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A causal role for endothelin-1 in the vascular adaptation to skeletal muscle deconditioning in spinal cord injury.

OBJECTIVE: Endothelin-1 (ET-1) contributes to the increased peripheral resistance in heart failure and hypertension. Physical inactivity is associated with cardiovascular disease and characterized by increased vascular tone. In this study, we assess the contribution of ET-1 to the increased vascular tone in the extremely deconditioned legs of spinal cord-injured (SCI) individuals before and after exercise training. METHODS AND RESULTS: In 8 controls and 8 SCI individuals, bilateral thigh blood flow was measured by plethysmography before and during the administration of an ET(A)/ET(B)-receptor blocker into the femoral artery. In SCI, this procedure was repeated after 6 weeks of electro-stimulated training. In a subset of SCI (n=4), selective ET(A)-receptor blockade was performed to determine the role of the ET(A)-receptors. In controls, dual ET-receptor blockade increased leg blood flow at the infused side (10%, P<0.05), indicating a small contribution of ET-1 to leg vascular tone. In SCI, baseline blood flow was lower compared with controls (P=0.05). In SCI, dual ET-receptor blockade increased blood flow (41%, P<0.001). This vasodilator response was significantly larger in SCI compared with controls (P<0.001). The response to selective ET(A)-receptor blockade was similar to the effect of dual blockade. Electro-stimulated training normalized baseline blood flow in SCI and reduced the response to dual ET-receptor blockade in the infused leg (29%, P=0.04). CONCLUSIONS: ET-1 mediates the increased vascular tone of extremely inactive legs of SCI individuals by increased activation of ET(A)-receptors. Physical training reverses the ET-1-pathway, which normalizes basal leg vascular tone.

Adult↗

Quantification of the effects of resperine on gonadotroph expression in the pituitary of goldfish (Carassius auratus).

In many teleosts, the control of gonadotropin II (or luteinizing hormone) secretion is under the dual control of stimulatory and inhibitory neuroendocrine factors. The principal stimulating factor is gonadotropin-releasing hormone and the main inhibitor is dopamine. Inhibiting the activities of dopamine by antidopaminergic drugs potentiates the actions of exogenous gonadotropin-releasing hormone analogs, resulting in a surge release of luteinizing hormone and ovulation and spawning in a number of different species. As the effects of blocking the inhibitory actions of dopamine on gonadotroph cytology have not been studied, goldfish were treated with 2, 4, 6 or 8 injections of reserpine (0.1 mg/kg body weight), at 48 h intervals, and the numbers of gonadotrophic cells studied at 48 h following last injection. After two injections, the number of gonadotrophic cells increased by 189% over controls; after four injections the increase was 234%; after six injections the increase was 259% and after eight injections, 288%. The results suggest that dopamine has an inhibitory influence on the numbers of gonadotrophs.

Adrenergic Uptake Inhibitors↗

Animal models for alcohol research.

Many animal models have been used for alcoholism research. No single model is suitable for all types of research about alcohol, its actions and abuse. This article surveys the varieties of models that have been used and categorizes them into classes called "chronic", "reinforcement" and "genetic" models and discusses the strengths, weaknesses and applications of each group. The diversity and scope of alcoholism offers unique challenges to the conduct of laboratory research with experimental animals. Animal models (AM) of the disease would have to encompass a broad range of variables No single model can incorporate all aspects of the disorder nor fulfill the needs of all research projects. Consequently, many different AM have been proposed. This review classifies those models, describes their underlying premises, experimental applications and their relative strengths and limitations. The scientific literature contains numerous examples of essentially sound experiments that lack credibility because of weaknesses in design aspects associated with the selection or use of AM. The alcoholism literature cannot be excluded from that statement. There are many examples of the inappropriate use of AM in alcoholism research and of poorly conceived attempts to use models developed for specific experimental applications in experiments requiring an entirely different approach. Furthermore, a persistent problem that is unique to alcoholism research relates to providing appropriate controls. Since alcohol (ALC) has caloric as well as pharmacological effects, dual controls must be established. The caloric effects of ALC can alter an animal's nutritional state in important ways. Therefore, studies involving more than one or two ALC doses must provide adequate controls for both the pharmacological and the non-specific nutritive effects. Unfortunately, such controls are often difficult to establish and validate.

