Biomedical subjects

W R Bauer

Publications and source records attributed to W R Bauer.

At least 19 recordsLinked to original sources

PubMed2006

Scaling laws for transverse relaxation times.

Simple scaling laws are useful tools in understanding the effect of changing parameters in MRI experiments. In this paper the general scaling behavior of the transverse relaxation times is discussed. We consider the dephasing of spins diffusing around a field inhomogeneity inside a voxel. The strong collision approximation is used to describe the diffusion process. The obtained scaling laws are valid over the whole dynamic range from motional narrowing to static dephasing. The dependence of the relaxation times on the external magnetic field, diffusion coefficients of the surrounding medium, and the characteristic scale of the field inhomogeneity is analyzed. For illustration the generally valid scaling laws are applied to the special case of a capillary, usually used as a model of the myocardial BOLD effect.

Algorithms↗

PubMed2005

Frequency distribution and signal formation around a vessel.

We describe the NMR signal formation properties of a single vessel. Instead of assuming the frequency distribution to be a simple Lorentzian or Gaussian one, we take into account that the frequency distribution around the vessel is a complex function. Considering the static dephasing regime we find a relationship between signal formation and frequency distribution. Analytical expressions for the frequency distribution in a voxel and the magnetization decay are obtained. In the case of small volume fractions of blood and week magnetic fields the results can be used for describing signal formation processes in a vascular network. A relationship between the frequency distribution and the properties of the vascular network is derived. The magnetization decay in different time regimes is discussed. The result is relevant for describing signal formation processes around a vessel for arbitrary pulse sequences.

Animals↗

PubMed2005

Transverse relaxation of cells labeled with magnetic nanoparticles.

We describe the NMR relaxation properties of magnetically labeled cells. The cells are labeled with magnetic nanoparticles (SPIO, USPIO), which generate susceptibility contrast. The geometry of the labeled cells and the surrounding tissue is considered. We assume that the magnetic nanoparticles accumulate to form a magnetic core of radius RC inside the cell. The correlation time tau, which describes the motion of spins around this core, is analyzed. Using the strong collision approach, explicit expressions are derived for the transverse relaxation rate R2* for tissue containing labeled cells as a function of the core radius, the diffusion coefficient, and the concentration of the nanoparticles. The predictions of this model agree well with numerical simulations and experimental data.

Cell Compartmentation↗

PubMed2004

Finite-element analysis of the displacement of closed DNA loops under torsional stress.

Closed DNA loops that contain intrinsic curvature occur in biologically important structures that are formed by bringing together proteins attached at distinct sites. Such loops constitute topological domains that are characterized by a linking number Delta Lk. We calculate, using finite-element analysis, the structural changes induced by small changes in this linking number, Delta Lk. Because of the intrinsic curvature, the slightest change in linking number induces writhe and the loop begins to fold in space. We previously studied the case in which the initial curvature is uniformly distributed along the DNA rod. We found that there are two different folding modes, depending on the amount of intrinsic curvature and the Poisson ratio, a quantity that measures the ratio of bending stiffness to torsional rigidity. For combinations of the Poisson ratio and curvature that lie below a critical curve, called the Fickel curve, the folding is monotonic in the sense that the writhe uniformly increases as Delta Lk increases, until self-contact occurs. For combinations below this curve, the folding is non-monotonic in the sense that as Delta Lk increases the writhe first increases, then decreases back to essentially zero, and then increases uniformly until self-contact occurs. The folding behaviour and the self-contact points in the two folding modes are completely different. In this paper we first review this previous work. We then extend those results to more-complex situations in which the curvature is initially distributed non-uniformly along the DNA rod. We show that the location of the Fickel curve depends upon both the extent of the initial curvature and upon its distribution along the rod. We also show that two DNAs with the same total intrinsic curvature will fold differently depending upon the distribution of that curvature along the DNA axis, and upon the point of the loop at which the applied rotation or change in Delta Lk is introduced.

Base Sequence↗

PubMed2004

Postcardiac injury syndrome following radiofrequeny ablation of atrial flutter.

