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Biomedical subjects

A M Smith

Publications and source records attributed to A M Smith.

At least 91 records · Page 5Linked to original sources
PubMed2000

Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence.

BACKGROUND AND AIMS: Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs. METHODS: A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression. RESULTS: Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps. CONCLUSIONS: This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.

Adenoma↗
PubMed2000

Generational differences in selenium status of women.

In this cross-sectional study of three generations of women, daughters (19-26 yr), mothers (40-58 yr) and maternal grandmothers (67-84 yr) from the same 10 families in central Ohio were studied to determine the effect of life-cycle differences, including estrogen status, on selenium status. Plasma and red blood cell (RBC) selenium and glutathione peroxidase (GPx) activities were determined and typical dietary selenium intakes were calculated from food-frequency questionnaires. Selenium status was lowest in the oldest generation. Plasma selenium of daughters and grandmothers were significantly lower than those of mothers, and plasma GPx and RBC selenium of grandmothers were also lower than those of the mothers. A positive correlation (r = 0.42, p < 0.04) was found between plasma estrogen and plasma selenium concentrations. Selenium intakes of all groups were adequate and no differences in selenium intakes were found among groups. The results of this study indicate that selenium status fluctuates during the female life cycle and is related to estrogen status.

Adult↗
PubMed2000

A multidisciplinary study of the 'yips' phenomenon in golf: An exploratory analysis.

BACKGROUND: The 'yips' is a psychoneuromuscular impediment affecting execution of the putting stroke in golf. Yips symptoms of jerks, tremors and freezing often occur during tournament golf and may cause performance problems. Yips-affected golfers add approximately 4.7 strokes to their scores for 18 holes of golf, and have more forearm electromyogram activity and higher competitive anxiety than nonaffected golfers in both high and low anxiety putting conditions. The aetiology of the yips is not clear. OBJECTIVE: To determine whether the yips is a neurological problem exacerbated by anxiety, or whether the behaviour is initiated by anxiety and results in a permanent neuromuscular impediment. METHODS: In phase I, golf professionals assisted investigators in developing a yips questionnaire that was sent to tournament players (<12 handicap) to establish the prevalence and characteristics of the yips. Phase II measured putting behaviour in scenarios that contribute to the yips response. Four self-reported yips and 3 nonaffected golfers putted 3 scenarios using an uncorrected grip and a standard length putter. Heart rate was superimposed on the videotape and the putter grip was instrumented with strain gauges to measure grip force. Electromyograms and relative putting performance were also measured. RESULTS: The questionnaire was sent to 2,630 tournament players, of whom 1,031 (39%) responded (986 men and 45 women). Of these, 541 (52%) perceived they experienced the yips compared with 490 (48%) who did not. Yips-affected golfers reported that the most troublesome putts were 3, 4 and 2 feet (0.9, 1.2 and 0.6 metres) from the hole. Fast, downhill, left-to-right breaking putts and tournament play also elicited the yips response. Golfers affected by the yips had a faster mean heart rate, increased electromyogram activity patterns and exerted more grip force than nonrffected golfers and had a poorer putting performance. CONCLUSIONS: For <10 handicap male golfers and <12 handicap female golfers, the prevalence of the yips is between 32.5% and 47.7%, a high proportion of serious golfers. This high prevalence suggests that medical practitioners need to understand the aetiology of the yips phenomenon so that interventions can be identified and tested for effectiveness in alleviating symptoms. Although previous investigators concluded that the yips is a neuromuscular impediment aggravated but not caused by anxiety, we believe the yips represents a continuum on which 'choking' (anxiety-related) and dystonia symptoms anchor the extremes. The aetiology may well be an interaction of psychoneuromuscular influences. Future research to test the effect of medications such as beta-blockers should assist in better identifying the contributions these factors make to the yips phenomenon.

Adaptation, Physiological↗
PubMed2000

[Degree of hemodynamic disturbance at the hyperacute phase of stroke: predictive value of 3D-TOF angiography and the T2 fast-FLAIR sequence].