Alcoholism↗

Differential effects of voltage-dependent inactivation and local anesthetics on kinetic phases of Ca2+ release in frog skeletal muscle.

In voltage-clamped frog skeletal muscle fibers, Ca(2+) release rises rapidly to a peak, then decays to a nearly steady state. The voltage dependence of the ratio of amplitudes of these two phases (p/s) shows a maximum at low voltages and declines with further depolarization. The peak phase has been attributed to a component of Ca(2+) release induced by Ca(2+), which is proportionally greater at low voltages. We compared the effects of two interventions that inhibit Ca(2+) release: inactivation of voltage sensors, and local anesthetics reputed to block Ca(2+) release induced by Ca(2+). Holding the cells partially depolarized strongly reduced the peak and steady levels of Ca(2+) release elicited by a test pulse and suppressed the maximum of the p/s ratio at low voltages. The p/s ratio increased monotonically with test voltage, eventually reaching a value similar to the maximum found in noninactivated fibers. This implies that the marked peak of Ca(2+) release is a property of a cooperating collection of voltage sensors rather than individual ones. Local anesthetics reduced the peak of release flux at every test voltage, and the steady phase to a lesser degree. At variance with sustained depolarization, they made p/s low at all voltages. These observations were well-reproduced by the "couplon" model of dual control, which assumes that depolarization and anesthetics respectively, and selectively, disable its Ca(2+)-dependent or its voltage-operated channels. This duality of effects and their simulation under such hypotheses are consistent with the operation of a dual, two-stage control of Ca(2+) release in muscle, whereby Ca(2+) released through multiple directly voltage-activated channels builds up at junctions to secondarily open Ca(2+)-operated channels.

Anesthetics, Local↗

Evaluation of a long-range adaptive predictive controller for computerized drug delivery systems.

A closed-loop adaptive control system, based on the generalized predictive control law with a terminal matching condition, has been developed for computerized drug delivery. The control law is a minimization of the squares of prediction errors over a small future prediction horizon plus weighted square of the prediction error at steady-state. A control-relevant, long-range identification algorithm is used for on-line parameter estimation. Since the control and identification are mutually compatible, the system truly satisfies the approximate dual control criterion. The system has been applied to the control of mean arterial pressure (MAP) by automatic infusion of sodium nitroprusside in the presence of physical and physiological constraints. Experimental evaluation on six mongrel dogs, in an ethics-approved manner, included setpoint tracking and regulation of MAP in the presence of unpredictable disturbances. The system was found to be capable of inducing hypotension in an average of 2.44 +/- 0.31 min (mean +/- standard error of mean) after probing without any overshoots in mean arterial pressure. The nitroprusside infusion was also free of any ringing. When the subjects were not disturbed, 96.2% of mean arterial pressure remained within 5 mm Hg of the target pressure. A series of disturbances introduced in the presence and absence of closed-loop control affirms the robustness and effectiveness of this control system.

Algorithms↗

Coordinate regulation of Drosophila tropomyosin gene expression is controlled by multiple muscle-type-specific positive and negative enhancer elements.

