Nuclear magnetic resonance spectroscopy studies of the brain.
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Animals↗
Biomedical subjects
S R Williams
Publications and source records attributed to S R Williams.
Early changes in cerebral sodium distribution following ischaemia monitored by 23Na magnetic resonance imaging.
23Na magnetic resonance imaging has been used in this preliminary study to investigate early changes in brain sodium signal intensity during and after cerebral ischaemia in a gerbil model. The total sodium signal in selected brain regions decreased between 15 and 30% within 4 min of the onset of ischaemia, and then remained constant throughout the ischaemic period. The same pattern was observed in the eyes. On reperfusion, there was no significant change in the sodium signal over the first 4 min, but by 8 min the signal intensity had returned to or passed through control levels in all regions measured, with the exception of the eyes. These observations are consistent with the loss and resynthesis of ATP as seen in this model, and may be reflecting the redistribution of tissue sodium resulting from energy failure and recovery.
Acute Disease↗
Vigabatrin-induced lesions in the rat brain demonstrated by quantitative magnetic resonance imaging.
Rats treated with 250 mg/kg/day vigabatrin showed lesions detected by magnetic resonance imaging (MRI) in the cerebellar white matter in vivo. No lesions were seen in any control animal. As well as these visually apparent lesions, quantitative T2 relaxation time measurements showed a 12 ms increase in cerebellar white matter from 66 +/- 4 ms (SD, n = 5) to 78 +/- 2 ms (SD, n = 7). This region, as expected from previous studies, showed microvacuolation on post-mortem pathology. Additionally, significant increases in T2 relaxation times of 4-9 ms were found in the cerebral cortex, thalamus and hippocampus. Microvacuolation was not detected by post-mortem histopathology in the cerebral cortex or hippocampus, however, immunohistochemical staining for glial fibrillary acidic protein and for macrophages (ED1) showed reactive astrocytes (gliosis) and in more severe cases, microglial proliferation in these regions; such changes were also seen in association with the microvacuoles. No T2 increase was found in the cerebellar grey matter or olfactory bulbs. MRI techniques, including T2 relaxometry, are therefore sensitive for detecting vigabatrin-induced changes, including reactive astrocytosis, microglial proliferation and vacuolation in the rat brain. These results suggest that quantitative MRI should be a useful method for evaluating whether vigabatrin has neuropathological effects when given to patients.
Animals↗
Magnetic resonance imaging of propagating waves of spreading depression in the anaesthetised rat.
Gradient echo magnetic resonance (MR) imaging was used to demonstrate propagating waves of cortical spreading depression (SD) in the anaesthetised rat. SD was initiated by remote perfusion with 150 mM KCl applied for 0.5-2 min to the left parietal cortex. Gradient echo MR images were obtained every 12-30 s in either a vertical coronal section or a horizontal section including the superficial cortex in plan view. Within 2 min of application of KCl, we observed a zone of increased signal intensity (3-15%) on the MR image, up to 2 mm across, lasting approximately 1 min and propagating away from the site of initiation. The mean velocity for 27 of such waves seen in seven animals was calculated to be 2.79 mm/min, with means (+/- SD) in individual animals averaging 2.90 +/- 0.46 mm/min (n = 7). Increased signal intensity in gradient echo images has been attributed to an increased level of oxygenation within the venous blood. Our results are consistent with this interpretation although other physiological changes during SD may also contribute to the signal changes.
Animals↗
Speech intelligibility in tone language (Chinese) laryngectomy speakers.
Tone language speakers use lexical tone or fundamental frequency to signal meaning. Therefore, native tone language alaryngeal speakers encountering difficulty imparting lexical tone variation would suffer loss of speech intelligibility. This study examines the intelligibility of lexical tone produced by four different alaryngeal speech methods, namely: oesophageal speech, electrolarynx, a pneumatic device and tracheo-oesophageal speech. Isolated and embedded monosyllabic Chinese words produced by 53 alaryngeal speakers were presented to three normally hearing, young adult listeners with no prior exposure to laryngectomy speech. The listeners transcribed the speech orthographically. Significant differences were found in the intelligibility level between the different speech methods. Listeners' responses were also pooled together and analysed for tone and segmental errors. Errors of tone alone were found to occur more often than segmental errors.