GOAL: To define during the hyperacute phase of stroke the value of 3D-TOF MR angiography (MRA) and T2 fast-FLAIR sequence for predicting the volume of tissue presenting a hemodynamic disturbance. MATERIAL: and method: Thirty-five cases of hyperacute stroke located in following territories: middle cerebral artery (MCA) (n=29), anterior choroidal artery (AChoA) (n=5) and watershed (n=1) were retrospectively reviewed. The vascular abnormalities defined on MRA (vessel stenosis or occlusion) or FLAIR sequence (vessel hyperintensity) were classified into 3 groups: normal (I), distal abnormalities (II), abnormalities of the entire arterial territory (III). These results were compared with the volume of tissue showing a prolonged mean transit time (MTT) determined on relative MTT maps calculated from bolus tracking MR perfusion images. RESULTS: The abnormal volume measured on the MTT map was significantly correlated to the results of the MRA and FLAIR sequence. In the 12 cases of group III defined on the MRA (abnormality from M1), the volume of hemodynamic disturbance was always higher than 100 ml. For the MCA territory, it was not possible to predict the presence of a hemodynamic disturbance in any of the 3 groups defined on the FLAIR sequence and in the groups I and II defined on the MRA. For the AChoA territory, a hemodynamic disturbance was never observed in groups I and II defined either on MRA or FLAIR sequence. CONCLUSION: When there was no flow within the M1 segment on the MRA, there was always a hemodynamic disturbance larger than 100 ml on the MTT map. In the case of AChoA ischemic lesion, when no vascular abnormality was observed on the MRA or FLAIR images, the MTT map was always normal.

Acute Disease↗
PubMed2000

Non-invasive quantification of liver perfusion with dynamic computed tomography and a dual-input one-compartmental model.

Various liver diseases lead to significant alterations of the hepatic microcirculation. Therefore, quantification of hepatic perfusion has the potential to improve the assessment and management of liver diseases. Most methods used to quantify liver perfusion are invasive or controversial. This paper describes and validates a non-invasive method for the quantification of liver perfusion using computed tomography (CT). Dynamic single-section CT of the liver was performed after intravenous bolus administration of a low-molecular-mass iodinated contrast agent. Hepatic, aortic and portal-venous time-density curves were fitted with a dual-input one-compartmental model to calculate liver perfusion. Validation studies consisted of simultaneous measurements of hepatic perfusion with CT and with radiolabelled microspheres in rabbits at rest and after adenosine infusion. The feasibility and reproducibility of the CT method in humans was assessed by three observers in 10 patients without liver disease. In rabbits, significant correlations were observed between perfusion measurements obtained with CT and with microspheres (r=0.92 for total liver perfusion, r=0.81 for arterial perfusion and r=0.85 for portal perfusion). In patients, total liver plasma perfusion measured with CT was 112+/-28 ml.min(-1).100 ml(-1), arterial plasma perfusion was 18+/-12 ml.min(-1).100 ml(-1) and portal plasma perfusion was 93+/-31 ml.min(-1).100 ml(-1). The measurements obtained by the three observers were not significantly different from each other (P>0.1). Our results indicate that dynamic CT combined with a dual-input one-compartmental model provides a valid and reliable method for the non-invasive quantification of perfusion in the normal liver.

Adult↗
PubMed2000

Phase I/II study of G17-DT, an anti-gastrin immunogen, in advanced colorectal cancer.

