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At least 1,657 records · Page 92Linked to original sources
PubMed1999

Prolonged allograft survival but no tolerance induction by modulating CD28 antibody JJ319 after high-responder rat heart transplantation.

BACKGROUND: Allograft rejection depends on T cell immune responses requiring antigen recognition and costimulatory signals through accessory T cell receptors, including CD28. Inhibition of CD28 signaling with a CTLA-4-immunoglobulin (Ig) fusion protein has resulted in immunosuppression and occasional T cell anergy in mouse transplant models, but not in rats. Because this approach also inhibits a potentially tolerizing signal through CTLA-4, selective blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance. METHODS: The effects of escalating doses of the rat CD28 monoclonal antibody JJ319 on allograft survival were studied after vascularized heterotopic heart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by flow cytometry. RESULTS: CD28 antibody JJ319 markedly prolonged cardiac graft survival compared with untreated controls (7 days, range: 6-8). A strictly dose-dependent increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p <0.001) after the administration of 8 x 1 mg JJ319 i.p. (days -1 to +6 before/after transplantation). However, indefinite graft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 receptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed significantly reduced responses to activation. CONCLUSIONS: CD28 antibody JJ319 induces profound immunosuppression after rat heart transplantation, however without development of transplant tolerance. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, there are no qualitative or quantitative differences to the treatment with CTLA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere. Thus, a CD28-modulating approach seems not to allow therapeutic exploitation of a tolerizing signal delivered by CTLA-4 but may still be clinically applicable, especially in combined immune interventions.

Abatacept↗
PubMedDate not supplied

Improving the human readability of Arden Syntax medical logic modules using a concept-oriented terminology and object-oriented programming expressions.

Medical logic modules are a procedural representation for sharing task-specific knowledge for decision support systems. Based on the premise that clinicians may perceive object-oriented expressions as easier to read than procedural rules in Arden Syntax-based medical logic modules, we developed a method for improving the readability of medical logic modules. Two approaches were applied: exploiting the concept-oriented features of the Medical Entities Dictionary and building an executable Java program to replace Arden Syntax procedural expressions. The usability evaluation showed that 66% of participants successfully mapped all Arden Syntax rules to Java methods. These findings suggest that these approaches can play an essential role in the creation of human readable medical logic modules and can potentially increase the number of clinical experts who are able to participate in the creation of medical logic modules. Although our approaches are broadly applicable, we specifically discuss the relevance to concept-oriented nursing terminologies and automated processing of task-specific nursing knowledge.

Attitude of Health Personnel↗
PubMedDate not supplied

Intensity-modulated radiation therapy (IMRT) reduces the dose to the contralateral breast when compared to conventional tangential fields for primary breast irradiation: initial report.

PURPOSE: This study was designed to compare the dose received by the contralateral breast during primary breast irradiation using intensity-modulated radiotherapy with the dose received via conventional tangential field techniques. METHODS/MATERIALS: Between March 2003 and March 2004, 44 patients with breast carcinoma were treated using 6-, 10-, or mixed 6/18-MV photons(36 with tangential intensity-modulated radiotherapy technique and eight with three-dimensional technique using tangential fields with wedges) for primary breast irradiation after breast-conserving surgery. Paired thermoluminescent dosimeters were placed on each patient's contralateral breast, 4 cm from the center of the medial border of the tangential field. The thermoluminescent dosimeters were left on the patient during a single fraction and then measured 24 hours later. RESULTS: The mean dose delivered with photons to the primary breast for all patients was 4998 cGy [SD = 52], and the mean single fraction dose was 200 cGy [SD = 9]. The mean percent of the prescribed dose to the contralateral breast was 7.74% (SD = 2.35) for patients treated with intensity-modulated radiotherapy, compared with 9.74% [SD = 2.04] for the patients treated with conventional tangential field techniques. This represented a 20% reduction in the mean dose to the contralateral breast with the use of intensity-modulated radiotherapy when compared with the dose received via the three-dimensional technique, a result that was statistically significant. CONCLUSION: Primary breast irradiation with tangential intensity-modulated radiotherapy technique significantly reduces the dose to the contralateral breast when compared with conventional tangential techniques.

