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Biomedical subjects

I C Smith

Publications and source records attributed to I C Smith.

At least 19 recordsLinked to original sources
PubMed1992

Lipoprotein(a) and CA125 levels in the plasma of patients with benign and malignant ovarian disease.

Elevated plasma levels of apolipoprotein (a) have been reported earlier in cancer patients. In order to investigate the potential of apolipoprotein(a) as an ovarian tumour marker, plasma apolipoprotein(a) and CA125 levels were measured in healthy women and women with benign or malignant pelvic masses. Among women younger than 49 years, 80% of healthy controls and ovarian cancer patients had apolipoprotein(a) levels below 350 U/l. Among women aged 49 years or older, 46% of healthy controls but 73% of ovarian cancer patients and 77% of women with successfully treated ovarian cancer, had low apolipoprotein(a) levels. For both age groups, apolipoprotein(a) is not a suitable marker for ovarian cancer. No correlation was found between apolipoprotein(a), triglyceride or cholesterol in plasma. Healthy women younger than 49 years had significantly higher CA125 levels than women 49 years or older (20 +/- 14 U/ml vs. 13 +/- 12 U/ml, p less than 0.005). Levels of CA125 above 35 U/ml were found in 12% of the younger and 4% of the older healthy women, 73% of the younger and 61% of the older patients with untreated or residual tumours, and in 33% of the younger and 31% of older patients with no evidence of disease, as well as in 58% of women of both age groups with benign pelvic masses. The sensitivity and specificity of CA125 levels for the detection of cancer were 73% and 74% respectively for women younger than 49 years, and 62% and 78% respectively for women 49 years or older.

Adult↗
PubMed1992

Molecular motions and dynamics of a diunsaturated acyl chain in a lipid bilayer: implications for the role of polyunsaturation in biological membranes.

The nature and dynamics of the motions of a diunsaturated fatty acyl chain in a lipid bilayer were examined using a comprehensive simulation program for 2H NMR line shapes developed by Wittebort et al. [Wittebort, R. J., Olejniczak, E. T., & Griffin, R. G. (1987) J. Chem. Phys. 36, 5411-5420]. A motional model in which the isolinoleoyl chain (18:2 delta 6,9) adopts two conformations consistent with the low energy structures proposed for 1,4-pentadiene [Applegate, K. R., & Glomset, J. A. (1986) J. Lipid Res. 27, 658-680], but undergoes a rapid jump between these states, is sufficient to account for the experimentally observed quadrupolar couplings, the 2H-2H and 1H-2H dipolar couplings, the longitudinal relaxation times, and the changes in the average conformation of the chain that occur with a variation in temperature. The jump motion originates via rotations about the C7-C8 and the C8-C9 carbon bonds and leads to the low order parameters assigned to the C8 methylene segment (0.18) and the C9-C10 double bond (0.11). In contrast, the C6-C7 double bond, which is not involved in the two-site jump, characterized by a relatively large order parameter (0.56). Fatty acyl chains containing three or more double bonds likely cannot undergo the same jump motion and consequently will be highly ordered structures. Correlation times for diffusion of the molecular long axis of the diunsaturated acyl chain about the bilayer normal (approximately 10(-10) s) and for the local jump motion (approximately 10(-10) s) were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical Phenomena↗
PubMed1992

Shielded gradient coils and radio frequency probes for high-resolution imaging of rat brains.

A shielded gradient system and radio frequency probes for a 4.7-T/30-cm horizontal bore magnet are described. The systems were designed principally to obtain images and localized spectra from rat brains. The gradients can operate in either a shielded or non-shielded mode. The rf probe, which combines both highest sensitivity and highest resolution, consists of a large modified saddle type transmitter and a small surface reception coil, actively decoupled using diodes. The system performance is demonstrated on phantoms and on a rat brain, where an image with in plane resolution of 80 microns and a slice thickness of 150 microns is obtained.

Animals↗
PubMed1992

A simple procedure for obtaining high-quality NMR spectra of semiquantitative value from small tissue specimens: cervical biopsies.

