Biomedical subjects

A Heerschap

Publications and source records attributed to A Heerschap.

At least 37 records · Page 2Linked to original sources

PubMed2004

Cerebral creatine kinase deficiency influences metabolite levels and morphology in the mouse brain: a quantitative in vivo 1H and 31P magnetic resonance study.

Creatine kinase (CK)-catalysed ATP-phosphocreatine (PCr) exchange is considered to play a key role in energy homeostasis of the brain. This study assessed the metabolic and anatomical consequences of partial or complete depletion of this system in transgenic mice without cytosolic B-CK (B-CK-/-), mitochondrial ubiquitous CK (UbCKmit-/-), or both isoenzymes (CK -/-), using non-invasive quantitative magnetic resonance (MR) imaging and spectroscopy. MR imaging revealed an increase in ventricle size in a subset of B-CK-/- mice, but not in animals with UbCKmit or compound CK mutations. Mice lacking single CK isoenzymes had normal levels of high-energy metabolites and tissue pH. In the brains of CK double knockouts pH and ATP and Pi levels were also normal, even though PCr had become completely undetectable. Moreover, a 20-30% decrease was observed in the level of total creatine and a similar increase in the level of neuronal N-acetyl-aspartate compounds. Although CKs themselves are not evenly distributed throughout the CNS, these alterations were uniform and concordant across different brain regions. Changes in myo-inositol and glutamate peaks did appear to be mutation type and brain area specific. Our results challenge current models for the biological significance of the PCr-CK energy system and suggest a multifaceted role for creatine in the brain.

Animals↗

PubMed2003

Correlation between 5-fluorouracil metabolism and treatment response in two variants of C26 murine colon carcinoma.

Following an i.p. dose of 150 mg x kg(-1) 5-fluorouracil (5-FU), drug uptake and metabolism over a 2-h period were studied by in vivo (19)F magnetic resonance spectroscopy (MRS) for the murine colon carcinoma lines C26-B (5-FU-insensitive; n=11) and C26-10 (5-FU-sensitive; n=15) implanted s.c. in Balb/C mice. Time courses for tumour growth, intracellular levels of FdUMP, thymidylate synthase (TS) activity, and 5-FU in RNA were also determined, and the effects of a 9.5-min period of carbogen breathing, starting 1 min before drug administration, on MRS-detected 5-FU metabolism and tumour growth curves were examined. Both tumour variants generated MRS-detectable 5-FU nucleotides and showed similar initial growth inhibition after treatment. However, the growth rate of C26-B tumours returned to normal, while the sensitive C26-10 tumours, which produced larger fluoronucleotide pools, still showed moderate growth inhibition. Carbogen breathing did not significantly influence 5-FU uptake or fluoronucleotide production but did significantly enhance growth inhibition in C26-10 tumours. While both tumour variants exhibited incorporation of 5-FU into RNA and inhibition of TS via FdUMP, clearance of 5-FU from RNA and recovery of TS activity were greater for the insensitive C26-B line, indicating that these processes, in addition to 5-FU uptake and metabolism, may be important determinants of drug sensitivity and treatment response.

Administration, Inhalation↗

PubMed2003

Presence of (phospho)creatine in developing and adult skeletal muscle of mice without mitochondrial and cytosolic muscle creatine kinase isoforms.

