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Biomedical subjects

C C Hanstock

Publications and source records attributed to C C Hanstock.

18 recordsLinked to original sources
PubMed1996

Chronic lithium does not alter human myo-inositol or phosphomonoester concentrations as measured by 1H and 31P MRS.

Lithium may act by decreasing intracellular concentrations of myo-inositol. The present study measured the effects of chronic lithium on myo-inositol concentrations in volunteers. Eleven subjects received either lithium (n = 7) or placebo (n = 4) for 7 days in a double-blind study. Myo-inositol concentrations at baseline and day 8 were measured in vivo using 1H magnetic resonance spectroscopy (MRS). The results showed that lithium did not alter brain myo-inositol concentrations compared to placebo. In 5 other subjects we used 1H MRS and 31P MRS to measure changes in both myo-inositol and phosphomonoester concentrations. This second study showed that lithium did not alter myo-inositol or phosphomonoester concentrations. Thus, the present studies do not support the hypothesis that lithium significantly affects the brain concentrations of myo-inositol or phosphomonoesters; however, it is possible these findings represent an inability to detect the changes in myo-inositol and phosphomonoester concentrations that may have occurred following lithium administration.

Brain↗
PubMed1994

Diffusion-weighted imaging differentiates ischemic tissue from traumatized tissue.

BACKGROUND AND PURPOSE: Diffusion-weighted magnetic resonance imaging (MRI) has been shown to be particularly effective in detecting early (0 to 4 hours) pathophysiological changes in localized brain regions after cerebral ischemia. The present study sought to establish whether diffusion-weighted MRI would be similarly effective in predicting outcome after traumatic brain injury. METHODS: Diffusion-weighted MRI images and T2-weighted MRI images were obtained over 4 hours after either moderate fluid percussion-induced traumatic brain injury or unilateral carotid ligation in rats. RESULTS: Diffusion-weighted MRI images of traumatic brain injury demonstrated focal regions of image hypointensity as early as 1 hour after trauma. The relative diffusion coefficient in these hypointense regions was significantly increased (P < .005) by 4 hours after trauma compared with the noninjured hemisphere, but only in the transverse plane in the x direction. In contrast, induction of diffuse, nonfocal ischemia by unilateral carotid ligation resulted in scattered regions of hyperintensity with a significant (P < .001) decrease in relative diffusion coefficient as early as 1 hour after ligation compared with the noninjured hemisphere. This decrease exhibited no directionality. CONCLUSIONS: We conclude that traumatic brain injury results in an increased water diffusion distance with the directionality indicative of bulk flow of extracellular fluid toward the lateral ventricles (vasogenic edema). In contrast, the decreased water diffusion distance with no apparent directionality observed in ischemia is most likely indicative of cytotoxic edema. Diffusion-weighted MRI therefore has the potential to differentiate cases of traumatic brain injury with no focal ischemia from those instances of traumatic brain injury in which focal ischemia is a complication.

Animals↗
PubMed1992

1H-[13C] NMR measurements of [4-13C]glutamate turnover in human brain.

A limitation of previous methods for studying human brain glucose metabolism, such as positron emission tomography, is that metabolic steps beyond glucose uptake cannot be studied. Nuclear magnetic resonance (NMR) has the advantage of allowing the nondestructive measurement of 13C distribution in specific carbon positions of metabolites. In this study 1H-[13C] NMR spectroscopy in conjunction with volume localization was used to measure the rate of incorporation of 13C isotope from infused enriched [1-13C]glucose to human brain [4-13C]glutamate. In three studies C4 glutamate turnover time constants of 25, 20, and 17 min were measured in a 21-cm3 volume centered in the region of the visual cortex. Based on an analysis of spectrometer sensitivity the spatial resolution of the method can be improved to < 4 cm3. In conjunction with metabolic modeling and other NMR measurements this method can provide a measure of regional rates of the brain tricarboxylic acid cycle and other metabolic pathways.

Brain↗
PubMed1992

Localized 1H NMR spectra of glutamate in the human brain.

