Relaxation Techniques

Relax Your Mind

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Chemical Relaxation Encompasses a Robust Range of Techniques

In the temperature-jump method, energy is added to a sample containing a reacting chemical system by discharging a capacitor sudden movement of ions in the imposed electric field creates frictional drag, resulting in uniform heating throughout the sample. This technique (described more fully below) permits the experimenter to analyze the kinetics of elementary reactions that make up a multi-stage chemical reaction mechanism. The equilibria and hence rate constants for chemical reactions having a non-zero volume change may also be perturbed by a sudden drop in pressure. In the pressure-jump technique, a system reaches equilibrium at an initial pressurization sudden rupture of a foil diaphragm immediately depressurizes the system. For reacting gases, a volume increase will enlarge the mean-free-path between reactants, thereby lowering the system's energy. Alternatively, shock tubes can also be used to suddenly generate sound waves that pass through the reacting system at 1,500-1,560 m s...

While Conceptually Straightforward Relaxation Rate Analysis Offers Powerful Insight into Complicated Chemical Processes

Although the derivation of numerous relaxation rate equations lies beyond the scope of this book, it is useful to consider a few examples (Table 10.8) to acquaint the reader with the basic approach. Those interested in advanced treatments should consult Alberty and Hammes (1958), Czerlinski (1966), Hammes and Schimmel (1970), Bernasconi (1976), and Ilgenfritz (1977). Of these, Hammes and Schimmel (1970) and Ilgenfritz (1977) are especially lucid. Eigen and de Maeyer (1973) is, of course, a ''must-read'' chapter for anyone seeking a thorough grounding in the theory underlying relaxation kinetic techniques.

C Relaxation Amplitudes for Single Elementary Reactions

Although the determination of reaction time constants provides considerable insight into the dynamic properties and mechanisms of various chemical reactions, additional information on the stoichiometry and thermodynamics of elementary reactions may be gleaned from evaluation of reaction amplitudes. Amplitude factors correlate with the advancement X of each individual reaction step. Moreover, determination of reaction amplitudes affords the experimenter the opportunity to improve the signal-to-noise ratio of relaxation data by choosing reaction conditions that favor observation of individual reaction amplitudes.

E Average Relaxation Times

In certain situations, determination of the complete spectrum of relaxation times and or relaxation amplitudes may be impossible to record because multiple steps occur or because the available instrumentation has a detector that is either not fast enough or not sensitive enough. For example, multiple relaxations may lie very close together on the time axis, or the signal-to-noise ratio is unacceptably low. In such situations, one may determine the average reciprocal relaxation time s* as shown in Fig. 10.15. As pointed out by Ilgenfritz (1977), in contrast to the individual relaxation times associated with a resolvable series of elementary reactions, s* contains the specific signal changes of the Although space limitations preclude the presentation of a more detailed account of multi-step relaxation rates and amplitudes, it is worth briefly considering how a multi-step process gives rise to complex relaxation spectra. The concentration of each species will depend on the magnitude of...

F Relaxation Behavior of Proton Transfer Processes

Chemical relaxation found greater utility than in the characterization of extremely fast proton transfer reactions (Eigen and De Maeyer, 1963 Eigen and Hammes, 1963) (see also Section 3.7.1 Water is a Uniquely Suited Solvent for Biochemical Processes). FIGURE10.15 Determination of the average relaxation time s* from the initial slope of the relaxation curve. See text for details. Scheme 10.7 FIGURE 10.16 Relaxational response for a two-step mechanism. The observed advancement of reaction plotted on a logarithmic time-base for different S2 values at a constant s1 value. The curves (left to right) correspond to s2 s1 s2 10 x s1 s2 100 x s1 and s2 1,000 x s1. Notice that, when s2 s1, the process has the appearance of a single exponential process with Dobs D1 + D2. FIGURE 10.16 Relaxational response for a two-step mechanism. The observed advancement of reaction plotted on a logarithmic time-base for different S2 values at a constant s1 value. The curves (left to right) correspond to s2 s1...

Smooth Muscle Relaxation

The contractile activity of all types of muscle (smooth, skeletal) is regulated primarily by the reversible phosphorylation of myosin. Myosin of smooth muscle consists of two heavy chains (molecular weight MW 200,000 each) that are coiled to produce a filamentous tail. Each heavy chain is associated with two pairs of light chains (MW 20,000 and 16,000) that serve as substrates for calcium- and calmodulin-dependent protein kinases in the contraction process. Together with actin (MW 43,000), they participate in a cascade of biochemical events that are part of the processes of muscle contraction and relaxation (Fig. 19.2). The activity of cGMP in smooth muscle relaxation is affected by exogenous and endogenous agents. It is suggested4 that nitrovasodilators undergo metabolic transformation in


This may be taught using a single technique, such as diaphragmatic breathing or progressive muscular relaxation, but patients may find one technique easier to use than another and may learn to use different techniques in different settings.30,31 V It is preferable to aim for a well-integrated and broadly applied set of techniques that facilitate goal attainment. Biofeedback is an effective technique for pain control and is more commonly used in the USA than elsewhere,32 but it is not essential to the process of achieving relaxation. Practice of techniques while moving, exercising, and otherwise working on goals is necessary to improve generalization.

Relaxation Kinetics

Chemical relaxation can be defined as the temporal relation between two conjugate variables, usually affinity A and extent of reaction X, that characterize the chemical reaction state (Eigen and De Maeyer, 1974). Affinity equals v i, where v, is the stochiometric coefficient


For the next 20 years NMR found purely physical applications in chemistry and physics, and it was not until 1971 that Raymond Damadian showed that the nuclear magnetic relaxation times of different tissues, especially tumors, differed, thus raising the possibility of using the technique to detect disease. Magnetic resonance imaging (MRI) was first demonstrated on small test tube samples in 1973 by Paul Lauterbur, and in 1975 Richard Ernst proposed using phase and frequency encoding and the Fourier transform, the technique that still forms the basis of MRI.

Mechanisms of Nitric Oxide Signaling

The main way in which NO acts as a signal is by binding reversibly to certain transition metal ions, such as ferrous (Fe2 +) heme prosthetic groups within proteins. In soluble guanylate cyclase, it causes a conformational change, increasing the enzyme's activity and resulting in elevated cyclic GMP levels which lead to smooth muscle relaxation 69 . Nitric oxide also reversibly binds other heme-containing proteins such as complex IV in mitochondria to decrease respiration at low levels of oxygen 70 . The physiological implications of this are not yet clear, but temporary inhibition of complex IV has been harnessed to allow extremely precise and diverse processes to take place, from firefly flashing 71 to modulation of transcription factor hypoxia inducible factor 1 (HIF-1) stability 72 (see Chapter 9).

Applications to the Synthesis of Commercial Drug Molecules

A number of syntheses targeting commercially available drugs have been reported, which demonstrate the utility and effectiveness of supported reagents for the rapid and efficient preparation of drug-like scaffolds. The introduction of Sildenafil45 4 for the treatment of male erectile dysfunction has been incredibly successful, resulting in it becoming one of the largest selling globally marketed prescription drugs.46 Sildenafil acts by inhibiting the phosphodiesterase enzyme PDE5, which is the main phosphodiesterase present in the smooth muscle of the corpus cavernosum. Upon sexual stimulus, nitric oxide is released from nerve terminals in the corpus cavernosum. The nitric oxide activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), causing the intracellular levels of cGMP within the smooth muscle cells of the penis to increase. In healthy tissue, the elevated cGMP is returned to basal levels by the action of the PDE5 enzyme. Inhibition of the PDE5 enzyme...

Using Other Compounds

Production in hippocampus (Markstein et al. 1986 Schoeffter and Hoyer 1989a) in the substantia nigra (Schoeffter and Hoyer 1989b), stimulation of PLC production in choroid plexus (Hoyer et al. 1989) or in smooth muscle cells, and contraction or relaxation of various vessels (Hoyer 1988a).

Synaptic Signaling by NO

Although NO was first identified as the endothelium-derived relaxing factor, it is now clear that the brain is the primary source of NO in the body. Peripherally NO often acts like a classical neurotransmitter. In the intestine nNOS is concentrated in axon varicosities of certain mysenteric neurons (52). The enzyme is then activated by Ca2+ influx through N-type channels via calmodulin (53). Newly synthesized NO diffuses to adjacent smooth muscle where it causes relaxation. Mutant mice deficient in NOS display severe intestinal dysfunction and a hypertrophic stomach (33,53). The function of NO in the central nervous system is still not completely understood. Again several excellent reviews of the literature have recently been published on this issue (2,4,17,54,55) and we will briefly summarize here only the most relevant findings to our work.

