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Biomedical subjects

J M Murray

Publications and source records attributed to J M Murray.

At least 55 records · Page 3Linked to original sources
PubMed1997

The optimal scheduling of two drugs with simple resistance for a problem in cancer chemotherapy.

In this paper we study the effects of drug resistance on the optimal schedule of two drugs in cancer chemotherapy. We analytically determine the optimal schedule when the tumour grows exponentially and the drugs have a linear killing action. Drug resistance enters into the model via an effectiveness term that decreases the cell loss as the accumulation of the drug grows.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Structure and periodicities of cross-bridges in relaxation, in rigor, and during contractions initiated by photolysis of caged Ca2+.

Ultra-rapid freezing and electron microscopy were used to directly observe structural details of frog muscle fibers in rigor, in relaxation, and during force development initiated by laser photolysis of DM-nitrophen (a caged Ca2+). Longitudinal sections from relaxed fibers show helical tracks of the myosin heads on the surface of the thick filaments. Fibers frozen at approximately 13, approximately 34, and approximately 220 ms after activation from the relaxed state by photorelease of Ca2+ all show surprisingly similar cross-bridge dispositions. In sections along the 1,1 lattice plane of activated fibers, individual cross-bridge densities have a wide range of shapes and angles, perpendicular to the fiber axis or pointing toward or away from the Z line. This highly variable distribution is established very early during development of contraction. Cross-bridge density across the interfilament space is more uniform than in rigor, wherein the cross-bridges are more dense near the thin filaments. Optical diffraction (OD) patterns and computed power density spectra of the electron micrographs were used to analyze periodicities of structures within the overlap regions of the sarcomeres. Most aspects of these patterns are consistent with time resolved x-ray diffraction data from the corresponding states of intact muscle, but some features are different, presumably reflecting different origins of contrast between the two methods and possible alterations in the structure of the electron microscopy samples during processing. In relaxed fibers, OD patterns show strong meridional spots and layer lines up to the sixth order of the 43-nm myosin repeat, indicating preservation and resolution of periodic structures smaller than 10 nm. In rigor, layer lines at 18, 24, and 36 nm indicate cross-bridge attachment along the thin filament helix. After activation by photorelease of Ca2+, the 14.3-nm meridional spot is present, but the second-order meridional spot (22 nm) disappears. The myosin 43-nm layer line becomes less intense, and higher orders of 43-nm layer lines disappear. A 36-nm layer line is apparent by 13 ms and becomes progressively stronger while moving laterally away from the meridian of the pattern at later times, indicating cross-bridges labeling the actin helix at decreasing radius.

Actins↗
PubMed1996

Orientation-dependent visibility of long thin objects in polarization-based microscopy.

Under conditions of directional illumination, the visibility of long, thin objects depends very strongly on the direction and polarization of the incident light. Solutions to Maxwell's equations for the case of an infinite cylinder in an electromagnetic field are well known, and have been used by others in the past for theoretical analysis of light scattering by long, thin objects. The existence of those solutions allows us to calculate the expected angular distribution and polarization of the light scattered from long, thin objects illuminated by a plane wave at any angle. In this paper we show for the first time how one can incorporate these solutions of Maxwell's equations into a quantitative description of the expected appearance of filamentous biological structures in polarization-based microscopy. Our calculations for unidirectional polarized illumination show that thin, dielectric linear objects such as microtubules (or shallow interfaces) observed with finite aperture optics 1) are totally invisible when the angle (phi) between the object's long axis and incident illumination is outside the range magnitude of 90 - phi < or = sin-1 [1.33/N.A.obj]degrees; and 2) are seen with maximum intensity when phi = 90 degrees for incident illumination and scattered light polarized, either both parallel or both perpendicular to the long axis of the object; whereas 3) two maxima appear at phi approximately equal to 90 +/- 25 degrees for polarization of the incident illumination parallel to, but the scattered light perpendicular to the long axis, or vice versa; and 4) in either of these latter conditions, the objects are invisible when the illumination is near normal incidence. These counterintuitive predictions were exactly borne out by our experimental measurements of light-scattering intensity from flagellar axonemes as a function of orientation in a polarizing microscope. These calculations and measurements provide a foundation for furthering our understanding of textural or form birefringence. Calculations based on a solid cylinder model accurately predict the shapes of the measured intensity versus orientation curves. However, the relative intensities of axonemes viewed with different polarizer-analyzer settings differ from those calculated for a homogeneous solid cylinder. Thus we find that these relative intensities can provide a sensitive probe for the structure of biological objects with diameters much smaller than the wavelength of light.

