«Delirium, a clinical syndrome characterized as an acute disorder of attention and cognitive function, is the most frequent complication of hospitalization for elders and a potentially devastating problem. Delirium often is unrecognized despite...» Document abstract
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SummaryDelirium, a clinical syndrome characterized as an acute disorder of attention and cognitive function, is the most frequent complication of hospitalization for elders and a potentially devastating problem. Delirium often is unrecognized despite sensitive methods for its detection, and its complications may be preventable.
Table of Contents- Definitions
- Etiology
- Incidence and Prevalence
- Epidemiology
- Pathogenesis
- Clinical Manifestations
- Diagnosis and Evaluation
«Prior to delineating the organization of specific intraneuronal signaling pathways, it is important to consider, in general terms, their role in helping neurons interpret and respond to the barrage of afferent stimulation impinging on them...» Document abstract
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SummaryPrior to delineating the organization of specific intraneuronal signaling pathways, it is important to consider, in general terms, their role in helping neurons interpret and respond to the barrage of afferent stimulation impinging on them continuously. From an evolutionary perspective, second messenger systems predate neurotransmitters and neurotrophins, examples of first messengers detected by cell surface receptors. Before the advent of neurotransmitters, prokaryotic organisms relied on cyclic adenosine monophosphate (cAMP) and other intracellular signaling pathways to coordinate diverse responses located in disparate parts of these unicellular organisms to changes in ambient nutrients or conditions. Neurotransmitters and neurotrophins have evolved subsequently to take advantage of these internal signaling pathways that have undergone a parallel growth process.
Table of Contents- Intraneuronal signaling pathways do more than merely enlarge the sphere of influence of afferent stimuli beyond the local environment of the cell surface receptor.
- Although the overwhelming majority of psychiatric drugs target extracellular receptors or uptake sites, the explosion of information on intraneuronal signaling pathways suggests that these may represent suitable drug targets.
- Psychiatrists have long been taught that a true understanding of normal and abnormal behavior requires an appreciation of the interplay of forces lurking beneath the surface.
- Neurotransmitter receptors may couple to adenylate cyclase via different classes of G proteins, referred to as Gs or Gi, depending on whether they stimulate or inhibit cyclic AMP formation.
- Cyclic GMP Besides cyclic AMP, another cyclic nucleotide, cyclic guanosine monophosphate (GMP) has been identified as a second messenger regulated by neurotransmitter receptor stimulation.
- Because the effects of cAMP are mediated to a large extent via activation of a kinase, it was generally assumed that each of these second messengers acted in a similar fashion.
- However, this view has been challenged recently in light of animal studies demonstrating that inositol levels in brain are unaffected by lithium concentrations within its therapeutic range.
- These alternate arrangements emphasize the notion that intracellular signaling cascades have evolved in ways that heighten their versatility, with each of the components having multiple signaling capacities.
- Another family of tyrosine kinases has been identified that differs from the receptor tyrosine kinases in that it contains only the cytoplasmic domain.
- Cross-Talk Among Signaling Pathways The organization of intraneuronal signaling pathways allows for a high degree of interaction or cross-talk among pathways
«Structure and Function of Voltage-Gated Ion Channels Voltage-gated ion channels allow the flow of ions in response to changes in membrane voltage and are key elements in neuronal excitation and inhibition. Although ion channels can usually pass more...» Document abstract
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SummaryStructure and Function of Voltage-Gated Ion Channels Voltage-gated ion channels allow the flow of ions in response to changes in membrane voltage and are key elements in neuronal excitation and inhibition. Although ion channels can usually pass more than a single type of ion, voltage-gated channels are named according to the predominant ion that flows when the channel is open. Ion channels that are selective for Na+, K+, Ca2+, or Cl– have been described in neuronal membranes. Certain ion channels that are gated directly by chemical neurotransmitters such as glutamate and acetylcholine are selective for Na+, K+, and Ca2+ but exclude Cl– and are called nonselective cationic channels.