Image Based Measures of Biological Function

Many imaged-based measures of biological and physiological function have arisen in imaging and medical research. For example, the Center for Biomarkers in Imaging (http makes available an online catalog of approximately 350 image- based biological measures that have been investigated primarily at Massachusetts General Hospital in Boston. Apart from differences in modality, such image-based measures may be classified into three general types according to the way in which image contrast is generated by endogenous biophysical mechanisms, exogenous contrast agents, or molecular probes 19 . For example, endogenous contrast can be produced by differences in MRI relaxation times such as T1, T2, T2*, macromo-lecular cross-relaxation, or transport mechanisms such as blood flow, perfusion, and diffusion. These contrast mechanisms are often enhanced by the use of exogenous contrast agents in CT and MRI as well as ultrasound. Table 1 lists some examples of endogenous and...

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Activation of endothelial NO synthase (eNOS, NOS-3) and production of NO which diffuses to adjacent smooth muscle cells, where it stimulates the soluble guanylyl cyclase and causes relaxation (see Chapters 1 and 6). Vasodilation also may arise indirectly due to inhibition of norepinephrine (NE) release from adrenergic nerve endings by ACh. If the endothelium is damaged, as occurs under various pathophysiological conditions, the direct effect of ACh on the muscarinic receptors on vascular smooth muscle cells predominates, and the resultant mobilization of cell Ca2+ causes vasoconstriction. There is also evidence of NO-based (nitrergic) neurotransmission in peripheral blood vessels.

The Medical Community and Supplements

Therapies, acupuncture, relaxation, and megavitamin treatments. They were least familiar with homeopathy and naturopathy treatments. While many felt CAM therapies can present a safety threat to the public, they also perceive that offering CAM therapies will attract patients to their practices and offer promising new forms of treatment. It is noted that by 1998, 64 percent of medical schools incorporated some form of CAM education into their curricula, indicating future physicians will be much better informed about CAM therapies and medicines.32

Historical Perspective of Pharmacology

A recent example of an integrated pharmacological approach to drug discovery is that of the novel anxiolytic AC-5216 (Kita et al., 2004). This compound was synthesized as a potent (Ki 0.3 nM), orally active agonist for the peripheral BZ receptor. Also known as the mitochondrial BZ receptor or translocator protein, this site is involved in the synthesis of endogenous neurosteroids that enhance GABAergic neurotransmission. Whole animal testing revealed that AC-5216 had anti-anxiety effects in mice in the Vogel-conflict test (0.1-3 mg kg p.o.), the light dark box (0.003-0.01 mg kg p.o.), and social interaction tests (0.01-0.3 mg kg p.o.). These actions were blocked by the peripheral BZ mitochondrial BZ receptor antagonist, PK 11195 (3 mg kg i.p.). Further behavioral tests revealed that AC-5216 was also active in the Porsolt forced swim test (3-30 mg kg p.o.), a measure of antidepressant activity. Unlike the classical BZ, diazepam, AC-5216 did not produce muscle relaxation, nor did it...

Preventing Trauma During Electroshock Therapy

Electroconvulsive therapy (ECT) of psychiatric disorders occasionally is complicated by trauma to the patient the seizures induced may cause dislocations or fractures. Inasmuch as the muscular component of the convulsion is not essential for benefit from the procedure, neuromuscular blocking agents and thiopental are employed. Succinylcholine or mivacurium is used most often because of the brevity of relaxation.

Discontinuation Of The Diet

If this protocol does not cause seizures to recur, it is followed by the relaxation of calorie restriction, then gradual introduction of carbohydrate-containing foods. The advantage of this approach is that it is far faster and, if seizures recur, it is easy to return to cream without fasting again and retraining the child. If the child is having significant difficulty with the KD or in the event of a severe intercurrent illness, the diet can be discontinued immediately, often without a dramatic increase in seizures.

Membrane Domain Of Complex Ii

Spin relaxation enhancer (125), which is consistent with the close spatial separation (8 A) between the two entities. The quinone site inhibitor 2-heptyl-4-hydroxyquin-oline -oxide (HQNO) was shown to affect the EPR spectrum of the 3Fe-4S cluster, suggesting that its binding site was also at or near the QP site. This suggestion was confirmed with the recent 2.7-A resolution of the X-ray structure of E. coli QFR containing HQNO that binds at the QP site (126). HQNO is nearly isosteric with menaquinol and it was found that two hydrogen bond donors, FrdB Lys228 and FrdD Trp14, were positioned within hydrogen bonding distance of the negatively charged -oxide (126). The hydroxyl group on the other side of the HQNO ring, like that for menaquinone, is within hydrogen bonding distance of FrdC Glu29 and FrdD Arg81. Thus, as noted above, replacement of FrdC Glu29 with a neutral amino acid such as leucine apparently disrupts this hydrogen bonding interaction and stabilizes the semiquinone...

Redox Modulation of Kca Channels

In vascular smooth muscle cells, plasma membrane permeability to K+ is a major determinant of membrane potential. K+ channel activation hyper-polarizes the cell, which in turn decreases the activity of voltage-operated Ca2+ channels, leading to muscle relaxation. Conversely, inhibition of K+ channel activity depolarizes the cell, thereby activating voltage-operated Ca2+ channels, leading to muscle contraction. The vascular smooth muscle cell contains four main types of K+ channel the large-conductance Ca2+-activated K+ (KCa) channel, the voltage-dependent K+ (Kv) channel, the ATP-dependent K+ (KATP) channel, and the inwardly rectifying K+ (KIR) channel

The effect of the support on the rate of solidphase reactions

One can dramatically sharpen the gel-phase 13C NMR line widths (and, possibly, enhance the reaction rate) by attaching a spacer arm between the bound molecule and the support. Bayer and Rapp 48,49 have found that attaching a long polyethylene glycol spacer (MW 2000-3000 Da) can dramatically sharpen the line widths and increase the relaxation time of the bound component. In fact, both commercially available PEG-incorporated supports (TentaGel and PEG-PS) exhibit almost 3 times narrower line widths as compared to standard polystyrene-1 -divinylbenzene and the polystyrene-polyacrylamide (Polyhype)-based composites 50,51 . How does this dramatic narrowing of the line width for the PEG-incorporated supports translate to a solid-phase reaction In the case of oligonucleotide synthesis, the TentaGel support was found to give a much higher isolated yield (87 ) in the solid-phase synthesis of a 5-oligonucleotide-PEG400 fragment as compared to polystyrene-1 -divinylbenzene (11 ) 52 . However,...

Interaction With Cytoskeleton

There have been numerous investigations aimed at establishing an interaction between mitochondria and intermediate filaments. A codistribution has been observed in a few instances see Reference 16 for references , but since there are few systems with highly organized, regular arrays of such filaments, model systems, especially cell-free systems, are lacking. Some observations point to a role of desmin in anchoring mitochondria in skeletal muscle cells to preserve their relative positions during repeated contraction-relaxation cycles, but a more definite proof is lacking. In nonmuscle cells deliberate attempts to demonstrate an alignment of mitochondria with intermediate filaments have failed.

Additional Cloned 5ht Receptors

Two other cloned receptors, 5-HT6 and 5-HT-, are linked to activation of adenylyl cyclase. Multiple splice variants of the 5-HT7 receptor have been found, although functional distinctions are not clear. Circumstantial evidence suggests that 5-HT7 receptors play a role in smooth-muscle relaxation in the GI tract and the vasculature. The atypical antipsychotic drug clozapine has a high

In vasodilation and bronchoconstriction

In the human periphery anandamide most likely acts in an auto- and or paracrine manner on TRPV1 receptors to cause vasodilatation of dermal microvasculature rather than as a circulating hormone (Movahed et al., 2005). Anandamide activates TRPV1 receptors to cause vasodilation at sub-micromolar doses (Andersson et al., 2002 Domenicali et al., 2005 Ho and Hiley, 2003 Ralevic et al., 2001 Zygmunt et al., 1999) and bronchoconstriction at higher concentrations (Andersson et al., 2002 Craib et al., 2001 Tucker et al., 2001). It is suggested that TRPV1-induced vasorelaxation is mediated through receptors at perivascular nerve endings inducing the release of calcitonin gene-related peptides via nitric oxide (NO) production. This in turn provokes hyperpolarization of smooth muscle and subsequent relaxation (Breyne et al., 2006 Mukhopadhyay et al., 2002 Zygmunt et al., 1999). In contrast to isolated tissue preparations, in vivo measurement of vasorelaxation via TRPV1 receptors requires high...