We assessed the relationship between phosphocreatine (PCr) and creatine (Cr) content and creatine kinase (CK) activity in skeletal muscle of mice. The PCr and total Cr (tCr) concentrations, as well as CK activity, in hindlimb muscles of mice, with or without the cytosolic and mitochondrial isoforms of muscle creatine kinase (wild-type or CK--/-- mice), were determined by in vivo magnetic resonance (MR) spectroscopy and by biochemical means during postnatal growth and adulthood. In wild-type muscle the [tCr], PCr/ATP ratio and CK activity increased rapidly in the first 4-7 weeks. Remarkably, CK--/-- mice showed a similar increase in the PCr/ATP ratio during the first month in the presence of only minor brain-type BB-CK activity. Uptake of Cr in muscle was seemingly unrelated to CK activity as tCr increased in the same way in the muscles of both mouse types. At older ages the PCr/ATP ratio decreased in CK--/-- muscles, in contrast to wild-type where it still slowly increased, whereas [tCr] was similar for muscle of both mouse types. Using a new in vivo MR approach with application of [4-13C]Cr, a lower PCr/tCr ratio was also observed in CK--/-- muscle. From these data it follows that in vivo global ATP levels at rest are similar in the presence or absence of CK. Although Cr could still be converted to PCr in mature CK--/-- muscle, the immediate availability of PCr decreased, and PCr became partly inconvertible at older ages. Apparently, catalysis of the CK reaction by BB-CK, although significant in muscles of newborn mice, gradually declines to very low levels in adulthood. Part or all of this BB-CK may arise from satellite cells fusing with myotubes, a process that is most active during the first months of life. Finally, our observation that the MR and chemical assessment of muscle [tCr] and PCr/tCr ratio were similar for all mice does not support the existence of a significant MR-invisible or immobile pool of Cr, with a role for CK in this phenomenon.

Adenylate Kinase↗

PubMed2003

Optimized detection of changes in glucose-6-phosphate levels in human skeletal muscle by 31P MR spectroscopy.

As glucose-6-phosphate (G6P) plays a central role in muscle energy metabolism, the possibility to observe changes in the tissue level of this compound in vivo is very relevant. G6P can be detected noninvasively by (31)P MR spectroscopy, but its visibility in vivo is severely hampered due to low tissue levels and spectral overlap with other, stronger phosphomonoester signals. To optimize the observation of changes in G6P levels in human calf muscle by (31)P MR spectroscopy at 1.5 T, we implemented an approach involving a new RF probe and a postacquisition correction method. An anatomically shaped circularly polarized (31)P coil was designed for high intrinsic sensitivity. Together with an additional (1)H coil and (1)H blocking circuits this allowed the application of NOE and (1)H decoupling to further enhance sensitivity. A hyperglycemic hyperinsulinemic clamp was used to increase G6P levels. The spectra were corrected for frequency and phase drift due to scanner instability and leg movements using an automated phase and frequency correction method. Difference (31)P spectroscopy was applied to detect changes of the G6P signal. The result, in five healthy subjects, demonstrated that the combination of sensitivity optimization with automated drift correction enabled a robust detection of G6P changes in time series experiments down to a resolution of 10 min.

Adult↗

PubMed2003

Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imaging.

Oligodendroglial tumors may not be distinguished easily from other brain tumors based on clinical presentation and magnetic resonance imaging (MRI) alone. Identification of these tumors however may have therapeutic consequences. The purpose of this study was to characterize and identify oligodendrogliomas by their metabolic profile as measured by (1)H MR spectroscopic imaging (MRSI). Fifteen patients with oligodendroglial tumors (eight high-grade oligodendrogliomas, seven low-grade oligodendrogliomas) underwent MRI and short echo time (1)H MRSI examinations. Five main metabolites found in brain MR spectra were quantified and expressed as ratios of tumor to contralateral white matter tissue. The level of lipids plus lactate was also assessed in the tumor. For comparison six patients with a low grade astrocytoma were also included in the study. The metabolic profile of oligodendrogliomas showed a decreased level of N-acetylaspartate and increased levels of choline-containing compounds and glutamine plus glutamate compared with white matter. The level of glutamine plus glutamate was significantly higher in low-grade oligodendrogliomas than in low-grade astrocytomas and may serve as a metabolic marker in diagnosis and treatment planning. In high-grade oligodendrogliomas large resonances of lipids plus lactate were observed in contrast to low-grade tumors.

Adult↗

PubMed2002

An additional phase in PCr use during sustained isometric exercise at 30% MVC in the tibialis anterior muscle.