Table of Contents- Sodium (Na+) Channels Na+ channels are primarily responsible for the fast upstroke of action potentials, although in some neurons Na+ channels also contribute to lower-level depolarizations and pacemaker firing.
- Relations between primary protein structure and ion channel function in Na+ channels have been examined using mutations of specific amino acid residues.
- The net effect is similar to the scorpion toxins. Finally, certain local anesthetic drugs, including lidocaine and procaine, block Na+ channels by binding reversibly to sites within the hydrophobic regions of the ion channel.
- Delayed-rectifier channels open slowly and show little inactivation during prolonged depolarizations.
- M channels represent a class of K+ channels that are activated in a time- and voltage-dependent fashion but are blocked by the neurotransmitter, acetylcholine, acting at muscarinic receptors.
- KATP channels exist in the CNS and appear to be involved in regulating the release of certain neurotransmitters and perhaps in determining the response of some neurons to changes in intracellular energy levels.
- Calcium (Ca2+) Channels Because Ca2+ is involved in numerous cellular events including enzyme activation, gene expression, and neurotransmitter release, the regulation of intracellular Ca2+ levels is of major importance to neurons.
- Most structural information about Ca2+ channels comes from skeletal muscle HVA Ca2+ channels.
«Classes of Neurotransmitters Much of the information transfer between neurons in the CNS occurs via chemical synapses. These synapses use a variety of messengers (neurotransmitters) that are released in a Ca2+-dependent fashion from presynaptic...» Document abstract
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SummaryClasses of Neurotransmitters Much of the information transfer between neurons in the CNS occurs via chemical synapses. These synapses use a variety of messengers (neurotransmitters) that are released in a Ca2+-dependent fashion from presynaptic terminals and act on specific protein receptors to produce biochemical and excitability changes in the receiving cell. There are two primary groups of neurotransmitters—low–molecular-weight amines and neuroactive peptides. These agents act on two classes of receptors, ligand-gated ion channels, at which the binding of the transmitter directly opens ion channels in the membrane, and G protein coupled receptors. The activated G protein then acts on ion channels or alters biochemical second-messenger systems. Physiologists classify synaptic transmission according to the speed of transmission (fast or slow) and according to the nature of the response (excitatory or inhibitory).
Table of Contents- Currently, there are nine low–molecular-weight amines that serve as neurotransmitters.
- Conductance Mechanisms Underlying Neurotransmitter Actions
- Structure of Neurotransmitter Receptors Considerable information now exists about the primary structure of neurotransmitter receptors.
- The ligand-gated ion channels gated by extracellular ATP (called P2X receptors) are exceptions to the scheme described above and have structures more typical of the inwardly rectifying K+ channels.
- G-protein coupled receptors have a distinctly different structure from the ligand-gated ion channels.
«In its simplest form, the postsynaptic response to neurotransmitter release can be mediated by a single protein complex. For example, nicotinic acetylcholine receptors are self-contained stimulus-response modules that both detect a stimulus,...» Document abstract
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SummaryIn its simplest form, the postsynaptic response to neurotransmitter release can be mediated by a single protein complex. For example, nicotinic acetylcholine receptors are self-contained stimulus-response modules that both detect a stimulus, acetylcholine, and generate a response, passage of ion currents. In a similar vein, other members of this superfamily of ionotropic receptors, including g-aminobutyric acid (GABA) and glutamate receptors, have the ability to function in a manner that is independent of the intracellular signaling pathways discussed. Thus, in contrast to growth factor or G-protein–coupled receptors, which often recruit elaborate cascades to elicit a response, the simplicity of self-sufficient ionotropic receptor complexes represents an optimal design for achieving reliability, precision, and speed. However, this view of ionotropic receptors as insulated from their social environment has had to be abandoned in the face of overwhelming evidence that this class of receptors is dynamically regulated by intraneuronal signaling pathways. Although these receptors do not rely on intraneuronal signaling pathways to operate ion channels, because these channels are an intrinsic feature of the receptor complex the linkage between ligand binding and ion channel gating is nevertheless subject to regulation by the network of intraneuronal signaling pathways just described. For example, phosphorylation of the GABA or glutamate receptors modulates their response to ligand exposure.