Pharmacological Properties

CCK peptides bind to CCKA and CCKB (alternatively, CCK1 and CCK2, respectively) receptors that are both coupled to G proteins. As ligands, CCKA receptors require CCKs that are amidated at the C-terminal, and sulfated on a tyrosine in the seventh position from the terminal. These receptors mediate contraction of gallbladder and relaxation of the sphincter of Oddi, and pancreatic growth and enzyme secretion. These receptors are also expressed in the peripheral nervous system and in the anterior pituitary expression in the brain is less prevalent than of the CCKB receptors. The latter are identical to the gastrin receptor, and besides brain, are abundantly expressed on gastric ECL-cells and parietal cells, and in the pancreas. CCKB receptors also bind non-sulfated CCK, CCK-5, and CCK-4 with high affinity. Importantly, the peripheral physiological responses mediated via CCKB receptors are elicited by gastrin, because the plasma levels of gastrin are much higher than those of CCK (Rehfeld...

Metabolic Modulation Of Microvascular Function

Our experiments also indicate that there is metabolic modulation of the response of the retinal microvasculature to PDGF-BB (46), which is expressed by vascular endothelial cells and whose receptors are on pericytes (47). Under normal conditions, exposure of retinal microvessels to this growth factor results in the activation of depolarizing NSC and ClCa currents, the elevation of intracellular calcium, the contraction of pericytes and the constriction of microvascular lumens. On the other hand, the NSC and ClCa channels do not open during exposure of ischemic microvessels to PDGF-BB. Rather this growth factor enhances the activation of KATP channels whose hyperpolarizing effect results in pericyte relaxation and vasodilation (46). Based on these observations, we have proposed that PDGF-BB causes blood flow to increase at hypoxic retinal sites, but to decrease when oxygenation is adequate. It seems likely that the dual vasoactive effects of extracellular molecules, such as PDGF-BB and...

Pharmacodynamic Variation

Doppler measurements of cardiac output and regional blood flow that have greatly facilitated the identification of true age-related changes. Such studies have demonstrated a reduction in the elasticity and compliance of the great arteries, in left ventricular ejection and the rate of cardiac relaxation, in the prolongation of isotonic contraction, and in the decrease in its velocity. Moreover, extensive studies of neurohormonal mechanisms controlling the cardiovascular system have confirmed classically defined changes in vascular control systems63 and revealed novel peripheral control vascular mechanisms for autonomic nerve transmitters, autocoid mediators, smooth muscle receptors, and ion channel mechanisms linked to age-related alterations of endothelial and vessel wall functions,64,65 In the neuroendocrine system as another example, age-related changes in response to psychosocial or physical stress have been observed in the hypothalamic-pituitary-adrenal (HPA) axis. For instance,...

Functional Evidence for NoveL Cannabinoid Receptors

Investigations of the vascular effects of anandamide in particular have revealed that it induces relaxation by means that are independent of either CB1 or CB2 receptors. It can act independently of GPCRs by activation of TRPV1 channels on sensory nerve endings in the vascular adventitia, which causes the release of the vasodilator calcitonin gene-related peptide (CGRP) (Zygmunt et al., 1999). But not all the vasodilator activity of anandamide (see Fig. 5.1) can be explained by this mechanism since, for example, relaxation of rat coronary arteries by the endocannabinoid is not sensitive to TRPV1 desensitization with capsaicin (White et al., 2001) and relaxation of rat mesenteric arteries is sensitive to PTX (White and Hiley, 1997a).

Systems with Different Geometries

One of the first physicochemical studies 61 dealing with diffusion in glassy polymers published in 1968 can be considered as the initiator of the realization that two apparently independent mechanisms of transport, a Fickian diffusion and a case- II transport, contribute in most cases to the overall drug release. Fick's law governs the former mechanism, while the latter reflects the influence of polymer relaxation on the molecules' movement in the matrix 62 . The first studies on this topic 63, 64 were focused on the analysis of Fickian and non-Fickian diffusion as well as the coupling of relaxation and diffusion in glassy polymers. The models used to describe drug release from different geometries are quoted below where ko is the Case-II relaxation constant and co is the drug concentration, which is considered uniform. where ko is the Case II relaxation constant and co is the drug concentration (considered uniform). The assumed value of the penetration layer speed is implied from the...

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Ginkgolide B is the most potent, followed by Ginkgolides A and C. Half maximal inhibition occurs for all three in the low micromolar range. Nonginkgolide, nonflavonoid fractions of ginkgo extract have a potent vasorelaxing effect, producing a dose-dependent relaxation of rabbit and human cavernosal smooth muscle (Paick and Lee 1996). A subfraction (304U-1) shows the most potent effects, which are mediated by cAMP and perhaps adrenergic effects. Thus, gingko may improve microcirculation by inhibiting platelet-aggregation by PAF.

Interaction with Heme Iron

Soluble guanylyl cyclase is a family of heterodimeric heme proteins exhibiting a pyridine hemochrome visual absorption spectrum typical for ferroprotoporphyrin IX and contains copper and iron as transition metals (Gerzer et al., 1981). The activation of soluble guanylyl cyclase by RNS is the principal mechanism of action in various RNS-induced cellular events such as smooth muscle relaxation (Ignarro and Kadowitz, 1985) and inhibition of platelet adhesion (Radomski et al., 1987). Many cellular consequences of RNS-induced guanylyl cyclase activation are listed in Table II. RNS bind to the heme moiety of guanylyl cyclase and, by disrupting the plane of the heme-iron, induce a conformational change that activates the enzyme allosterically (Ignarro et al., 1984). The cGMP synthesized further modulates an array of mediators including ion channels, phosphodiesterases, and protein kinases (Schmidt et al., 1993). Activation of guanylyl cyclase was the first RNS-induced signaling mechanism...

Types Of Cam Therapies

Complementary Techniques or additional therapies that are used in conjunction with recognized mainstream medical practices for example, when music or relaxation is used with medication for low back pain. Cognitive behavioral approaches or mind body work, such as relaxation, biofeedback, meditation, distraction, and imagery Muscle relaxation Many patients are interested in using the complementary methods of relaxation, biofeedback, self-hypnosis, and imagery to provide additional pain relief (APS, 2002 D'Arcy, 2007). Not all patients find these techniques to their liking. For those patients who are willing to invest the time and energy in learning how to use these methods, a good outcome can be expected. Music is an easy to use and greatly appreciated form of distraction and relaxation therapy. In early days music was incorporated into healing rituals. For pain relief music can be used in several different ways for example Music can be used to help structure breathing, provide a base...

Signaling downstream of Ga12 and Ga13

In the vasculature, and perhaps more importantly in view of the discovery of GPR55 in human umbilical vein endothelial cells, Ga13 signaling regulates endothelial cell migration as shown by its involvement in the effects of activation of the cell membrane-bound estrogen receptor-a (Simoncini et al., 2006). In this case, Rho activates Rho-associated kinase to phosphorylate Thr558 of moesin, one of the proteins that regulates membrane cytoskeleton interactions. This modifies the binding of moesin to actin and leads to the remodeling of the actin cytoskeleton and cellular shape changes. Thus GPR55 may regulate endothelial cell migration after stimulation with an exogenous cannabinoid, an endocannabinoid, or other endogenous ligand. There is also evidence that the vasodilator-associated protein (VASP) pathway is activated by Ga13 and VASP also regulates cell shape and activation in platelets and endothelial cells (Profirovic et al., 2005). However, Ga13 and RhoA signaling is usually...

Digital EEG Nomenclature

Digitization is carried out at sampling rates that are often called sampling frequency.'' To avoid confusion with frequencies in EEG signals, this will be expressed in samples s units. High-pass section is mostly carried out by digital filters and expressed in Hertz, normally set at 0.3-0.5 Hz. In the old literature, this section was determined by RC-circuits, and its characteristics are expressed in time constants t s, the shorter its value, the faster the relaxation is dampened. A t of 0.6 corresponds roughly with 0.3 Hz high pass. EEG frequency bands are also expressed in Hertz, but one can still find the expression cycles-per-second, cycles s or cps.

Receptors for autonomic neurotransmitters

As discussed in the previous section, all the effects of the ANS in tissues and organs throughout the body, including smooth muscle contraction or relaxation alteration of myocardial activity and increased or decreased glandular secretion, are carried out by only three substances acetylcholine, norepi-nephrine, and epinephrine. Furthermore, each of these substances may stimulate activity in some tissues and inhibit activity in others. How can this

Implications for New Integrated Treatments

In resynchronization therapy, an explanation of why some patients respond to device implantation whereas others fail to improve is not forthcoming. The issue is not that the left ventricle should contract simultaneously with (most of the indexes developed are aimed at the detection of this phenomenon) rather, what is crucial is the sequence of contraction of the descendant and ascendant segments. In fact, knowledge of the natural sequence of electromechanical ventricular activation 4, 17 should open the way to study the effects of selective stimulation of the band segments on ventricular function, and should provide a rationale for ventricular pacing protocols. In this respect, two recent studies using microcrystals selectively placed in the descendant and ascendant segments of the band have shown the hemodynamic disruption caused by right or left ventricular pacing 18 . This disruption is not solved by atrio-biventricular pacing, which compares less favorably (QRS complex, systolic...