Breast Neoplasms↗
PubMed2006

Nutrients with immune-modulating effects: what role should they play in the intensive care unit?

PURPOSE OF REVIEW: This review will summarize recent clinical and experimental data on the use of immune-modulating nutrients in critical illness. It will present the concept of these nutrients as pharmacologic agents or 'nutraceuticals' administered in addition to protein, calorie, vitamin, and trace element sources. RECENT FINDINGS: Studies have defined the physiologic roles of arginine in critical illness, such as its role as a precursor for the production of nitric oxide. Investigations have determined that, in critical illness, glutamine levels decrease and severe glutamine deficiency is associated with increased mortality. Experimental studies have revealed that glutamine attenuates proinflammatory cytokine responses, improves gut barrier and immune cell functions, increases the ability to mount a stress response, and decreases mortality. Clinical trials and meta-analyses of studies testing immune-modulating nutritional formulations have reported numerous benefits but also some conflicting results. Dose and route of administration are key factors that influence the benefit, or lack thereof, of these nutraceuticals. SUMMARY: Cumulative studies of enteral immune-modulating nutritional formulations report benefits in surgical critically ill patients such as burn, trauma, or gastrointestinal surgery populations. Conflicting data in patients with sepsis warrant concern and further evaluation; in particular, controversy seems to stem around the use of arginine. Glutamine is beneficial when given in high doses or via the parenteral route (>0.20-0.30 g/kg per day or >or=30 g/day). Providing both omega-3 and omega-6 polyunsaturated fatty acids is important in immune modulation. The best doses and combinations of immune-modulating components remain unclear.

Arginine↗
PubMed2006

Down-modulation of granulocyte macrophage-colony stimulating factor receptor on monocytes during human septic shock.

OBJECTIVE: Loss of surface human leukocyte antigen-DR (HLA-DR) on monocytes is a major factor of immunosuppression in sepsis. Granulocyte macrophage-colony stimulating factor (GM-CSF) up-regulates HLA-DR expression on monocytes via the GM-CSF receptor (GM-CSFr) through a transcriptional mechanism involving the class II transactivator factor (CIITA). We investigated monocyte GM-CSFr expression and its relationship with HLA-DR in septic patients. DESIGN: Prospective clinical experimental study. SETTING: University hospital intensive care unit and research facility. PATIENTS: Septic patients with and without septic shock, control patients. INTERVENTIONS: Flow cytometry and real-time quantitative reverse polymerase chain reaction were used to characterize GM-CSFr expression and transcription in septic patients and in ex vivo stimulated healthy monocytes. MEASUREMENTS AND MAIN RESULTS: We showed an early GM-CSFr down-modulation in patients with septic shock compared with those without septic shock and controls. A persistent low GM-CSFr expression was observed in patients who acquired secondary infections or in those who died, and this persistent defect correlated with severity scores. We demonstrated that GM-CSFr down-modulation occurs at a posttranscriptional level since we observed no alteration in GM-CSFr transcription in monocytes isolated from septic patients. Furthermore, we demonstrated that GM-CSFr expression levels on monocytes correlated not only with HLA-DR expression and transcription levels but also with RNA levels of its main transcriptional factor CIITA. Because we previously showed in septic patients a relationship between high cortisol plasma level and low monocyte HLA-DR expression, we investigated the effects of glucocorticoids on monocyte GM-CSFr expression and observed a similar posttranscriptional down-modulation of GM-CSFr by steroids. However, the in vivo putative role of steroids in HLA-DR down-regulation via GM-CSFr down-modulation needs further investigation. CONCLUSION: Monocyte GM-CSFr down-modulation occurred in septic shock, was associated with severity, and might be either another manifestation of monocyte deactivation linked to sepsis or an additional mechanism participating in immunosuppression.