The occurrence of an abrupt acceleration in phosphocreatine hydrolysis in the tibial anterior muscle during the last part of a sustained isometric exercise at 30% maximal voluntary contraction until fatigue is demonstrated in seven out of eight healthy subjects by applying in vivo 31P NMR spectroscopy at 1.5 T field strength. This additional third phase in PCr hydrolysis, is preceded by a common biphasic pattern (first fast then slow) in PCr use. The NMR spectra, as localized by a surface coil and improved by proton irradiation, were collected at a time resolution of 16 s. Mean rates of PCr hydrolysis during exercise were -0.44 +/- 0.19% s(-1), -0.07 +/- 0.04% s(-1), and -0.29 +/- 0.10% s(-1) for the three successive phases. The increased rate of PCr hydrolysis, and also the loss of fine force control evident in the force records are consistent with increased involvement of large, fast-fatiguable units later in the contraction.

Adult↗

PubMed2002

Automated correction of unwanted phase jumps in reference signals which corrupt MRSI spectra after eddy current correction.

A commonly applied step in the postprocessing of gradient localized proton MR spectroscopy, is correction for eddy current effects using the water signal as a reference. However, this method can degrade some of the metabolite signals, in particular if applied on proton MR spectroscopic imaging data. This artifact arises from the water reference signal in the presence of a second signal which resonates close to the main water resonance. The interference of both resonances will introduce jumps in the phase of the reference time domain signal. Using this phase for eddy current correction will result in a ringing artifact in the frequency domain of the metabolite signal over the whole frequency range. We propose a moving window correction algorithm, which screens the phase of reference signals and removes phase jumps in time domain caused by interference of signals from multiple spin systems. The phase jumps may be abrupt or gradually distributed over several time data points. Because the correction algorithm only corrects time data points which contain phase jumps, the phase is minimally disrupted. Furthermore, the algorithm is automated for large datasets, correcting only those water reference signals which are corrupted. After correction of the corrupted reference signals, normal eddy current correction may be performed. The algorithm is compared with a method which uses a low-pass filter and tested on simulated data as well as on in vivo proton spectroscopic imaging data from a healthy volunteer and from patients with a brain tumor.

Algorithms↗

PubMed2001

Method for quantitative mapping of dynamic MRI contrast agent uptake in human tumors.

A method is presented for the acquisition and analysis of dynamic contrast-enhanced (DCE) MRI data, focused on the characterization of tumors in humans. Gadolinium (Gd) contrast was administered by bolus injection, and its effect was monitored in time by fast T1-weighted MRI. A simple algorithm was developed for automatic extraction of the arterial input function (AIF) from the DCE-MRI data. This AIF was used in the pixelwise pharmacokinetic determination of physiological vascular parameters in normal and tumor tissue. Maps were reconstructed to show the spatial distribution of parameter values. To test the reproducibility of the method 11 patients with different types of tumors were measured twice, and the rate of contrast agent uptake in the tumor was calculated. The results show that normalizing the DCE-MRI data using individual coregistered AIFs, instead of one common AIF for all patients, substantially reduces the variation between successive measurements. It is concluded that the proposed method enables the reproducible assessment of contrast agent uptake rates.

Algorithms↗

PubMed2001

Common processing of in vivo MR spectra.

This introductory article addresses approaches currently in use to process in vivo spectra. First, a brief overview is given of the information content represented by the parameters of MR signals. Subsequently, common steps in the processing of MR spectra such as pre-processing, normalisation and quantification and the use of prior knowledge are described. Finally, some prospects for more advanced processing are given.

Humans↗

PubMed2001

Radio-frequency probe for 1H decoupled 31P MRS of the head and neck region.

For optimal performance of 31P MRS at 1.5 Tesla, the use of a double resonant probe is essential to enable the application of 1H decoupling and Nuclear Overhauser Enhancement. This note describes the design, evaluation and safety validation of a versatile and compact probe optimized for 1H decoupled 31P MRS studies of tumors close to the surface of the body, in particular the head and neck region.

Equipment Design↗

PubMed2001

Metabolic information from the human fetal brain obtained with proton magnetic resonance spectroscopy.