Modifications Of Injected Proteins And Peptides In The Sc Space

Efforts have been made to obtain accurate local pH information that could be applied to analyzing the events in the SC space after injection of a protein or peptide. Both magnetic resonance and positron emission methodologies have been described (57,58). That these methods lack sensitivity has been the rationale to introduce a doping probe such as gadolinium (Gd3+) ions to function as a chelate relaxation agent (59). More recently, a method using hyperpolarized 13C-labeled bicarbonate to monitor the pH environment experienced by this physiological buffering agent has been described (60). Although this most recent method looks appealing, it is not trivial to prepare this probe material, and its addition to a formulation injected into the SC space would still suffer from the axiom known as the price of peeking. In general terms, this axiom emphasizes that there is always a price paid for any analysis the act of disrupting the site to collect its contents or the introduction of a probe...

Magnetic Resonance Imaging and Computed Tomography

Of the extracellular extravascular space (EES). However, signal enhancement will also be affected by the native Tl-relaxation time of each tissue, by the contrast agent dose, and by the chosen sequence parameters, which makes quantitation of the results more difficult than with DCE-CT 8, 9 . In general, anatomical information to localize the tumor is acquired initially. Next, sequences that allow calculation of baseline tissue Tl-values before contrast agent administration are performed to enable subsequent analysis. Finally, dynamic data are acquired every few seconds in Tl-weighted images over a period of around 5-10 min. Several analysis methods can then be applied to the acquired data. Parameters that describe the shape of the contrast agent concentration-time curve represent a combination of blood flow, blood volume, vessel permeability, and EES volume. One such parameter, the initial area under the contrast agent concentration-time curve (IAUC), is easy to calculate, reasonably...

Gastrointestinal Tract

Large Intestine Propulsive peristaltic waves in the colon are diminished or abolished after administration of morphine, and tone is increased to the point of spasm. The resulting delay in the passage of bowel contents causes considerable desiccation of the feces, which, in turn, retards their advance through the colon. The amplitude of the nonpropulsive type of rhythmic contractions of the colon usually is enhanced. The tone of the anal sphincter is augmented, and reflex relaxation in response to rectal distension is reduced. These actions, combined with inattention to the normal sensory stimuli for defecation reflex owing to the central actions of the drug, contribute to morphine-induced constipation.

Additional physiological properties of flavonoids

During the past five years, numerous research groups have reported on the biological effects of cocoa, and its flavanol and oligomer components. As is discussed above, it has been reported that in vitro, cocoa, and isolated cocoa flavanols and their oligomers, have the ability to increase the antioxidant capacity of solutions and slow the oxidation of LDL and liposomes 9-11 . While the ability of flavonoids to inhibit oxidative damage may explain some of their health benefits, it is important to recognize the fact that they can have numerous other effects. For example, in in vitro models, they have been shown to induce endothelium dependent vessel relaxation (EDR) 26 reduce the production of inflammatory cytokines, while increasing the production of anti-inflammatory cytokines 29,30 increase the synthesis of the antithrombotic lipid prostacyclin, while reducing the production of the proinflammatory cysteinyl leukotrienes 31 protect against peroxynitrite-dependent oxidation and...

Kinetics of Flash Induced Absorbance Changes

In Type II preparations with an electron donor system just enough to keep P700 reduced under a weak measuring beam, a pulse of a saturating actinic flash (pulse width several microseconds to several hundred microseconds) induces typical absorbance changes. At 700 and 430 nm, these are absorbance decreases, and at 820 nm, it is an increase. A typical case is shown in Figure 9.3. These changes are almost instantaneous in a millisecond timescale and are followed by a much slower relaxation (recovery) phase with a half time ranging from 30 to 100 msec (Figure 9.3, left). The half decay time varies from preparation to preparation. This half time does not depend on the

Generalization and maintenance strategies

For all of the components, adherence to program content and methods is important. One dimension of this is checking that patients are, in fact, doing as instructed, whether it is relaxing during relaxation sessions or monitoring thoughts when distressed. Staff adherence to the treatment protocol, irrespective of discipline, is important inconsistency in therapy or in providing explanations undermines the efficacy of the technique and patents' confidence in staff. To help maintain consistency, protocols for each component of the program should be regularly reviewed in the light of local outcomes and published evidence.

Mindful Cam Therapies

Pain clinics in the United States frequently utilize mindful therapies (MT) for patients with pain because they have been found experientially to be beneficial. Frequently, nurses or psychologists receive training in one or more of these therapies and teach the patients to utilize them on a regular basis, for both prevention of pain and to manage pain flares. These therapies include relaxation breathing, meditation, mindfulness-based stress reduction (MBSR), self-hypnosis, guided imagery, autogenic training, and progressive muscle relaxation (PMR).79

Interventions not supported by evidence

The German FMS guideline group found inconsistent results in eight RCT on patient education as single intervention and seven studies with massage with conflicting results 24, 65 . Furthermore, inconsistent results of five controlled trials each on biofeedback and relaxation therapy (including autogenic training and progressive muscle relaxation) were found 69 .

The Adrenergic Receptors

When the catecholamine neurotransmitters bind to receptors they produce different responses that depend on the tissue concerned. In general, binding to the a-receptors brings about a constriction while binding to the b-receptors brings about a relaxation of a response. The receptors are G-protein-coupled receptors. The structure of the binding site in the receptor contains some key amino acids. There are two serines whose primary alcohols may act as hydrogen-bond donors to the dihydroxyphenol. The side chain of an aspartic acid unit has a free carboxyl group, which may bind to the amine while there is a phenyl-alanine in which the aromatic ring may interact with the electron-rich aromatic catechol ring. Finally, the b-receptors may be distinguished from the a-receptors by the presence of a hydrophobic pocket into which the isopropyl group of isoprenaline can fit.

Antibodyhapten Interactions

Lancet (1977) in Chemical Relaxation in Molecular Biology (I. Pecht & R. Rigler, eds.) pp. 2-3, Springer-Verlag, Berlin. 2M. Eigen (1974) in Quantum Statistical Mechanics in the Natural Sciences (S. L. Minz & S. M. Wiedermayer, eds.) pp. 37-61, Plenum Press, New York.

Alpha2Adrenergic Agonists

A2-Adrenergic agonists (e.g., clonidine) are available for epidural administration for neuropathic pain (Eisenach et al. 1995). Hypotension and bradycardia may result from use of these agents, but the risk is reduced if low doses are used. Adverse effects include hemodynamic instability. There is a risk of rebound hypertension with acute withdrawal of therapy. Topical clonidine gel is being developed for use in neuropathic pain states. Tizanidine, another a2-adrenergic agonist, is used for muscle relaxation.

Psychologic treatment

Skills training for adults, including relaxation Chapter 14, Biofeedback Chapter 15, Contextual cognitive-behavioral therapy and Chapter 16, Graded exposure in vivo for pain-related fear in the Practice and Procedures volume of this series. In principle, the management approach is as appropriate to chronic pain sufferers with neurologic disease as to other groups, with perhaps two qualifications.

Ca Transients for Gpcr Hts

Several photoproteins have been isolated and cloned, although the one most widely used for measuring GPCR-i nduced Ca++ transients is aequorin, originally isolated from jellyfish 26, 29, 31 . This protein has a central hydro-phobic core which binds the imidazopyrazinone chromophore, coelenterazine 32, 33 , and Ca++ binding to aequorin induces oxidation of coelenterazine to the excited form, coelenteramide. Relaxation from the excited state results in

Current Standard Of Care For Metastatic Colorectal Cancer

Irinotecan (CPT-11), a prodrug of SN 38, achieves its anti-carcinogenic effect through inhibiting topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA (21). Oxaliplatin is a platinum analog that inhibits DNA synthesis through the formation of intra-strand DNA adducts and is currently approved by the FDA for use both in adjuvant and metastatic settings (22). CPT-11 and oxaliplatin, when combined with 5-FU LV based chemotherapy regimens, have boosted response rates (RR) and overall-survival (OS) to 50 and at least 16 months, respectively, compared to 20 and 10-12 month with 5-FU LV mono-chemotherapy (23).

Adrenergic Receptor Antagonists

Heart failure is characterized by sympathetic hyperactivation. Sympathetic activation supports circulatory function by enhancing contractility (inotropy), augmenting ventricular relaxation and filling (lusitropy), and increasing heart rate (chronotropy). For many years, pharmacological approaches to the treatment of heart failure involved the use of drugs that would further stimulate sympathetic responses, reflecting the viewpoint that the fundamental abnormality in CHF is the reduction of stroke volume cardiac output that occurs as a consequence of myocardial dysfunction. Paradoxically, many of these sympathomimetics increased mortality in CHF patients, while an unexpected mortality benefit was seen with the administration of P adrenergic blocking drugs. The recognition that sustained activation of sympathetic nerves in the context of myocardial injury contributes to the progression of contractile dysfunction is now well established and derives support from the demonstrable adverse...