Localized 1H NMR spectra at TE = 12 ms were obtained from cerebral cortex of human subjects using ISIS with surface suppression. The 2.29-ppm resonance was assigned to C4 glutamate with contributions from C4 glutamine and GABA using in vivo spectral editing and comparison of chemical shift with pure compounds. The measured intensity ratio between the 2.29 resonance and the creatine resonance at 3.03 ppm was in good agreement with the ratio predicted from previously reported measurements of glutamate, glutamine, and GABA concentrations in biopsied human brain tissue.

Aspartic Acid↗
PubMed1991

Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.

Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

Acclimatization↗
PubMed1990

Measurement of ethanol in the human brain using NMR spectroscopy.

Ethanol in the human brain is readily observable by noninvasive 1H NMR spectroscopy. We have made such observations in a human subject with a time resolution per measurement of 6.5 min and volume resolution of 16 cc. The ethanol methyl proton signal is well separated from signals of other metabolites in 1H spectra from human brain and it is one of the most intense signals in such spectra when blood ethanol concentration is 0.1% (21.7 mM)--the legal definition of alcoholic intoxication in many jurisdictions. These properties, plus the fact that the ethanol signal can be further isolated from other resonances by spectral editing, open several possibilities for further investigation.

Alcoholic Intoxication↗
PubMed1988

The application of depth-pulse localized 31P NMR spectroscopy to monitor tumor metabolism and response to chemotherapy in the rat kidney.

To illustrate the spatial variations in metabolism within tumors, 31P spectral data are presented from a predefined, depth-pulse localized region of a rat kidney impregnated with Walker sarcoma cells. These data display the changes in energy metabolism during infiltration of the kidney by the tumor and during treatment of the tumor with cyclophosphamide.

Animals↗
PubMed1988

In vivo assessment of focal brain lactate alterations with NMR proton spectroscopy.

Spectral editing techniques and localization of 1H signals were applied to monitor lactate accumulation in a circumscribed region of brain damage. The experiments were performed at 2.35 T (100 MHz) in a 40-cm bore magnet. Following unilateral craniectomy in anesthetized adult cats, a two-turn surface coil was positioned over the dural surface. Proton spectra were obtained before and 1-5 h after production of a cortical cold lesion from three curved shells of brain tissue, each approximately 3 mm thick. The localized spectrum was obtained from each region with and without spectral difference editing for the lactate CH3 protons, but always with the maximum excitation produced by the semiselective binomial pulse centered on the lactate CH3 resonance. Region 1 represented the damaged area, Region 2 was located immediately below Region 1, and Region 3 was immediately below Region 2. Spin-echo magnetic resonance imaging was used to confirm the relationship between the location of the lesion and the regions from which the spectra were obtained. Spectra obtained without lactate editing showed, in addition to the N-acetylaspartate peak, a large lactate peak in Region 1 after production of the cold lesion. In Regions 2 and 3, changes in lactate were more difficult to assess owing to the presence of a lipid peak at a similar frequency that results from incomplete suppression by the spin-echo pulse sequence alone. Spectra acquired using lactate editing did not contain the lipid peak and clearly showed relatively small lactate accumulations in Regions 2 and 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Surface coil localization of 31P NMR signals from orthotopic human kidney and liver.

By incorporating the hyperbolic secant inversion pulses with the image-selected in vivo spectroscopy localization technique and by applying a gradient-echo imaging method, we have selected only the 31P NMR signals from orthotopic human kidney and liver, using a single concentric 1H/31P surface coil. Corresponding to the experimental results on animal studies, the phosphocreatine signal is dramatically reduced in the localized spectra. Our localization strategy also allows us to shim easily on the well-defined volume of interest and leads to high-resolution spectra that exhibit multiplet structure. Our results indicate that we can obtain localized signals from deep small organs and point the way for other human metabolism studies.

Humans↗
PubMed1988

Spatially localized 1H NMR spectra of metabolites in the human brain.