OBJECTIVE: To study the feasibility of proton magnetic resonance spectroscopy for the examination of human fetal brain metabolism. STUDY DESIGN: Proton magnetic resonance spectroscopy was performed from a selected volume of brain tissue of 21 single normal fetuses of 36 to 41 weeks' gestational age. Absolute brain metabolite tissue levels were estimated by using the brain water content as an internal reference. RESULTS: Proton magnetic resonance spectra showed resonances for four dominating brain metabolites. Inositol, choline, creatine, and N-acetylaspartate could be detected with average tissue levels of 7.42 mmol/L, 3.31 mmol/L, 4.16 mmol/L, and 5.03 mmol/L, respectively. The resonance for N-acetylaspartate could not always be resolved from contaminating lipid signals. CONCLUSION: Proton magnetic resonance spectroscopy of the human fetal brain is feasible and can provide useful information about the fetal condition. The metabolite tissue levels for the fetal brain obtained in this study were in the range observed for neonates of similar gestational age.

Aspartic Acid↗

PubMed2001

pH heterogeneity in tibial anterior muscle during isometric activity studied by (31)P-NMR spectroscopy.

The occurrence of pH heterogeneity in human tibial anterior muscle during sustained isometric exercise is demonstrated by applying (31)P-nuclear magnetic resonance (NMR) spectroscopy in a study of seven healthy subjects. Exercise was performed at 30 and 60% of maximal voluntary contraction (MVC) until fatigue. The NMR spectra, as localized by a surface coil and improved by proton irradiation, were obtained at a high time resolution (16 s). They revealed the simultaneous presence of two pH pools during most experiments. Maximum difference in the two pH levels during exercise was 0.40 +/- 0.07 (30% MVC, n = 7) and 0.41 +/- 0.03 (60% MVC, n = 3). Complementary two-dimensional (31)P spectroscopic imaging experiments in one subject supported the supposition that the distinct pH pools reflect the metabolic status of the main muscle fiber types. The relative size of the P(i) peak in the spectrum attributed to the type II fiber pool increases with decreasing pH levels. This phenomenon is discussed in the context of the size principle stating that the smaller (type I) motor units are recruited first.

Adult↗

PubMed2000

Adenylate kinase 1 gene deletion disrupts muscle energetic economy despite metabolic rearrangement.

Efficient cellular energy homeostasis is a critical determinant of muscle performance, providing evolutionary advantages responsible for species survival. Phosphotransfer reactions, which couple ATP production and utilization, are thought to play a central role in this process. Here, we provide evidence that genetic disruption of AK1-catalyzed ss-phosphoryl transfer in mice decreases the potential of myofibers to sustain nucleotide ratios despite up-regulation of high-energy phosphoryl flux through glycolytic, guanylate and creatine kinase phosphotransfer pathways. A maintained contractile performance of AK1-deficient muscles was associated with higher ATP turnover rate and larger amounts of ATP consumed per contraction. Metabolic stress further aggravated the energetic cost in AK1(-/-) muscles. Thus, AK1-catalyzed phosphotransfer is essential in the maintenance of cellular energetic economy, enabling skeletal muscle to perform at the lowest metabolic cost.

Adenine↗

PubMed2000

Skin temperature increase during local exposure to high-power RF levels in humans.

The local temperature response of the skin on heating due to prolonged exposure to RF radiation by a surface coil was investigated in five healthy volunteers. Temperature changes induced by RF radiation were measured at the skin of the calf muscle by a fluoroptic probe. Exposure to superficial specific absorption rate (SAR) levels of 6.5, 12 and 22 W/kg resulted in skin temperature increases, the highest temperature recorded was 38.3 degrees C. Although the maximum values of each temperature curve correlated with the applied superficial SAR levels, these values did not exceed the recommended temperature limit for the extremities such as given by the Food and Drug Administration (FDA).

Adult↗

PubMed2000

Proton MR spectroscopy of wild-type and creatine kinase deficient mouse skeletal muscle: dipole-dipole coupling effects and post-mortem changes.

