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PubMedDate not supplied

Clinical implications of combination therapy on the future of asthma management.

Current guidelines for the treatment of moderate persistent asthma list the combination of long-acting beta-agonists and inhaled corticosteroids (ICSs) as the treatment of choice. This decision is based on their efficacy compared with other dual controller combinations such as increased doses of ICSs or adding leukotriene modifiers, especially when the forced expiratory volume in 1 second value is used as the primary comparator. The main purpose of this study is to examine this form of dual controller therapy in terms of anti-inflammatory effects. One of the concerns with the combination of long-acting beta-agonists and ICSs is what happens to patients on this therapy during an asthma exacerbation. The existing data indicate that when combination therapy was compared with high-dose ICSs alone, it did not alter the ability to detect deteriorating asthma, it led to faster recovery after an exacerbation, it did not disguise deteriorating asthma, and it did not increase/mask airway inflammation. This study also examines how to approach patients placed on this dual controller therapy after control of their asthma is attained. Suggestions for the transition from initial therapy to maintenance therapy that may involve single controller medications are made. Innovative methods of handling asthma exacerbations with dual controller therapy also are made.

Administration, Inhalation↗

PubMed1995

[Dual mode control of head movements during eye-head coordination].

Eye-head coordination during the shift of gaze is investigated. Dynamic trajectories of eye movements and head movements were measured for exploring the control mechanism of the head movement in eye-head coordination. The experimental results revealed the dual mode control of the head movement in eye-head coordination: a linear control for small amplitude movement (less than 30 degree), and a Bang-Bang control for larger amplitude.

Eye Movements↗

PubMedDate not supplied

High-speed scanning by dual feedback control in SNOM/AFM.

We have developed a high-speed scanning near-field optical microscope (SNOM)/atomic force microscope (AFM) system including dual feedback controllers. The system includes an additional piezoelectric actuator with fast response in the z direction and a correction circuit to eliminate unnecessary components from the feedback signal. From the measurement of a patterned chromium layer of 2 x 2 microm2 checks on a quartz glass plate, we confirmed that our system had more effective feedback control and faster scanning than current SNOM/AFM systems that use only a piezo-tube. The scanning speed of the present system was estimated to be about five times faster than that of current SNOM/AFM systems.

Journal Article↗

PubMed2026

Efficacy and Safety of a Single-Pill Triple Combination of Valsartan, Amlodipine, and Chlorthalidone in Patients With Essential Hypertension Inadequately Controlled on Dual Therapy With Valsartan and Amlodipine: A Randomized, Double-Blind, Multicenter, Phase 3 Trial.

Many hypertensive patients require three or more antihypertensive agents to achieve target blood pressure. This randomized, double-blind, multicenter phase 3 trial conducted in South Korea evaluated the efficacy and safety of a single-pill triple combination therapy with valsartan (Val), amlodipine (Aml), and chlorthalidone (CTD) in patients whose blood pressure remained inadequately controlled on Val/Aml dual therapy. Patients uncontrolled after 4 weeks of Val/Aml 80/5 mg were randomized 1:1 to either Val/Aml/CTD 80/5/12.5 mg or Val/Aml 80/5 mg using a double-dummy design. After 2 weeks, doses were escalated to Val/Aml/CTD 160/5/25 mg or Val/Aml 160/5 mg, respectively, for a total treatment duration of 6 weeks. The primary endpoint was the change in mean sitting systolic blood pressure (MSSBP) from baseline to week 8. Of 193 randomized patients, 178 completed the study. The least squares mean ± SE change in MSSBP was -19.70 ± 1.31 mmHg in the Val/Aml/CTD group versus -8.71 ± 1.26 mmHg in the control group, yielding a statistically significant between-group difference of -10.99 ± 1.81 mmHg (95% CI, -14.56 to -7.41; p < 0.0001). No serious adverse events occurred in the Val/Aml/CTD group, compared with an incidence of 1.98% in the control group (p = 0.4985). Triple combination therapy with Val/Aml/CTD demonstrated superior blood pressure reduction and a favorable safety profile in patients with essential hypertension inadequately controlled on Val/Aml dual therapy, supporting its use as an effective treatment option in this population. Trial Registration: This trial was prospectively registered at ClinicalTrials.gov (identifier: NCT06416865).