Adult↗
PubMed2007

Increased oxidative stress impairs endothelial modulation of contractions in arteries from spontaneously hypertensive rats.

OBJECTIVES: The endothelium modulates vascular contractions. We investigated the effects of oxidative stress on endothelial modulation of contractions in hypertension. METHODS: Changes in isometric tension of femoral arterial rings from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were recorded. RESULTS: The contractile response to norepinephrine of arteries with endothelium was greater in SHR than in WKY rats (P < 0.0001). Endothelium removal augmented the norepinephrine-induced contraction (P < 0.05). The augmentation was more pronounced in WKY than in SHR, which resulted in comparable contraction of arteries without endothelium in both strains. Nomega-nitro-L-arginine methyl ester (100 micromol/l) mimicked the effect of endothelium removal. Production of nitric oxide (NO, assessed by measuring nitrite/nitrate concentrations) during the contraction was not different between SHR and WKY. Vitamin C suppressed the contraction of arteries with endothelium from SHR but not from WKY (P < 0.05). Diphenyleneiodonium and apocynin, inhibitors of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase, attenuated the contraction of arteries with endothelium from SHR (P < 0.001) but not WKY, but did not affect contractions induced by serotonin. Superoxide generated by xanthine oxidase/hypoxanthine enhanced the norepinephrine-induced contraction of arteries with endothelium from WKY (P < 0.0001), and this effect was reversed by vitamin C. CONCLUSIONS: In rat femoral arteries, NO released from the endothelium modulates vascular contraction. In SHR, production of superoxide by NADH/NADPH oxidase, which may be activated by norepinephrine, is enhanced, resulting in the inactivation of NO and impairment of endothelial modulation of vascular contractions. Vascular oxidative stress may contribute to the altered circulation in hypertension by impairing endothelial modulation of vascular contractions.

Animals↗
PubMed2005

A network of transcriptionally coordinated functional modules in Saccharomyces cerevisiae.

Recent computational and experimental work suggests that functional modules underlie much of cellular physiology and are a useful unit of cellular organization from the perspective of systems biology. Because interactions among modules can give rise to higher-level properties that are essential to cellular function, a complete knowledge of these interactions is necessary for future work in systems biology, including in silico modeling and metabolic engineering. Here we present a computational method for the systematic identification and analysis of functional modules whose activity is coordinated at the level of transcription. We applied this method, Search for Pairwise Interactions (SPIN), to obtain a global view of functional module connectivity in Saccharomyces cerevisiae and to provide insight into the biological mechanisms underlying this coordination. We also examined this global network at higher resolution to obtain detailed information about the interactions of particular module pairs. For instance, our results reveal possible transcriptional coordination of glycolysis and lipid metabolism by the transcription factor Gcr1p, and further suggest that glycolysis and phosphoinositide signaling may regulate each other reciprocally.

Gene Expression Profiling↗
PubMed2005

De novo discovery of a tissue-specific gene regulatory module in a chordate.

We engage the experimental and computational challenges of de novo regulatory module discovery in a complex and largely unstudied metazoan genome. Our analysis is based on the comprehensive characterization of regulatory elements of 20 muscle genes in the chordate, Ciona savignyi. Three independent types of data we generate contribute to the characterization of a muscle-specific regulatory module: (1) Positive elements (PEs), short sequences sufficient for strong muscle expression that are identified in a high-resolution in vivo analysis; (2) CisModules (CMs), candidate regulatory modules defined by clusters of overrepresented motifs predicted de novo; and (3) Conserved elements (CEs), short noncoding sequences of strong conservation between C. savignyi and C. intestinalis. We estimate the accuracy of the computational predictions by an analysis of the intersection of these data. As final biological validation of the discovered muscle regulatory module, we implement a novel algorithm to search the genome for instances of the module and identify seven novel enhancers.