Using a surface coil, we have obtained 1H NMR spectra from metabolites in the human brain. Localization was achieved by combining depth pulses with image-selected in vivo spectroscopy magnetic field gradient methods. 1H spectra in which total creatine (3.03 ppm) has a signal/noise ratio of 95:1 were obtained in 4 min from 14 ml of brain. A resonance at 2.02 ppm consisting predominantly of N-acetylaspartate was measured relative to the creatine peak in gray and white matter, and the ratio was lower in the white matter. The spin-spin relaxation times of N-acetylaspartate and creatine were measured in white and gray matter and while creatine relaxation times were the same in both, the N-acetylaspartate relaxation time was longer in white matter. Lactate was detected in the normoxic brain and the average of three measurements was approximately equal to 0.5 mM from comparison with the creatine plus phosphocreatine peak, which was assumed to be 10.5 mM.

Algorithms↗
PubMed1985

High field 1H-NMR analysis of the 1:1 intercalation complex of the antitumor agent mitoxantrone and the DNA duplex [d(CpGpCpG)].

Complete 1H-nmr assignment has been achieved of the stoichiometric 1:1 complex of the antitumor agent mitoxantrone with the duplex oligomer [d(CpGpCpG)]2. The techniques used included 2D-COSY, 1D-NOE and 2D-HH-INADEQUATE. Comparisons of 1H and 13C chemical shift changes upon addition of drug suggest symmetrical intercalative binding to the center of the tetramer. NOE difference measurements and 31P studies suggest binding of the terminal OH groups of the side chains to the central phosphate groups such that the methylene groups are proximate to C(3)6, C(3)6 and G(4)8 base protons all in the major groove. The data suggest that the side chains bind to the neighboring base pairs from the intercalation site. This is in accord with independent evidence of G,C base preference for binding from spectroscopic and electron microscopy studies.

Intercalating Agents↗
PubMed1985

Complete 1H assignments of the non-exchangeable protons of the non self-complementary heptadeoxyribonucleotide d[(GTCGTCA).(TGACGAC)] and its component strands by high field NMR.

The non self complementary heptadeoxyribonucleotides d(GTCGTCA) and d(TGACGAC) were synthesized by the phosphotriester method. While complete 1H-NMR assignments of the former were obtained by a combination of one and two-dimensional techniques at room temperature, extensive stacking of the latter under these conditions dictated analysis at 50 degrees C when the lines were sharply resolved. The duplex form of the annealed strands under the conditions of the 1H-NMR experiment was established independently of the NMR evidence by 32P end labeling with T4 polynucleotide kinase followed by butt end joining using the absolute specificity of T4 ligase for double strand DNA. Analysis of the resulting ladder of polymers was performed using gel electrophoresis and autoradiography. Complete 1H-NMR assignments of the non-exchangeable protons in the self complementary heptamer was achieved. The assignments were confirmed using NOE differences, and two-dimensional COSY, and HH-INADEQUATE experiments at 400 and 500 MHz. The assignments are in accord with a conformation for the heptamer belonging to the B family of structures.

Base Sequence↗
PubMed1985

1H-NMR assignments of the non-exchangeable protons of the consensus donor exon:intron junctioń d(CpApGpGpTpApApGpT).

The consensus donor exon:intron junction d(CpApGpGpTpApApGpT) has been synthesized by a modified phosphotriester method. The non-self-complementary nonamer has, in principle, only two G,C or four A,T points of self-recognition. The inference that it exists in the single strand form at 20 degrees C was confirmed by temperature variable 1H-NMR and NOE measurements. The proton assignments were secured using two-dimensional COSY which provided intra-nucleotide correlations, then NOE difference measurements as well as inversion recovery T1 experiments. Systematic procedures were developed for the assignment of the individual bases and their component protons based on the effects of molecular environment on chemical shifts. These latter procedures should be useful for the assignment of other random-coil single strand oligodeoxyribonucleotides.