Localized proton MR spectra of mouse skeletal muscle obtained at 7 T show dipole-dipole coupling effects for creatine and putative taurine resonances and for the lactate methine signal. These effects are independent of the presence of creatine kinase. The intensity of the methylene (1)H resonance of creatine is not different between wild-type and creatine kinase deficient mice, which have a lower phosphocreatine content. (1)H-MR spectra acquired post-mortem from wild-type mouse skeletal muscle parallel to B(0) show a linewidth decrease for the methyl resonance of creatine and a 20% signal intensity loss for its methylene peak concurrent with the total breakdown of phosphocreatine as observed by (31)P-MR spectroscopy. However, with the muscle at the magic angle no changes in the appearance and intensity of creatine (and taurine) resonances are observed. These results indicate that the changes observed for creatine resonances are related to altered dipolar couplings and that the intensity of the methylene peak does not necessarily reflect muscular phosphocreatine content.

Animals↗

PubMed2000

SAR and tissue heating with a clinical (31)P MRS protocol using surface coils, adiabatic pulses, and proton-decoupling.

In MRS studies using surface transmit coils, accurate assessment of local SAR and RF heating represents a difficult problem involving the coil geometry and electromagnetic and geometric tissue properties. Methodologies to determine the optimum operating parameters for dual-resonant surface coil measurements are presented, based on a standardized coil and protocol used in a multicenter (31)P MRS clinical trial, using adiabatic pulses and bilevel proton decoupling. Spatial distributions of absorbed radiation in human calf and in a tissue-equivalent gel phantom were modeled using finite-element simulations and realistic conductivity and permittivity values. Local SAR in worst-case 1 cm(3) volumes of interest (VOIs) in calf is predicted to be below international guidelines, and the temperature at the skin surface was found to increase due to the RF by less than 2 degrees C and remain below 37 degrees C. The heating rate and maximum temperature in the gel, at positions guided by the simulations, were within guideline values for both extremities and trunk and in reasonable agreement with that predicted.

Adult↗

PubMed2000

Automatic correction for phase shifts, frequency shifts, and lineshape distortions across a series of single resonance lines in large spectral data sets.

A new model-free method is presented that automatically corrects for phase shifts, frequency shifts, and additional lineshape distortions of one single resonance peak across a series of in vivo NMR spectra. All separate phase and frequency variations are quickly and directly derived from the common lineshape in the data set using principal component analysis and linear regression. First, the new approach is evaluated on simulated data in order to quantitatively assess the phase and frequency shifts which can be removed by the proposed correction procedure. Subsequently, the value of the method is demonstrated on in vivo (31)P NMR spectra from skeletal muscle of the hind leg of the mouse focusing on the phosphocreatine resonance which is distorted by the experimental procedure. Phase shifts, frequency shifts, and lineshape distortions with respect to the common lineshape in the spectral data set could successfully be removed.

Animals↗

PubMed2000

Proton MR spectroscopy of prostatic tissue focused on the detection of spermine, a possible biomarker of malignant behavior in prostate cancer.

To investigate whether polyamines may be valuable diagnostic and prognostic markers in prostate cancer, the presence of polyamines was studied in various human prostatic tissues using both proton magnetic resonance (MR) spectroscopy and high-pressure liquid chromatography (HPLC). The HPLC results showed that normal and benign hyperplastic prostatic tissues were characterized by a high content of spermine. Spermine levels were reduced in tumor tissue, especially in prostatic carcinoma with metastases, and in xenografts of human prostatic carcinoma cells. These preliminary results indicate that spermine may be used as a biomarker for malignant behavior. The MR spectroscopy study showed that it is possible to detect spermine resonances in prostatic biopsy material by one-dimensional and two-dimensional J-resolved MR spectroscopy at high field (600 MHz). Localized one-dimensional in vitro MR spectra obtained at the clinical field strength of 1.5 T showed spermine signals in the region between 3.0 and 3.3 ppm. In in vivo MR spectra of the human prostate, however, these signals were obscured by resonances of choline (3.2 ppm) and creatine (3.0 ppm).

Biomarkers, Tumor↗