Biomedical subjects

R M de Jong

Publications and source records attributed to R M de Jong.

9 recordsLinked to original sources

PubMed2003

Structure and mechanism of a bacterial haloalcohol dehalogenase: a new variation of the short-chain dehydrogenase/reductase fold without an NAD(P)H binding site.

Haloalcohol dehalogenases are bacterial enzymes that catalyze the cofactor-independent dehalogenation of vicinal haloalcohols such as the genotoxic environmental pollutant 1,3-dichloro-2-propanol, thereby producing an epoxide, a chloride ion and a proton. Here we present X-ray structures of the haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1, and complexes of the enzyme with an epoxide product and chloride ion, and with a bound haloalcohol substrate mimic. These structures support a catalytic mechanism in which Tyr145 of a Ser-Tyr-Arg catalytic triad deprotonates the haloalcohol hydroxyl function to generate an intramolecular nucleophile that substitutes the vicinal halogen. Haloalcohol dehalogenases are related to the widespread family of NAD(P)H-dependent short-chain dehydrogenases/reductases (SDR family), which use a similar Ser-Tyr-Lys/Arg catalytic triad to catalyze reductive or oxidative conversions of various secondary alcohols and ketones. Our results reveal the first structural details of an SDR-related enzyme that catalyzes a substitutive dehalogenation reaction rather than a redox reaction, in which a halide-binding site is found at the location of the NAD(P)H binding site. Structure-based sequence analysis reveals that the various haloalcohol dehalogenases have likely originated from at least two different NAD-binding SDR precursors.

Amino Acid Sequence↗

PubMed2001

Measurement of myocardial beta-adrenoceptor density in clinical studies: a role for positron emission tomography?

The beta-adrenoceptor (beta-AR) plays an important role in the regulation of heart function and has been extensively studied in recent decades. In vitro studies have shown down-regulation of beta-AR density in heart failure and cardiac conditions that may lead to heart failure. As in vitro measurements on cardiac tissue samples do not allow longitudinal and regional assessment of myocardial beta-ARs in humans, new methods are being developed to measure beta-ARs in vivo using positron emission tomography (PET). Studies using PET and the radioligand [(11)C]CGP 12177 have shown promising results that are in agreement with those of in vitro studies. However, the radiochemical synthesis of [(11)C]CGP 12177 is very demanding, preventing its widespread use. Hence, new radioligands are being developed using simpler methods of radiochemical synthesis. ( S)-[(11)C]CGP 12388 has been presented as a promising new radioligand. So far, in vivo measurements of beta-AR density using PET have mainly been performed to confirm in vitro studies. Using the full potential of PET, performance of regional measurements and longitudinal studies might add further knowledge on the pathophysiological role of the beta-AR in cardiac disease and the effect of interventions. Furthermore, PET might gain a role in the clinical management of patients with abnormalities of cardiac contractile function.

Carbon Radioisotopes↗

PubMed2001

Abnormal contractile responses during dobutamine stress echocardiography in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: In chronic heart failure augmented wall stress leads to increased energy demand. Supply, however, may be reduced due to coronary vasoconstriction and endothelial dysfunction. This might lead to a mismatch between demand and supply. In the present study we further explored the effect of increased demand during dobutamine stress echocardiography. METHODS AND RESULTS: Sixteen patients with idiopathic dilated cardiomyopathy (mean age 44+/-13 years, New York Heart Association class II-III, mean left ventricular ejection fraction 0.27+/-0.10) underwent dobutamine stress echocardiography (5-40 microg/min per kg bodyweight+atropine if required). Wall motion and thickening was assessed in 16 segments using a four-point scale. Eleven patients (69%) showed regions with worsening of wall motion or a biphasic response during dobutamine infusion. Of the remaining five patients one patient did not show any wall motion changes and one patient showed a partial improvement while only in three patients wall motion improvement in the whole heart was found. CONCLUSION: A majority of patients with idiopathic dilated cardiomyopathy showed decreased wall motion during increased demand, i.e. ischemia-like myocardial contractile responses during dobutamine stress echocardiography. These findings further support the concept that an energy mismatch between demand and supply might play a pathophysiological role in idiopathic dilated cardiomyopathy.

Adult↗

PubMed1999

Parametric polar maps of regional myocardial beta-adrenoceptor density.