Muscle development involves the coordinated regulation of transcription of muscle-type-specific genes and their encoded proteins during myogenesis. We show here that transcriptional regulation of the Drosophila tropomyosin I (TmI) gene during myogenesis is under the control of at least two muscle enhancer regions located within the first intron of the gene. Together these enhancer regions contain multiple muscle-type-specific positive and negative cis-acting elements which together contribute toward full expression of the gene. One of these enhancers is contained within a 355-bp fragment that is sufficient to direct high levels of temporally regulated expression from a heterologous promoter in all muscles of transgenic flies. Dissection of this enhancer region into smaller fragments has allowed us to identify a 91-bp enhancer fragment sufficient for directing expression in all somatic and visceral muscles of the larva and adult but not in the indirect flight muscles and tergal depressor of the trochanter or jump muscles of the adult. We also show that this somatic/visceral muscle element(s) can be repressed through an adjacent negative control region, suggesting that the regulation of expression in these muscles is under dual control during both phases of myogenesis. We propose a model in which transcriptional regulation of the Drosophila TmI gene is controlled by the cooperative interaction of multiple positive and negative cis-acting regulatory elements that control the temporal and muscle-type pattern of expression. The distribution of enhancer elements and their control of TmI gene expression are similar to those regulating transcription of the muscle promoter of the TmII gene and provide a framework for the coordinate expression of the two genes.

Animals↗

Local control model of excitation-contraction coupling in skeletal muscle.

This is a quantitative model of control of Ca release from the sarcoplasmic reticulum in skeletal muscle, based on dual control of release channels (ryanodine receptors), primarily by voltage, secondarily by Ca (Ríos, E., and G. Pizarro. 1988. 3:223-227). Channels are positioned in a double row array of between 10 and 60 channels, where exactly half face voltage sensors (dihydropyridine receptors) in the transverse (t) tubule membrane (Block, B.A., T. Imagawa, K.P. Campbell, and C. Franzini-Armstrong. 1988. 107:2587-2600). We calculate the flux of Ca release upon different patterns of pulsed t-tubule depolarization by explicit stochastic simulation of the states of all channels in the array. Channels are initially opened by voltage sensors, according to an allosteric prescription (Ríos, E., M. Karhanek, J. Ma, A. González. 1993. 102:449-482). Ca permeating the open channels, diffusing in the junctional gap space, and interacting with fixed and mobile buffers produces defined and changing distributions of Ca concentration. These concentrations interact with activating and inactivating channel sites to determine the propagation of activation and inactivation within the array. The model satisfactorily simulates several whole-cell observations, including kinetics and voltage dependence of release flux, the "paradox of control," whereby Ca-activated release remains under voltage control, and, most surprisingly, the "quantal" aspects of activation and inactivation (Pizarro, G., N. Shirokova, A. Tsugorka, and E. Ríos. 1997. 501:289-303). Additionally, the model produces discrete events of activation that resemble Ca sparks (Cheng, H., M.B. Cannell, and W.J. Lederer. 1993. 262:740-744). All these properties result from the intersection of stochastic channel properties, control by local Ca, and, most importantly, the one dimensional geometry of the array and its mesoscopic scale. Our calculations support the concept that the release channels associated with one face of one junctional t-tubule segment, with its voltage sensor, constitute a functional unit, termed the "couplon." This unit is fundamental: the whole cell behavior can be synthesized as that of a set of couplons, rather than a set of independent channels.

Animals↗

Control by stimulus features during fading.

Sixteen children were given four successive circle-size discrimination problems with luminance as the fading stimulus. Children who were first presented with a difficult size discrimination failed to acquire this discrimination. Those who first received an easy discrimination learned the difficult discrimination. At the end of each 10-trial block, two probe stimuli were presented to monitor any shift in control from luminance to size. One probe was the same size as the positive stimulus but of different luminance; the other was the same luminance but of different size. If, in the course of fading, size and luminance both controlled responding, fading was successful. If luminance alone controlled responding until the end of fading, the size discrimination was not established. Dual control, and thus successful fading, resulted when the target stimuli were very discriminable, or when the target stimuli were subtly different provided that previous fading series had first established less subtle discriminations.

Child↗

Interchangeability of repressors for the control of the uxu and uid operons in E. coli K12.