The handling of small tissue biopsy samples (< 100 microliters) for NMR investigations poses special problems. Optimal and stable positioning of the samples within the sensitive volume of the radiofrequency coil can be achieved by inserting the sample in a capillary. Methods for quantitation of the spectral information from samples requiring histological evaluation after the NMR experiment are discussed, in particular with respect to cervical biopsies.

Biopsy↗
PubMed1992

Interactions of aminoglycoside antibiotics with phospholipids. A deuterium nuclear magnetic resonance study.

The effect of several aminoglycoside (AG) antibiotics on aqueous multilamellar dispersions of mixtures of phosphatidylinositol (PI) and deuterated phosphatidylcholine (PC) has been studied by deuterium (2H) NMR. Isepamicin and amikacin gave rise to no significant changes in 2H-NMR lineshape relative to that of the lipid mixture without antibiotic. Both kanamycin A and B, which have a greater affinity for PI than the other two antibiotics examined in this study, induced temperature-dependent changes in 2H-NMR lineshapes and associated spectral moments. The results are consistent with an antibiotic-induced lateral phase separation giving rise to PC-enriched domains free of drug and PI-AG domains. These effects are correlated with the inhibitory potency of aminoglycosides towards PC degradation.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Influence of the membrane surface on glycolipid conformation and dynamics. An interpretation of NMR results using conformational energy calculations.

Glycolipids constitute an important class of biomolecules that are involved in biomolecular recognition. The importance of carbohydrate head group conformation in such processes is well recognized. Glycolipids typically occur as minor components of the complex heterogeneous matrix of a biological membrane. As a result, the membrane surface may not only influence head group conformation but also serves as a spatial frame in which the glycolipid is oriented and recognized. In this study, conformational energy calculations have been used to assess the conformational space available to the glucose head group of 1,2-di-O-tetradecyl-3-O-(beta-D-glucopyranosyl)-sn-glycerol (beta-DTGL) in a liquid-crystalline membrane matrix. 2H NMR quadrupolar splittings are calculated and compared with those observed experimentally. This study demonstrates the importance of including surface interactions when considering the conformational space accessible to cell surface carbohydrates. The empirical approach taken here provides considerable insight at the molecular level, and offers the possibility of exploring even more complex systems.

Cell Membrane↗
PubMed1992

Effects of thioridazine on mechanical responses of human vas deferens induced by noradrenaline or potassium.

Thioridazine (0.1-10 mumol l-1) inhibited shortening of specimens of human vasa deferentia induced by noradrenaline (100 mumol l-1) or high extracellular potassium (136 mmol l-1). Thioridazine did not inhibit the lengthening response. In Ca(2+)-free media with EGTA (0.5 mmol l-1) similar results were obtained with responses to noradrenaline, but exposure to potassium elicited small contractions that were potentiated by thioridazine. Both shortening and lengthening responses to noradrenaline were antagonized by the alpha-adrenoceptor blockers prazosin (1-10 mumol l-1) and phentolamine (1-10 mumol l-1) and by the Ca2+ antagonists verapamil (10 mumol l-1) and diltiazem (10 mumol l-1). Responses to potassium were virtually abolished by the Ca2+ antagonists. These results show that thioridazine specifically inhibits longitudinal muscle of the human vas deferens and that its action cannot be entirely accounted for by a blockade of voltage-gated Ca2+ channels.

Culture Techniques↗
PubMed1991

Effect of calcium on the dynamic behavior of sialylglycerolipids and phospholipids in mixed model membranes. A 2H and 31P NMR study.