Animals↗
PubMed1996

Demand valve ventilation in a swine pneumothorax model.

Bag-valve-mask (BVM) and oxygen-powered demand valve (OPDV) are two available adjuncts for artificial ventilation. Use of OPVDs has been limited by concern for causing or worsening pneumothorax. This study examined the effect of OPDV and BVM ventilation in swine with pneumothorax. This was a randomized, crossover design. Five female swine (16 to 23 kg) were sedated (ketamine/xylazine), anesthetized (alpha chloralose), and intubated. Right chest injury was induced, through an incision, using a 14-gauge needle to produce disruption of underlying lung parenchyma. An 18F Foley catheter was inserted and sealed in the right pleural space at the cut-down site. For each trial, a pneumothorax was induced by instilling 300 mL of air. Each subject underwent 10-minute ventilation trials with OPDV and with BVM by the same investigator, blinded to instrumentation. Post-trial pneumothorax volume, heart rate, blood pressure, end-tidal CO2 (ETCO2), and arterial blood gases were measured. There was no significant difference in pneumothorax volume after OPDV ventilation (310.8 mL) versus BVM ventilation (315.4 mL) (P = .821). There were no significant differences between heart rates, blood pressures, or arterial blood gases, although ETCO2 showed statistically significant decreases from baseline in both OPDV (33.0 to 28.6) and BVM (33.8 to 30.2) trials. However, multiple comparisons showed no significant differences between OPDV and BVM at any time points. In this model, OPDV and BVM ventilation did not differ in their effects on pneumothorax volume or hemodynamic variables. No animal showed signs of tension pneumothorax.

Animals↗
PubMed1996

A phase III, multicenter, open-label, randomized, comparative study evaluating the effect of sevoflurane versus isoflurane on the maintenance of anesthesia in adult ASA class I, II, and III inpatients.

STUDY OBJECTIVE: To compare the clinical efficacy and safety of sevoflurane and isoflurane when used for the maintenance of anesthesia in adult ASA I, II, and III inpatients undergoing surgical procedures of at least 1 hour's duration. DESIGN: Phase III, randomized, open-label clinical trial. SETTING: 12 international surgical units. PATIENTS: 555 consenting inpatients undergoing surgeries of intermediate duration. INTERVENTIONS: Subjects received either sevoflurane (n = 272) or isoflurane (n = 283) as their primary anesthetic drug, each administered in nitrous oxide (N2O) (up to 70%) and oxygen (O2) after an intravenous induction using thiopental and low-dose fentanyl. The concentration of volatile drug was kept relatively constant but some titration in response to clinical variable was permitted. Comparison of efficacy was based on observations made of the rapidly and ease of recovery from anesthesia and the frequency of untoward effects for the duration of anesthesia in the return of orientation. Safety was evaluated by monitoring adverse experiences, hematologic and non-laboratory testing, and physical assessments. In 25% of patients (all patients 171 both treatment groups at selected investigational sites), plasma inorganic fluoride concentrations were determined preoperatively, every 2 hours during maintenance, at the end of anesthesia, and at 1, 2, 4, 8, 12, 24, 48, and 72 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Emergence, response to commands, orientation, and the first request for postoperative analgesia were all more rapid following discontinuation of sevoflurane than following discontinuation of isoflurane (sevoflurane, 11.0 +/- 0.6, 12.8 +/- 0.7, 17.2 +/- 0.9, 46.1 +/- 3.0 minutes, respectively, versus isoflurane, 16.4 +/- 0.6, 18.4 +/- 0.7, 24.7 +/- 0.9, 55.4 +/- 3.2 minutes). The incidence of adverse experiences was similar for sevoflurane and isoflurane patients. Forty-eight percent of patients on the sevoflurane group had no untoward effect versus 39% in the isoflurane group. Three patients who received sevoflurane had serum inorganic fluoride levels 50 microM/I. or greater though standard tests indicated no evidence of associated renal dysfunction. CONCLUSION: Sevoflurane anesthesia, as compared with isoflurane, may be advantageous in providing a smoother clinical course with a more rapid recover.