We report the case of a 64-year-old woman who was admitted to our hospital for radiofrequency ablation of isthmus-dependent counterclockwise atrial flutter. Following an initially uncomplicated right atrial linear isthmus ablation that was associated with conversion of atrial flutter to sinus rhythm and evidence of complete isthmus block, the patient developed a small pericardial effusion, a marked and recurrent left-sided pleural effusion, and had significantly elevated inflammatory markers. After an extensive diagnostic work-up which excluded infectious, malignant and thromboembolic causes of the effusions, a diagnosis of postcardiac injury syndrome was made and the patient was treated with oral corticosteroids and nonsteroidal anti-inflammatory drugs. Over a treatment period of 2 months there was complete resolution of the pericardial and left-sided pleural effusions and normalization of inflammatory markers. Postcardiac injury syndrome is a rare complication of radiofrequency ablation that is characterized by signs of pericardial, pleural and pulmonary parenchymal inflammation.

Adrenal Cortex Hormones↗

PubMed2003

Detection of myocardial viability in acute infarction using contrast-enhanced (1)H magnetic resonance imaging.

BACKGROUND: Reperfusion strategies salvage myocardium at risk in acute myocardial infarction (MI). This clinical study was performed to determine whether areas without evidence of delayed MRI contrast enhancement in MI correspond to viability by means of percent systolic wall thickening (%SWT) and enddiastolic wall thickness (EDWT) in chronic infarction. METHODS: Twenty MRI studies were performed in ten patients within 6 days of MI and 3 months post-MI. On a segmental basis the percentage of viable myocardium as defined by contrast-enhanced MRI (no delayed MRI contrast enhancement) in acute MI was measured and was compared with %SWT and EDWT in chronic MI. RESULTS: Of the 1718 segments in acute infarction in which the percentage of viable myocardium was measured 1333 were found to be completely viable by means of contrast-enhanced MRI (no delayed MRI contrast enhancement). All of these segments revealed %SWT on day 90 post-MI, and 97% of segments were viable by means of an EDWT of more than 5.5 mm. In 85 segments the proportion of viable myocardium was 50-99% (mean 56+/-8%), with 92% segments found to be viable by means of %SWT and 92% by EDWT, and of 156 segments with viable myocardium between 1-49% (36+/-8%) 79% were found to be viable by means of %SWT and 82% by EDWT. Corresponding proportions of 144 segments with transmural delayed MRI contrast enhancement in acute MI were 45% and 17%. CONCLUSIONS: In acute reperfused MI viable myocardium as delineated by contrast-enhanced MRI is correlated with clinical parameters of viability. Delayed MRI contrast enhancement resolves nontransmural MI and may become a valuable clinical tool when planning revascularization procedures.

Adult↗

PubMed2003

Cardiac magnetic resonance imaging in small animal models of human heart failure.

The aim of this study was to test the feasibility of cine magnetic resonance imaging (MRI) for assessment of the infarcted rat and mouse heart and to compare the results with established methods. These models have been proven to predict genesis and prevention of heart failure in patients. The value of cine MRI was tested in studies investigating interventions to change the course of the remodeling process. MRI was performed for determination of left ventricular (LV) volumes and mass, myocardial infarct (MI) size and cardiac output. LV wet weight was determined after MRI. Rats underwent conventional hemodynamic measurements for determination of cardiac output and LV volumes by electromagnetic flowmeter and pressure-volume curves. Infarct size was determined by histology. MRI-acquired MI-size (18.5+/-2%) was smaller than that found by histology (22.8+/-2.5%, p<0.05) with close correlation (r=0.97). There was agreement in LV mass between MRI and wet weight (r=0.97, p<0.05) and in the MRI- and flowmeter measurements of cardiac output (r=0.80, p<0.05). Volume by MRI differed from pressure-volume curves with good correlation (r=0.96, p<0.05). In a serial study of mice after coronary ligation, LV hypertrophy at 8 weeks was detected (Sham 105.1+/-7.9 mg, MI 144.4+/-11.7 mg, p<0.05). Left ventricles were enlarged in infarcted mice (end-diastolic volume, week 8: Sham 63.5+/-4 microl, MI 94.2 microl, p<0.05). In conclusion, cine MRI is a valuable diagnostic tool applicable to the rat and mouse model of MI. Being non-invasive and exact it offers new insights into the remodeling process after MI because serial measurements are possible. The technique was applied to study several interventions and proved its usefulness.

Animals↗

PubMed2001

Serial magnetic resonance imaging of microvascular remodeling in the infarcted rat heart.