Humans↗

PubMed2007

Dual transcriptional control of claudin-11 via an overlapping GATA/NF-Y motif: positive regulation through the interaction of GATA, NF-YA, and CREB and negative regulation through the interaction of Smad, HDAC1, and mSin3A.

The expression of claudin-11, a key integral tight junction protein, is tightly regulated to ensure that the integrity of the seminiferous epithelium could be maintained during the translocation of spermatocytes at the blood-testis barrier at stages VIII-IX. In this study, we elucidate how the overlapping GATA/NF-Y motif within the core promoter of claudin-11 gene is modulated by differential binding of various transcription factors, resulting in dual transcriptional control. Using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we confirmed that GATA, nuclear factor YA (NF-YA), and cAMP response element-binding protein (CREB) form a complex in vivo and bind to the GATA/NF-Y region to promote claudin-11 gene transcription. Such gene activations were significantly reduced in the presence of siRNA specific to these transcription factors. GATA and CREB transactivation could be further modulated by the presence of Smad3 and Smad4 proteins. Binding of Smad proteins at the GATA/NF-Y motif could repress the GATA and CREB transactivation of claudin-11 gene. Such repression which required the recruitment and physical interactions of histone deacetylase 1 and its co-repressor, mSin3A with Smad proteins, was abolished by treatment with Trichostatin A, thus suggesting the involvement of histone deacetylation at the site of the promoter region. It is believed that cyclic changes in the ratio of positive regulators (GATA, NF-Y, and CREB) to negative regulators (Smads) in the seminiferous epithelium during the spermatogenic cycle might provide a precise control in claudin-11 gene transcription.

Acylation↗

PubMed2006

Dual negative control of spx transcription initiation from the P3 promoter by repressors PerR and YodB in Bacillus subtilis.

The spx gene encodes an RNA polymerase-binding protein that exerts negative and positive transcriptional control in response to oxidative stress in Bacillus subtilis. It resides in the yjbC-spx operon and is transcribed from at least five promoters located in the yjbC regulatory region or in the yjbC-spx intergenic region. Induction of spx transcription in response to treatment with the thiol-specific oxidant diamide is the result of transcription initiation at the P(3) promoter located upstream of the spx coding sequence. Previous studies conducted elsewhere and analyses of transcription factor mutants using transformation array technology have uncovered two transcriptional repressors, PerR and YodB, that target the cis-acting negative control elements of the P(3) promoter. Expression of an spx-bgaB fusion carrying the P(3) promoter is elevated in a yodB or perR mutant, and an additive increase in expression was observed in a yodB perR double mutant. Primer extension analysis of spx RNA shows the same additive increase in P(3) transcript levels in yodB perR mutant cells. Purified YodB and PerR repress spx transcription in vitro when wild-type spx P(3) promoter DNA was used as a template. Point mutations at positions within the P(3) promoter relieved YodB-dependent repression, while a point mutation at position +24 reduced PerR repression. DNase I footprinting analysis showed that YodB protects a region that includes the P(3) -10 and -35 regions, while PerR binds to a region downstream of the P(3) transcriptional start site. The binding of both repressors is impaired by the treatment of footprinting reactions with diamide or hydrogen peroxide. The study has uncovered a mechanism of dual negative control that relates to the oxidative stress response of gram-positive bacteria.

Bacillus subtilis↗

PubMed1987

Energy expenditure in the control of biochemical systems by covalent modification.

Regulation by reversible, covalent modification of proteins requires a continuous expenditure of energy, even in a steady-state situation. The cost of this energy drain is evaluated for the case of an effector controlling the modifying enzyme and an effector controlling the demodifying enzyme and for the case of dual control in which an effector activates one of these enzymes and inhibits the other. Energy consumption is determined when the converter enzymes are functioning in the first-order and zero-order domains. The profile of energy expenditure versus fractional protein modification at steady state varies both as a function of the mechanism of control of the converter enzymes and of the kinetic domain in which they operate. This theory allows one to predict the strategies that would minimize energy costs. Dual control appears to provide maximum sensitivity with minimal energy expenditure. The analysis is applied to two experimental systems. Comparison of ATP turnover rates with rates for individual modification enzymes in living systems shows that a significant fraction of the total energy expenditure of an organism is required for the large number of reactions which involve covalent modification of proteins. It is concluded that there will be selection pressure for energy-efficient control of covalent regulation.