Gastrin is a growth factor for colorectal cancer, and therefore, anti-gastrin hormone therapy has a potential role in treatment of this disease. The gastrin immunogen gastrin-17-diphtheria toxoid (G17-DT; Gastrimmune) produces anti-G17 antibodies that have been shown to be effective in the treatment of colorectal carcinoma in preclinical models. Fifty patients with advanced colorectal cancer were treated with G17-DT in a multicenter, sequential group, open label Phase I/II study. Primary injections with two booster doses were given by i.m. injection. The main aim of the study was to assess the safety and efficacy of the production of antigastrin antibodies. Locally developed and standard WHO toxicity measurements with RIA and Scatchard analysis for antibody assessment were used. One center measured tumor response radiologically. Eighty % of patients produced a measurable antibody response. Antibodies of high affinity (median Kd, 0.295 nM; interquartile range, 0.16-0.41 nM) were detected between 4 and 12 weeks after primary injection. The antigen binding capacity was high at 2.8 x 10(-9) M (interquartile range, 5.1 x 10(-10) to 7.25 x 10(-9) M). The treatment was well tolerated with no systemic side effects seen. Myalgia at the injection site was seen in 46% of patients with severe pain caused by the formation of a sterile abscess seen in 14% of patients. The abscesses were all drained under ultrasound guidance, and the patients recovered fully within 6 weeks. No radiological responses were seen, but two patients had stable disease. G17-DT immunization produces anti-G17 antibodies in patients with advanced colorectal cancer. The antibodies were of an affinity high enough to compete with the cholecystokinin B/gastrin receptor for G17 binding with adequate capacity to neutralize postprandial gastrin surges. Additional dose-ranging studies have been performed in patients with gastric cancer using 100- and 200-microg doses of G17-DT formulated without adjuvant and the emulsifier aluminum monostearate. In addition, the effect of immunizing at different time intervals has been determined.

Adult↗
PubMed1999

Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.

Adult↗
PubMed1999

Interaction with amylopectin influences the ability of granule-bound starch synthase I to elongate malto-oligosaccharides.

This paper examines the properties in soluble form of two isoforms of starch synthase. One of these, granule-bound starch synthase I (GBSSI), is responsible for the synthesis of amylose inside the amylopectin matrix of the starch granule in vivo. The other, starch synthase II (SSII), is involved in amylopectin synthesis. Both isoforms can use amylopectin and malto-oligosaccharide as substrates in vitro. As well as acting as a substrate for GBSSI, amylopectin acts as an effector of this isoform, increasing the rate at which it elongates malto-oligosaccharides and promoting a processive rather than distributive mode of elongation of these compounds. The affinity of GBSSI for amylopectin as an effector is greater than its affinity for amylopectin as a substrate. The rate and mode of elongation of malto-oligosaccharides by SSII are not influenced by amylopectin. These results suggest that specific interaction with amylopectin in the matrix of the starch granule is a unique property of GBSSI and is critical in determining the nature of its products.

Amylopectin↗
PubMed1999

Granule-bound starch synthase I in isolated starch granules elongates malto-oligosaccharides processively.

Isoforms of starch synthase belonging to the granule-bound starch synthase I (GBSSI) class synthesize the amylose component of starch in plants. Other granule-bound isoforms of starch synthase, such as starch synthase II (SSII), are unable to synthesize amylose. The kinetic properties of GBSSI and SSII that are responsible for these functional differences have been investigated using starch granules from embryos of wild-type peas and rug5 and lam mutant peas, which contain, respectively, both GBSSI and SSII, GBSSI but not SSII and SSII but not GBSSI. We show that GBSSI in isolated granules elongates malto-oligosaccharides processively, adding more than one glucose molecule for each enzyme-glucan encounter. Granule-bound SSII can elongate malto-oligosaccharides, but has a lower affinity for these than GBSSI and does not elongate processively. As a result of these properties GBSSI synthesizes longer malto-oligosaccharides than SSII. The significance of these results with respect to the roles of GBSSI and SSII in vivo is discussed.

Adenosine Diphosphate Glucose↗
PubMed1999

A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.

The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.

Animals↗
PubMed1999

Cloning, expression, and properties of a nonneuronal secreted acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis.

We have isolated a full-length cDNA encoding an acetylcholinesterase secreted by the nematode parasite Nippostrongylus brasiliensis. The predicted protein is truncated in comparison with acetylcholinesterases from other organisms such that the carboxyl terminus aligns closely to the end of the catalytic domain of the vertebrate enzymes. The residues in the catalytic triad are conserved, as are the six cysteines which form the three intramolecular disulfide bonds. Three of the fourteen aromatic residues which line the active site gorge in the Torpedo enzyme are substituted by nonaromatic residues, corresponding to Tyr-70 (Thr), Trp-279 (Asn), and Phe-288 (Met). High level expression was obtained via secretion from Pichia pastoris. The purified enzyme behaved as a monomeric hydrophilic species. Although of invertebrate origin and possessing the above substitutions in the active site gorge residues, the enzyme efficiently hydrolyzed acetylthiocholine and showed minimal activity against butyrylthiocholine. It displayed excess substrate inhibition with acetylthiocholine at concentrations over 2. 5 mM and was highly sensitive to both active site and "peripheral" site inhibitors. Northern blot analysis indicated a progressive increase in mRNA for AChE B in parasites isolated from 6 days postinfection.