BACKGROUND: Alterations in the coronary circulation are important determinants of myocardial function. Few data are available, however, about microvascular changes in reactive hypertrophy. With MRI, serial determination of myocardial microcirculation after myocardial infarction (MI) is feasible. METHODS AND RESULTS: We quantitatively determined myocardial perfusion and relative intracapillary blood volume using an MRI technique. Infarct size, myocardial mass, and left ventricular volumes were determined with cine MRI. Rats were investigated at 8, 12, and 16 weeks after MI (mean MI size 24.1+/-2.0%) or sham operation. Vasodilation was induced by adenosine. In the infarcted group, maximum perfusion decreased significantly from 8 to 16 weeks (5.6+/-0.3 versus 3.5+/-0.2 mL. g(-1). min(-1), P<0.01) compared with sham animals (5.5+/-0.3 versus 5.0+/-0.2 mL. g(-1). min(-1), P=0.17). Myocardial mass increased significantly (559.1+/-20.8 mg at 8 weeks versus 690.9+/-42.7 mg at 16 weeks, P<0.05) compared with sham-operated animals (516.3+/-41.7 versus 549.2+/-32.3 mg). Basal relative intracapillary blood volume increased significantly to 15.7+/-0.5 vol% at 8 weeks after MI and remained elevated (16.8+/-0.6 vol%) at 16 weeks compared with 12.1+/-0.3 vol% (P<0.01) in sham-operated rats. CONCLUSIONS: Our results indicate that significant microvascular changes occur during cardiac remodeling. Hypoperfusion in the hypertrophied myocardium is related to an increase in vascular capacity, suggesting a compensatory vasodilatory response at the capillary level. These microvascular changes may therefore contribute to the development of heart failure.

Animals↗

PubMed2001

Fast high-resolution magnetic resonance imaging demonstrates fractality of myocardial perfusion in microscopic dimensions.

The fractal nature of heterogeneity of myocardial blood flow and its implications for the healthy and diseased heart is not yet understood. The main hindrance for investigation of blood flow heterogeneity and its role in physiology and pathophysiology is that conventional methods for determination of myocardial perfusion have severe limitations concerning temporal and spatial resolution and invasiveness. In isolated rat hearts, we developed a nuclear magnetic resonance technique that does not depend on contrast agents and in which the apparent longitudinal relaxation time is made perfusion sensitive by selective preparation of the imaging slice. This perfusion-sensitive relaxation time is determined within 40 seconds as a map with a high spatial in-plane resolution of 140x140 microm(2) and a thickness of 1.5 mm. Perfusion imaging was validated with the established microsphere technique. Additionally, the congruence between perfusion-sensitive T:(1) maps and first-pass perfusion imaging was demonstrated. As an application of high-resolution perfusion imaging, fractal analysis of the spatial distribution of perfusion was performed. We were able to demonstrate that the fractality of this distribution exists even in microscopic dimensions. Vasodilation by nitroglycerin modulated the fractal pattern of perfusion, and the decrease of the fractal dimension indicated a shift toward homogeneity. This implies that parameters of the fractal distribution depend on the microvascular tone rather than on anatomic preformations; ie, fractality is a functional characteristic of perfusion.

Animals↗

PubMed2001

Serial cine-magnetic resonance imaging of left ventricular remodeling after myocardial infarction in rats.