UNLABELLED: Quantification of myocardial beta-adrenoceptor density (Bmax) is of interest in cardiac diseases in which altered function of the sympathetic nervous system is thought to play a pathophysiological role. PET provides an unrivaled means of taking regional measurements of cardiac microcirculatory function, tissue metabolism and autonomic nervous system activity. Measurements in small regional areas may be biased because of increased noise levels. This study examined the parametric polar map approach for the regional quantification of Bmax. METHODS: Dynamic PET with parametric polar map imaging was performed in 10 healthy volunteers and 4 patients with hypertrophic cardiomyopathy using (S)-[11C]-(4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzidimaz ole-2)-on hydrochloride (CGP)-12177 and a double-injection protocol. Time-activity curves were corrected for partial volume, spill-over and wall motion effects. The mean Bmax of the left ventricle was calculated in two ways. First, the average time-activity curve of all segments, having the highest achievable signal-to-noise ratio, was used to calculate Bmax(mTAC) (the myocardial beta-adrenoceptor density of the left ventricle calculated using the average time-activity curve). The bias in Bmax(mTAC) introduced by noise is minimal. Second, an estimate of whole-heart receptor density was calculated using the polar map method by averaging the values of Bmax obtained for 576 individual segments. In these calculations, three different filters (3 x 5, 3 x 9 and 3 x 13 segments) were used to smooth the time-activity curves before calculating Bmax. Mean values of whole-left-ventricular receptor density obtained by averaging regional values using the different filters (Bmax(PMF1/2/3)) were compared with Bmax(mTAC) to assess bias introduced by the polar map approach. Segments with a calculated Bmax outside the range 0.1-50 pmol/g were considered unreliable and were excluded from the analysis. RESULTS: The differences between the two methods of calculating Bmax were small (7.8%, 4.8% and 3.2%, with the three filters, respectively). Reliable results were obtained in >95% of the segments and in 9 volunteers and all 4 patients. CONCLUSION: When using PET for the quantification of beta-adrenoceptor density, the regional variation in Bmax can be reliably assessed using the parametric polar map approach.

Adrenergic beta-Antagonists↗

PubMed1997

Coronary vasomotion in patients with syndrome X: evaluation with positron emission tomography and parametric myocardial perfusion imaging.

The aim of this study was to elucidate further the causative mechanism of abnormal coronary vasomotion in patients with syndrome X. In patients with syndrome X, defined as angina pectoris and documented myocardial ischaemia during stress testing with normal findings at coronary angiography, abnormal coronary vasomotion of either the micro- or the macrocirculation has been suggested as the causative mechanism. Accordingly, we evaluated endothelial function, vasodilator reserve, and perfusion heterogeneity in these patients. Twenty-five patients with syndrome X (definitely normal coronary arteriogram, group A), 15 patients with minimal coronary artery disease (group B) and 21 healthy volunteers underwent [13N]ammonia positron emission tomography at rest, during cold pressor stimulation (endothelial function) and during dipyridamole stress testing (vasodilator reserve). Heterogeneity of myocardial perfusion was analysed by parametric polar mapping using a 480-segment model. In both patient groups, resting perfusion was increased compared to the normal subjects: group A, 127+/-31 ml.min-1.100 g-1; group B, 124+/-30 ml.min-1.100 g-1 normal subjects, 105+/-21 ml.min-1.100 g-1 (groups A and B vs normals, P<0.05). These differences were abolished after correction for rate-pressure product. During cold pressor stimulation, the perfusion responses (ratio of cold pressor perfusion to resting perfusion) were similar among the patients and the control subjects (group A, 1.20+/-0.23; group B, 1.24+/-0.22; normal subjects, 1.23+/-0.14). Likewise, during dipyridamole stress testing, perfusion responses were similar among the three groups (group A, 2.71+/-0.67; group B, 2.77+/-1.29; normal subjects, 2. 91+/-1.04). In group A the heterogeneity of resting perfusion, expressed as coefficient of variation, was significantly different from the volunteers (20.1+/-4.5 vs 17.0+/-3.0, P<0.05). In group B (coefficient of variation 19.4+/-3.9) the difference from normal volunteers was not significant. In this study, patients with syndrome X and patients with minimal coronary artery disease showed normal perfusion responses during cold pressor stimulation and dipyridamole stress testing. Our findings therefore suggest that endothelial dysfunction and impaired vasodilator reserve are of no major pathophysiological relevance in patients with syndrome X. Rather, other mechanisms such as increased sympathetic tone and focal release of vasoactive substances may play a role in the pathogenesis of syndrome X.

Adult↗

PubMed1996

Compression and its effect on the speech signal.

