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Biomedical subjects

R S Marshall

Publications and source records attributed to R S Marshall.

At least 37 records · Page 2Linked to original sources
PubMed1997

Motor behavior in stroke patients with isolated medial frontal ischemic infarction.

BACKGROUND AND PURPOSE: Current interpretation of hemiparesis in anterior cerebral artery infarction holds that whereas leg weakness correlates with destruction of the corticospinal tract at the paracentral lobe, faciobrachial symptoms indicate extension of the infarct to the upper lateral convexity or to subcortical structures, where the corticospinal tract subserving the arm would be interrupted. We analyzed the motor behavior in eight patients with purely medial hemispheric infarctions who had face, arm, and leg involvement. METHODS: In addition to careful clinical testing, we performed neuroimaging or pathological studies to exclude the involvement of the primary motor cortex or subcortical structures. Motor function was further tested in three patients by studying the reaction time to an auditory stimulus and by stimulating the motor cortex and the cervical and lumbar spine with a magnetic stimulator. RESULTS: All patients had signs of motor neglect, such as lack of spontaneous movement in the upper limb, unilateral reaction to pain stimuli, clumsy voluntary movements, or motor impairment on bimanual tasks. Electrophysiologically, we found absent or poor voluntary activity in both upper and lower limbs contralateral to the infarction. However, whereas cortical stimulation showed absent responses in the lower limb, it disclosed normal latencies in the upper limb, indicating that the corticospinal tract to paretic muscles of the upper limb was intact. CONCLUSIONS: Our findings suggest that faciobrachial symptoms in purely medial hemispheric infarctions in the anterior cerebral artery territory reflect motor neglect caused not by involvement of primary motor pathways but by damage to medial premotor areas.

Aged↗
PubMed1997

Anterior translocation of language in patients with left cerebral arteriovenous malformation.

We studied seven patients with left cerebral atriovenous malformation (AVM) with superselective arterial injection of anesthetics during angiography to determine whether there was translocation of some language functions to other regions in the ispilateral hemisphere. All patients were right handed. With a catheter inserted into each target vessel, patients underwent aphasia examination in an A-B-A design: (A) baseline, no anesthetic; (B) 1 minute after anesthetic injection; and (A) 12 minutes after injection (when its effects had dissipated). The results showed that six of seven patients had no significant aphasia at baseline or 12 minutes after anesthetic injection. One patient had a mild conduction aphasia at baseline and after anesthetic effects had dissipated. In the six patients with temporoparietal AVM, anesthetic injections into vessels in the lower division of the middle cerebral artery (MCA) not feeding the AVM (e.g., the left angular artery) produced a wide range of language function--from conduction aphasia to dense Wernicke's syndromes. When upper division MCA vessels were injected (e.g., the prefrontal branch), all developed a major aphasic disorder with significant comprehension defects. A seventh patient with a frontal opercular AVM had a mild anomia, semantic paraphasias, and decreased word-list generation when the prefrontal branch was injected. Her comprehension, however, was intact. These data show that patients with posterior cerebral AVM can show language abnormalities where such deficits are not typically seen after acute brain injury. These findings support a posterior-to-anterior extension of some language skills under conditions of brain disease.

Adolescent↗
PubMed1996

"Semantic" conduction aphasia from a posterior insular cortex infarction.

A unique infarction limited to the posterior insula and intrasylvian parietal opercular cortex produced a subtype of conduction aphasia, characterized by a predominance of semantic paraphasias. Temporal lobe hypoperfusion seen on hexamethylpropyleneamineoxime single-photon emission computed tomography in the absence of any signs of ischemia suggested that cortical diaschisis played a role in the emergence of this syndrome.

Aphasia, Conduction↗
PubMed1996

Continuous time estimation as a behavioural index of human cerebral ischaemia during temporary occlusion of the internal carotid artery.

OBJECTIVE: To determine whether a continuous time estimation task during test occlusions of either internal carotid artery would increase the ability to detect the earliest signs of cerebral ischaemia in the anterior circulation. METHODS: Four patients were involved in real time measurement of their timing accuracy before, during, and after each test occlusion. While under each test condition, patients were instructed to press a mouse button connected to a computer and then to press it again no sooner than 10 seconds from the previous response but no longer than 13 seconds later. While being given automated feedback on accuracy, patients were instructed to continually press the mouse on the target schedule to maximise correct responses until told to stop. RESULTS: The data showed deterioration of timing accuracy during carotid occlusion (P < 0.05), which always preceded the onset of physical signs and correlated in one patient with the presence of reduced regional cerebral blood flow. CONCLUSION: Decline of sustained attention under conditions of test balloon occlusion of either internal carotid artery was an indicator of failure to maintain adequate cerebral blood flow to sustain normal neurological function. The demonstration of the behavioural effects of early cerebral ischaemia shows the feasibility of an experimental model for the study of human brain function, and may now make it possible to quantify more precisely the time course of acute ischaemic events.