Animals↗
PubMedDate not supplied

Opioid modulation of Fos protein expression and olfactory circuitry plays a pivotal role in what neonates remember.

Paradoxically, fear conditioning (odor-0.5 mA shock) yields a learned odor preference in the neonate, presumably due to a unique learning and memory circuit that does not include apparent amygdala participation. Post-training opioid antagonism with naltrexone (NTX) blocks consolidation of this odor preference and instead yields memory of a learned odor aversion. Here we characterize the neural circuitry underlying this switch during memory consolidation. Experiment 1 assessed post-training opioid modulation of Fos protein expression within olfactory circuitry (olfactory bulb, piriform cortex, amygdala). Odor-shock conditioning with no post-training treatment (odor preference) induced significant changes in Fos protein expression in the granule cell layer of the olfactory bulb and anterior piriform cortex. Post-training opioid receptor antagonism (odor aversion) prevented the learning-induced changes in the anterior piriform cortex and also induced significant changes in Fos protein expression in the central nucleus of the amygdala. Experiment 2 assessed intra-amygdala opioid modulation of neonate memory consolidation. Post-training infusion of NTX within the amygdala permitted consolidation of an odor aversion, while vehicle-infused pups continued to demonstrate an odor preference. Overall, results demonstrate that opioids modulate memory consolidation in the neonate via modulating Fos protein expression in olfactory circuitry. Furthermore, these results suggest that opioids are instrumental in suppressing neonate fear behavior via modulating the amygdala.

Amygdala↗
PubMed2000

Laser pulse modulation instabilities in plasma channels

In this paper the modulational instability associated with propagation of intense laser pulses in a partially stripped, preformed plasma channel is analyzed. In general, modulation instabilities are caused by the interplay between (anomalous) group velocity dispersion and self-phase modulation. The analysis is based on a systematic approach that includes finite-perturbation-length effects, nonlinearities, group velocity dispersion, and transverse effects. To properly include the radial variation of both the laser field and plasma channel, the source-dependent expansion method for analyzing the wave equation is employed. Matched equilibria for a laser beam propagating in a plasma channel are obtained and analyzed. Modulation of a uniform (matched) laser beam equilibrium in a plasma channel leads to a coupled pair of differential equations for the perturbed spot size and laser field amplitude. A general dispersion relation is derived and solved. Surface plots of the spatial growth rate as a function of laser beam power and the modulation wave number are presented.

Journal Article↗
PubMed2001

Stability of modulated-gravity-induced thermal convection in magnetic fields.

A stability analysis is presented of modulated-gravity-induced thermal convection in a heated fluid layer subject to an applied magnetic field. The nearest correction to the critical Rayleigh number for both single and multiple frequency oscillating-gravity components is obtained by solving the linearized magnetohydrodynamic equations using the small parameter perturbation technique. The correction depends on both the applied magnetic field and the oscillating frequency. In the absence of an applied magnetic field, the correction depends on the Prandtl number only when the exciting frequency is small. However, it asymptotically approaches zero as the frequency increases, with or without the presence of a magnetic field. The heated fluid layer is more stable with gravity modulation than with any type of wall temperature modulation. The difference becomes smaller with decreasing Prandtl number Pr. This finding is of critical importance in that ground-based experiments with appropriate wall temperature modulations may be conducted to simulate the oscillating-gravity effects on the onset of thermal convection in lower-Prandtl-number fluids. For conducting melts considered for microgravity applications, it is possible to apply an external magnetic field to further inhibit the onset of modulated-gravity-induced thermal convection. This effectiveness increases with the Hartmann number Ha. For large Ha, the nearest correction term R02 approximately Ha2 as the magnetic Prandtl number Pm<<1. However, R02 approximately Ha(4/3) for Ha>>1 and Pm>>1, provided that Ha<0.5pi(Pm/Pr(3/2)), which is satisfied by a majority of space melt experiments. Thus, under normal laboratory conditions applied magnetic fields are more effective in stabilizing a conducting fluid subject to an oscillating-gravity field than one subject to a constant field. If Ha>0.5pi(Pm/Pr(3/2)), R02 approximately -Ha2 for Ha>>1 and Pm>>1 and the magnetic field becomes less effective in stabilizing thermal convection driven by oscillating gravity than that driven by the constant gravity. This is in contrast with the existing studies on thermal convection stability in a magnetic field, which show that marginal stability is independent of Pm and always increases with increasing applied field.