The purpose of the present study was the serial investigation of morphological and functional changes after left coronary artery ligation in the intact rat using cine-magnetic resonance imaging (MRI). MRI studies were performed 4, 8, 12, and 16 weeks after myocardial infarction (MI) with an echocardiogram (ECG)-triggered cine-fast low-angle shot (FLASH)-sequence in a 7-Tesla magnet. MI-size, left ventricular (LV) mass and volumes, cardiac index, ejection fraction (EF), and remote wall and scar thickness of 11 Wistar rats were compared to four sham-operated rats. Stress MRI with dobutamine (10 microl/kg x minute) was performed at 16 weeks. In MI groups (small MI < 30%, N = 5, large MI > 30%, N = 6), there was significant increase of LV mass (small MI + 47.8% increase, large MI + 74.1%) and wall thickness (large MI 1.21 +/- 0.03 to 1.84 +/- 0.07 mm). Scar thickness declined from four to 16 weeks (large MI 0.92 +/- 0.06 to 0.38 +/- 0.02 mm, P < 0.05). End-diastolic volume of both MI groups was significantly elevated but increased further only in animals with large MI from four to 16 weeks (657.1 +/- 38.6 to 869.7 +/- 60.7 microL, P < 0.05). Compared to sham, EF was significantly depressed in MI (large MI 31.5 +/- 2.0%). Wall thickening declined from four to 16 weeks post-MI (large MI 50.9 +/- 9.9 to 28.9 +/- 4.4%, P < 0.05). During stress, sham and MI rats increased wall thickening from 66.5 +/- 8.2 to 111.2 +/- 6.7% and from 30.8 +/- 4.3 to 47.5 +/- 5.8%, respectively (P < 0.05). Hypertrophy was found in all animals with MI throughout the entire period of observation, whereas dilatation after four weeks was only detected in animals with large MI. These morphologic changes were accompanied by an early decline of EF; myocardial function characterized by wall thickening deteriorated later.

Animals↗

PubMed2001

Combined high-speed NMR imaging of perfusion and microscopic coronary conductance vessels in the isolated rat heart.

Noninvasive characterization of microcirculation at the level of both coronary conductance and resistance vessels is of major importance for the understanding of microvascular adaptive processes in the heart. The objective of this study was to determine simultaneously myocardial perfusion and microvessel diameters in the myocardium by magnetic resonance (MR) imaging within the same heart. A MR imaging method is presented which combines high-resolution perfusion measurement (140 x 140 microm2) by spin labeling with flow-weighted MR microscopy of coronary microvessels (phi > 140 microm). We determined changes in myocardial perfusion and vessel diameters of isolated beating rat hearts (n = 10) at rest and during administration of nitroglycerin (0.5 mg/min). Alterations in perfusion were validated by microsphere measurements. Under the influence of nitroglycerin an increase in perfusion (+2.51 +/- 0.4 ml x min(-1) x g(-1), mean +/- SEM) and vessel diameters (+14.22 +/- 1.92%) could be observed. Endocardial perfusion revealed a modest enhanced susceptibility to nitroglycerin in comparison to epicardial perfusion. Analysis of vessels according to their diameters showed no significant differences. MR imaging allows the noninvasive and simultaneous determination of conducting arteries and smaller resistance vessels in one and the same beating rat heart. Due to an excellent spatial resolution of these methods, transmural characterization of both parameters at rest and during vasodilation is feasible.

Animals↗

PubMed2001

Myocardial perfusion imaging using a non-contrast agent MR imaging technique.

INTRODUCTION: A MR imaging (MRI) method has been developed to determine quantitatively myocardial perfusion (P) in the rat heart in vivo. This method has the potential to non-invasively measure cardiac perfusion without the use of a contrast agent by exploiting the endogenous contrast from flowing blood itself. METHOD AND RESULTS: Principle of the technique is the arterial spin labeling of endogenous water protons within the short axis imaging slice. Arterial spin labeling techniques are based on a model that uses inflow effects to relate intrinsic changes in longitudinal relaxation (T1) to tissue perfusion. Perfusion is determined from the difference between a slice selective and a global inversion recovery experiment. Perfusion was determined at rest and during hyperemia induced by intravenous adenosine (3 mg/(kg min)). The MR perfusion values were compared with perfusion data obtained in the same animal using the colored microspheres (MS) technique as the gold standard. The MR perfusion (mean +/- SEM) was 3.3 +/- 0.2 ml/min/g at rest and 4.6 +/- 0.6 ml/min/g during adenosine. Perfusion values obtained by colored MS were 3.4 +/- 0.2 and 4.7 +/- 0.8 ml/min/g at rest and during vasodilation, respectively. Adenosine decreased mean arterial pressure (MAP) from 120 to 65 mmHg which implies a reduction of coronary resistance (CR) to about 50% of baseline. CONCLUSION: Our study shows that quantitative mapping of perfusion may be performed non-invasively by MRI. The MR perfusion data are in excellent correlation with data obtained by the well-established colored MS technique. Determination of perfusion reserve confirms that coronary perfusion is highly dependent on blood pressure due to changes in CR.

Animals↗

PubMed2000

Myocardial perfusion and intracapillary blood volume in rats at rest and with coronary dilatation: MR imaging in vivo with use of a spin-labeling technique.