DTSL, a sialic acid bearing glyceroglycolipid, has been deuteriated at the C3 position of the sialic acid headgroup and at the C3 position of the glycerol backbone. The glycolipid was studied as a neat dispersion and in multilamellar dispersions of DMPC (at a concentration of 5-10 mol % relative to phospholipid), using 2H and 31P NMR. The quadrupolar splittings, delta v Q, of the headgroup deuterons were found to differ in the neat and mixed dispersion, suggesting different headgroup orientations in the two systems. In DTSL-DMPC liposomes, two quadrupolar splittings were observed, indicating that the axial and equatorial deuterons make different angles with respect to the axis of motional averaging. The splittings originating from the equatorial and axial deuterons were found to increase and decrease with increasing temperature, respectively, indicating a temperature-dependent change in average headgroup orientation. Longitudinal relaxation times, T1Z, were found to be short (3-6 ms). The field dependence of T1Z suggests that more than one motion governs relaxation. At 30.7 MHz a T1Z minimum was observed at approximately 40 degrees C. At 46.1 MHz the T1Z values were longer and increased with temperature, demonstrating that the dominant rigid-body motions of the headgroup at this field are in the rapid motional regime (greater than 10(8) s-1). DTSL labeled at the glycerol C3 position was studied in DMPC multilamellar dispersions. Whereas two quadrupolar splittings have been observed for other glycolipids labeled at this position, only a single delta nu Q was observed. This shows that the orientation of the C2-C3 segment of DTSL relative to the bilayer normal differs from that of other glycolipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1991

Average structural and motional properties of a diunsaturated acyl chain in a lipid bilayer: effects of two cis-unsaturated double bonds.

Isolinoleic acid (18:2 delta 6,9) deuterated at 10 different positions was esterified to form 1-palmitoyl-2-isolinoleoyl-sn-glycero-3-phosphocholine (PiLPC), and the average structural and motional properties of the diunsaturated chain, in aqueous dispersions of PiLPC, were examined by 2H NMR spectroscopy. For each sample, 2H spectra were acquired over a temperature range of 1-40 degrees C and the quadrupolar splittings interpreted in terms of carbon-deuterium bond order parameters, SCD. Furthermore, definition of the average orientation of the C8 methylene unit with respect to the bilayer normal [Baenziger, J. E., Smith, I. C. P., Hill, R. J., & Jarrell, H. C. (1988) J. Am. Chem. Soc. 110, 8229-8231] provided sufficient information to calculate both the average orientations and the molecular order parameters, Smol (which reflects the amplitudes of motion), for the C6-C7 and the C9-C10 double bonds. The results indicate that both the motional freedom (reflected in the order profile) and the average structure (reflected in the orientation of carbon segments with respect to the bilayer normal) are strongly affected by the presence of two cis-unsaturated double bonds. The data were interpreted in terms of two possible models whereby, in each case, the chain adopts a conformation consistent with the low-energy conformation of 1,4-pentadiene [Applegate, K. R., & Glomset, J. A. (1986) J. Lipid Res. 27, 658-680] but undergoes a two-site jump between the conformations. The jump motion arises mainly from rotations about the C7-C8 and the C8-C9 single bonds that disorder the C8 and the C9-C10 segments (Smol = 0.15 and 0.08, respectively) but leave the C6-C7 double bond relatively immobile (Smol = 0.55; all at 40 degrees C). It is suggested that acyl chains containing three or more double bonds could not undergo a similar jump motion and therefore would be highly ordered and not "fluid" as is generally thought.

Deuterium↗
PubMed1991

Paradoxical effects of thioridazine on electromechanical coupling in the human and rat vas deferens.

The effects of thioridazine on the responses of isolated human and rat vas deferens to high [K+]0, A23187 and caffeine were examined. In the presence of Ca2+ (2.5 mM), thioridazine (1-10 microM) induced spontaneous contractions but caused a dose-related inhibition of the phasic and secondary parts of the response to high [K+]0 (136 mM). The relaxation phase of the high [K+]0 response of the human vas deferens was unaffected by thioridazine (up to 10 microM). In Ca2(+)-free/EGTA (0.5 mM) media, thioridazine caused a dose-related potentiation, shortened the latency and prolonged the duration of high [K+]0 responses. Contractions to caffeine (20 mM) and A23187 (20-50 microM) were relatively unchanged by thioridazine (10 microM). The spontaneous activity caused by thioridazine (10 microM) was sensitive to the Ca2(+)-channel blockers nifedipine (10 microM) or verapamil (10 microM). These results indicate that the action of thioridazine during electromechanical coupling in the human and rat vas deferens may involve more than its blockade of voltage gated Ca2+ channels.