Table of Contents- Long-Term Depression The principle that ion channels are regulated by second messenger pathways is of central importance in considering how neuronal responses are altered by experience.
- Long-Term Potentiation The notion that coactivation of multiple second messenger pathways can have a qualitatively different impact than any one individually is also borne out in another well-known model of synaptic plasticity, long-term potentiation.
- This unusual property of NMDA receptors provides a molecular mechanism for conferring associative properties on long-term potentiation.
- Role of Phosphorylation The associative property of this model of synaptic plasticity has focused attention on deciphering the intraneuronal signaling pathways that mediate the long-term change in synaptic transmission triggered by NMDA receptor stimulation.
- Actions of Psychotropic Drugs In addition to providing insight into the molecular mechanism underlying synaptic plasticity, studies of intraneuronal signaling pathways are also directly relevant to deciphering the mode of action of psychotropic drugs.
- Evidence supporting this theory has been provided by recent studies demonstrating that opiate withdrawal is attenuated in transgenic animals that are deficient in CREB.
«Resting Membrane Potential In nerve cells, potassium ions (K+) are at higher concentration inside the membrane than outside whereas the opposite is true for sodium (Na+), calcium (Ca2+), and chloride (Cl–) ions (Fig. 1.9-1). The bulk solutions on...» Document abstract
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SummaryResting Membrane Potential In nerve cells, potassium ions (K+) are at higher concentration inside the membrane than outside whereas the opposite is true for sodium (Na+), calcium (Ca2+), and chloride (Cl–) ions (Fig. 1.9-1). The bulk solutions on either side of the membrane are electrically neutral, with most of the intracellular negative charge being contributed by large organic anions (acids and proteins). The differential distribution of ions across neuronal membranes results in part from the action of membrane pumps that use energy from adenosine triphosphate (ATP) to drive ions against a concentration gradient into or out of the cell. The best characterized pump is the Na+-K+ adenosine triphosphatase (ATPase) that transports 3 Na+ out of and 2 K+ into the cell during each cycle. Because an unequal amount of charge is moved during each cycle, the pump is electrogenic and produces an electrochemical potential across the membrane that makes the inside of the membrane negative with respect to the outside. Na+-K+ ATPase activity is a major contributor to brain energy utilization, with as much as 40 percent of brain oxygen consumption resulting from pump activity required to reestablish ionic homeostasis following action potential firing and synaptic transmission. The cardiac glycosides digoxin (Lanoxin) and ouabain are effective inhibitors of Na+-K+ ATPase in the heart and improve myocardial contractility by depolarizing cardiac myocytes and increasing intracellular Ca2+.
Table of Contents- At rest, neuronal membranes are permeable to K+ and Cl– and to a lesser extent to Na+, partly because of the flow of ions through nongated leakage channels.
- For each ion in solution there is a specific membrane potential at which the opposing forces of the electrical gradient and concentration gradient are balanced.
- Because ions do not directly penetrate the lipid membrane but rather flow through ion channels, the ion channels can be thought of as variable resistors.
- Active Membrane Properties: Action Potentials Changes in membrane potential have important effects on excitability because certain ion channels are activated (gated) by voltage changes.
- Many axons are encased in myelin sheaths that allow them to send action potentials over longer distances.
«Neuropeptide receptors have undergone the same process of discovery and characterization that receptors for other neurotransmitters have enjoyed. The process begins with the pharmacological characterization of the receptor's physicochemical binding...» Document abstract
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SummaryNeuropeptide receptors have undergone the same process of discovery and characterization that receptors for other neurotransmitters have enjoyed. The process begins with the pharmacological characterization of the receptor's physicochemical binding properties by assessing the affinity of various metabolically derived and synthetic peptide fragments, and the native molecule, for the receptor binding site found in membrane preparations. Peptide receptor locations are mapped with radioactive or fluorescent tags that are inserted into peptide molecules, which often contain substituted amino acids at the most vulnerable peptidase cleavage sites. Previously, once the peptide receptor was characterized pharmacologically, it was usually purified from some relatively enriched biological tissue source or brain region by affinity column chromatography. After it had been purified, binding parameters and activity were recharacterized for the reconstituted purified receptor protein and structural information obtained by X-ray crystallography. This process was closely followed in the purification of the neurotensin-neuromedin N receptor.