Adult↗
PubMed1996

Effect of the addition of alfentanil to lignocaine during axillary brachial plexus anaesthesia.

Peripheral administration of opioids has been suggested as a means of improving regional block. We studied 60 patients receiving axillary brachial plexus anaesthesia, allocated randomly to receive either normal saline 10 ml or normal saline 10 ml with alfentanil 10 micrograms/kg body weight through an axillary cannula. All patients received 1.5% lignocaine at a dose of 7 mg/kg body weight with adrenaline 1 in 200,000. The incidence of satisfactory block was similar in both groups. Although the percentage of patients with complete anaesthesia in the median nerve distribution was greater in the alfentanil group, there was no significant difference in any other distribution. The time to return of sensation and motor function was prolonged significantly in the alfentanil group (P < 0.05). After return of normal sensation, there was no significant difference between groups in postoperative analgesia. In a second part of the study, there was no significant increase in plasma concentrations of alfentanil in 10 patients given lignocaine and alfentanil, as outlined above. These observations suggest that alfentanil may have a peripheral local anaesthetic action.

Adolescent↗
PubMed1996

Intravenous lidocaine does not attenuate the cardiovascular and catecholamine response to a rapid increase in desflurane concentration.

This study was designed to investigate the effect of intravenous lidocaine on the sympathetic activity after a rapid increase in desflurane concentration. Twenty ASA grade I and II patients, were allocated randomly to a control group (C) and a lidocaine group (L). After induction of anesthesia with intravenous propofol 2 mg/kg and muscle relaxation with intravenous vecuronium 0.1 mg/kg, desflurane was given to achieve an end-tidal minimum alveolar anesthetic concentration (MAC) of 0.7 Group L received 1.5 mg/kg lidocaine intravenously, while Group C received an equal volume of 0.9% sodium chloride solution intravenously. These solutions were prepared and coded by a colleague who took no further part in the study. The concentration of desflurane was then abruptly increased to 1.5 MAC. Heart rate and mean arterial pressure were noted every half minute. Blood samples were taken for plasma catecholamines at rest, 0.7 MAC, and at 1-min intervals for 5 min after the increase in desflurane concentration. There was a significant increase in heart rate and mean arterial pressure in both groups. The increase in heart rate was significantly less in Group L from 0.5 until 2.5 min (P < 0.05). There was no difference in mean arterial pressure between the groups except at 4.5 and 5.0 min (P < 0.05). Plasma catecholamines were not significantly different between the groups. Intravenous lidocaine did not attenuate the sympathetic response to a rapid increase in desflurane concentration. It is unlikely that airway irritation is the cause of this phenomenon.

Adolescent↗
PubMed1996

The effect of alkalinisation of lignocaine on axillary brachial plexus anaesthesia.