Animals↗
PubMed1991

Evaluation of a simple line width test involving magnetic resonance spectroscopy of plasma in carcinoma of the ovary.

Magnetic resonance spectroscopic (MRS) measurement of human plasma has been reported as a generally applicable marker for malignancy: patients with malignancy had a MRS line width significantly different from patients with benign diseases or healthy controls. The authors investigated the value of this test in 213 women with ovarian carcinoma, benign pelvic masses, benign nongynecologic diseases, and healthy controls. The MRS measurements were performed on plasma samples at 21 degrees C or 27 degrees C. The line width parameters were obtained by averaging the width at half the height of the methyl and methylene peaks on the resonance spectra. At 27 degrees C using 33 Hz as the threshold for an abnormal result, there was a significant correlation between the result of the test and the presence or absence of malignancy. However, the study demonstrates that the specificity (0.44) and positive predictive value (0.42) are too low for the test to be useful in the management of patients with carcinoma of the ovary. At 21 degrees C no correlation between the results of the test and the clinical status of women with carcinoma of the ovary were observed. In 47 patients the test did not predict preoperatively the benign or malignant nature of a pelvic mass.

Carcinoma↗
PubMed1991

Biological and NMR markers for cancer.

The search for a universal tumor marker continues. Present markers range from tumor products (polyamines, glycoproteins, peptides, hormones or carbohydrate-linked markers) to reaction products produced by the host tissues during tumor invasion. Techniques used to identify them include the classical methods of histology and cytochemistry as well as the more recent radioimmunoassay and metabolic probes. The in vivo techniques of increasing use for patient monitoring are MRS (magnetic resonance spectroscopy) and MRI (magnetic resonance imaging). The efficiency of some markers and statistical methods used in analyzing data are discussed, as are the ethical problems surrounding the use of new testing methods. Recent developments in MRI and MRS, marker elucidation, and evidence for a new autocrine differentiation-inhibiting factor (ADIF) are reviewed. Future needs and approaches focus on greater utilization of indicators of the preneoplastic state and of risk to cancer, as well as more careful attention to statistical analysis.

Biomarkers, Tumor↗
PubMed1991

Slow motions in lipid bilayers. Direct detection by two-dimensional solid-state deuterium nuclear magnetic resonance.

Two-dimensional solid-state 2H NMR spectroscopy of specifically deuteriated lipids is used to detect and to characterize the rate and mode of slow motions in two lipid bilayer systems. Lateral diffusion of lipid molecules over the curved surface of dipalmitoylphosphatidylcholine liposomes can be detected by two-dimensional exchange 2H NMR and it is shown that molecular orientational exchange is complete on the timescale of 100 ms. In contrast, it is shown that for the glycolipid 1,2-di-O-tetradecyl-3-O-Beta-D-glucopyranosyl)-sn-glycerol (beta-DTGL), there is no evidence of a corresponding orientational exchange in the liquid-crystalline phase suggesting that this lipid forms relatively flat bilayers. In the gel phase of hydrated multibilayers of beta-DTGL, a slow (10(3) s(-1)) whole molecule axial motion is demonstrated at 40 degrees C. Comparison of the experimental and simulated 2D-NMR ridge patterns suggests that large angle jumps about the long molecular axis, rather than small step Brownian diffusion, can best account for the 2D-exchange spectra of beta-DTGL in the gel phase. The significance of this technique for the study of dynamics in other biological systems is discussed.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

Dynamics of glycolipids in the liquid-crystalline state. 2H NMR study.