The uidA and uxuAB operons are each under the dual control of two repressor molecules: the uidR and uxuR encoded repressors negatively control the uidA operon whereas the uxuAB operon is regulated by the uxuR and exuR gene products. Plasmids overproducing the regulatory molecules encoded by exuR, uxuR, or uidR were used to investigate the regulation of these two operons. Large amounts of either exuR or uxuR repressor caused a complete repression of the uxuAB operon in exuR and uxuR double-deleted mutants, suggesting that the two repressors, when they are overproduced, are totally interchangeable for the control of the uxuAB operon. In contrast, the UxuR molecule has no effect on the other exu regulon operons controlled by the exuR gene product. The uidR and uxuR gene products appear to be partially interchangeable for the regulation of the uidA gene since addition of multicopy plasmids bearing uidR+, in uxuR deleted mutant strains, only partially suppresses the derepression of the uidA gene. Inversely, multicopies of uidR weakly reduced the synthesis of the uxuB gene product in uxuR derepressed mutants. The restrictions placed by these phenomena on the formulation of the mechanism of cooperation between the two repressor molecules for repressing the uxuAB and uidA operons are discussed.

Escherichia coli↗

A fast, high precision and inexpensive analog to digital board for PC-AT or compatible.

We describe a simple and inexpensive circuit for analog data acquisition with high speed and high resolution, for use in an IBM PC-AT or compatible. The circuit is suitable for a wide range of applications in electrophysiology. Features of the circuit include multichannel reading, programmable sampling rate, and direct memory access controlled dual buffering for continuous recording. A program written in the C programming language for control of data acquisition is also given.

Computers↗

Adenosine A(2A) receptor enhances GABA(A)-mediated IPSCs in the rat globus pallidus.

1. The actions of adenosine A(2A) receptor agonists were examined on GABAergic synaptic transmission in the globus pallidus (GP) in rat brain slices using whole-cell patch-clamp recording. GP neurones were characterized into two major groups, type I and type II, according to the degree of time-dependent hyperpolarization-activated inward rectification and the size of input resistance. 2. The A(2A) receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido- adenosine (CGS21680; 0.3-3 microM) enhanced IPSCs evoked by stimulation within the GP. The actions of CGS21680 were blocked by the A(2A) antagonists (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). 3. The CGS21680-induced increase in IPSCs was associated with a reduction in paired-pulse facilitation. CGS21680 (0.3 microM) increased the frequency of miniature IPSCs (mIPSCs) without affecting mIPSC amplitude. These observations demonstrated that the enhancement of IPSCs in the GP was attributable to presynaptic, but not postsynaptic, A(2A) receptors. 4. The results suggest that A(2A) receptors in the GP serve to inhibit GP neuronal activity, thereby disinhibiting subthalamic nucleus neurone activity. Thus, the A(2A) receptor-mediated presynaptic regulation in the GP, together with the A(2A) receptor-mediated intrastriatal presynaptic control of GABAergic neurotransmission described previously, may play a crucial role in controlling the neuronal functions of basal ganglia. This A(2A) receptor-mediated presynaptic dual control in the striatopallidal pathway could also afford the mode of action of A(2A) antagonists for ameliorating the symptoms of Parkinson's disease in an animal model.

Animals↗

Neural circuitry in the regulation of adrenal corticosterone rhythmicity.

Adrenal cortical secretion of glucocorticoids is an essential adaptive response of an organism to stress. Although the hypothalamic-pituitary-adrenal axis regulates the adrenal cortex via release of ACTH, there is strong evidence supporting a role for sympathetic innervation in modulating adrenal glucocorticoid secretion. The dissociation between changes in ACTH and glucocorticoids under non-stress and stress conditions has reinforced the concept that neural control of the adrenal cortex acts to modulate steroidogenic responses to circulating ACTH. A dual control of the adrenal cortex has been implicated in the prominent circadian rhythm in glucocorticoids. However, the central neural substrate for circadian changes in glucocorticoids that are mediated by peripheral neural innervation of the adrenal cortex has not been conclusively delineated. The hypothesis to be addressed is that neurons in the paraventricular nucleus of the hypothalamus receive input from the suprachiasmatic nucleus and project to sympathetic preganglionic neurons in the spinal cord to provide inhibitory and excitatory input to the adrenal cortex that drives the circadian rhythm. This review examines anatomical and physiological evidence that forms the basis for this putative neural circuit.

