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PubMed2001

Surround modulation of perceived contrast and the role of brightness induction.

We studied iso- and cross-orientation surround modulation of perceived contrast (contrast-contrast phenomenon) with a contrast-matching method. Our results indicate (1) iso-oriented surrounds at all contrasts suppress perceived contrast of the test pattern. Cross-orientation surrounds, however, tend to enhance the perceived contrast of the test, particularly for high-contrast test patterns. Iso-orientation modulation acts over larger distances than does cross-orientation modulation. Surround modulation of perceived contrast is not accompanied by a simultaneous change of discrimination threshold. (2) Iso-orientation surround suppression is phase insensitive when brightness induction due to local luminance contrast is eliminated by a small center-surround gap. (3) Perceived contrast is similarly affected when the surround spatial frequency is equal to or higher than the center spatial frequency, but lower spatial frequency surrounds markedly enhance perceived contrast as a result of brightness induction. These data indicate that the contrast-contrast phenomenon is often mixed with brightness induction when it is measured with sinusoidal grating stimuli, and we suggest that this may account for some of the individual differences. After excluding the role of brightness induction, surround modulation of perceived contrast appears to be a second-order process that is phase independent and not tuned or very broadly tuned to spatial frequency.

Contrast Sensitivity↗
PubMed2003

Cross- and iso- oriented surrounds modulate the contrast response function: the effect of surround contrast.

The detectability and appearance of visual targets can be modulated by surround stimuli. In this study we asked how cross- and iso-oriented surrounds modulate contrast detection and discrimination in foveal vision. We systematically measured the Threshold-versus-Contrast (TvC) functions over a wide range of pedestal and surround contrasts. Our results show that cross-oriented surrounds lower the contrast threshold over the entire range of pedestal and surround contrasts, but iso-surround modulation of the TvC function is dependent on the relative contrast, being facilitative when the surround/pedestal contrast ratio Csur/Cped < 1 and suppressive when Csur/Cped > 1. Data fitting indicates that cross-surround modulation (facilitation) is mainly due to improved gain, except at very low and high surround contrasts. Iso-surround modulation on the other hand is more complicated, probably reflecting more than one surround process as determined by the relative contrast.

Adult↗
PubMed1992

Constitutive and modulated expression of the human alpha 1 antitrypsin gene. Different transcriptional initiation sites used in three different cell types.

alpha 1-Antitrypsin (alpha 1 AT) is plasma glycoprotein that constitutes the principle inhibitor of neutrophil elastase in tissue fluids. It has been considered a prototype for liver-derived acute phase proteins in that its concentration in plasma increases three- to fourfold during the host response to inflammation/tissue injury. However, recent studies have shown that alpha 1 AT is expressed in several types of extrahepatic cells, including mononuclear phagocytes and enterocytes, and that there are distinct transcriptional units used in hepatocytes and at least one extra-hepatic cell type, blood monocytes. In this study, we have used a combination of ribonuclease protection assays, primer elongation analysis, and transcriptional run-on assays to further characterize mechanisms of basal and modulated alpha 1 AT gene expression in hepatocytes, enterocytes, and macrophages. The hepatoma cell line HepG2, intestinal epithelial cell line Caco2, and primary cultures of human peripheral blood monocytes were used as examples of the cell types. The results indicate that there are three macrophage-specific transcriptional initiation sites upstream from a single hepatocyte-specific transcriptional initiation site. Macrophages use these sites during basal and modulated expression. Hepatoma cells use the hepatocyte-specific transcriptional initiation site during basal and modulated expression but also switch on transcription from the upstream macrophage transcriptional initiation sites during modulation by the acute phase mediator interleukin 6 (IL-6). Caco2 cells use the hepatocyte-specific transcriptional initiation site during basal expression. There is a marked increase in the use of this site and an increase in the rate of transcriptional elongation of alpha 1 AT mRNA during differentiation of Caco2 cells from crypt-type to villous-type enterocytes. Caco2 cells also switch on transcription from the upstream macrophage transcriptional initiation sites during modulation by IL-6. These results provide further evidence that there are differences in the mechanisms of constitutive and regulated expression of the alpha 1 AT gene in at least three different cell types, HepG2-derived hepatocytes, Caco2-derived enterocytes and mononuclear phagocytes.

Base Sequence↗
PubMed2006

Non-ocular circadian oscillators and photoreceptors modulate long term memory formation in Aplysia.