Table of Contents- The neurotensin receptor was first characterized by photoaffinity labeling and cross-linking of radioiodinated ligands, which resulted in two labeled subunits of about 49 Kd and 51 Kd from rat brain synaptosomes.
- The much more powerful tools of molecular biology have been utilized more recently.
- Neuropeptide receptors have been associated with just about every type of second messenger signal transduction system that has been identified.
- Peptides are degraded to smaller fragments, and eventually to single amino acids, by specific enzymes termed peptidases.
- The metabolism of TRH has been investigated fairly completely, principally because of the limited number of fragments that can be generated from a tripeptide.
- The peptides involved in neuroendocrine regulation have cell bodies residing in the hypothalamus that receive feedback from all levels of the endocrine axes.
- Regional differences in CRF receptor regulation by corticosterone have also been reported, which have been shown to partly result from differential glycosylation of the CRF receptor.
- Alzheimer's Disease Dementia of the Alzheimer's Type represents up to two thirds of the demented population encountered in clinical practice, and over half of the nursing home beds in the United States are currently occupied by such patients.
- The CRF-containing interneurons of the cortex are also consistently depleted in Alzheimer's disease. As with SRIF, subcortical areas containing CRF neurons may be spared, but unlike SRIF, CRF receptors are increased in number (up-regulated) with no change in affinity.
- Corticotropin-Releasing Factor After a search spanning nearly three decades, CRF was isolated and characterized in 1981 as a 41-amino acid peptide.
- A series of studies have demonstrated significant elevations of CRF concentrations in the CSF of drug-free patients with major depression or following suicide.
- Like many other neuropeptide transmitters, central administration of SRIF produces a variety of behavioral and physiological effects.
- Decreased neurotensin concentrations in CSF have been reported in several populations of patients with schizophrenia when compared to controls or patients with other psychiatric disorders.
«The past several decades have witnessed a veritable explosion of knowledge about the central nervous system (CNS), and in no area has this been as impressive as in peptide neurobiology. Numerous peptide neurotransmitter candidates have been...» Document abstract
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SummaryThe past several decades have witnessed a veritable explosion of knowledge about the central nervous system (CNS), and in no area has this been as impressive as in peptide neurobiology. Numerous peptide neurotransmitter candidates have been identified and characterized, their CNS distributions mapped, and their genes cloned. The tenet “one neuron-one transmitter” erroneously attributed to Dale has been convincingly refuted with numerous demonstrations of neurons containing multiple peptides or combinations of peptide and nonpeptide neurotransmitters. Additionally, since the early 1980s there has been an embarrassment of riches in the form of knowledge about neurotransmitter receptor diversity, diversity of receptor-effector coupling, and neurotransmitter transporters. These discoveries have not yet been fully integrated into what is known about normal or aberrant CNS function, although dysfunction at virtually any level could conceivably lead to neuropsychiatric deficits.
Table of Contents- By definition, a neuropeptide is a chain of two or more amino acids linked by peptide bonds, and differs from other proteins only in the length of the amino acid chain.
- Many of the known behavioral effects of neuropeptides are observed only after their direct injection into the CNS because most peptides do not penetrate the blood-brain barrier in amounts sufficient to produce effects before being inactivated by serum and tissue enzymes that degrade them.
- The tertiary structure for recognition is also used by the immune system for the production of specific antibodies, as well as by biological receptors.
- Neuropeptides are found throughout the CNS, as well as in various peripheral organs, such as the gastrointestinal tract, pancreas, and adrenal glands.