Alkalinisation of local anaesthetic drugs is a controversial technique for improving regional blockade. Forty-two patients scheduled for upper limb surgery received axillary brachial plexus anaesthesia using a cannula technique. Patients were randomly allocated to receive either lignocaine 1.5% with 1 in 200,000 adrenaline (pH = 4.2) or lignocaine 1.5% with 1 in 200,000 adrenaline (pH = 7.2). There was no significant difference in the incidence of satisfactory blockade or distribution of anaesthesia between the two groups. The percentage of patients with complete anaesthesia at 10, 20 and 30 min following injection was significantly increased in the alkalinized group with regard to the ulnar and median nerves, and the median cutaneous nerve of the arm (p < 0.05). In the alkalinized group, there was a significant reduction in the time to useful anaesthesia and a reduced requirement for adjuvants (p < 0.05). There was no effect on the duration of anaesthesia.

Adjuvants, Immunologic↗
PubMed1996

Isolation of the Schizosaccharomyces pombe RAD54 homologue, rhp54+, a gene involved in the repair of radiation damage and replication fidelity.

The RAD54 gene of Saccharomyces cerevisiae encodes a putative helicase, which is involved in the recombinational repair of DNA damage. The RAD54 homologue of the fission yeast Schizosaccharomyces pombe, rhp54+, was isolated by using the RAD54 gene as a heterologous probe. The gene is predicted to encode a protein of 852 amino acids. The overall homology between the mutual proteins of the two species is 67% with 51% identical amino acids and 16% similar amino acids. A rhp54 deletion mutant is very sensitive to both ionizing radiation and UV. Fluorescence microscopy of the rhp54 mutant cells revealed that a large portion of the cells are elongated and occasionally contain aberrant nuclei. In addition, FACS analysis showed an increased DNA content in comparison with wild-type cells. Through a minichromosome-loss assay it was shown that the rhp54 deletion mutant has a very high level of chromosome loss. Furthermore, the rhp54 mutation in either a rad17 or a cdc2.3w mutant background (where the S-phase/mitosis checkpoint is absent) shows a significant reduction in viability. It is hypothesized that the rhp54+ gene is involved in the recombinational repair of UV and X-ray damage and plays a role in the processing of replication-specific lesions.

Amino Acid Sequence↗
PubMed1995

Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing.

The structure of the human gene encoding the double-stranded RNA (dsRNA) adenosine deaminase (DRADA) was characterized. This nuclear localized enzyme is involved in the RNA editing required for the expression of certain subtypes of glutamate-gated ion channel subunits. The DRADA gene span 30 kb pairs and harbors 15 exons. The transcription of the DRADA gene driven by the putative promoter region, which contains no typical TATA or CCAAT box-like sequences, is initiated at multiple sites, 164 to 216 nucleotides upstream of the translation initiation codon. The three dsRNA binding motifs (DRBM), 70 amino acid residues long, are each encoded by two exons plus an intervening sequence that interrupts the motif at the identical amino acid position. This finding is consistent with the notion that the dsRNA binding domains may be composed of two separate functional subdomains. Fluorescent in situ hybridization localized the DRADA gene on the long arm chromosome 1, region q21. The gene structure and sequence information reported in this study will facilitate the investigation of involvement of DRADA in hereditary diseases that may be the result of malfunction of glutamate-gated ion channels.

Adenosine Deaminase↗
PubMed1995

Factor VNew Brunswick: Ala221-to-Val substitution results in reduced cofactor activity.