In Aplysia californica, memory formation for long-term sensitization (LTS) and for a more complex type of associative learning, learning that food is inedible (LFI), is modulated by a circadian clock. For both types of learning, formation of long-term memory occurs during the day and significantly less during the night. Aplysia eyes contain a well-characterized circadian oscillator that is strongly coupled to the locomotor activity rhythm. Thus, the authors hypothesized that the ocular circadian oscillator was responsible for the circadian modulation of LFI and LTS. To test this hypothesis, they investigated whether the eyes were necessary for circadian modulation of LFI and LTS. Eyeless animals trained during the subjective day and tested 24 h later demonstrated robust long-term memory for both LFI and LTS, while eyeless animals trained and tested during the subjective night showed little or no memory for LFI or LTS. The amplitude of the rhythm of modulation in eyeless animals was similar to that of intact Aplysia, suggesting that extraocular circadian oscillators were mainly responsible for the circadian rhythms in long-term memory formation. Next, the authors investigated whether the eyes played a role in photic entrainment for circadian regulation of long-term memory formation. Eyeless animals were exposed to a reversed LD cycle for 7 days and then trained and tested for long-term memory using the LFI paradigm. Eyeless Aplysia formed significant long-term memory when trained during the projected shifted day but not during the projected shifted night. Thus, the extraocular circadian oscillator responsible for the rhythmic modulation of long-term memory formation can be entrained by extraocular photoreceptors.

Animals↗
PubMed2002

Reflections across boundaries: the European nursing module.

This article explores the development and implementation of an internationally agreed module, the European Nursing Module. This module comprises 4 weeks of student learning and is coordinated by a network of 26 colleges in 14 European countries. It is hoped that through the module, students are helped to acquire cultural sensitivity, which leads toward the development of a culturally competent health care practitioner. The development of the module, the student experience, and the added value of the network are shared. It is argued that considerable cultural learning can occur from short international electives when students and teaching staff are well prepared and sensitised to cultural issues prior to their exchange.

Attitude of Health Personnel↗
PubMed2001

Gain modulation in the central nervous system: where behavior, neurophysiology, and computation meet.

Gain modulation is a nonlinear way in which neurons combine information from two (or more) sources, which may be of sensory, motor, or cognitive origin. Gain modulation is revealed when one input, the modulatory one, affects the gain or the sensitivity of the neuron to the other input, without modifying its selectivity or receptive field properties. This type of modulatory interaction is important for two reasons. First, it is an extremely widespread integration mechanism; it is found in a plethora of cortical areas and in some subcortical structures as well, and as a consequence it seems to play an important role in a striking variety of functions, including eye and limb movements, navigation, spatial perception, attentional processing, and object recognition. Second, there is a theoretical foundation indicating that gain-modulated neurons may serve as a basis for a general class of computations, namely, coordinate transformations and the generation of invariant responses, which indeed may underlie all the brain functions just mentioned. This article describes the relationships between computational models, the physiological properties of a variety of gain-modulated neurons, and some of the behavioral consequences of damage to gain-modulated neural representations.

Animals↗
PubMed2004

Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy.

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

In vitro testing of elastomeric modules.

This study describes the in vitro testing of elastomeric modules. Measurements were first made from study models to establish the clinical distance over which modules are used for canine retraction. From this preliminary study, a typodont, banded with 0.018" x 0.025" standard edgewise brackets, was set up with the canine-molar distance at 28 mm. Modules for canine retraction were then fitted by 11 clinicians. The applied force ranged from 125 to 310 g (221 +/- 51 g). A similar, but more extensive study using six different types of modules and two clinician groups (experienced and less experienced clinicians) was then undertaken. Mean force values for different module types ranged from 195 +/- 45 g to 318 +/- 90 g. There was no statistically significant difference between the force values applied by experienced and less experienced clinicians.

Cuspid↗
PubMed2003

Transient down-modulation of CD20 by rituximab in patients with chronic lymphocytic leukemia.

Lymphoid cells in most patients with chronic lymphocytic leukemia (CLL), when treated with rituximab, become CD20-. This is thought to be due to masking of CD20 by rituximab. We used specific antimouse immunoglobulin antibodies to detect rituximab on the surface of CLL lymphocytes and we demonstrate that rituximab is rarely detectable after therapy. Only 3 of 65 patients with CLL had rituximab detectable on their lymphocytes after rituximab therapy despite the fact that most had no detectable CD20 expression. In vitro mixing of CLL or Raji cells with rituximab demonstrated that rituximab was detectable on the surface of cells due to its binding to CD20. However, the addition of plasma led to the down-modulation of CD20 expression, and the rituximab became undetectable. This down-modulation of CD20 protein expression was associated with a down-modulation of CD20 mRNA. CLL cells that lost their CD20 expression regained CD20 expression after 24 hours in culture. These data suggest that rituximab therapy leads to a substantial but transient down-modulation of CD20 expression and that negativity for CD20 in cells from patients treated with rituximab is not necessarily due to CD20 masking. The importance of this down-modulation in the efficacy of current therapy with rituximab needs further investigation.

Antibodies, Monoclonal↗
PubMed2006

Dopamine presynaptically and heterogeneously modulates nucleus accumbens medium-spiny neuron GABA synapses in vitro.

