine naproxen purchase persantine 25mg on line. It depends on the presence of tight junctions between endothelial cells and a relative lack of transcytotic vesicular transport symptoms 16 dpo discount persantine 100mg. The tightness of the barrier depends on the close apposition of astrocytes to blood capillaries medications vascular dementia purchase persantine 25 mg online. Moreover treatment centers in mn discount 25mg persantine otc, there are certain areas of the adult brain in which the endothelial cells do not have tight junctions treatment diabetes generic 25mg persantine fast delivery, and a free exchange of molecules occurs between blood and adjacent brain. Most of these areas are situated close to the ventricles and are known as circumventricular organs. It is also associated with primary the territory ensheathed by an oligodendrocyte process defines an internode. The interval between internodes is called a node of Ranvier, and the territory immediately adjacent to the nodal gap is a paranode, where loops of oligodendrocyte cytoplasm abut the axolemma. Nodal axolemma is contacted by the end-feet of perinodal cells, which have been shown in animal studies to have a presumptive adult oligodendrocyte progenitor phenotype; their function is unknown (Butt and Berry 2000). A sheath of astrocytic end-feet wraps around the vessel and, in vessels larger than capillaries, its investment of pial meninges. Vascular endothelial cells are joined by tight junctions and supported by pericytes; perivascular macrophages lie outside the endothelial basal lamina. Their function is unknown, but their structure suggests that they may play a role in the transport of molecules across the myelin sheath. A single oligodendrocyte may ensheathe up to 50 separate axons, depending on their calibre, whereas myelinating Schwann cells ensheathe axons on a 1: 1 basis. Because there is considerable overlap between the size of the smallest myelinated axons and the largest unmyelinated axons, axonal calibre is unlikely to be the only factor in determining myelination. Additionally, the first axons to become ensheathed ultimately reach larger diameters than do later ones. There is a reasonable linear relationship between axon diameter and internodal length and myelin sheath thickness. The oligodendrocyte soma is shown in the centre, and its myelin sheaths are unfolded to varying degrees to show their extensive surface area. B and C, Confocal micrographs of a mature myelin-forming oligodendrocyte (B) and astrocyte (C) iontophoretically filled in the adult rat optic nerve with an immunofluorescent dye by intracellular microinjection. In this way, it is thought that the compacted external surfaces of the plasma membrane of the ensheathing glial cell produce the minor dense lines, and the compacted inner cytoplasmic surfaces produce the major dense lines, of the mature myelin sheath. These correspond to the intraperiod and period lines, respectively, defined in X-ray studies of myelin. The inner and outer zones of occlusion of the spiral process are continuous with the minor dense line and are called the inner and outer mesaxons. There are significant differences between central and peripheral myelin, reflecting the fact that oligodendrocytes and Schwann cells express different proteins during myelinogenesis. Myelin membrane contains protein, lipid and water, which forms at least 20% of the wet weight. The major lipid species are cholesterol (the most common single molecule), phospholipids and glycosphingolipids. Minor lipid species include galactosylglycerides, phosphoinositides and gangliosides. The major glycolipids are galactocerebroside and its sulphate ester sulphatide; these lipids are not unique to myelin but are present in characteristically high concentrations. Gangliosides, which are glycosphingolipids characterized by the presence of sialic acid (N-acetylneuraminic acid), account for less than 1% of the lipid. A relatively small number of protein species accounts for the majority of myelin protein. Myelination does not occur simultaneously in all parts of the body in late fetal and early postnatal development. White matter tracts and nerves in the periphery have their own specific temporal patterns, related to their degree of functional maturity. Mutations of the major myelin structural proteins have now been recognized in a number of inherited human neurological diseases. As would be expected, these mutations produce defects in myelination and in the stability of nodal and paranodal architecture, consistent with the suggested functional roles of the relevant proteins in maintaining the integrity of the myelin sheath. The molecular organization of myelinated axons is described in Scherer and Arroyo (2002). They form a single-layered epithelium that varies from squamous to columnar in form. At the ventricular surface, cells are joined by gap junctions and occasional desmosomes. There is considerable regional variation in the ependymal lining of the ventricles, but four major types have been described: the general ependyma that overlies grey matter, the general ependyma that overlies white matter, specialized areas of ependyma in the third and fourth ventricles and the choroidal epithelium. The ependymal cells overlying areas of grey matter are cuboidal; each cell bears approximately 20 central apical cilia, surrounded by short microvilli. The cells are joined by gap junctions and desmosomes and do not have a basal lamina. Beneath them there may be a subependymal zone, two to three cells deep, consisting of cells that generally resemble ependymal cells. They have numerous mitochondria, well-formed Golgi complexes and a rather flattened basal nucleus. They are joined laterally by tight junctions that form a barrier to the passage of materials across the ependyma and by desmosomes. Many of the cells are tanycytes (ependymal astrocytes) and have basal processes that project into the perivascular space surrounding the underlying capillaries. The ependyma is highly modified where it lies adjacent to the vascular layer of the choroid plexus. Where the ependyma overlies myelinated tracts of white matter, the cells are much flatter, and few are ciliated. There are gap junctions and desmosomes between cells, but their lateral margins