Compression systems are often used in hearing aids to increase the wearing comfort. A patient has to readjust frequently the gain of a linear hearing aid because of the limited dynamic hearing range and the changing acoustical conditions. A great deal of attention has been given to the static parameters but very little to the dynamic parameters. We present a general method to describe the dynamic behavior of a compression system by comparing modulations at the output with modulations at the input. The use of this method resulted in a single parameter describing the temporal characteristics of a compressor, the cut-off modulation frequency. In this paper its value is compared with known properties of running speech. A limitation of this method is the use of only small modulation depths, and the consequence of this limitation is tested. The use of this method is described for an experimental digital compressor developed by the authors, and the effects of some temporal parameters such as attack and release time are studied. This method shows the rather large effects of some of the parameters on the effectiveness of a compressor on speech. This method is also used to analyze two generally accepted compression systems in hearing aids. The theoretical method is next compared to the effects of compression on the distribution of the amplitude envelope of running speech, and it could be shown that single-channel compression systems do not reduce the distribution width of speech filtered in frequency bands. This finding questions the use of compression systems for fitting the speech banana in the dynamic hearing range of impaired listeners.

Correction of Hearing Impairment↗

PubMed1995

Mechanisms of angina pectoris in syndrome X assessed by myocardial perfusion dynamics and heart rate variability.

The fundamental abnormality in syndrome X (angina pectoris, ischaemia-like stress ECG despite angiographically normal coronary arteries) might be patchily distributed increased tone in pre-arteriolar coronary vessels with compensatory release of adenosine. The aim of this study was to confirm this hypothesis and to explore its relationships with autonomic system functioning. Using parametric positron emission tomography, myocardial perfusion was examined in 480 segments in 16 syndrome X patients and 16 age- and sex-matched healthy volunteers. Autonomic function was explored by Holter monitoring of time domain parameters of heart rate variability. Compared to volunteers, both mean perfusion (123 +/- 35 vs 87 +/- 16 mg.min-1.100 g-1; P < 0.01) and its coefficient of variation (17.0 +/- 3.2 vs 13.6 +/- 2.2%; P < 0.01) as a measure of perfusion heterogeneity, were higher in patients with syndrome X. In contrast to the findings in the control subjects, patients showed an inverse relationship between perfusion heterogeneity (coefficient of variation of segmental perfusion) and autonomic tone (heart rate variability parameters). Since marked perfusion heterogeneity (inversely related to autonomic tone) and higher overall perfusion were found, the study supports the data that in syndrome X hyperreactivity of small coronary vessels with compensatory release of adenosine may be patchily distributed.

Adult↗

PubMed1995

Posterolateral defect of the normal human heart investigated with nitrogen-13-ammonia and dynamic PET.

UNLABELLED: The posterolateral defect is a common artifact seen when static 13N-ammonia imaging with PET is used to assess myocardial perfusion. The aim of this study was to compare dynamic and static. 13N-ammonia PET and to obtain more insight into the cause of the posterolateral defect. METHODS: Dynamic 13N-ammonia PET was performed in 19 healthy nonsmoking volunteers at rest. Perfusion was assessed in the early phase of the study using a curve fit method over the first 90 sec. Nitrogen-13 accumulation (static PET) was assessed 4 to 8 min after injection. Each study was normalized to a mean of 100. The average distribution of normalized perfusion and activity was calculated in 24 segments. Heterogeneity of both activity and perfusion distribution were assessed and the activity distribution was compared with perfusion distribution. RESULTS: Perfusion distribution was homogeneous, with the exception of the inferior and apical regions. Activity distribution was inhomogeneous, with a lower activity in the posterolateral and apical regions. In the whole left ventricle, significant differences in distribution were found between static and dynamic imaging. CONCLUSION: Perfusion distribution was significantly different on dynamic images compared to static images. The posterolateral defect was not found on dynamic images. The posterolateral defect and other inhomogeneities in activity distribution are caused by tracer-dependent features, probably a redistribution of metabolites of 13N-ammonia.

Adult↗

PubMed1995

Quantitative myocardial mapping of perfusion and metabolism using parametric polar map displays in cardiac PET.

UNLABELLED: Most efficacy studies of cardiac PET in demonstrating myocardial ischemia and viability have been performed using one or more transversal static images of the heart. In contrast, in this paper we describe a method of functional imaging of the complete left ventricular myocardium for perfusion with nitrogen-13-ammonia, both at rest and during a dipyridamol stress test, and of glucose metabolism with 18F-fluorodeoxyglucose (18FDG). METHODS: This was performed by using the data of each of 48 radial segments of 10 short-axis images as tissue data and LV cavity data of three basal planes as blood pool data. The study describes the results of 19 normal volunteers and 36 patients with coronary artery disease. From the data of the normal volunteers a 95% normal confidence interval was calculated for each imaging modality. These intervals were then used to describe the patient data as normal, ischemic or infarcted. RESULTS: The results of analysis of the parametric images was compared with the results of static analysis of the same patient data and found to be less dependant on the detection threshold used. CONCLUSION: The described method enables the routine application of functional PET imaging of the total myocardium by the semi-automatic construction of parametric flow and metabolism polar maps. It thus provides an increased performance in the diagnosis, quantification and localization of myocardial ischemia and viability over conventional PET imaging.

Adult↗