Other Interventional Practices

What does this mean for the patient with LBP There has now been some research evaluation of common techniques for relieving pain in LBP patients and indicating which practices produce the best outcomes for the patient. For the acute phase, patients should stay active and use heat, and medication such as acetaminophen and NSAIDs, if the patient is a good candidate, will produce the best outcome (Chou et al., 2007). If the pain persists, adding in a rehabilitation program and relaxation will provide benefit and reduce absenteeism from work (Chou et al., 2007).

Aspartate Carbamoyltransferase

Selected entries from Methods in Enzymology vol, page(s) Activation, 64, 177 concerted allosteric model, 64, 173 isotope exchange properties, 64, 10 negative cooperativity, 64, 189 rapid relaxation measurement, 64, 188, 189 sequential model, 64, 173 site-directed mutagenesis, 202, 717, 725 structure-function analysis, 202, 694 supersecondary structures, genetic exchange within domains, 202, 704 allosteric mechanism, 259, 614, 627 binding site number, 259, 615-616 concentration, 259, 615 differential scanning calorimetry assembly effects, 259, 624-625 buffer sensitivity, 259, 625 ligation effects, 259, 625 mutation effects, 259, 626 electrostatic interactions, 259, 626-628 Escherichia coli ATCase cooperativity in (allosteric structures and model testing, 249, 554-555 experimental evaluation, 249, 548554 heterotropic, 249, 552-553 homotropic, 249, 551-552 mutational analysis, 249, 554 structural model, 249, 549-551) inter-subunit ligand binding sites, 249, 559-560 site-directed mutants,...

Diastolic Heart Failure

Approximately 30-40 of CHF cases occur in patients with normal or preserved left ventricular systolic function. Despite intact systolic function, such patients will present with typical signs and symptoms of heart failure, including dyspnea, impaired functional capacity, and pulmonary systemic venous congestion. The pathogenesis of diastolic heart failure includes structural and functional abnormalities of the ventricle that are associated with impaired ventricular relaxation and impaired left ventricular distensibility (i.e., abnormal LV compliance with increased chamber stiffness). Consonant with the definition of heart failure outlined above, the diagnosis of diastolic heart failure is made when the left ventricle is unable to fill to a volume that is sufficient to maintain normal cardiac output without exceeding the upper range of normal diastolic pressure. The underlying problem in diastolic heart failure is the inability to fill (rather than to empty) the ventricle.

Oxidative Stress In Patients With Diabetes Mellitus

Lately, considerable effort has been devoted to gain insights into the role of oxidative stress in the development and progression of late micro-and macrovascular complications in diabetes (17,23,27,28,31-34). Although hyperglycemia is an acknowledged pathogenic factor in diabetic complications, it is not known through which mechanism an excess of glucose results in tissue damage. Accumulating data support the hypothesis that oxidative stress might play an important role in the pathogenesis of late diabetic complications. Several pathways are leading to oxidative stress associated with acute or chronic hyperglycemia, such as the polyol pathway, prostanoid synthesis, glucose autoxidation, and protein glycation by increasing the production of free radicals (35-39). A close relationship of oxidative stress with glycemic control has been described, showing a significant positive correlation between malondialdehyde (MDA) and both fasting blood sugar and glycosilated hemoglobin (40)....

Nonpharmacological Options

Non-pharmacologic options for trauma patients include transcutaneous electrical nerve stimulation (TENS), acupuncture, and relaxation techniques. In general, these therapies tend to be most useful as adjuncts to either nerve blocks or pharmacotherapy or in patients with mild pain. Relaxation techniques such as guided imagery, self-hypnosis, and biofeedback are most beneficial in patients with high anxiety levels, whereas the best candidates for eye movement desensitization and reprocessing (EMDR) and cognitive-behavioral therapies are cognitively intact patients willing to take an active role in treatment. The treatment of coexisting psychopathology is critical to optimizing pain treatment outcomes and should not be underestimated. In fact, long-standing anxiety from poorly managed pain has been associated with depression and posttraumatic stress disorder.

Dosage Of Opioid Analgesics In Postoperative Pain Treatment

Patient teaching should include procedural and sensory information, instruction to decrease treatment and activity-related pain (e.g., pain caused by deep breathing, coughing) and information about the use of relaxation. Cognitive-behavioral (e.g., relaxation, distraction, imagery) and physical interventions (e.g., heat, cold, massage) are intended to supplement, not replace, pharma-cologic interventions. Cognitive behavioral interventions include a variety of methods that help patients understand more about their pain and take an active role in pain assessment and management. Simple relaxation strategies can be effective in helping to manage pain. Patients benefit from periodic reinforcement and coaching in the use of relaxation techniques. Commonly used physical agents include applications of heat and cold, massage, movement, and rest or immobilization. Applications of heat and cold alter the pain threshold, reduce muscle spasm, and decrease local swelling. Transcutaneous electrical...

Formation of AGEs in Diabetes

Increased levels of AGE-modified low-density lipoprotein (LDL) with a markedly impaired clearance have been found in the plasma of diabetic patients, suggesting a pathway for pathogenic modification of LDL (62). The mediating role of AGEs in development of late diabetic complications (Table 1) (49,63-70) has been studied in animal models by short- and long-term administration of AGEs. Short-term administration of AGEs led to increased vascular permeability and leakage, impaired endothelial relaxation, subendo-thelial mononuclear recruitment, activation of NF-kB, and subsequent VCAM-1 gene expression (71-73). Long-term administration of AGEs resulted in arteriolar basement thickening and complex vascular dysfunction (74) and in glomerular basement thickening, mesangial expansion, glomerulosclerosis, and proteinuria (68).

Project Title Cardiac Naca Exchanger Hypertrophic Regulation

Reducing Ca2+ i to a low resting level during relaxation. SERCA expression and activity are decreased in hypertrophy and failure and we and others have shown that expression and activity in NCX1 is increased in this situation. Recent reports have demonstrated that upregulation of the exchanger appears to be a critical link between contractile dysfunction and arrhythmogenesis. Additional studies have documented the cardio-protective effect resulting from inhibition of calcium influx via NCX1 in ischemia reperfusion, digitalis toxicity and atrial fibrillation-induced shortening of atrial refractiveness. So far these results are solely based on acute studies and do not address long-term treatment. We discovered that inhibition of NCX1 calcium influx pathway (reverse mode) either by KB-R7943 or by lowering Ca2+ o, resulted in the activation of signaling factors that leads to specific upregulation of the exchanger gene. This novel and exciting finding should have a profound impact on...

Phosphodiesterase Type 5 Inhibitors

As discussed throughout this chapter, the cyclic nucleotide phosphodiesterases constitute a group of enzymes that catalyze the hydrolysis of various cyclic nucleotides including cAMP and cGMP. The contractility of all muscle types is regulated primarily by reversible phosphorylation of the protein myosin. The phosphorylation of myosin allows it to interact with actin, which results in muscle contraction. Through different mechanisms, cAMP and cGMP interfere with the ability of myosin to be phosporylated and or interact with actin. This, in turn, results in muscle relaxation. Agents that interfere with the degradation of the cyclic nucleotide have usefulness in treating hypertension, erectile dysfunction, etc. Phosphodiesterase type 5 (PDE5) is responsible for the catalytic hydrolysis of cGMP in the smooth muscle of the arteries in the penis and lungs. Inhibitors of this particular phos-phodiesterase have been shown to relax arteries in the penis, thus allowing the corpus cavernosum to...

Principles and Role in Psychopharmacology

MRI is a biomedical imaging technique applied in both research laboratories and radiology to visualize the structure and function of the body. MR images represent a weighted distribution of hydrogen atoms (protons) in living tissue, the major contribution being due to water constituting approximately 60-80 of tissue mass (Vlaardingerbroek and den Boer 1999). Hydrogen atoms possess an intrinsic magnetic moment. From a technical point of view, three key components are required to generate the MR signals allowing the formation of an image the static magnetic field aligning the protons in the direction of the field, the radiofrequency (RF) coil(s) for excitation and reception of the MR signal, and the magnetic gradient field coils for spatial encoding of the MR signal. MRI systems measure the magnetic properties of the protons, which are influenced by electrical and magnetic characteristics of their environment. The local environment varies between tissues or the structures in which the...

Magnetic Resonance Imaging

The way in which MRI actually recovers its signal is by first perturbing the examined system. This instrumental perturbation is performed by applying short radiofrequency (RF) pulses that, when appropriately tuned, are able to transiently tip the orientation of the spins away from the applied magnetic field. However, the tendency of the spins is to return to the orientation coherent with the applied magnetic field, given that the latter state is characterized by a lower energy. The relaxation process occurs through the emission of an RF wave that is detected by the same RF hardware that emits the excitation pulses. In MR terminology, this is referred to as the RF coil, which has the form of a small cylindrical cage that surrounds the subject's head in the scanner. The emitted RF wave or, more precisely, the temporal signature of its decay as the excited spins relax constitutes the actual MR signal and depends on the molecular characteristics of the local tissue, as well on the...