PURPOSE: To validate a magnetic resonance (MR) imaging technique that is not first pass and that reveals perfusion and regional blood volume (RBV) in the intact rat. MATERIALS AND METHODS: Measurement of perfusion was based on the perfusion-sensitive T1 relaxation after magnetic spin labeling of water protons. RBV was determined from steady-state measurements of T1 before and after administration of an intravascular contrast agent. The colored microsphere technique was used as a reference method for perfusion measurement. RBV and perfusion maps were obtained with the rats at rest and during administration of 3 mg of adenosine phosphate per kilogram of body weight per minute. RESULTS: At MR imaging, perfusion during resting conditions was 3.5 mL/g/min +/- 0.1 (SEM), and RBV was 11.6% +/- 0.6 (SEM). Adenosine phosphate significantly increased perfusion to 4.5 mL/g/min +/- 0.3 (SEM) and decreased mean arterial pressure from 120 mm Hg to 65 mm Hg, which implies a reduction of coronary resistance to 40% of baseline. RBV increased consistently to 23.8% +/- 0.6 (SEM). CONCLUSION: The study results show that quantitative mapping of perfusion and RBV may be performed noninvasively by means of MR imaging in the intact animal. The presented method allows determination of vasodilative and perfusion reserve, which reflects the in vivo regulation of coronary microcirculation for a given stimulus.

Adenosine↗

PubMed2000

In vivo assessment of cardiac remodeling after myocardial infarction in rats by cine-magnetic resonance imaging.

The rat infarct model offers important parallels to the process of remodeling after myocardial infarction (MI) in humans. The aim of this study was to test the feasibility of cine fast low-angle shot (FLASH) magnetic resonance imaging (MRI) for assessment of the infarcted and noninfarcted rat heart and to compare the results with established methods. In group A, MRI was done 8-16 weeks after MI on a 7-T scanner using an electrocardiogram-triggered cine-FLASH sequence. We determined left ventricular (LV) volumes and mass, wall thickness, MI size, cardiac output, and ejection fraction. Afterward, MI size was histologically determined. In group B, after MRI eight controls and eight rats 16 weeks after MI underwent conventional hemodynamic measurements for determination of cardiac output, LV volumes, and ejection fraction by electromagnetic flowmeter and pressure-volume curves. LV wet weight was determined. In group A, MRI-acquired MI size (18.5 +/- 2%) was smaller than histology (22.8 +/- 2.5%, p < 0.05) with close correlation (r = 0.97). In group B, agreement in LV mass was found between MRI and wet weight (controls, 537.6 +/- 19.6 vs. 540.3 +/- 18.4 mg; MI, 865.1 +/- 39.2 vs. 865.1 +/- 41.3 mg; for the difference p = ns, r = 0.97, p < 0.05) and in the MRI and flowmeter measurements (cardiac output, controls 73.1 +/- 2.9 vs. 75.2 +/- 2.6 ml/min; MI 82.4 +/- 5.2 vs. 81.9 +/- 3.7 ml/min; for the difference p = ns, r = 0.80, p < 0.05). End-diastolic volume by MRI differed from pressure-volume curves with good correlation (controls, 343.9 +/- 8.4 vs. 262.7 +/- 12.8 microl; MI, 737.0 +/- 70.5 vs. 671.1 +/- 64.1 microl; p < 0.05 each, r = 0.96, p < 0.05). Cine-FLASH-MRI is a valuable diagnostic tool applicable to the rat model of MI. Being noninvasive and exact, it offers new insights in the remodeling process after MI because serial measurements are possible.

Animals↗

PubMed1999

Effect of salt-dependent stiffness on the conformation of a stressed DNA loop containing initially coplanar bends.