Adrenal Cortex↗

In vitro permeation study of a mucoadhesive drug delivery system for controlled delivery of nonoxynol-9.

A carbopol 934P-based drug delivery system (AmDDS) was developed to achieve the dual-controlled delivery of Nonoxynol-9 (N-9), a spermicidal agent, and EDTA, a potentiator of spermicidal activity. This gel-type system made intimate contact with vaginal mucosa and maintained an effective drug concentration within the vagina for a prolonged period of time. An existing mathematical model, based on a unilayer diffusion membrane, was applied for describing permeation of N-9 through vaginal mucosa. Vaginal permeation of N-9 from AmDDS was negligible over the initial 5 hr, then increased in a Q versus t pattern, but remained low. A relationship was observed between the permeation rate (Js) of drug through vaginal mucosa and the release flux (Q/t1/2) from AmDDS, which showed that the permeation rate (Js) increased with increased square of the release flux [(Q/t1/2)2] in a hyperbolic manner. This result indicated that release of N-9 from AmDDS is still the rate-limiting step at doses within the tested range. EDTA, at concentration of up to 0.32%, did not change the permeation rate of N-9 through vaginal mucosa. It is thus concluded that the developed AmDDS can control the intravaginal delivery of N-9 as well as its permeation through vaginal mucosa.

Adhesives↗

Spinal cord stimulation for axial low back pain: a prospective, controlled trial comparing dual with single percutaneous electrodes.

STUDY DESIGN: A prospective, controlled, clinical trial comparing single and dual percutaneous electrodes in the treatment of axial low back pain from failed back surgery syndrome. OBJECTIVES: To clarify technical requirements and test the hypothesis that placing two linear arrays in parallel, thereby doubling the number of contacts, improves outcome. SUMMARY OF BACKGROUND DATA: Technical improvements have enhanced outcomes of spinal cord stimulation for chronic axial low back pain. Dual, parallel electrodes reportedly improve these outcomes. METHODS: Acting as their own controls, 20 patients who passed screening with single, 4-contact electrodes received permanent dual, 4-contact electrodes with 7- or 10-mm intercontact distances at the same vertebral level(s). We quantified and compared the technical and clinical results of the single and dual electrodes, adjusting stimulation parameters to specific psychophysical thresholds. RESULTS: Single electrodes provided significant (P < 0.01) advantages in patient- and computer-calculated ratings of pain coverage by paresthesias and in the scaled amplitude necessary to cover the low back, compared with dual 7-mm electrodes. Slight advantages without statistical significance were observed for the single over the dual 10-mm electrodes. Amplitude requirements were significantly lower for the single electrode than for either dual electrode. At long-term follow-up, 53% of patients met the criteria for clinical success. CONCLUSIONS: While we observed disadvantages for dual electrodes in treating axial low back pain, we achieved technical success with single or dual electrodes in most patients and maintained this success clinically with dual electrodes in 53%.

Adult↗

Isolation and characterization of csbB, a gene controlled by Bacillus subtilis general stress transcription factor sigma B.

In the bacterium Bacillus subtilis (Bs), the alternative transcription factor sigma B is activated by environmental stresses to control the expression of a large set of unlinked genes. However, the range of physiological functions mediated by these sigma B-controlled genes is presently unknown. We report here that the newly identified gene csbB is under the dual control of a sigma B-dependent and a sigma B-independent promoter. The predicted product of csbB is a 329 residue protein containing two potential membrane-spanning segments in its C-terminal region, leading us to speculate that one class of sigma B-controlled genes acts to modify the cell envelope as part of the general stress response.