- In the cortex of rats SRIF is found in some of the large stellate-shaped neurons and in abundance among the fusiform-shaped, nonpyramidal neurons of layers II to V, and particularly in layer V of the sensory cortex.
- Through the use of retrograde tracing methods and dual staining techniques, several pathways for certain peptides have now been delineated.
- Some of the noradrenergic locus ceruleus neurons, in turn, project to the hypothalamic paraventricular nucleus where their input increases CRF synthesis and release.
- The neurotensin-neuromedin N gene was originally cloned from canine ileal mucosa, and complementary deoxyribonucleic acid (cDNA) probes constructed against this form were used to clone the rat gene.
«Endometrium/decidua is the anatomical site of blastocyst apposition, implantation, and placental development. The endometrium is the mucosal lining of the uterine cavity and the decidua is the highly modified and specialized endometrium of...» Document abstract
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SummaryEndometrium/decidua is the anatomical site of blastocyst apposition, implantation, and placental development. The endometrium is the mucosal lining of the uterine cavity and the decidua is the highly modified and specialized endometrium of pregnancy. From an evolutionary perspective, the human endometrium is highly developed in order to accommodate a hemochorioendothelial type of placentation. Endometrial development of a magnitude similar to that observed in women, that is with special spiral (or coiling) arteries, is restricted to only the catarrhine primates—such as humans, great apes, and Old World monkeys. Trophoblasts of the blastocyst invade these endometrial arteries during implantation and placentation to establish uteroplacental vessels.
Table of Contents- MATERNAL TISSUES OF THE FETAL-MATERNAL COMMUNICATION SYSTEM
- THE CARDINAL FUNCTION OF THE UTERUS
- OVERVIEW OF ENDOMETRIAL FUNCTION
- THE ACCOMMODATION OF PREGNANCY IS THE CARDINAL FUNCTION OF THE ENDOMETRIUM/DECIDUA.
- SPECIALIZED FUNCTIONS OF THE DECIDUA.
- ESTROGEN ACTION.
- PROGESTERONE ACTION.
«Chromatography is a technique used to separate and analyze chemicals. It was initially discovered in the early 1900’s by chemist Mikhail Tsvett who was researching chlorophyll to separate plant pigments.1 The components undergoing separation are...» Document abstract
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SummaryChromatography is a technique used to separate and analyze chemicals. It was initially discovered in the early 1900’s by chemist Mikhail Tsvett who was researching chlorophyll to separate plant pigments.1 The components undergoing separation are divided into two phases, a stationary phase, and a mobile phase. The stationary phase does not move while the mobile phase, which includes the sample, passes through the stationary phase. Different chemicals are impeded at different rates through the stationary phase based on individual properties which make them unique.2
Table of Contents- Once the mobile phase has passed completely through the stationary phase and the molecules have hopefully been separated they enter a detector which senses individual components.
- To begin the experiment we constructed our own homemade, small-scale gas chromatograph using a glass column, Tide, clothespins, polyester fiber, copper coil, and latex tubing.
- Using a commercial gas chromatograph and the same halocarbons, Freon 22 and Freon 123, we were able to calculate the concentrations of each halocarbon and analyze them to compare our findings to our homemade gas chromatograph.
- For each halocarbon the green-blue flame appeared, intensified, and disappeared as portrayed in Figure 1.
- The computer calculated the retention times from an unknown concentration mixture of Freon 22 and Freon 123 after being run through the commercial gas chromatograph.
- The hypothesis I made prior to the experiment held true. Freon 22 had a shorter retention time than Freon 123 in both the homemade and commercial gas chromatographs.
- There was a positive correlation between both boiling point and molecular weight and the retention time.
- By using the commercial gas chromatograph we were able to calculate quantitative information by creating a plot using calibration data and comparing our area under the curve to the determined areas on the graph.
- By using the commercial gas chromatograph we were able to calculate quantitative information by creating a plot using calibration data and comparing our area under the curve to the determined areas on the graph.
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