Acetylcholinesterase↗
PubMed1999

Neural pathways involved in the processing of concrete and abstract words.

The purpose of this study was to delineate the neural pathways involved in processing concrete and abstract words using functional magnetic resonance imaging (fMRI). Word and pseudoword stimuli were presented visually, one at a time, and the participant was required to make a lexical decision. Lexical decision epochs alternated with a resting baseline. In each lexical decision epoch, the stimuli were either concrete words and pseudowords, or abstract words and pseudowords. Behavioral data indicated that, as with previous research, concrete word stimuli were processed more efficiently than abstract word stimuli. Analysis of the fMRI data indicated that processing of word stimuli, compared to the baseline condition, was associated with neural activation in the bilateral fusiform gyrus, anterior cingulate, left middle temporal gyrus, right posterior superior temporal gyrus, and left and right inferior frontal gyrus. A direct comparison between the abstract and concrete stimuli epochs yielded a significant area of activation in the right anterior temporal cortex. The results are consistent with recent positron emission tomography work showing right hemisphere activation during processing of abstract representations of language. The results are interpreted as support for a right hemisphere neural pathway in the processing of abstract word representations.

Adult↗
PubMed1999

MR imaging of hypervascular liver tumors: timing optimization during the arterial phase.

To analyze the optimal timing strategy for the detection of hypervascular liver tumors during the arterial phase of magnetic resonance (MR) imaging, a test examination after injection of 2 mL of gadopentetate dimeglumine was performed in 47 patients. The time course of the tumor-to-liver contrast-to-noise ratio (CNR) for all studies together was determined relative to the start of injection, the time of peak aortic enhancement, and the time of peak enhancement in the tumor. All studies were grouped together and the highest CNR was transiently observed at the time of peak tumor enhancement. This CNR was significantly higher than those observed at fixed delays after peak aortic enhancement. However, the CNRs at peak tumor enhancement+/-1.5 seconds did not differ significantly from those obtained after peak aortic enhancement. Finally, the CNRs obtained at fixed delays after the start of injection remained significantly lower. In hypervascular liver tumors, a higher CNR can be obtained during the arterial phase when the MR imaging delay is determined relative to the time of peak enhancement in the tumor or the aorta rather than being fixed after the start of contrast material injection. Timing based on the enhancement profile in the tumor rather than in the aorta should be performed only if rapid MR imaging is available with a time resolution of about 1.5 seconds to image the whole liver.

Adenoma↗
PubMed1999

Investigation of low frequency drift in fMRI signal.

Low frequency drift (0.0-0.015 Hz) has often been reported in time series fMRI data. This drift has often been attributed to physiological noise or subject motion, but no studies have been done to test this assumption. Time series T*2-weighted volumes were acquired on two clinical 1.5 T MRI systems using spiral and EPI readout gradients from cadavers, a normal volunteer, and nonhomogeneous and homogeneous phantoms. The data were tested for significant differences (P = 0.001) from Gaussian noise in the frequency range 0.0-0.015 Hz. The percentage of voxels that were significant in data from the cadaver, normal volunteer, nonhomogeneous and homogeneous phantoms were 13.7-49.0%, 22.1-61.9%, 46.4-68.0%, and 1.10%, respectively. Low frequency drift was more pronounced in regions with high spatial intensity gradients. Significant drifting was present in data acquired from cadavers and nonhomogeneous phantoms and all pulse sequences tested, implying that scanner instabilities and not motion or physiological noise may be the major cause of the drift.

Adult↗
PubMed1999

The effects of muscimol inactivation of small regions of motor and somatosensory cortex on independent finger movements and force control in the precision grip.