Arterial Occlusive Diseases↗
PubMed1995

'Steal' is an unestablished mechanism for the clinical presentation of cerebral arteriovenous malformations.

BACKGROUND AND PURPOSE: Focal neurological deficits (FNDs) in patients with arteriovenous malformations (AVMs) have been widely attributed to the phenomenon of "cerebral steal." The incidence of focal deficits was investigated in a large prospective sample. METHODS: Using data from patient history and examination, CT or MRI, and transcranial Doppler sonography, we studied 152 consecutive, prospective AVM patients for evidence of FNDs unrelated to a hemorrhagic event. Feeding mean arterial pressure was measured during superselective angiography. RESULTS: Two (1.3%) of 152 patients met the criteria for a progressive FND. Nonprogressive FNDs were seen in 11 (7.2%) patients (stable in 4.6%, reversible in 2.6%). The median observation time period was 17 months (range, 1 to 60 months). There were no differences in transcranial Doppler mean velocities in feeding arteries in FND versus non-FND groups (118 +/- 44 versus 112 +/- 37 cm/s, P > .05) or pulsatility indexes (0.53 +/- 0.20 versus 0.55 +/- 0.15, P > .05). Feeding artery pressure was similar in FND (n = 10) and non-FND (n = 96) groups (39 +/- 16 versus 39 +/- 16 mm Hg at a systemic pressure of 82 +/- 18 versus 75 +/- 14 mm Hg, NS). CONCLUSIONS: Nonhemorrhagic focal neurological syndromes in AVM patients are infrequent. Progressive deficits are especially rare. There was no relation between feeding artery pressure or flow velocities and FND. There does not appear to be sufficient evidence to assign steal as an operative pathophysiological mechanism in the vast majority of AVM patients.

Adult↗
PubMed1994

Intrahemispheric localization of drawing dysfunction.

We evaluated drawing disability in 37 patients with right hemispheric stroke and in eight controls with no brain disease. Blinded evaluations included measures of overall recognizability and hemineglect. By mapping the CT lesions of patients, we found that damage to parieto-occipital cortex in poor drawers correlated with poor performance on a line bisection task whereas frontal, subcortical damage in poor drawers did not. We propose that drawing disability may be produced by visual-spatial dysfunction in patients with posterior lesions and by a disturbance of integrated motor function in those with frontal, subcortical damage.

Adult↗
PubMed1993

Cellular approaches to bioreductive drug mechanisms.

Mitomycin C is being used as an adjunct to ionizing radiation in the treatment of some solid tumors. A rationale for this is that radioresistant hypoxic cells in solid tumors will have enhanced sensitivity to this bioreductively activated drug, compared to aerobic cells. The role of oxygen concentration and enzymatic drug reduction in bioreductive drug activation have been investigated. Techniques are reviewed for the in vitro determination of the oxygen concentration dependency of bioreductive drug activation. One of these techniques, an open cell suspension system using Chinese hamster ovary cells, is described. Results are shown that indicate that the oxygen concentration dependency of toxicity of mitomycin C and one of its analogues profiromycin, though qualitatively complementing the oxygen dependency of ionizing radiation toxicity, are not quantitatively optimal. Using a mitomycin C resistant human cell strain (3437T) from a cancer prone family, a possible role for DT-diaphorase, an oxygen insensitive 2-electron transfer enzyme, is suggested. A correlation between a low level of DT-diaphorase in 3437T cells and mitomycin C resistance under aerobic exposure conditions is seen. Under hypoxic exposure conditions this resistance is lost, suggesting 1-electron transfer enzymes control hypoxic cell bioreductive activation. An activation role for DT-diaphorase in mitomycin C toxicity in the treatment of solid tumors is contrasted to a potential detoxification role for the enzyme with other xenobiotics in the cancer prone family phenotype.

Animals↗
PubMed1991

Studies on the mechanism of resistance to mitomycin C and porfiromycin in a human cell strain derived from a cancer-prone individual.