Aged↗
Phenylalanine embryopathy in three siblings: implications of maternal diet therapy.
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Adult↗
NMR spectroscopy: current status and future possibilities.
Nuclear magnetic resonance (NMR) spectroscopy is now established as a non-invasive method of studying metabolism in living systems, ranging from cellular suspensions to man. With respect to clinical applications, recent developments include the successful implementation of new techniques for spatial localisation, and in particular the acquisition of excellent 1H spectra from selected regions of the human brain. Localised 1H spectroscopy opens the way to monitoring a wide range of compounds that are inaccessible to 31P NMR, and should add considerably to the information that is available from 31P studies. NMR spectroscopy does, however, have its limitations, which arise primarily from the fact that it is an insensitive technique. This lack of sensitivity limits the spatial resolution for metabolic studies, and means that metabolites must be present at fairly high concentrations in order to produce detectable signals. In this article, we illustrate the scope and limitations of NMR spectroscopy by describing a few examples of studies undertaken on animals and humans.
Animals↗
Applications of magnetic resonance spectroscopy and diffusion-weighted imaging to the study of brain biochemistry and pathology.
The first practical demonstration that nuclear magnetic resonance (NMR) spectroscopy could be applied to the study of brain biochemistry in vivo came in 1980, with the studies of the rat brain using a surface coil. Since then the technique has been rapidly and extensively developed into a versatile, non-invasive tool for the investigation of various aspects of brain biochemistry, physiology and disease. NMR is non-destructive and can be used to examine a wide variety of samples, ranging from localized regions within the whole brain in humans or animals, through tissue preparations (perfused organ, tissue slices and homogenates), to isolated cells and aqueous solutions, such as tissue extracts. 31P and 1H NMR spectra deriving from endogenous compounds of the brain in situ allow assessment of tissue metabolites and provide information about high-energy phosphates, lactate, certain amino acids, intracellular pH and ionic concentrations. Exogenous substrates or probes labelled with stable isotopes can also be introduced into the brain and used to monitor metabolism. Animal models of brain diseases have given some impetus to rapid progress in clinical NMR spectroscopy and also magnetic imaging techniques. The purpose of this article is to highlight the type of information available from these NMR techniques, and to present this in a neuroscience context, emphasizing the biochemical, physiological and pathological information that can be obtained using these methods.
Animals↗
Salpingitis isthmica nodosa: a review of the literature, discussion of clinical significance, and consideration of patient management.
OBJECTIVES: To examine and discuss the pathology, diagnosis, incidence, and patient profile of salpingitis isthmica nodosa and to question its natural history, propose management strategies, and identify areas of promising research. DESIGN: Over 50 studies were reviewed, evaluated, and compared to offer the clinician a foundation on which to generate treatment plans. RESULTS: Salpingitis isthmica nodosa is diagnosed by the pathological presence of isthmic diverticula and may be suggested by characteristic changes on hysterosalpingogram. Its incidence in healthy, fertile women ranges from 0.6% to 11%, but it is significantly more common in the setting of ectopic pregnancy and infertility. There are no studies, retrospective or prospective, that clearly dictate appropriate therapy. CONCLUSION: Given its progressive nature and probable deleterious effects on fertility, we propose that microtubal surgery be the definitive treatment for qualified women who have salpingitis isthmica nodosa.
Fallopian Tubes↗
Palpation compared with ultrasound in the assessment of malignant cervical lymph nodes.
This prospective study compares the results of pre-operative clinical examination and simple ultrasound examination of the neck in 18 patients with proven head and neck primary tumours and palpable cervical lymphadenopathy, who then underwent 21 radical neck dissections. Neck palpation and ultrasound examination were compared with histological examination. Ultrasound did not add significantly to the information obtainable by simple neck palpation in this group of patients.
Carcinoma, Squamous Cell↗
Applications of NMR spectroscopy to the study of experimental stroke in vivo.