This study investigated the effects of inactivating small regions of the primary somatosensory (SI) and motor (MI) cortex on the control of finger forces in a precision grip. A monkey was trained to grasp and lift a computer-controlled object between the thumb and index finger and to hold it stationary within a narrow position window for 2 s. The grip force applied perpendicular to the object surface, the lifting or load force applied tangentially in the vertical direction, and the vertical displacement were sampled at 100 Hz. Also, the ability of the monkey to extract small pieces of food from narrow wells of a Klüver board was analyzed from video-tape. Preliminary single-unit recordings and microstimulation studies were used to map the extent of the thumb and index-finger representation within SI and MI. Two local injections of 1 microl each (5 microg/microl) of the GABA(A)-agonist muscimol were used to inactivate the thumb and index region of either the pre- or post-central gyrus. The precision grip was differently affected by muscimol injection into either SI or MI. MI injections produced a deficit in the monkey's ability to perform independent finger movements and a general weakness in the finger muscles. Whole-hand grasping movements were inappropriately performed in an attempt to grasp either the instrumented object or morsels of food. Although the effect seemed strongest on intrinsic hand muscles, a clear deficit in digit extension was also noted. As a result, the monkey was unable to lift and maintain the object within the position window for the required 2 s, and, over time, the grip force decreased progressively until the animal stopped working. Following SI injections, the most obvious effect was a loss of finger coordination. In grasping, the placement of the fingers on the object was often abnormal and the monkey seemed unable to control the application of prehensile and lifting forces. However, the detailed analysis of forces revealed that a substantial increase in the grip force occurred well before any deficit in the coordination of finger movements was noted. This observation suggests that cutaneous feedback to SI is essential for the fine control of grip forces.

Animals↗
PubMed1999

Fast FLAIR sequence for detecting major vascular abnormalities during the hyperacute phase of stroke: a comparison with MR angiography.

In the hyperacute phase of stroke, occluded vessels can be seen as high signal on fast-FLAIR images or as absence of flow-related enhancement in maximum-intensity projection (MIP) MR angiography (MRA). To compare these techniques, we examined 53 patients within 6 h of a stroke, using a standardised MRI protocol including fast-FLAIR and 3D time-of-flight TOF MR to detect vessel occlusion or reduced flow corresponding to the suspected ischaemic territory. Brain infarcts were confirmed on MRI after 1-5 days in 41 cases (77%). The overall accuracy of 3D-TOF MRA was 68% and sensitivity, specificity, positive and negative predictive values were 67%, 71%, 87%, and 43% respectively. Values for the fast-FLAIR sequence were: 65%, 85%, 93% and 44%, with an overall accuracy of 70%. The fast-FLAIR sequence was thus able to show occluded vessels or reduced flow with about the same accuracy as 3D-TOF MRA and enabled better prediction of the ischaemic area.

Adult↗
PubMed1999

The diverse role of selenium within selenoproteins: a review.

Selenium functions within mammalian systems primarily in the form of selenoproteins. Selenoproteins contain selenium as selenocysteine and perform a variety of physiological roles. Eleven selenoproteins have been identified: cellular or classical glutathione peroxidase; plasma (or extracellular) glutathione peroxidase; phospholipid hydroperoxide glutathione peroxidase; gastrointestinal glutathione peroxidase; selenoprotein P; types 1, 2, and 3 iodothyronine deiodinase; selenoprotein W; thioredoxin reductase; and selenophosphate synthetase. Of these, cellular and plasma glutathione peroxidase are the functional parameters used for the assessment of selenium status. Glutathione peroxidases catalyze the reduction of peroxides that can cause cellular damage. Thioredoxin reductase provides reducing power for several biochemical processes and defends against oxidative stress. Selenoprotein P appears to play a role in oxidant defense. Selenoprotein W may play a role in oxidant defense and be involved with muscle metabolism. Thyroid deiodinases function in the formation and regulation of active thyroid hormone. Selenophosphate synthetase is an enzyme required for the incorporation of selenocysteine into selenoproteins. In addition, a protein in the sperm mitochondrial capsule, which is vital to the integrity of sperm flagella, may be a unique selenoprotein. Recommended intakes, food sources, and status assessment of selenium, as well as selenium's role in health and disease processes, are reviewed.

Animals↗