The mechanism of aerobic resistance to the quinone-containing anti-tumour agents mitomycin C (MMC) and porfiromycin (PM) has been investigated using non-transformed human cells. One of the cell strains used (3437T) was derived from an afflicted member of a cancer-prone family. This cell strain had been shown previously to be six times more resistant to the cytotoxic effects of these agents under aerobic but not hypoxic conditions when compared to a cell strain derived from an unrelated, normal donor (GM38). Differences could not be detected in the ability of cell sonicates prepared from either cell strain to produce alkylating species under aerobic conditions using a 4-(p-nitrobenzyl)pyridine assay. However, using 3H-labelled PM to monitor rapid drug uptake and subsequent accumulation due to drug metabolism, results were obtained indicating that the resistant cell strain (3437T) was deficient in an enzymatic pathway capable of metabolizing these compounds under aerobic but not hypoxic conditions. Dicumarol, an inhibitor of the quinone reductase DT-diaphorase (EC 1.6.99.2), decreased aerobic drug accumulation and cytotoxicity in the control cell strain, but did not alter the lack of accumulation noted in the resistant cell strain. Under hypoxic conditions, dicumarol increased cytotoxicity and drug accumulation in both cell strains. The mechanism of this enhanced cytotoxicity remains unclear. These results suggested that the resistant cells were deficient in the enzyme DT-diaphorase, a potential activator of PM. Enzymatic assays confirmed this and revealed no alterations in cytochrome P450 reductase (EC 1.6.2.4) activity or glutathione content. No protein characteristic of DT-diaphorase was detected in the resistant cell strain using a polyclonal rabbit-anti-rat antibody raised against this enzyme. Southern blot analysis using a rat DT-diaphorase cDNA probe demonstrated differences between the normal and resistant cell strains in the restriction fragment patterns. The present results are consistent with the hypothesis that decreased DT-diaphorase levels are causally associated with PM and MMC resistance in these cells under aerobic exposure conditions.

Cell Line↗
PubMed1991

Dissociated vertical nystagmus and internuclear ophthalmoplegia from a midbrain infarction.

We describe a patient with a dissociated vertical nystagmus and an internuclear ophthalmoplegia. The vertical nystagmus consisted of a left downward nystagmus with a synchronous right intorting nystagmus when the patient looked down and to the left. This rare type of nystagmus has been described both in isolation and in association with an internuclear ophthalmoplegia. Previous authors postulated a lesion in the midbrain in the region of the medial longitudinal fasciculus. In our patient, a discrete midbrain infarction was demonstrated on magnetic resonance imaging in the hypothesized location, thus providing supportive anatomical evidence for a vertical gaze coordination pathway in the region of the medial longitudinal fasciculus.

Cerebral Infarction↗
PubMed1991

DT-diaphorase activity and mitomycin C sensitivity in non-transformed cell strains derived from members of a cancer-prone family.

Non-transformed skin fibroblasts derived from five members of a cancer-prone family and three unrelated healthy volunteers were assayed for their levels of activity of the quinone reductase DT-diaphorase and for their sensitivity to the antitumor quinone mitomycin C (MMC). Previous studies of skin fibroblasts derived from one afflicted member of this family (3437T) demonstrated increased resistance to MMC under aerobic exposure conditions and a reduced level of DT-diaphorase. In the present study 3437T cells and a cell strain derived from another afflicted member of the cancer-prone family were found to be hyperresistant to the cytotoxic effects of MMC, and demonstrated negligible DT-diaphorase activity (30 +/- 10 nmol/min/mg protein). Cell strains derived from the three other family members demonstrated intermediate DT-diaphorase activity (400-800 nmol/min/mg protein). Enzyme activities of 1800-6000 nmol/min/mg protein were measured in the three control cell strains. A protein that was reactive with a rabbit polyclonal antibody raised against rat DT-diaphorase and corresponded to the known mol. wt of DT-diaphorase was clearly evident in the three control cell strains, but absent in the two MMC-hyperresistant cell strains. This protein was present in intermediate amounts in the remaining members of the cancer-prone family. Southern analysis of DNA isolated from all eight cell strains and restricted with EcoRI demonstrated the presence of a DNA sequence of approximately 15 kb which hybridized to a rat DT-diaphorase cDNA probe. Northern analysis revealed the presence of an RNA species approximately 1200 bp in size, consistent with that for a human DT-diaphorase mRNA, in all cell strains derived from family members. A post-transcriptional defect would, therefore, appear to be responsible for the decreased enzyme activity observed in the resistant cell strains. These results suggest a role for DT-diaphorase in MMC bioactivation and that reduced levels of the protein may be causally related to the cancer-prone tendency of this family.