Adenosine Triphosphate↗

PubMed2000

Dual specificity phosphatases: a gene family for control of MAP kinase function.

Mitogen-activated protein (MAP) kinases are important players in signal transduction pathways activated by a range of stimuli and mediate a number of physiological and pathological changes in cell function. MAP kinase activation requires phosphorylation on a threonine and tyrosine residue located within the activation loop of kinase subdomain VIII. This process is reversible even in the continued presence of activating stimuli, indicating that protein phosphatases provide an important mechanism for MAP kinase control. Dual specificity phosphatases (DSPs) are an emerging subclass of the protein tyrosine phosphatase (PTP) gene superfamily, which appears to be selective for dephosphorylating the critical phosphothreonine and phosphotyrosine residues within MAP kinases. Some DSPs are localized to different subcellular compartments and moreover, certain family members appear highly selective for inactivating distinct MAP kinase isoforms. This enzymatic specificity is due in part to powerful catalytic activation of the DSP phosphatase after tight binding of its amino-terminal to the target MAP kinase. DSP gene expression is induced strongly by various growth factors and/or cellular stresses, providing a sophisticated transcriptional mechanism for targeted inactivation of selected MAP kinase activities.

Amino Acid Sequence↗

PubMed2003

Cognitive impairment decreases postural control during dual tasks in geriatric patients with a history of severe falls.

OBJECTIVES: To investigate the influence of dual tasks, cognitive strategies, and fear of falling on postural control in geriatric patients with or without cognitive impairment and with a history of falls resulting in injury. DESIGN: Experimental three-group design. SETTING: Geriatric hospital. PARTICIPANTS: Twenty young healthy adults (mean age+/-standard deviation=25.4+/-4.4), 20 geriatric patients with a history of severe falls without cognitive impairment (mean age=82.6+/-5.5, mean Mini-Mental State Examination (MMSE) score=27.8+/-2.0) and 20 geriatric patients with a history of severe falls and cognitive impairment (mean age=83.2+/-5.5, mean MMSE=19.2+/-3.3). MEASUREMENTS: Motor performance: sway area and lateral and anterior-posterior sway angles. Cognition: semiautomated calculation steps (serial 2 forward) and nonautomated calculation derived from MMSE (serial 7 retro). Motor and cognitive performances were examined as single and dual tasks. Strategy decision, fear of falling, and subjective perception of motor and cognitive performance were assessed as covariates for dual-task performances. RESULTS: Motor performance decreased significantly during all dual tasks in geriatric patients with cognitive impairment and a history of falls resulting in injury. Cognitive performance was different depending on the task and group. Choice of cognitive strategies or fear of falling did not influence the dual-task performances. CONCLUSION: Even simple additional tasks substantially decrease postural stability due to attention-related cognitive deficits in cognitively impaired geriatric patients with a history of severe falls. The findings may help to explain the increased incidence and severity of falls in geriatric patients with cognitive impairment and a history of falls resulting in injury.

Accidental Falls↗

PubMed2001

Mutagenesis and modelling of linoleate-binding to pea seed lipoxygenase.

We have produced a model to define the linoleate-binding pocket of pea 9/13-lipoxygenase and have validated it by the construction and characterization of eight point mutants. Three of the mutations reduced, to varying degrees, the catalytic centre activity (kcat) of the enzyme with linoleate. In two of the mutants, reductions in turnover were associated with changes in iron-coordination. Multiple sequence alignments of recombinant plant and mammalian lipoxygenases of known positional specificity, and the results from numerous other mutagenesis and modelling studies, have been combined to discuss the possible role of the mutated residues in pea 9/13-lipoxygenase catalysis. A new nomenclature for recombinant plant lipoxygenases based on positional specificity has subsequently been proposed. The null-effect of mutating pea 9/13-lipoxygenase at the equivalent residue to that which controlled dual positional specificity in cucumber 13/9-lipoxygenase, strongly suggests that the mechanisms controlling dual positional specificity in pea 9/13-lipoxygenase and cucumber 13/9-lipoxygenase are different. This was supported from modelling of another isoform of pea lipoxygenase, pea 13/9-lipoxygenase. Dual positional specificity in pea lipoxygenases is more likely to be determined by the degree of penetration of the methyl terminus of linoleate and the volume of the linoleate-binding pocket rather than substrate orientation. A single model for positional specificity, that has proved to be inappropriate for arachidonate-binding to mammalian 5-, 12- and 15-lipoxygenases, would appear to be true also for linoleate-binding to plant 9- and 13-lipoxygenases.