It has been shown previously that two types of motion are adequate to describe the partially relaxed 2H NMR line shapes (inversion recovery experiment) for the backbone portion of the glycolipid 1,2-di-O-tetradecyl-3-O-(beta-D-glucopyranosyl)-sn-glycerol (beta-DTGL) in the highly ordered gel phase (Auger, M.A., D. Carrier, I.C.P. Smith, and H. C. Jarrell. 1990. J. Am. Chem. Soc. 112:1373-1381). This study extends the latter investigation to the more fluid liquid-crystalline phase, where more complex motions are anticipated. Analyses of the powder line shapes and oriented sample relaxation data for both the glycerol backbone and head group regions of this lipid have been performed. The dynamics of glycerol at the C3 position in the gel state have been described by large angle jumps about the C2-C3 bond with a correlation time in the fast-limit motional regime (omega o tau c much less than 1) and site populations 0.46, 0.34, and 0.20. The present data show that in the liquid-crystalline phase the internal jump rate is maintained, and two additional motions are necessary to describe the dependence of the relaxation rate on the orientation of the director with respect to the magnetic field direction. These are rotation about the molecular long axis with a correlation time in the slow-limit motional regime very near to the T1 minimum (omega o tau c approximately 0.65), and molecular fluctuations about the order director (modeled by a Maier-Saupe restoration potential). This treatment was also extended to the glucose head group where additional segmental motion about the glycosidic bond has been reported previously. While the two motions dominating relaxation at the glycerol C3 segment reproduce the general relaxation features of the glucose head group, the results suggest that additional motion about the glycosidic linkage must be present. This study is a stringent test of the motional model chosen earlier because relaxation data were obtained at two 2H NMR frequencies using two relaxation experiments (T1Z and T1Q) and two types of sample preparation (oriented and dispersed multibilayers). The results strongly uphold the choice of model and indicate the utility of both oriented samples and the T1Q experiment.

Biophysical Phenomena↗
PubMed1991

Molecular details of anesthetic-lipid interaction.

By means of isotopic labeling with deuterium (2H) and observation by nuclear magnetic resonance (NMR), it has been possible to measure the conformational ordering and dynamics of lipids and anesthetics in membranes. The local anesthetic tetracaine causes disordering in the acyl chains of the lipids, very little effect near the glyceryl residue, and minor ordering effects in the charged head group. The anesthetic itself is well ordered within the lipid matrix. The magnitudes of these effects depend upon the nature of the lipid, and upon whether or not the anesthetic is charged. A model can be constructed for the location of the anesthetic within the lipid bilayers. Confirmation of the model comes from Fourier transform infrared spectroscopy (FTIR), which also shows directly the pressure-driven exclusion of local anesthetic from lipid, and the augmentation of this effect by the presence of cholesterol. Future studies by solid-state NMR of protein, and neutron diffraction of specifically deuterated components of anesthetic-nerve systems, should reveal even more precise details of the molecular events involved in anesthesia.

Anesthesia↗
PubMed1991

Identification of a multiprotein complex interacting with the c-fos serum response element.

The serum response element (SRE) is essential for serum and growth factor stimulation of the c-fos gene. We have examined the nuclear proteins, obtained from tissues with elevated expression of the c-fos gene (proliferating rat liver and hepatocarcinoma), that bind to the SRE sequence. A synthetic oligonucleotide containing the SRE sequence from the mouse c-fos gene promoter (-299 to -322) was radioactively labeled, used as a probe for the mobility shift assay and Southwestern (DNA-protein) blotting, and also used for sequence-specific affinity chromatography. We have identified a group of nuclear proteins of molecular sizes 36, 45, 62, 67, 72, and 112 kDa capable of interacting with the SRE sequence. The 36-, 67-, and 112-kDa proteins have DNA-binding properties, but the presence of the others in the SRE-protein complex could be the result of protein-protein interaction. All of these protein factors were present in nuclei obtained from intact and proliferating rat liver as well as from 5123tc Morris hepatoma. The DNA-binding activity (on Southwestern blots) of the 67- and 112-kDa proteins was not affected by alkaline phosphatase treatment, but the ability of the dephosphorylated nuclear proteins to form the complex with the SRE sequence under gel shift assay conditions was severely impaired. The same alkaline phosphatase treatment completely abolished the DNA-binding properties of the c-fos cyclic AMP-responsive element-specific proteins. Therefore, transcriptional activation of the c-fos gene at the SRE must require the presence of a multiprotein complex the formation of which is governed by phosphorylation. The binding of the 67- and 62-kDa proteins to the c-fos SRE has been previously reported; however, the 36-. 45-, 72-, and 112-kDa proteins are novel factors involved in the multifaceted regulation of c-fos gene expression in vivo.

Animals↗