Adolescent↗
PubMed1989

Deficient activation by a human cell strain leads to mitomycin resistance under aerobic but not hypoxic conditions.

Two non-transformed human skin fibroblast strains, GM38 and 3437T, were found to be more sensitive to the bioreductive alkylating agents mitomycin C (MMC) and porfiromycin (PM) under hypoxic compared to aerobic conditions. One of these strains, 3437T, was 6-7 times more resistant to these agents under aerobic exposure conditions, but was identical in sensitivity to the normal strain, GM38, under hypoxic conditions. Aerobic 3437T cells demonstrated no increased resistance to cisplatin compared to the normal strain, arguing against enhanced ability to repair DNA interstrand cross-links as the underlying explanation for the mitomycin resistance. The aerobic resistance of 3437T was not altered by dicumarol, an inhibitor of the enzyme DT-diaphorase which is believed to be involved in aerobic activation of MMC and PM. Dicumarol did increase the resistance of GM38, but not to the same level of resistance demonstrated by 3437T. These results suggest that the aerobic MMC and PM resistance of 3437T may arise, in part, from a deficiency in DT-diaphorase activity. The identical sensitivities under hypoxic conditions indicate that drug activation pathways operative in the absence of oxygen are similar in both the normal and 3437T cells.

Biotransformation↗
PubMed1988

Oxygen and exposure kinetics as factors influencing the cytotoxicity of porfiromycin, a mitomycin C analogue, in Chinese hamster ovary cells.

Some factors affecting the cytotoxicity of porfiromycin (PM), an analogue of mitomycin C (MMC), were investigated in suspension cultures of wild-type (AA8-4) and repair-deficient (UV-20) Chinese hamster ovary cells. Oxygen was an important modulator of PM toxicity in AA8-4 cells. The aerobic toxicity was significantly less, and toxicity under extremely hypoxic conditions was significantly greater for PM than MMC. Porfiromycin cytotoxicity at intermediate O2 levels was similar to that observed previously for MMC. While the aerobic/hypoxic ratio was greater for PM than MMC, survival at intermediate oxygen concentrations could limit the therapeutic utility of these drugs as adjuncts to radiotherapy. Ascorbic acid was found to increase the aerobic, but not hypoxic, cytotoxicity of PM in AA8-4 cells, as was observed previously for MMC. Investigation of various exposure times and drug concentrations revealed that drug toxicity for both aerobic and hypoxic cells was dependent on the product of drug concentration and time, and that the aerobic/hypoxic differential observed in AA8-4 cells was constant over a broad range of exposure conditions. The sensitivity of UV-20 cells was also a linear function of concentration and time, but no aerobic/hypoxic differential was observed in these cells. It is suggested that the sensitivity of UV-20 to PM and MMC, and its lack of an hypoxic/aerobic differential could result from lethality being due to a different lesion than in wild-type cells.

Animals↗
PubMed1988

Interpretation in doctor-patient interviews: a sociolinguistic analysis.

This paper discusses interpretation in doctor-patient interviews from a sociolinguistic perspective. A meaning-centered orientation to clinical practice calls for practitioners to create a clinical picture of the illness that is compatible with the patient's experience. This requires that appropriate interpretation of symptoms take place. Using transcripts of doctor-patient interviews, this paper demonstrates that another interpretive process, necessary to understanding illness, occurs at the level of conversation. Contrasting examples illustrate that without an adequate degree of "conversational cooperation," interpretation cannot take place. The results of poor conversational interpretation are the creation of an inaccurate clinical picture and the loss of clinically relevant information. The anthropological and sociolinguistic paradigms are linked by showing how differing perspectives on the illness affect conversational interpretation.

Attitude to Health↗
PubMed1988

Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.

Cultured cells subjected to oxygen deprivation have been shown to undergo anomalous DNA synthesis, which can result in DNA overreplication and the generation of cellular variants [Rice, G. C., Hoy, C. & Schimke, R. T. (1986) Proc. Natl. Acad. Sci. USA 83, 5978-5982]. In the present study, murine tumor cells were exposed to severe hypoxia and then tested for their ability to form experimental metastases. Upon reoxygenation, cells transiently, yet dramatically, increased their metastatic potential. Flow cytometric analysis confirmed that hypoxia and reoxygenation induced cell cycle perturbations and DNA overreplication in these tumor cell lines. Fibrosarcoma cells with overreplicated DNA isolated by fluorescence-activated cell sorting proved to be highly metastatic, although cells with 2-4 times the haploid DNA content in populations treated with hypoxia were also markedly more metastatic than oxic populations. These results support the hypothesis that hypoxic conditions existing in regions of solid tumors promote cellular heterogeneity and tumor progression.