BACKGROUND AND PURPOSE: Magnetic resonance spectroscopy and imaging enable us to investigate biochemical and pathophysiological changes associated with cerebral ischemia. The specific aims of these studies were to establish the relationships between energy metabolites and regional cerebral blood flow and to determine whether diffusion-weighted imaging is sensitive to the known thresholds for cerebral tissue energy failure and disturbance of transmembrane ionic gradients in gerbils. METHODS: Magnetic resonance spectroscopy measurements of energy metabolites in the gerbil brain were obtained as a function of cerebral blood flow (measured with the hydrogen clearance technique) before, during, and after unilateral or bilateral occlusion of the common carotid arteries. Diffusion-weighted and T2-weighted images were obtained in a separate series of experiments. RESULTS: Major changes in brain energy metabolites were observed at flow values of 20 ml.100 g-1.min-1 and below. The cerebral blood flow threshold for maintenance of energy status was lowered in hypothermia, consistent with a protective effect. Diffusion-weighted imaging intensity increased at cerebral blood flow values of 15 to 20 ml.100 g-1.min-1 and below and increased gradually following the onset of severe global cerebral ischemia, but with a delay of about 2.5 minutes. CONCLUSIONS: The spectroscopic observations suggest that the flow thresholds for electrical function and edema are a direct consequence of energy failure. Comparison of the spectroscopy and imaging data suggests that diffusion-weighted imaging is sensitive to disruption of tissue energy metabolism or to a consequence of this disruption. The possibilities arise of visualizing energy failure with the spatial resolution characteristic of magnetic resonance imaging and detecting compromised but recoverable tissue.
Animals↗
Epstein-Barr virus-derived vectors for transient and stable expression of recombinant proteins.
The transient expression level of foreign proteins in primate cells can be enhanced by incorporating the replication elements derived from Epstein-Barr virus (EBV). Specifically, we have constructed expression plasmids with the replication origin region (OriP) from EBV and an adenovirus-transformed cell line that expresses the EBV nuclear antigens-1 (EBNA-1). As EBV vectors can replicate as episomes in the nuclei, such vectors can have a stable transfection efficiency as high as 25% and provide a straightforward way of obtaining large amounts of recombinant proteins transiently or stably.
Antigens, Viral↗
Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types.
Proton nuclear magnetic resonance (1H NMR) spectroscopy is a noninvasive technique that can provide information on a wide range of metabolites. Marked abnormalities of 1H NMR brain spectra have been reported in patients with neurological disorders, but their neurochemical implications may be difficult to appreciate because NMR data are obtained from heterogeneous tissue regions composed of several cell populations. The purpose of this study was to examine the 1H NMR profile of major neural cell types. This information may be helpful in understanding the metabolic abnormalities detected by 1H NMR spectroscopy. Extracts of cultured cerebellar granule neurons, cortical astrocytes, oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells, oligodendrocytes, and meningeal cells were analyzed. The purity of the cultured cells was > 95% with all the cell lineages, except for neurons (approximately 90%). Although several constituents (creatine, choline-containing compounds, lactate, acetate, succinate, alanine, glutamate) were ubiquitously detectable with 1H NMR, each cell type had distinctive qualitative and/or quantitative features. Our most unexpected finding was a large amount of N-acetyl-aspartate (NAA) in O-2A progenitors. This compound, consistently detected by 1H NMR in vivo, was previously thought to ne present only in neurons. The finding that meningeal cells have an alanine:creatine ratio three to four times higher than astrocytes, neurons, or oligodendrocytes is in agreement with observations that meningiomas express a higher alanine:creatine ratio than gliomas. The data suggest that each individual cell type has a characteristic metabolic pattern that can be discriminated by 1H NMR, even by looking at only a few metabolites (e.g., NAA, glycine, beta-hydroxybutyrate).(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗
Endoplasmic reticulum: the major contributor to the PDE peak in hepatic 31P-NMR spectra at low magnetic field strengths.
31P-NMR spectra of liver in vivo, subcellular fractions and model systems were acquired in order to characterise further the hepatic phosphodiester peak seen at low magnetic field strengths previously shown to be predominantly due to phospholipid bilayers. The data obtained in this study in vitro suggested that the phospholipid membranes of the endoplasmic reticulum provide the dominant contribution to this phosphodiester peak. Support for this hypothesis was provided by experiments on rats. Phenobarbitone, which is known to induce proliferation of the endoplasmic reticulum produced a considerable increase in intensity of the phosphodiester peak in liver spectra in vivo.
Animals↗
Multiple primary cancers in Hong Kong Chinese patients with squamous cell cancer of the head or neck.