interdigitate, unlike those overlying grey matter. Specialized areas of ependymal cells are found in four areas around the margins of the third ventricle. These areas, called the circumventricular organs, consist of the lining of the median eminence of the hypothalamus, the subcommissural organ, the subfornical organ and the vascular organ of the lamina terminalis (Ch. The area postrema, at the inferoposterior limit of the fourth ventricle, has a similar structure. In all these sites the ependymal the ependymal cells in the choroid plexus resemble those of the circumventricular organs, except that they do not have basal processes; instead, they form a cuboidal epithelium that rests on a basal lamina adjacent to the enclosed fold of pia mater and its capillaries. Cells have numerous long microvilli, with only a few cilia interspersed between them. The choroid plexus has a villous structure where the stroma is composed of pial meningeal cells, and it contains fine bundles of collagen and blood vessels. In adult life, the stroma contains phagocytic cells, and these, together with the cells of the choroid plexus epithelium, phagocytose particles and proteins from the ventricular lumen. Age-related changes occur in the choroid plexus that can be detected on imaging of the brain. The visible calcification is usually restricted to the glomus region of the choroid plexus, the vascular bulge in the choroid plexus as it curves to follow the anterior wall of the lateral ventricle into the temporal horn. Evidence largely supports the view that they are derived from fetal monocytes or their precursors, which invade the developing nervous system. An alternative hypothesis holds that microglia share a lineage with ependymal cells and are thus neural tube derivatives. Later they lose their motility and transform into typical microglia, bearing branched processes that ramify in non-overlapping territories within the brain. All microglial domains, defined by their dendritic fields, are equivalent in size and form a regular mosaic throughout the brain. The expression of microglia-specific antigens changes with age: many are downregulated as microglia attain the mature dendritic form. The scant cytoplasm is pale staining and contains granules, scattered cisternae of rough endoplasmic reticulum and Golgi complexes at both poles. Two or three primary processes stem from opposite poles of the cell body and branch repeatedly to form short terminal processes. Lymphocytes are able to enter the brain in response to viral infections and as part of the autoimmune response in multiple sclerosis. Activated, but not resting, lymphocytes pass through the endothelium of small venules, a process that requires the expression of recognition and adhesion molecules, which are induced following cytokine activation. Lymphocytes probably drain along lymphatic pathways to regional cervical lymph nodes. These cells probably enter the nervous system following the expression of adhesion molecules on endothelium and pass through the endothelial layer. Widely variable numbers of peripheral nerve fibres are grouped into bundles (fasciculi). Their number increases and their size decreases some distance proximal to a point of branching. Where nerves are subjected to pressure, such as deep to a retinaculum, fasciculi are increased in number but reduced in size, and the amount of associated connective tissue and degree of vascularity also increase. At these points, nerves may occasionally show a pink, fusiform dilatation, sometimes termed a pseudoganglion or gangliform enlargement. The classification of peripheral nerve fibres is based on various parameters, such as conduction velocity, function and fibre diameter. Of the two classifications in common use, the first divides fibres into three major classes designated A, B and C, corresponding to peaks in the distribution of their conduction velocities. In humans, group A fibres are subdivided into, and subgroups; group B fibres are preganglionic autonomic efferents, and group C fibres are unmyelinated. Group A fibres are the largest and conduct most rapidly, and group C fibres are the smallest and slowest. The largest afferent axons (A fibres) innervate encapsulated cutaneous, joint and muscle receptors and some large alimentary enteroceptors. A fibres innervate thermoreceptors and nociceptors, including those in dental pulp, skin and connective tissue. Frond-like projections of vascular stroma derived from the pial meninges are covered with a low columnar epithelium that secretes cerebrospinal fluid. Epineurium Epineurium is a condensation of loose (areolar) connective tissue and is derived from mesoderm. As a general rule, the more fasciculi present in a peripheral nerve, the thicker the epineurium. Loss of this protective layer may be associated with pressure palsies seen in wasted, bedridden patients. The epineurium also contains lymphatics (which probably pass to regional lymph nodes) and blood vessels- the vasa nervorum-which pass across the perineurium to communicate with a network of fine vessels within the endoneurium. At unencapsulated endings and neuromuscular junctions, the perineurium ends openly. It consists of alternating layers of flattened polygonal cells, which are thought to be derived from fibroblasts, and collagen. It can often contain 15 to 20 layers of such cells, each layer enclosed by a basal lamina up to 0. Cells within each layer interdigitate along extensive tight junctions, and their cytoplasm contains numerous pinocytotic vesicles and, often, bundles of microfilaments. Individual axons, myelinated and unmyelinated, are arranged in a small fascicle bounded by a perineurium (P). The fibrous and cellular components of the endoneurium are bathed in endoneurial fluid at a slightly higher pressure than that outside in the surrounding epineurium. The major cellular constituents of the endoneurium are Schwann cells, associated with axons, and endothelial cells. Other cells that are always present within the endoneurium are fibroblasts (constituting approximately 4% of the total endoneurial cell population), resident macrophages and mast cells. Endoneurial arterioles have a poorly developed smooth muscle layer and do not autoregulate well.

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