Closed DNA loops containing one or more bent regions are important structures that occur in the regulation of gene expression. We analyze the response of structures of this type to a change in applied rotation (change in linking deficiency, delta Lk). Our results apply to a closed loop formed from an elastic rod that is intrinsically bent in Nb discrete, 20 degrees steps up to a maximum of 240 degrees, the bent regions being initially coplanar with the plane of the relaxed DNA loop. We determine the effect of changing the intrinsic elastic resistance of the DNA loop to bending and torsional deformations. This relative resistance is expressed by Poisson's ratio v, which depends upon the ratio of bending stiffness to torsional rigidity. Poisson's ratio is primarily a function of salt type and concentration. We find that the tertiary structure of DNA loops changes with delta Lk, but that the geometric response can be either of two quite different types, depending upon the precise (Nb, v) pair. For combinations of Nb and v that are above a critical curve (the Fickel curve), the response to increasing delta Lk is nonmonotonic (NMT region): the distance between the loop closure point and its diametric opposite first decreases, then increases, as delta Lk increases. For combinations of Nb and v that are below the Fickel curve (NMT region), the corresponding diameter never increases, but always decreases with increasing delta Lk. In addition to these results, we define and implement a new measure of tertiary structure in closed DNA: the absolute writhe, AWr.

Animals↗

PubMed1999

Theory of the BOLD effect in the capillary region: an analytical approach for the determination of T2 in the capillary network of myocardium.

This article presents an analytical approach for the quantification of the blood oxygen level dependent (BOLD) effect in the capillary region. The capillary geometry of myocardium is considered. The relaxation rate R*2 is determined as a function of the capillary radius Rc, the intracapillary volume fraction RBV, and the diffusion coefficient D. When the intracapillary volume fraction is small, the approximation R*2 = RBV x tau(-1) x (square root of (1+(taudeltaomega)2)-1) is valid, with the correlation time tau = (Rc2/4D) x (absolute value (ln RBV)/(1 - RBV)). The predictions of this model agree well with numerical simulations and experimental data of others and with data recently measured by our group.

Animals↗

PubMed1999

Changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole: assessment using T*2 and T1 measurements.

The aim of this pilot-study was to evaluate changes in myocardial oxygenation and perfusion under pharmacological stress with dipyridamole (DIP) by means of MRI. Twenty healthy volunteers were examined using a multi-echo gradient-echo sequence. The differential myocardial signal response due to the blood oxygen level dependent (BOLD) effect was studied under variable conditions of myocardial oxygen supply caused by the vasodilator DIP. Unlike contrast agents (CA) methods, which require at least two injections of CA and DIP, the presented methods require only a single infusion of DIP. To assess changes in myocardial perfusion, a saturation recovery TurboFLASH (SRTFL) sequence with centric reordering for T1 measurements was used with global and slice-selective spin-preparation (five volunteers). The signal response was measured at baseline conditions and when myocardial blood flow was increased during pharmacological stress with DIP. Administration of DIP induced a 17 +/- 9% increase in T2*. Enhanced perfusion resulted in a 15 +/- 5% decrease of T1 after slice-selective spin preparation and a calculated increase in absolute perfusion of about 5.1 ml/(g x min), which reflects coronary reserve. The study shows that DIP-induced alterations in the relationship between myocardial oxygen supply and demand are detectable in healthy volunteers using T2* and T1 measurements. A combination of T2* and T1 examinations could become a useful diagnostic tool for the non-invasive assessment of myocardial oxygenation and perfusion in patients with coronary artery disease (CAD).

Adult↗

PubMed1999

Perfusion-corrected mapping of cardiac regional blood volume in rats in vivo.

Measurement of regional blood volume (RBV) in the myocardium in vivo is important for the assessment of tissue viability and function. The method in this work is based on the acquisition of a T(1) map before and after intravascular contrast agent application. It is known that this method is influenced by perfusion that causes an overestimation of RBV values. In order to solve this problem, the new method is proposed which acquires T(1) maps with slice selective inversion pulses. Due to blood flow nonexcited spins enter the detection slice, which leads to an acceleration of the relaxation time. A model that divides tissue into two compartments is adapted to slice selective inversion in order to derive a simple expression for perfusion-corrected RBV. The aim of the study is to demonstrate the feasibility and accuracy of this technique for quantification of RBV in rat myocardium in vivo. RBV maps were obtained for five rats, and the reproducibility was determined by repeating the experiment several times. A mean RBV value of 12.8 +/- 0.7% (v/v) over all animals was obtained in the myocardium. The results were compared with RBV maps obtained with perfusion-sensitive RBV imaging in the same five rats and with first-pass RBV studies. In order to demonstrate the strength of the new method the vasodilator adenosine was administered and alterations in microcirculation were imaged. Magn Reson Med 42:500-506, 1999.

Adenosine↗