We have characterized the factor V protein and cDNA of a patient displaying factor V deficiency (parahemophilia) and correlated the reduced activity with a missense mutation of Ala221-to-Val. Plasma from the subject individual (C1) presented reduced factor V antigen (39% of normal) that displayed reduced activity (approximately 26% of normal). Factor V purified from this individual by standard techniques shows normal migration on sodium dodecyl sulfate gels and a normal pattern of activation by thrombin. Purified antigen from sibling C2 gives a much reduced specific activity of 263 U/mg (17% of normal). Sibling C3, the mother, and the father have antigen within the normal range (57% to 200%) that has approximately normal specific activity. The cDNA encoding the factor Va heavy and light chains of the subject individual was polymerase chain reaction-amplified and sequenced and revealed an A-to-G substitution at position 3 of codon 51 (silent mutation), a C-to-T substitution in position 2 of codon 221 (Ala221-Val), a T-to-C substitution at position 3 of codon 708 (silent mutation), and a G-to-A substitution at position 1 of codon 2185 (Thr2185-Ala). The latter mutation was also observed in control individuals and is proposed to be a possible polymorphism. Restriction analyses demonstrated the presence of one mutant and one normal allele in the father. The subject individual (C1) and sibling C2 carry only the mutant allele. The mother and sibling C3 carry only the normal allele. The inheritance pattern suggests the presence of a missing or nonexpressed allele in the mother that is passed on to all the siblings. Expression of only the mutant allele by the subject individual (C1) and sibling C2 is consistent with reduced factor V antigen and activity in these patients. We have designated this mutant as Factor VNew Brunswick.

Adolescent↗
PubMed1995

An example of the effects of drug resistance on the optimal schedule for a single drug in cancer chemotherapy.

In this paper the authors study the effects of drug resistance on the optimal drug schedule of a single drug in cancer chemotherapy. The optimal schedule is analytically determined when the tumour grows exponentially and the drug has a linear killing action. Drug resistance enters into the model via an effectiveness term that decreases the cell loss as the accumulation of the drug grows. It is found that the optimal schedule is one where the drug is given at its maximum feasible dose from the onset, with some difference at the end of treatment depending on the relative speeds with which resistance develops.

Antineoplastic Agents↗
PubMed1995

Molecular sieves: an alternative method of carbon dioxide removal which does not generate compound A during simulated low-flow sevoflurane anaesthesia.

Molecular sieves are used in industry to 'scrub' industrial gases. We examined, during simulated low-flow closed system anaesthesia, (1) the carbon dioxide adsorbing potential of molecular sieves and (2) the reactivity of the sieves compared to soda lime using sevoflurane as an indicator. A low-flow anaesthetic system containing 13X molecular sieves was connected to a model lung. End-tidal concentrations of CO2 were measured continuously at an O2 flow of 800 ml.min-1 and a CO2 flow of 200 ml.min-1. In the second study, sevoflurane (FE'sevo 1.7%) was added to the system after which samples were taken from the inspiratory limb of the anaesthetic system. This experiment was performed both during carbon dioxide removal with soda lime and with the molecular sieves. The samples were stored in gas-tight syringes and analysed by gas chromatography. The temperature of both absorbents was measured throughout the study. The molecular sieves adsorbed carbon dioxide (20%) efficiently for a period of 5 h. There was a gradual increase from the baseline of 4.4% to 4.5, 5.4, and 6.0% at 90, 180, and 300 min, respectively. When sevoflurane was added to the system, compound A was detected at the start of both experiments. However, when soda lime was used the concentrations of compound A increased 10-fold after 2.5 h compared with baseline values. No increase in compound A was observed when molecular sieves were used for carbon dioxide removal. The highest mean (SD) temperature of the molecular sieves was 41.5 (3.2) degrees C. Molecular sieves are effective adsorbents of carbon dioxide when used in a simulated low-flow, closed anaesthetic system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1995

The rad18 gene of Schizosaccharomyces pombe defines a new subgroup of the SMC superfamily involved in DNA repair.

The rad18 mutant of Schizosaccharomyces pombe is very sensitive to killing by both UV and gamma radiation. We have cloned and sequenced the rad18 gene and isolated and sequenced its homolog from Saccharomyces cerevisiae, designated RHC18. The predicted Rad18 protein has all the structural properties characteristic of the SMC family of proteins, suggesting a motor function--the first implicated in DNA repair. Gene deletion shows that both rad18 and RHC18 are essential for proliferation. Genetic and biochemical analyses suggest that the product of the rad18 gene acts in a DNA repair pathway for removal of UV-induced DNA damage that is distinct from classical nucleotide excision repair. This second repair pathway involves the products of the rhp51 gene (the homolog of the RAD51 gene of S. cerevisiae) and the rad2 gene.