Base Sequence↗
PubMed1984

Synthesis, complete 1H assignments and conformations of the self-complementary hexadeoxyribonucleotide [d(CpGpApTpCpG)]2 and its fragments by high field NMR.

The two deoxyribonucleotides [d(CpGpApTpCpG)]2 and [d(CpGpCpG)]2 were synthesized by the phosphotriester method. Their duplex form under the conditions of the 1H-nmr experiments was proven by end 32P labeling with T4 polynucleotide kinase followed by butt end joining employing the absolute specificity of T4 ligase for double stranded DNA and analysis using gel electrophoresis and autoradiography. Complete nmr assignment of the 1H chemical shifts and coupling constants was achieved. The assignments were secured using sequential decoupling, NOE difference measurements, and two-dimensional COSY and SECSY experiments. Spectrum simulation confirmed the experimental values of chemical shifts and coupling constants. The techniques for the assignment outlined together with 31P and 2-D heteronuclear shift correlation permit an approach to a systematic analysis of more complex single-strand and duplex oligodeoxyribonucleotides.

Base Sequence↗
PubMed1984

Interactions of the antitumor agents mitoxantrone and bisantrene with deoxyribonucleic acids studied by electron microscopy.

The interactions of the low cardiotoxic antitumor agents 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazoyl-2-yl)hydrazone] (bisantrene) with pBR322 and PM2 DNA have been examined by electron microscopy. Direct evidence was obtained for intercalative binding of both drugs, with mitoxantrone causing a 13% average length increase in pBR322 corresponding to approximately 580 drug molecules per circle at saturation and bisantrene causing an 11% increase in length corresponding to approximately 480 drug molecules bound per circle. Considerations of the known GC preference for non-nearest neighbor binding of the drugs and inspection of the known sequence of pBR322 suggest that the available intercalation sites are occupied and that additional external electrostatic binding of the cationic drugs also occurs. An apparent difference in behavior of mitoxantrone as compared with that of bisantrene in causing no net increase in length of supercoiled pBR322 was shown to be attributable to an offsetting compaction due to extensive supercoiling by mitoxantrone molecules. This conclusion was confirmed by independent experiments with PM2 covalently closed-circular DNA--both native, negatively supercoiled and relaxed--with calf thymus topoisomerase, using ethidium for comparison. Ethidium caused a 21.3 +/- 3.6% length increase in nicked, open-circular PM2-DNA, or 2100 molecules bound per 10,300 base pairs. Mitoxantrone caused a 16.6% length increase in nicked PM2-DNA equivalent to approximately 1700 drug molecules per circle. Electron microscopic measurements on relaxed PM2-DNA with progressively increasing proportions of mitoxantrone (from 1.4:1 to 14:1 drug molecules per base pair) revealed the onset of formation of lacelike networks of DNA circles linked together. This phenomenon, which is not produced by bisantrene, is attributed to inter-DNA links by the charged side arms of mitoxantrone and is in accord with previous reports that mitoxantrone causes severe compaction and distortion of chromatin. Electron microscopic examination of the interaction of six additional mitoxantrone derivatives, two of which produced lacelike DNA networks, revealed strict structural requirements for this phenomenon.

Anthracenes↗
PubMed1983

Structure and conformation of saframycin R determined by high field 1H and 13C NMR and its interactions with DNA in solution.

The chemical structure and conformation of the new antitumor antibiotic saframycin R have been determined by high field 1H and 13C NMR as well as FAB mass spectrometry. Unlike other members of the saframycin family, saframycin R contains a reduced quinone ring bearing a glycolic ester moiety. Saframycin R exhibits acid promoted equilibrium and reversible covalent binding to DNA templates and, in the presence of a reducing agent, oxygen dependent single strand scission of supercoiled DNA. The extent of DNA scission is enhanced by in situ porcine carboxyl esterase or base catalyzed cleavage of the glycolic ester function plausibly by the release of the more reactive reduced saframycin A. This suggests that saframycin R may be regarded as a less toxic pro-drug for the active forms of saframycins A or S.

Animals↗