Northern USA and Canada

The primary external parasite in summer would be hornflies. The primary winter ectoparasites are lice (both biting and sucking) and mites (psoroptic and chorioptic) as hair length on the cattle increases and UV light decreases. Nematode faecal egg counts in adult cows will rise quickly after calving, and will remain relatively high for 4-6 weeks as a result of relaxation of the immune system (Stromberg et al., 1991). This impact allows for the presence of fresh larvae for calves as they begin to ingest grass at 2-3 months of age.

Overview Of Functionaland Motility Disorders Of The Bowel

GI motility disorders include achalasia of the esophagus (impaired relaxation of the lower esophageal sphincter associated with defective esophageal peristalsis that results in dysphagia and regurgitation), gastroparesis (delayed gastric emptying), myopathic, and neuropathic forms of intestinal dysmotility. These disorders can be congenital, idiopathic, or secondary to systemic diseases (e.g., diabetes mellitus or scleroderma). For most of these disorders, treatment remains empirical and symptom-based, reflecting our ignorance of the specific derangements in pathophysiology involved.

Psychological and environmental aspects

There are a variety of approaches for dealing with psychological and environmental contributors. These may include the use of anxiolytic and antidepressant medications and or cognitive-behavioral treatment.105 III , 106 III It may also be necessary to address other external factors that are believed to be contributing to the pain. It is evident that psychological factors influence the experience of pain, and therefore it is likely that cognitive-behavioral interventions may improve the quality of life in pain patients. Relaxation techniques are suggested to be of benefit in SCI pain and may alter the attitude towards pain. Well-designed studies are needed to determine the effects of the non-pharmacological treatment of SCI pain.

Activation of Endocannabinoid Biosynthesis

For more than a century, paracetamol has been among the most popular medicines, being widely used as analgesic, antipyretic, and nonsteroidal antiinflammatory drug. Its mode of action, however, remained a mystery until 2005, when it was demonstrated that it indirectly causes the activation of cannabinoid receptors (Hogestatt et al., 2005). In the brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with AA to form N-arachidonoylphenolamine, also known as AM404, which is a blocker for the endocannabinoid transporter. Therefore, paracetamol causes CB1 and CB2 receptors activation by preventing endo-cannabinoids reuptake and subsequent metabolization. Interestingly, AM404 is also an inhibitor of COX enzymes in the brain (Bertolini which is likely to further contribute to endocannabinoid built-up, since COX is implicated in the nonhydrolytic, metabolization of endocannabi-noids in the CNS and peripheral tissues. For instance, the...

Blood pressure throughout systemic circulation

The pressure generated by left ventricular contraction is the driving force for the flow of blood through the entire systemic circulation, from the aorta all of the way back to the right atrium. The mean pressure in the aorta and large arteries is typically very high (90 to 100 mmHg) due to the continual addition of blood to the system by the pumping action of the heart. However, this pressure is pulsatile in other words, it fluctuates because of the alternating contraction and relaxation phases of the cardiac cycle. In a healthy resting adult, systolic pressure is approximately 120 mmHg and diastolic pressure is approximately 80 mmHg (see Figure 15.2). The pulse pressure is the difference between the systolic and diastolic pressures

Free Radicals In Carcinogenesis And Apoptosis The Critical Balance

Under normal physiological conditions, ROS and RNS play a role in signal transduction and gene transcription in cells. Nitric oxide (NO) generated by activated macrophages is an important mediator of immune response. NO produced in the nervous system by neurons acts as a neurotransmitter. In addition, NO produced by the endothelial cells is essential for regulating vascular tone and vasodilation besides the relaxation and proliferation of vascular smooth muscle cells, leukocyte adhesion, platelet aggregation, and angiogenesis.

Physiology and disease relevance

Important physiological consequences of -adrenoceptor activation include stimulation of cardiac rate and force, relaxation of vascular, urogenital, and bronchial smooth muscle, stimulation of renin secretion from the juxta-glomerular apparatus, stimulation of insulin and glucagon secretion from the endocrine pancreas, stimulation of glycogenolysis in liver and skeletal muscle, and stimulation of lipolysis in the adipo-cyte. Prejunctional -adrenoceptors are present on some central and peripheral nerve terminals, where their activation results in facilitation of stimulation-evoked neurotrans-mitter release (Majewski and Rand 1984). However, in contrast to the prejunctional a2-adrenoceptors, these prejunctional receptors do not appear to have major physiological significance.

Nonpharmacological Treatment

Physical treatment modalities, such as hot and cold packs, ultrasound and electrical stimulation, improvement of posture, relaxation, and exercise programs, have all been used. However, the majority of these treatments have not been properly evaluated, and most of the reported studies are not controlled. In one open-label study, the beneficial long-term effect of physical therapy was excellent,114 IV whereas a controlled study reported only a minor effect on headache frequency after eight weeks of standardized treatment.115,116 II A recent controlled study concluded that there was no significant effect of spinal manipulation on patients with episodic tension-type headache.98 II Likewise botulinum toxin plays no role in the treatment of tension-type headache or migraine.117,118 II

Management and prognosis

It is a common clinical experience that various physical strategies (e.g. stretching, relaxation, etc.) can be effective for the management of different types of TMD pain. Unfortunately, it has been much more difficult to support this with proper research data adhering to randomized controlled trial (RCT) principles. Critical reviews and meta-analysis have, however, started to appear to evaluate the claimed efficacy of the procedures.48,49 III There have been attempts to calculate the number needed to treat (NNT) values for oral splints. The available NNT estimates range between three and four for management of myofascial TMD patients and around five and six for TMJ arthralgia patients,50 suggesting a moderate efficacy of oral splints.51,52 I Very recently, another controlled study compared the conventional hard splint with a soft splint and a usual self-care-based treatment approach.53 This study failed to show any significant differences between the three different treatment groups...

Table 78 Psychiatrists guide for assessing patient decisionmaking capacity

Other factors that may raise concerns about patient suitability for various interventions may include a history of treatment nonadherence, use of large amounts of narcotics and or anxiolytics (raising concerns regarding substance dependence), and concerns over behaviors suggesting secondary gain (e.g., ongoing litigation issues) (Block et al. 2003). Careful consideration of such factors might warrant that invasive procedures be delayed until corrective measures can be put in place (e.g., treatment of comorbid depression or substance dependence). Similarly, psychiatrists may be instrumental in eliciting patient adherence with other related facets to the patient's treatment. It may be particularly helpful to engage the patient in weight reduction measures, smoking cessation, participation in exercise programs, and relaxation training, before attempts are made at intervening with more aggressive interventions. When undertaken, such endeavors convey that the patient is taking on a...

Postintervention Role

It may become necessary to assist patients who are disappointed over unachieved outcomes, or less than optimal results, after an intervention has been undertaken. Pain relief may be only partial, and there may be residual physical activity limitations that persist after an intervention, necessitating psychiatric follow-up. Strong reactions such as alarm ( Something has gone wrong ), disappointment ( I was hoping I would be better. ), and futility ( Nothing will help. ) may undermine rehabilitative treatment measures and any potentially achievable gains. Adjunctive treatment modalities such as hypnosis, relaxation and imagery, guided imagery, and biofeedback may be helpful in mitigating pain perception and distress in such cases (see also Chapter 6 in this book). Psychotherapeutic measures may be helpful in assisting patients with reframing such reactions to mitigate any potential undermining of rehabilitative endeavors. Ongoing collaborative endeavors between the psychiatrist and...

Molecular characterization

The existence of a third CB receptor has recently been suggested on the basis of several reports of unique pharmacology. These include (1) in the rat mesenteric artery, the endogenous CB receptor agonist anandamide, but not the synthetic agonist HU210, causes relaxation blocked by the CB1 receptor antagonist SR141716A, (2) an analogue of canna-bidiol ('abnormal cannabidiol') causes mesenteric vasodilation in CB1 CB2 knockout mice and this is antagonized by cannabidiol (Jarai et al. 1999), (3) in CB1 knockout mice, the behavioural effects of THC, but not anandamide, are decreased, (4) in the same knockout mice, anandamide (but not THC) is able to enhance 35S-GTPyS binding to brain membranes but this effect is insensitive to CB1 and CB2 antagonists (Di Marzo et al. 2000), (5) in rat astrocytes in vitro, the highly potent CB agonists WIN 55212 and CP55940 inhibit (-adrenoceptor-mediated cAMP formation, in an SR141716-insensitive fashion, in the absence of any evidence for CB2 receptors.