BACKGROUND: The striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections. RESULTS: We examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABAA, GABAB, norepinephrine and serotonin modulation, revealing a multiplicity of modulatory autoreceptors and heteroreceptors on individual varicosities. In some instances, autaptic connections had two components that were differentially modulated by dopamine agonists, suggesting that dopamine receptors could be distributed heterogeneously on the presynaptic varicosities making up a single synaptic (i.e. autaptic) connection. CONCLUSION: Differential trafficking of dopamine receptors to different presynaptic varicosities could explain the many controversial studies reporting widely varying degrees of dopamine receptor colocalization in medium-spiny neurons, as well as more generally the diversity of dopamine actions in target areas. Longer-term changes in the modulatory actions of dopamine in the striatal complex could be due to plasticity in the presynaptic distribution of dopamine receptors on medium-spiny neuron varicosities.

Animals↗
PubMed2005

The outcomes of using self-study modules in energy conservation education for people with multiple sclerosis.

OBJECTIVE: To determine whether there were any differences in the outcomes of individuals with multiple sclerosis who attended all six sessions of an energy conservation education programme compared with people who missed a session and received a self-study module. DESIGN: Secondary analysis of data from two naturally occurring groups emerging from a randomized control trial--compliers who received the intervention as intended (group 1) and noncompliers who received a modified intervention with self-study modules (group 2). SETTING: Community settings in Chicago, Illinois and Minneapolis, Minnesota, USA. PARTICIPANTS: Ninety-two community-dwelling people with multiple sclerosis who were participating in an energy conservation education programme. INTERVENTION: Energy conservation education groups based on the 'Managing Fatigue' programme, which were facilitated by an occupational therapist. Self-study modules were sent to participants who missed a session. OUTCOME MEASURES: Fatigue Impact Scale (FIS), Self-Efficacy for Performing Energy Conservation Strategies Assessment, Energy Conservation Strategies Survey (ECSS), six subscales from the Medical Outcomes Study Short-Form Health Survey (SF-36). RESULTS: When comparing individuals who attended all six sessions with individuals who missed one or more sessions and received a self-study module, no significant differences were found after adjusting for multiple comparisons. CONCLUSIONS: Participants who used the self-study modules because they missed sessions of the Managing Fatigue programme experienced benefits from the course similar to those experienced by participants who fully complied with the intervention as intended. A new prospective study to validate the findings of this secondary analysis is required.

Energy Metabolism↗
PubMed2005

The human LGR7 low-density lipoprotein class A module requires calcium for structure.

The relaxin and INSL3 receptors, LGR7 and LGR8, are the only human G-protein-coupled receptors to contain a low-density lipoprotein class-A (LDL-A) module. LDL-A modules are well characterized in a variety of diverse biological functions that involve ligand binding to elicit a response. Common features of the LDL-A modules characterized to date are the conservation of three disulfide bonds and the structural arrangement around a bound calcium ion. In this study we recombinantly produce the human LGR7 LDL-A module for NMR studies and demonstrate that calicum is required for the module to form a stable and correctly folded structure.

Amino Acid Motifs↗
PubMed2004

Volume-sensitive organic osmolyte/anion channels in cancer: novel approaches to studying channel modulation employing proteomics technologies.

Key elements of tumor development include proliferation, migration, invasiveness, and angiogenesis. Activation of the volume-sensitive organic osmolyte/anion channel (VSOAC) has been suggested to play a role in all of these processes. VSOACs may therefore represent an important therapeutic target in the etiology of cancer. However, pharmacological inhibitors of VSOAC are nonselective and of low potency, highlighting the importance of identifying novel regulators of the channel. The use of electrophysiological methods coupled with techniques such as pull-down assays, yeast 2-hybrid, and functional protein arrays have already proved valuable in studying protein-protein interactions in a variety of systems. Some of these methods have been used to identify small molecules that modulate the function of other types of ion channels. Given that several proteins have already been identified as putative modulators of VSOACs, proteomics technologies may prove useful in elucidating the molecular identity of VSOACs and helpful in identifying novel modulators of channel function. In this paper, we review the involvement of VSOACs in tumor development processes and its regulation by pharmacological agents and cellular proteins. Proteomic approaches to study protein-protein interactions and how such approaches may be used to study VSOACs are also discussed. We speculate on how modulation of protein-protein interactions may result in the identification of a novel class of compounds for modulating VSOACs.

Animals↗
PubMed1996

The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study.