Journal Article↗
PubMed2002

Monte Carlo simulation of sinusoidally modulated superlattice growth.

The fabrication of ZnSe/ZnTe superlattices grown by the process of rotating the substrate in the presence of an inhomogeneous flux distribution instead of the successively closing and opening of source shutters is studied via Monte Carlo simulations. It is found that the concentration of each compound is sinusoidally modulated along the growth direction, caused by the uneven arrival of Se and Te atoms at a given point of the sample, and by the variation of the Te/Se ratio at that point due to the rotation of the substrate. In this way we obtain a ZnSe(1-x)Tex alloy in which the composition x varies sinusoidally along the growth direction. The period of the modulation is directly controlled by the rate of the substrate rotation. The amplitude of the compositional modulation is monotonic for small angular velocities of the substrate rotation, but is itself modulated for large angular velocities. The average amplitude of the modulation pattern decreases as the angular velocity of substrate rotation increases and the measurement position approaches the center of rotation. The simulation results are in good agreement with previously published experimental measurements on superlattices fabricated in this manner.

Journal Article↗
PubMed2003

Modulational instability arising from collective Rayleigh scattering.

It is shown that under certain conditions a collection of dielectric Rayleigh particles suspended in a viscous medium and enclosed in a bidirectional ring cavity pumped by a strong laser field can produce a new modulational instability transverse to the wave-propagation direction. The source of the instability is collective Rayleigh scattering i.e., the spontaneous formation of periodic longitudinal particle-density modulations and a backscattered optical field. Using a linear stability analysis a dispersion relation is derived which determines the region of parameter space in which modulational instability of the backscattered field and the particle distribution occurs. In the linear regime the pump is modulationally stable. A numerical analysis is carried out to observe the dynamics of the interaction in the nonlinear regime. In the nonlinear regime the pump field also becomes modulationally unstable and strong pump depletion occurs.

Journal Article↗
PubMed2006

Renewal, modulation, and superstatistics in times series.

We consider two different approaches, to which we refer to as renewal and modulation, to generate time series with a nonexponential distribution of waiting times. We show that different time series with the same waiting time distribution are not necessarily statistically equivalent, and might generate different physical properties. Renewal generates aging and anomalous scaling, while modulation yields no significant aging and either ordinary or anomalous diffusion, according to the dynamic prescription adopted. We show, in fact, that the physical realization of modulation generates two classes of events. The events of the first class are determined by the persistent use of the same exponential time scale for an extended lapse of time, and consequently are numerous; the events of the second class are identified with the abrupt changes from one to another exponential prescription, and consequently are rare. The events of the second class, although rare, determine the scaling of the diffusion process, and for this reason we term them as crucial events. According to the prescription adopted to produce modulation, the distribution density of the time distances between two consecutive crucial events might have, or not, a diverging second moment. In the former case the resulting diffusion process, although going through a transition regime very extended in time, will eventually become anomalous. In conclusion, modulation rather than ruling out the action of renewal events, produces crucial events hidden by clouds of exponential events, thereby setting the challenge for their identification.

Journal Article↗
PubMed2006

Multicolored coherent population trapping in a system using phase modulated fields.