Phenolic Reaction Products of Nitric Oxide ONOO or Both

Although the overall yield is small, 4-nitrosophenol is a significant product from addition of ONOO alone (Fig. 3). ONOO -mediated formation of nitroso adducts in biological systems, particularly nitrosothiols, likely accounts for the ability of ONOO to produce nitric oxide-like effects such as vascular relaxation (Wu et al., 1994 Liu et al., 1994). The yield of 4-nitrosophenol from ONOO is not significantly affected by lowering the pH to 6.0 but does increase at pH 8.0 (Fig. 3). At pH 7.4 the yield of nitrosophenol increased severalfold when ONOO and nitric oxide were added simultaneously. The yield of nitrosophenol from ONOO plus nitric oxide was essentially no different from that of nitric oxide alone at pH 6.0 or pH 8.0.

Introduction A Historical Considerations

The term purinergic was coined 25 years ago by Burnstock (1) to explain the potential signaling role of ATP in noncholinergic, nonadrenergic transmission. Although the action of ATP on discrete cell surface receptors was recognized during subsequent years, it was not until 1978 (2) that receptors activated by ATP or ADP (P2-purinoceptors, or P2 receptors) were differentiated from those activated by the ATP metabolite adenosine (P1- purinoceptors). P2 purinoceptors were further subdivided into two major groups P2X-purinoceptors, which mediate vasoconstriction and smooth muscle contraction and were most potently activated by a,b-methylene ATP (a,b-meATP), and P2Y-purinoceptors, which promoted vasodilatation and smooth muscle relaxation and were potently activated by 2-methylthio-ATP (2MeSATP) (3). Additional P 2-purinoceptor subtypes have been subsequently proposed. For example, the stimulatory action of ADP on platelets was ascribed to a so-called P2T-purinoceptor at which ATP acts as...

Concluding Remarks

With few exceptions, this chapter has focused on steady-state methods for defining inhibitor action. The analytical power of rapid-mixing and relaxation kinetics (see Chapter 9) in efforts to define the subtle details of inhibitor action should not be underestimated. In fact, fast reaction techniques are perfectly suited for understanding ligand-induced conformational changes. Knowledge of the number of kinetically discrete steps in the isomerization reactions may provide new clues about the action of transition-state analogues, mechanism-based inhibitors, and other slow, tight-binding enzyme antagonists. An interesting example of inhibitor characterization is provided in the studies of Nair and Cooperman (1998) on the action of the serpin antichymotrypsin. They observed that chymotrypsin and its serpin reacted to form an E*I* complex via a three-step mechanism, E + I E I EI ' E*I*, in which E I and EI ' are intermediates and E*I* corresponds to a covalent adduct of E and I, either as...

Table 81 Evaluation of the headache patient

Effective psychotherapeutic modalities include biofeedback training and relaxation training (see Chapter 6, Psychotherapy, of this book). Stress management therapy and cognitive-behavioral therapy (CBT) may also be helpful in reducing stress levels, but they are probably most effective when combined with relaxation or biofeedback training (Holroyd et al. 1977). Characteristics of patients who are likely to improve with the use of psychotherapeutic treat- ment are summarized in Table 8-3. Of these factors, the most striking is that those patients in relaxation training who show positive responses by the fourth session (as measured by muscle level reactivity on electromyogram EMG ) are likely to have an excellent response to relaxation or biofeedback training (Bogaards and ter Kuile 1994). Uncontrolled studies have revealed that dental complications may predispose some persons to tension headache, and these persons may

Antiinflammatory and antiasthmatic effects of PGE2

It is concluded that one major effect of PGE2 on the airways includes inhibition of stimulation-evoked responses such as mediator secretion from epithelium and inflammatory cells. In addition to its effects on inflammatory cells and its ability to cause relaxation of airway smooth muscle, PGE2 may also inhibit the release of acetylcholine from airway cholinergic nerves 357 . This effect is thought to occur through stimulation of presynaptic receptors and would obviously add another beneficial anti-asthmatic action. Furthermore, the protective effects of PGE2 may not be limited to the airways, because the allergen-induced late cutaneous reaction in atopics was inhibited by the stable PGE2 analog misoprostol 358 and PGE2 also reduced ischemic reperfusion injury in the heart in one model 359 . Therefore, it appears that the potential of PGE2 as a tool for pharmacological intervention with asthmatic and inflammatory responses deserves more attention. At the moment, the initial cough...

Nitric Oxide as a Biological Messenger Molecule

The gaseous nitrogen radical, nitric oxide (NO), is an important mediator of physiological and pathophysiological processes in animals and has intrigued researchers over the past decade. This interest has resulted in the birth of a new field of research, the award of the 1998 Nobel Prize in Medicine, and in the appearance of a number of international journals dedicated to the what, where, how and why of NO biochemistry. Prominent roles for NO have been established in the regulation of blood vessel relaxation, the control of synaptic transmission, and the response of macrophages to infectious agents and to tumor cells (Stamler et al., 1992 Wink and Mitchell, 1998). Central to these studies has been the identification and characterization of a class of enzymes called nitric oxide synthases (NOSs) responsible for the release of NO during their five-electron oxidation of the guanidino nitrogen of L-arginine to yield L-citrulline (Knowles and Moncada, 1994). This reaction has mechanistic...

Freezedried Formulations

Testing of lead compound would preferably involve freezing and studying using DSC. In some cases, an endotherm caused by stress relaxation may be superimposed on the glass transition. It is possible to resolve these events using the related technique, modulated DSC (MDSC) or dynamic DSC (DDSC). Differential scanning calorimetry is used to determine a wide range of physical properties of materials, including the glass transition temperature Tg, the melting temperature Tm, and solid-solid transitions. In this technique, a sample and a reference material are subjected to a controlled temperature program. When a phase transition, such as melting, occurs in the sample, an input of energy is required to keep the sample and the reference at the same temperature. This difference in energy is recorded as a function of temperature to produce the DSC trace. The MDSC provides the same qualitative and quantitative information about the physical and chemical changes as conventional DSC, and in...

NMR Screening General Aspects

It is clear that to carry out ligand screening by NMR, the library compounds (ligands) must be distinguished from the target. One of the most important methods of achieving this is through their vastly different molecular masses. Several NMR parameters are dependent on the rotational and translational diffusion rates of the subject molecule, and therefore on molecular mass. Notably, the transverse (entropic) relaxation of the NMR signal is dependent on the rotational diffusion rate. Large, slowly tumbling target molecules relax much faster than rapidly tumbling small molecules. As the transverse relaxation rate is directly related to linewidth, small molecules can be distinguished by their narrow lines. Also, filters suppressing broad signals can be used to minimize signals from the target. Other relaxation-related parameters, such as the nuclear overhauser effect (NOE), are also related to rotational diffusion rates small These differences in NMR properties between small and large...

Scaffolding Functions for the Cardiac ZDisc

Obscurin is another Z disc protein that interacts with titin, the giant elastic filamentous sarcomeric protein that acts as a molecular ruler during sarcomeric assembly and maintains normal cardiac muscle cell length during contraction relaxation cycles. The C-terminal region of obscurin contains both an IQ motif that is a binding site for calmodulin and a Rho-GEF domain that could activate Rho family small G proteins, suggesting an important heretofore unrecognized signaling function for obscurin in the sarcomere (Young et al. 2001)

Doctor What Is Causing My Chronic Low Back Pain

In contrast, the osteopathic view of the etiology of CLBP suggests that a lesion defined as somatic dysfunction''63 is identified (see below under Spinal manipulation). Others have postulated that spinal manipulation treats lesions that may include the release of entrapped synovial folds or plica within facet joints, relaxation of hypertonic muscle by sudden stretching, disruption of articular or periarticular adhesion, or unbuckling of motion segments that have undergone disproportionate displacements.64 Others have recently put forward an argument that atherosclerosis of the lumbar vessels is responsible for low back pain.65

The Role Of Nitric Oxide

Nitric oxide was identified in 1987 as the endothelial-relaxing factor, which is produced in the endothelial cell walls of the arteries. The nitric oxide spreads through the cell walls to the underlying muscle cells relaxing their constriction and leading to a dilation of the arteries. In this way it controls blood pressure. It also causes a relaxation of the gastrointestinal muscle and this affects stomach motility. The macrophages that are part of the immune response to infection, also produce nitric oxide to kill bacteria. In the case of a severe infection enough nitric oxide may be produced to induce sufficient vasodilation to seriously lower the blood pressure and bring about a 'septic shock', which can be fatal.

Classification mechanism and duration of action

Whereas competitive blockers potentiate it.3 The muscle fasiculations of depolarizing agents are followed by relaxation. Paralysis caused by depolarizing agents is terminated by metabolism of the agent by pseudocholinesterase. Succinylcholine is primarily used for short-acting paralysis such as intubation. Decamethonium has a higher risk of fatality and is no longer used therapeutically in the USA.