Amino Acid Sequence↗

PubMed2002

The neuroanatomical basis of oculomotor disorders: the dual motor control of extraocular muscles and its possible role in proprioception.

Current investigations show that two separate sets of motoneurons control the extraocular eye muscles, and that is there is a dual final common pathway. We propose that one set of motoneurons are the major source of tension generating eye movements, whereas the other may participate in a proprioceptive system concerned more with the exact alignment and stabilization of the eyes. In this article we discuss the structures that may participate in the proprioceptive circuits; and consider several recent publications in the light of this sensory feedback hypothesis, emphasizing the relevance to eye movement disorders.

Animals↗

PubMed1997

Suboptimal dual adaptive control for blood pressure management.

This paper presents a new approach for adaptive control of blood pressure using vasoactive drugs. The idea is to use an adaptive controller that incorporates the concept of duality in the sense of Feldbaum and to consider the cost functional M-steps ahead in time. The dual property means that the control signal is chosen in such a way that estimation of the model parameters and regulation of the output signals are optimally balanced. Extensive computer simulations for different values of M shows that the sample mean of the achieved cost tends asymptotically to a limiting value while the variance is reduced. The proposed subotimal adaptive controller has also an improved transient response when compared to a certainty equivalent controller.

Antihypertensive Agents↗

PubMed1991

Suppression of malignancy targeting the intracellular signal transducing proteins of cAMP: the use of site-selective cAMP analogs, antisense strategy, and gene transfer.

An hypothesis has been presented suggesting that two isoforms of cAMP receptor proteins are crucial effectors in tumorigenesis. The evidence in support of this hypothesis shows that: (1) cAMP transduces dual controls, both positive and negative, on cell growth and differentiation. (2) Such dual controls are respectively governed by two isoforms of cAMP receptor proteins, the type I and type II regulatory subunits of cAMP-dependent protein kinase. (3) In normal physiology, the functional balance of these cAMP receptor isoforms is strictly controlled to meet either stimulation or inhibition of cell growth as it is required, whereas such control is lost in cancer cells. (4) Cancer cells can also be made to differentiate and acquire growth control when the functional balance of these intracellular signal transducers of cAMP is restored by the use of site-selective cAMP analogs, antisense strategy, or gene transfer, suggesting new approaches to cancer therapy.

Animals↗

PubMed2000

Emergency derepression: stringency allows RNA polymerase to override negative control by an active repressor.

The uspA promoter, driving production of the universal stress protein A in response to diverse stresses, is demonstrated to be under dual control. One regulatory pathway involves activation of the promoter by the alarmone guanosine 3',5'-bisphosphate, via the beta-subunit of RNA polymerase, whereas the other consists of negative control by the FadR repressor. In contrast to canonical dual control by activation and repression circuits, which depends on concomitant activation and derepression for induction to occur, the ppGpp-dependent activation of the uspA promoter overrides repression by an active FadR under conditions of severe cellular stress (starvation). The ability of RNA polymerase to overcome repression during stringency depends, in part, on the strength of the FadR operator. This emergency derepression is operative on other FadR-regulated genes induced by starvation and is argued to be an essential regulatory mechanism operating during severe stress.

Bacterial Proteins↗

PubMed2005

Kinematic and EMG characteristics of simple shoulder movements with proprioception and visual feedback.

The objective of this study was to determine if simple, shoulder movements use the dual control hypothesis strategy, previously demonstrated with elbow movements, and to see if this strategy also applies in the absence of visual feedback. Twenty subjects were seated with their right arm abducted to 90 degrees and externally rotated in the scapular plane. Subjects internally rotated to a target position using a custom shoulder wheel at three different speeds with and without visual feedback. Kinematics were collected with a motion analysis system and electromyographic (EMG) recordings of the pectoralis major (PECT), infraspinatus (INFRA), anterior and posterior (ADELT, PDELT) deltoid muscles were used to evaluate muscle activity patterns during movements. Kinematics changed as movement speed increased with less accuracy (p<0.01). Greater EMG activity was observed in the PECT, PDELT, and INFRA with shorter durations for the ADELT, PDELT and INFRA. Movements with only kinesthetic feedback were less accurate (p<0.01) and performed faster (p<0.01) than movements with visual feedback. EMG activity suggests no major difference in CNS control strategies in movements with and without visual feedback. Greater resolution with visual feedback enables the implementation of a dual control strategy, allowing greater movement velocity while maintaining accuracy.