PURPOSE: To construct a breast cancer-specific quality-of-life questionnaire (QLQ) module to be used in conjunction with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and to test its reliability and validity cross-culturally. PATIENTS AND METHODS: Module construction took place after the EORTC guidelines for module development. The module--the QLQ-BR23--consists of 23 items covering symptoms and side effects related to different treatment modalities, body image, sexuality, and future perspective. This module was tested in 170 Dutch, 168 Spanish, and 158 American cancer patients at two points in time. The timing for the Dutch and Spanish patients was before and during treatment with radiotherapy or chemotherapy. For the American patients, the questionnaire was administered at admission at the breast clinic and 3 months after the first assessment. RESULTS: Multitrait scaling analysis confirmed the hypothesized structure of four of the five scales. Cronbach's alpha coefficients were, in general, lowest in Spain (range; .46 to .94) and highest in the United States (range; .70 to .91). On the basis of known-groups comparisons, selective scales distinguished clearly between patients differing in disease stage, previous surgery, performance status, and treatment modality, according to expectation. Additionally, selective scales detected change over time as a function of changes in performance status and treatment-induced change. CONCLUSION: These results lend support to the clinical and cross-cultural validity of the QLQ-BR23 as a supplementary questionnaire for assessing specific quality-of-life issues relevant to patients with breast cancer.

Adult↗
PubMed2003

Na(+)-channel modulation, a new principle of inotropic intervention: effects on hemodynamic and myocardial energetics in the immature rabbit heart.

Na+-channel modulators exert their positive inotropic action without affecting the adenylate-cyclase pathway by an increase in the open probability of the sarcolemmal Na+ channels. Although inotropic effects in neonatal hearts are less pronounced compared with adult hearts, the Na+-channel modulator BDF 9148 increases contractility and relaxation velocity in immature myocardium. Effects on hemodynamics and myocardial energetics are not known. Therefore, we studied the Na+-channel modulator BDF 9148 in isolated antegrade perfused rabbit hearts of different ages (2-28 d) and compared the effects with isoproterenol, enoximone, and ouabain. ANOVA showed significant effects in the concentration response curves for heart rate, stroke volume, cardiac output, and oxygen consumption but not for myocardial efficiency (p = 0.06). Age-dependent differences were observed for heart rate and stroke volume. Administration of BDF 9148 resulted in a maximal increase in stroke volume and cardiac output up to 25% in neonatal and 40% to 60% in adult preparations. Heart rate decreased by 15% in adult hearts only. Myocardial oxygen consumption was increased in a concentration-dependent manner between 25% in neonatal and 50% in adult hearts. Myocardial efficiency was increased by 35% in adult and by 10% in neonatal preparations. Although positive hemodynamic and energetic effects were less pronounced in immature compared with adult hearts, neonatal hearts also profited from the administration of the Na+-channel modulator BDF 9148. Further studies are necessary to clarify the risk of arrhythmia during application of Na+-channel modulators such as BDF 9148.

Age Factors↗
PubMed2005

Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes.

Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.

Analysis of Variance↗
PubMed1979

Cyclic nucleotide-dependent protein kinase modulators in thyroid tissue.

A heat-stable protein which inhibits cAMP dependent protein kinase was prepared from the bovine thyroid 100,000 X g supernatant. This protein inhibited the cAMP-dependent protein kinase both from bovine thyroid cytosol and bovine thyroid plasma membranes. The inhibitory effect was noncompetitive with histone as substrate of the cytosolic enzyme. The stimulatory modulator for cGMP-dependent protein kinase was separated from the 100,000 X g supernatant by Sephadex G-100 gel filtration. The stimulatory modulator had no stimulating effect on cAMP-dependent phosphorylation, and the inhibitory modulator of cAMP-dependent enzyme had no effect on cGMP-requiring phosphorylations. The inhibitory modulator may regulate cAMP-dependent protein kinase activity in cytosol and plasma membrane, and the stimulatory modulator for cGMP-dependent protein kinase may have a role in thyroid function independent of the cAMP-requiring system.

Animals↗
PubMed1987

Insulin generates an enzyme modulator from hepatic plasma membranes: regulation of adenosine 3',5'-monophosphate phosphodiesterase, pyruvate dehydrogenase, and adenylate cyclase.

Some of the acute actions of insulin may be mediated by the intracellular generation of a chemical substance that modulates certain enzymes. Such a substance has been identified which is released from liver plasma membranes after exposure to insulin. This substance was purified on sequential ion exchange, reverse phase, and gel permeations columns. The purified substance modulated the activities of cAMP phosphodiesterase, adenylate cyclase, and pyruvate dehydrogenase. The activities that modulated each of these enzymes exhibited singular chromatographic behavior and sensitivity to a variety of chemical reagents. Each activity was also produced by treatment of membranes with a phosphatidylinositol-specific phospholipase C. These results suggested that each of the enzyme-modulating activities was due to a single complex carbohydrate substance which contained inositol, phosphate, glucosamine, and other monosaccharides. The actions of this substance on these three enzymes mimicked those of insulin, suggesting that the release of this enzyme modulator might play a role in mediating some of the actions of the hormone.

3',5'-Cyclic-AMP Phosphodiesterases↗