Vascular Blood Flow

In the macrovessels, increases in contractility found in diabetes are due to a delay in the relaxation response after contraction induced by cholinergic agents (72-75). These abnormal responses can also be prevented by PKC inhibitors (76), suggesting that PKC activation plays a general role in causing abnormal peripheral hemodynamics in diabetes.

Multiple Mechanisms Regulating Endothelial Nitric Oxide Synthase

Nitroglycerin has been used since the early 1870's as a vasodilator in the treatment of angina pectoris, however the cellular mechanisms involved in its actions were not elucidated until early in 1970. Murad et al. (1979) reported that nitroglycerin and other nitro-containing compounds stimulated guanylyl cyclase leading to an increase in cGMP accumulation in smooth muscle cells 1 . Later experiments by Ignarro et al. (1980) in various tissues, showed that the addition of nitroglycerin in combination with thiols resulted in the generation of unstable S-nitrothiols which degrade to form nitric oxide leading to vasorelaxation 2 , Experiments performed by Furchgott and Zawadzki in 1980 using artery rings illustrated the dependence of acetylcholine-induced relaxation on an intact endothelium 3 . Acetylcholine acts on muscarinic receptors on endothelial cells leading to an increase in an endothelium-derived relaxing factor (EDRF), which in turn diffuses to the underlying smooth muscle...

Mouse Models Of Human Disorders Created By Gene Targeting

Nitric oxide (NO), a potent vasodilator produced by endothelial cells, acts as a relaxing factor'' (EDRF) that mediates vascular relaxation in many vascular beds and regulates blood pressure and regional blood flow abnormalities in its production are associated with atherosclerosis, diabetes, and hypertension. Homozygous endothelial nitric oxide synthase (eNOS) mutant mice generated by gene targeting are viable, fertile, and indistinguishable from wild-type and heterozygous littermates but their mean blood pressure is 35 higher than in control littermates (110 vs. 81 mm Hg), confirming that endothelial nitric oxide plays a role in normal blood pressure regulation, and in fact may be a primary

Inhibitory neurotransmitter receptors targets for novel analgesic drugs

Unlike glycine receptors, GABAA receptors are extensively used as therapeutic targets. The classical benzodiazepines, which enhance GABA responses at benzodiazepine-sensitive GABAA receptors, cause sedation, anxiolysis, and central muscle relaxation and are anti-convulsive. Antinociceptive actions of benzodiazepines have been repeatedly described in animal models of pain, in particular after spinal injection (e.g., Goodchild and Serrao 1987), and a few studies have reported analgesic effects of agonists at GABAA receptors in human patients (for reviews, see Jasmin et al. 2004 and Krogsgaard-Larsen et al. 2004). However, classical benzodiazepines are not routinely used as analgesics. Underlying reasons may include the accompanying sedation, which probably occurs at lower doses than that needed for analgesia, and possible pronociceptive effects of benzodiazepines at supraspinal sites (Tatsuo et al. 1999), which may counteract spinal antinociception. This may not necessarily be the case...

Table 815 Treatment of patients with complex regional pain syndrome

Substance abuse disorders also are common among this population. There is controversy about whether premorbid psychological disturbances predispose one to CRPS. In any event, psychiatric treatment for these conditions is warranted. Biofeedback and relaxation training can reduce distress and foster adaptive strategies with which to deal with pain (Barowsky et al. 1987).

Grape seed proanthocyanidin extract

A number of actions on the tissues of the arterial wall have been reported for GPSE, including inhibition of histidine decarboxylase involved in the atheromatous process, vascular relaxation by increasing endothelial nitric oxide production, and inhibition of endothelin-1 formation.126 Recent research using the atherosclerotic hamster model found approximately 49 and 63 reduction in foam cells, which is a biomarker of the early stage of atherosclerosis, following administration of 50 and 100 mg kg GSPE, respectively. In a human trial, GSPE supplementation of 100 mg twice daily significantly reduced oxidised LDL.127

Gastrointestinal and Lower Urinary Tract

In terms of inducing gastrointestinal smooth muscle relaxation, several relatively old compounds are available including pinaverium, cimetropium, fendoverine, mebeverine, and milverine. Although lacking selectivity for muscarinic M3 receptors, they possess many other properties, such as calcium channel blockade, a property that will contribute to the antispasmodic actions of the drug. Two other examples of compounds with muscarinic antagonist properties and nonspecific muscle relaxant properties are terodiline (now withdrawn due to the occurrence of Torsades de Pointes) and imipramine (104). Although these properties may result in preferential action on smooth muscle, newer compounds, with selectivity for the muscarinic M1 and M3 receptor over the M2 or M4 receptors, and lacking nonspecific effects, have been clinically evaluated. These include zamifenacin (40), darifenacin (41), and vamicamide (105).

Substrate Concentration Jumps

Within the past several years, the application of piezo-switched glutamate jumps to excised outside-out patches has been introduced to study glutamate transporter kinetics with high time resolution. This technique is a powerful approach to study transporters as one can easily and completely control the ion concentrations in both the intracellular and extracellular environment of the transporters. L-glutamate (and or alkali cations) can be applied rapidly (

Stress And The Immune System

Infective mononucleosis), herpes simplex virus type 1 (that causes cold sores), and cytomegalovirus (which causes the monucleosis syndrome) were raised prior to examinations but returned to normal levels following the examination (Glaser, Kiecolt-Glaser, and Stout, 1985). There were additional changes in mitogen stimulated lymphocyte replication associated with academic stress. Thus, the incidence of self-reported infectious illness was also increased in these individuals. The effect of relaxation techniques on these immune parameters was also studied and showed that although the percentage of helper T-cells did not decline so markedly in those subjects that were given relaxation exercises, natural killer cell activity was unaffected by such an intervention. It may be concluded from these studies of the effects of stress and adverse life events that adaptive changes in the immune system are not pronounced in man.

Table 816 Common painrelated disorders associated with Hivaids

Ules should be simple to maximize adherence and should be administered in the least invasive manner. Persistent pain requires around-the-clock dosing of analgesics. Certainly psychiatric interventions, including pharmacotherapy and psychotherapy, are prudent in conditions in which there is psychiatric comorbidity. Adjunctive techniques (e.g., hypnosis, relaxation training, bio-

Simulation Of Transport Behavior With Kinetic Modeling

By applying glutamate concentration jumps to excised patches at different membrane potentials and with different intracellular solutions, we can functionally isolate a subset of the rates constants to better constrain the form of the overall model and the individual rates. For example, replacement of intracellular K+ ions with Na+ and glutamate shifts the transporter to an exchange mode, eliminating the contribution of the K+-dependent rate constants. As a result, the relaxation time constants to baseline following glutamate removal are dominated primarily by the backward rate constants of the Na-hemicycle, which thus leads to the isolation of an even smaller number of rate constants (Otis and Kavanaugh, 1998). In addition, paired pulse data help constrain the cycling rate of the transporters under these different ionic conditions.

Chronic prostatitischronic pelvic pain syndrome

Chronic prostatitis chronic pelvic pain syndrome (CP CPPS) is defined as pain attributed to the prostate in the absence of identifiable pathology and has often been referred to as prostatodynia. Hallmark features consist of persistent complaints of urinary urgency, dysuria, poor urinary flow, and perineal discomfort without evidence of bacteria or white blood cells in prostatic fluids. It serves as a male-specific corollary to interstitial cystitis in that it has similar symptomatology, is a diagnosis of exclusion, and has a presumed site of pain generation. Infectious, inflammatory, neurological, and referred gastro-enterological etiologies of the pain need to be ruled out. Cystoscopic findings of interstitial cystitis have been found in males with the diagnosis of prostatodynia.61 Wesselmann et al.98 have suggested that interstitial cystitis, CP CPPS (male), and vulvodynia (female) may all be variations of a generalized disorder of the epithelium of the urogenital sinus. To further...

Recurrent urolithiasis

Stones located within the urinary system (renal pelvis calices, ureters, bladder, urethra) can produce severe pain (renal colic) and if sufficiently obstructive to urine flow can destroy kidney function. It occurs in 15 percent of white men and 6 percent of all women in industrialized countries.132 Recurrent in stone-formers, it may produce continuous pain when numerous or large renal pelvic (staghorn) calculi are present. Diagnosis is based on history of stone formation and or imaging studies (intravenous pyelogram or computed tomography). The definitive treatment is the removal of the stone by spontaneous passage which may be assisted by fragmentation using lithotripsy or surgical removal. Drugs producing a relaxation effect in the ureters include NSAIDs, nifedipine, and tamsulosin. Pain treatments employed for renal colic are intended to be temporizing until stone removal occurs. As such, narcotics and NSAIDs are the mainstay of treatment. There may be particular benefit to the use...

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