Amino Acid Sequence↗

Dopaminergic inhibition of reproduction in teleost fishes: ecophysiological and evolutionary implications.

In many teleosts, dopamine (DA) exerts direct inhibitory control on gonadotropes, counteracting the stimulatory effect of gonadotropin-releasing hormone (GnRH) on gonadotropin release. This dual control by GnRH and DA has been demonstrated in various adult teleosts and has major implications for aquaculture. Because of its unique life cycle, the European eel has provided a powerful model for demonstrating the key role of DA in the control of puberty. Data from tetrapods suggest that the inhibitory role of DA on reproduction is not restricted to the teleosts. Thus, DA inhibitory control could represent an ancient evolutionary component in the neuroendocrine regulation of reproduction that may have been differentially maintained throughout vertebrate evolution. The intensity of DA inhibition, its main site of action, and its involvement in the control of puberty, seasonal reproduction, ovulation, spermiation, or even sex change may differ among classes of vertebrates, as well as within smaller phylogenetic units such as teleosts or mammals. An inhibitory role for DA has been reported also in some invertebrates, indicating that neuronal DA pathways may have been recruited in various groups of metazoa to participate in the control of reproduction. In addition to the incontestable GnRH neurons, the recruitment of DA neurons for the neuroendocrine control of reproduction provides an additional brain pathway for the integration of various species-specific, internal, and environmental cues. In teleosts, the plasticity of the DA neuroendocrine role may have contributed to their large diversity of biological cycles and to their successful adaptation to various environments.

Animals↗

pH and oxidation-reduction potential control strategy for optimization of nitrogen removal in an alternating aerobic-anoxic system.

An alternating aerobic and anoxic (AAA) system is a continuous-flow, activated-sludge process in which the environmental conditions necessary to meet the specific requirements for aerobic nitrification and anoxic denitrification are created. Because of stricter regulations on wastewater effluent and concerns on energy consumption, the process control of the system is now becoming more important. A bench-scale AAA system with different fixed aeration ratios was operated for more than 8 months to evaluate effects of the total cycle time and aeration ratio on the system performance and to develop a feasible control scheme. With supplemental organic addition, the system shows removal efficiencies of 85 to 90% and 78 to 82% for chemical oxygen demand and total nitrogen, respectively. The oxidation-reduction potential (ORP) and pH profiles indicate that the aerobic cycle can be controlled by a control point (ammonia valley) on the pH profile indicating the end of nitrification and the anoxic cycle controlled by another point (nitrate knee) on the ORP profile signifying the end of denitrification. Thus, a dual control strategy with the pH and ORP control points was used for terminating aerobic-anoxic and initiating anoxic-aerobic cycles in an AAA system. The performance of the online control system is excellent, with a significant energy saving (average aeration ratio, fa = 0.23) as compared to the fixed time systems (fa = 0.33 to approximately 0.5).

Ammonia↗

Mucoid Pseudomonas aeruginosa in cystic fibrosis: signal transduction and histone-like elements in the regulation of bacterial virulence.

The profuse production of the exopolysaccharide alginate results in mucoidy, a critical virulence factor expressed by Pseudomonas aeruginosa during chronic respiratory tract infections in cystic fibrosis. Studies of the regulation of this pathogenic determinant have unravelled at least two levels of control, including bacterial signal transduction systems and histone-like elements. Although only in its initial phase, an understanding of the dual control of mucoidy may help to illuminate adaptive processes that depend on the combination of these regulatory factors. Integration of specific signals transduced by the two-component systems with inputs generated by the general state of bacterial nucleoids may govern the expression of certain virulence determinants and provide a framework facilitating selection of phenotypes successful under particular environmental conditions and selective pressures.

Alginates↗