We demonstrate the simultaneous occurrence of coherent population trapping at a series of frequencies separated by modulation frequency of phase-modulated fields. The two arms of the system are coupled to two phase-modulated fields and the response of the atomic system to such fields is calculated nonperturbatively. A judicious choice of modulation characteristics allows one to selectively switch on or off the occurrence of coherent population trapping at specific frequencies. A new technique is developed to compute two-dimensional tridiagonal matrix equations. This generalized technique provides the vital methodology needed to calculate the response of such systems in the strong modulation regime and for arbitrary field strengths.

Journal Article↗
PubMed2002

The incommensurate modulation of the structure of Sr2Nb2O7.

The incommensurately modulated structure of Sr(2)Nb(2)O(7) at room temperature is reported, as determined by single-crystal X-ray diffraction. The crystal structure of Sr(2)Nb(2)O(7) comprises slabs with a perovskite-type structure that are separated by planes of additional O atoms. The driving force for the modulation is shown to be internal strain around the Sr atoms that lie at the interface between the slabs. At room temperature, Sr(2)Nb(2)O(7) crystallizes in the superspace group Cmc2(1)(alpha00)0s0, with lattice parameters a = 3.9544 (7), b = 26.767 (6) and c = 5.6961 (8) A. The modulation wave vector is determined as q = 0.488 (3) a(*). X-ray diffraction data were collected at a synchrotron using a CCD area detector. A total of 3626 unique main reflections and 1262 unique first-order satellites with I > 3sigma(I) were obtained. Refinements using a single harmonic modulation wave converged at R = 0.057 (R = 0.051 for the main reflections and R = 0.121 for the satellite reflections). The modulated structure is interpreted in terms of rotations of NbO(6) octahedra and displacements of the Sr atoms.

Journal Article↗
PubMed2003

The modulated structure of Ba0.39Sr0.61Nb2O6. I. Harmonic solution.

The structure of a crystal of Sr(0.61)Ba(0.39)Nb(2)O(6) has been solved and refined as an incommensurate structure in five-dimensional superspace. The structure is tetragonal, superspace group P4bm(pp1/2,p - p1/2), unit-cell parameters a = 12.4566 (9), c = 7.8698 (6) A, modulation vectors q(1) = 0.3075 (6) (a* + b*), q(2) = 0.3075 (6) (a* - b*). The data collection was performed on a KUMA-CCD diffractometer and allowed the integration of weak first-order satellite reflections. The structure was refined from 2569 reflections to a final value of R = 0.0479. The modulation affects mainly the positions of the O atoms, which are displaced by as much as 0.5 A, and the site 4c that is occupied by Sr and Ba atoms. Only a simplified model, in which this atomic position is occupied by an effective atom Sr/Ba, could be refined from the data set. The modulation of displacement parameters has been used to account for the modulated distribution of Sr and Ba. The whole refinement uses only first-order modulation waves, but there are strong indications that for a complete solution the use of higher-order satellites and a more complicated model is necessary.

Journal Article↗
PubMed2004

Quininium (R)-mandelate, a structure with large Z' described as an incommensurately modulated structure in (3+1)-dimensional superspace.

Quininium (R)-mandelate, C(20)H(25)N(2)O(2)(+).C(8)H(7)O(3)(-), is an organic salt with an incommensurately modulated structure. The superspace approach is required for a precise description of the structure at room temperature. In addition to the main reflections, the diffraction pattern also exhibits higher-order satellite reflections. The large number of first- and second-order satellite reflections with relatively strong intensities indicates a significant modulation. No average structure solution could be obtained on the basis of the main reflections only and hence the structure solution was performed in two suitable superstructure approximations, including satellite intensities. Positional modulation functions and modulation functions for the anisotropic atomic displacement parameters were introduced. The modulation originates from a competition between intramolecular and intermolecular forces, which is reflected, in the superspace formalism, in the modification of hydrogen bonds along the internal space variable t.

Journal Article↗