Adult↗

PubMed1975

Amygdala and masseteric reflex. II Mechanism of the diphasic modifications of the reflex elicited from the "defence reaction area". Role of the spinal trigeminal nucleus (pars oralis).

It has been demonstrated (Gary Bobo and Bonvallet 1975) that long-lasting stimulation of the "amygdaloid area for the defence reaction" (basal nucleus, pars magnocellularis) elicits, after an initial facilitation, a delayed inhibition of the monosynaptic masseteric reflex (MR), while stimulation of the amygdalofugal fibers running in the ansa lenticularis provokes an immediate inhibition of the reflex. In present study, the structure which mediates these inhibitions has been identified. Using combined techniques of limited transections, localized coagulations and localized stimulation and recording, it has been demonstrated that these ingibitions are mediated by the rostral portion of the spinal trigeminal nucleus, the subnucleus oralis (NO). After localized coagulation of this nucleus, or after lesions which interrupt slectively the connections between the NO and the masticatory nucleus, long-lasting stimulation of the basal nucleus elicits only well maintained facilitation of the MR. Hence, the delayed decrease in amplitude of the reflex, observed during stimulation of the basal nucleus in the preparations with intact brain, cannot be explained by the reversal of an initial facilitatory influence to an ingibitory one. The one ingibition of the reflex is due to the superimposition, on a background of sustained facilitation of the masseteric motoneurons, of the inhibitory influence exerted on the monosynaptic masseteric circuit by a trigeminal sensory nucleus, itself activated by delayed discharges of the basal nucleus. A tentative representation of the dual control exerted on the masseteric activity by the basal nucleus is given in Fig. 9. The functional implications of this dual control during the "defence reaction" are briefly discussed.

Amygdala↗

PubMed1992

[Lumbar inter-apophyseal arthrosis and bone mineral content: prospective study versus controls with dual photonic absorptiometry and tomodensitometry].

Dual photon absorptiometry (DPA) is a non invasive and repeatable technique to measure vertebral bone mineral content (BMC). This method can be altered, in frontal incidence, by superposition of abnormal calcifications as calcified aorta or interapophyseal arthrosis. The authors studied nineteen females with lumbar apophyseal arthrosis compared with twenty one controls matched by age. Bone densitometry was performed by Am-Ba DPA and monoenergetic computerised tomodensitometry (CT) from L2 to L4. Arthrosis was studied by standard X ray radiographs and CT. Our results showed that inter-apophyseal arthrosis does increase BMC determined by DPA, especially when expressed as linear BMC (g/cm). The body mass index [weight (kg)/size (m2)] also increased these measures by DPA. CT results were, at the opposite, not influenced by osteo-arthrosis nor body mass index. Detailed analysis of DPA pictures allowed to recognize most of patients with osteo-arthrosis and to correct their results by using adjacent vertebral measures (L1) or abandoning pictures of unusual aspect. The authors mentionned necessity to match populations for age and body mass index and to include L1 in routine vertebral bone mineral content determination. By this way they supposed that osteo-arthrosis may not alter lumbar BMC measured with DPA technique.

Absorptiometry, Photon↗

PubMed2000

Sub-regional tissue morphometry in male athletes and controls using dual X-Ray absorptiometry (DXA).

Athletes have traditionally been evaluated for body composition by percent fat, percent muscle, and somatotype. Since the late 1980s, dual X-ray absorptiometry (DXA) has offered total and regional body composition of bone mineral content (BMC), lean tissue and fat, but studies involving athletes are rare (11) and have not included regional tissue distribution. In the present study, DXA was used to compare a total of 121 male subjects belonging to 9 different athletic groups and controls. ANOVA showed total tissue percent BMC, lean tissue, and fat were significantly different between the various athletic groups (p <.001). Regional differences in tissue distribution between different athletic groups affect BMC and lean tissue (p <.001), but not fat (p >.05). However, athletes of the leanest groups had different fat distribution to that of nonexercising controls (p <.01). It appears that fat distribution is nonspecific in its response to exercise, while lean and BMC distributions show highly specific adaptations to specific sports.

Absorptiometry, Photon↗