Amino Acid Sequence↗
PubMed1995

Energy expenditure of below-knee amputees during harness-supported treadmill ambulation.

Traditional rehabilitation of amputees is primarily aimed at strengthening remaining musculature necessary for prosthetic use and gait training. Available gait training time, however, is often limited by pain, residual limb skin tolerance, and the patient's cardiovascular endurance. Harness-supported treadmill ambulation is a rehabilitation technique being used by physical therapists to decrease an individual's body weight by a given percentage during exercise. This, theoretically, allows an amputee to ambulate on a prosthesis at a lower energy cost. The purpose of this study was to compare the energy expenditure of healthy below-knee amputee volunteers with healthy able-bodied volunteers during harness-supported treadmill ambulation in order to determine if energy conservation is achieved. Subjects were tested on a treadmill, walking at .67 m/sec (1.5 mph) and 1.34 m/sec (3.0 mph) during each of the following randomized harness-supported treadmill ambulation situations: full body weight, 20% body weight supported, and 40% body weight supported. During the last minute of each trial, rate of perceived exertion, heart rate, and standardized indirect calorimetry oxygen consumption (VO2, ml/kg/min) measures were collected. Caloric expenditure (kl/min) was calculated using metabolic conversion equations. Peak heart rate, peak VO2, and peak kl/min were measured after the conclusion of the last walking trial by taking each subject to volitional fatigue. Data were analyzed for each harness-supported treadmill ambulation situation and group using analysis of variance (ANOVA). The researchers identified significantly lower ratings of perceived exertion, heart rates, and VO2s for able-bodied subjects vs. below-knee amputees for all trials. Both groups demonstrated significantly lower heart rates, VO2s, and kl/min at 1.34 m/sec with 40% body weight supported.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Localization of a neutralizing epitope on the envelope protein of dengue virus type 2.

Two neutralization-resistant variants of dengue virus type 2 were selected using the neutralizing monoclonal antibody G8D11. Virus N-GV4 was derived from the New Guinea C strain and virus P-GV3 from the PUO-218 strain. Both variants had an identical change at nucleotide 919 in the E gene, causing a substitution of glutamic acid for lysine at residue 307 in the E glycoprotein. The substitution abolished the ability of antibody G8D11 to bind to the E glycoprotein in radioimmunoprecipitation experiments. The epitope was sensitive to treatment with SDS and was dependent on the formation of a disulfide bridge. This dependency was determined by mutagenesis of Cys residues 11 and 12 in the E glycoprotein.

Antibodies, Monoclonal↗
PubMed1994

Purification and characterization of double-stranded RNA adenosine deaminase from bovine nuclear extracts.

The double-stranded RNA (dsRNA) adenosine deaminase (DRADA) deaminates adenosine residues to inosines and creates I-U mismatched base pairs in dsRNAs. Its involvement in RNA editing of glutamate-gated ion channel gene transcripts in mammalian brains has been proposed as one of the biological functions for this recently identified cellular enzyme. We purified a mixture of three forms, 93, 88, and 83 kDa, of bovine DRADA proteins, all likely to be active enzymes. We determined that DRADA has a native molecular mass of approximately 100 kDa, suggesting that the enzyme exists as a monomer. The purified enzyme was not inhibited by 2'-deoxycoformycin, a transition state analog inhibitor of adenosine deaminase and AMP deaminase, suggesting that the catalytic mechanism of DRADA might be different from that of other deaminases. DRADA binds specifically to dsRNA with a dissociation constant of 0.23 nM for a synthetic dsRNA, and the Michaelis constant is 0.85 nM. These values indicate that DRADA has a much higher affinity for its substrate than other deaminases such as adenosine deaminase and AMP deaminase. DRADA may need this extremely high affinity to catalyze efficiently the modification of relatively rare substrate RNAs in the cell nucleus.

Adenosine Deaminase↗