Animals↗
PubMed1986

Modification of the cytotoxic activity of mitomycin C by oxygen and ascorbic acid in Chinese hamster ovary cells and a repair-deficient mutant.

The cellular and molecular damage produced by mitomycin C (MMC) in Chinese hamster ovary cells, AA8-4, and a repair deficient mutant of this line, UV-20, was studied by utilizing a system in which oxygen levels could be altered and monitored in solution during acute drug exposures. The cytotoxic activity of MMC decreased from hypoxic conditions to 1% oxygen in solution, while from 1 to 20% there was little change. The relative level of DNA cross-linking in cells was examined under these conditions by alkaline elution and found to increase as cell survival decreased. Utilizing a cell-free assay which detects formation of alkylating species it was confirmed that, while alkylation was observed under aerobic conditions, overall levels increased in the absence of oxygen. The presence of ascorbic acid in the exposure medium (0.284 mM) increased the aerobic but not the hypoxic cytotoxicity of MMC. This resulted in a diminished differential toxicity for cells exposed under aerobic versus hypoxic conditions in the presence of ascorbic acid. When ascorbic acid was present, net alkylation increased under aerobic conditions but was unchanged under hypoxic conditions. One interpretation of these results is that at least two mechanisms of activation of MMC to toxic intermediates may be present in these cells.

Alkylation↗
PubMed1986

Measurement of low levels of oxygen and their effect on respiration in cell suspensions maintained in an open system.

The presence of low levels of oxygen may have profound effects on the cytotoxic activity of radiation, radiosensitizers, and bioreductive alkylating agents. As others have shown, low oxygen tensions may significantly alter rates of cellular and chemical oxygen consumption. When experiments are performed at very low oxygen concentrations, the opposing effects of oxygen leakage into and cellular/chemical oxygen consumption from the system can lead to unpredictable results. Use of a newly designed, highly sensitive Clark-type oxygen sensor has permitted accurate and reproducible measurement of low levels of oxygen. Cellular depletion of oxygen at various cell densities has been monitored for a series of oxygen tensions in solution and the corresponding respiration rates have been calculated. Although oxygen depletion was found to be quite significant at low oxygen tensions, not all oxygen present could be removed by cellular respiration. Respiration rate decreased as oxygen tension decreased and approached zero at low oxygen tensions. This result was independent of cell density. A model is presented to account for the observed effect of oxygen tension on cellular oxygen utilization.

Animals↗
PubMed1985

A bioassay to measure cytotoxicity of plasma from patients treated with mitomycin C.

The unpredictable clinical toxicity observed in patients treated with mitomycin C and the observation that this agent must be reduced to an active form before alkylating target molecules have led to the development of a bioassay which is capable of detecting biologically active forms of mitomycin C in the plasma of drug-treated patients. The bioassay makes use of a repair-deficient mutant of Chinese hamster ovary cells, UV-20, which is 40 to 60 times more sensitive to mitomycin C than its wild-type parent. A standard curve relating in vitro cell colony-forming ability of UV-20 versus drug concentration in the plating medium has been determined. Mitomycin C levels in patient plasma as low as 1 ng/ml can be detected, compared to the 5-ng/ml limit of detection obtained with a high-pressure liquid chromatography assay for the parent compound. This assay has been utilized to detect active drug in plasma obtained from patients with colorectal cancer treated with mitomycin C as a single agent. At the completion of drug injection, serial blood samples were collected in heparinized tubes, and aliquots of plasma were extracted and assayed for mitomycin C levels by high-pressure liquid chromatography, diluted and assayed directly for their toxicity for UV-20 cells, or frozen at -20 degrees C to be assayed at a later time. The activity detected by immediate bioassay was stable up to 2 mo in frozen samples. Plasma pharmacokinetics determined by the bioassay in seven patients were no different than those determined by high-pressure liquid chromatography. No stable, cytotoxic species other than the parent compound were detected by the bioassay in the plasma of patients treated with mitomycin C.

Animals↗