BACKGROUND: The risk of multiple primary tumors in the head and neck area is higher than that in other areas of the body. METHODS: A total of 573 patients with squamous cell carcinoma of the head or neck were studied prospectively during a 4.5-year period to determine the incidence of associated synchronous and metachronous second primary carcinoma. RESULTS: Multiple primary carcinoma was found in 2.4% of these patients (69% with synchronous primary tumors). Sixty-three percent of all second primary tumors occurred in the esophagus. CONCLUSIONS: This report emphasizes the importance of esophagoscopy in the initial assessment of patients with squamous cell carcinoma of the head or neck.
Alcohol Drinking↗
Random PCR mutagenesis screening of secreted proteins by direct expression in mammalian cells.
We have developed a general method for screening randomly mutagenized expression libraries in mammalian cells by using fluorescence-activated cell sorting (FACS). The cDNA sequence of a secreted protein is randomly mutagenized by PCR under conditions of reduced Taq polymerase fidelity. The mutated DNA is inserted into an expression vector encoding the membrane glycophospholipid anchor sequence of decay-accelerating factor (DAF) fused to the C terminus of the secreted protein. This results in expression of the protein on the cell surface in transiently transfected mammalian cells, which can then be screened by FACS. This method was used to isolate mutants in the kringle 1 (K1) domain of tissue plasminogen activator (t-PA) that would no longer be recognized by a specific monoclonal antibody (mAb387) that inhibits binding of t-PA to its clearance receptor. DNA sequence analysis of the mutants and localization of the mutated residues on a three-dimensional model of the K1 domain identified three key discontinuous amino acid residues that are essential for mAb387 binding. Mutants with changes in any of these three residues were found to have reduced binding to the t-PA receptor on human hepatoma HepG2 cells but to retain full clot lysis activity.
Amino Acid Sequence↗
Detection of thymosin beta 4 in situ in a guinea pig cerebral cortex preparation using 1H NMR spectroscopy.
In the present work we have investigated the macromolecules that contribute to the brain 1H NMR spectrum. The cerebral cortex showed distinct resonances at the uncrowded methyl- and methylene chemical shift scale of the spin-echo 1H NMR spectrum. The peaks at 1.22 and 1.40 ppm (relative to the methyl protons of N-acetyl aspartate at 2.02 ppm) arise from cerebral macromolecules without evidence for co-resonances from low molecular weight metabolites as shown by the spin-spin relaxation decays of these resonances. In addition to these NMR signals, peaks at 0.9 and 1.7 ppm from macromolecules were detected. These resonances are from proteins, and we have identified the polypeptides that contributed to the 1H NMR peaks. Two proteins that were present at concentrations of 250 and 350 micrograms/g of dryed tissue showed 1H NMR spectra that resembled the macromolecular pattern in the cerebral 1H NMR spectrum. They were identified as thymosin beta 4 and histone H1, respectively. Thymosin beta 4 was present in soluble high speed cytoplasmic fraction and in P2 pellet, whereas histone H1 was detected in nuclear enriched fraction. A chemical shift-correlated two-dimensional 1H NMR spectrum of thymosin beta 4 in vitro revealed a coupling pattern that matched the macromolecule in the cerebral cortex which we have previously noted (Kauppinen R. A., Kokko, H., and Williams, S. R. (1992) J. Neurochem. 58, 967-974). On the basis of both one- and two-dimensional NMR evidence, subcellular distribution and high concentration, we assign the 1H NMR signals at 0.9, 1.22, 1.40, and 1.7 ppm in the cerebral cortex to thymosin beta 4.
Amino Acid Sequence↗
Perfusion and diffusion MR imaging.
Diffusion-weighted images of the rat brain were obtained using the pulsed-gradient spin-echo method. An attempt was made to extract perfusion-related parameters from signal intensity data taken from the caudate-putamen region of the images, by using a nonlinear least-squares calculation to fit the Le Bihan biexponential expression (Le Bihan et al., Radiology, 168, 497 (1988)) to the data. The perfusion-related parameters could not be obtained with sufficient accuracy to be useful, although the perfusion-weighted images appear to contain meaningful qualitative information. An analysis of the perfusion model is presented and shows why the Le Bihan pseudo-diffusion coefficient is particularly difficult to measure with reasonable accuracy.
Animals↗