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Biomedical subjects

R Murphy

Publications and source records attributed to R Murphy.

At least 37 records · Page 2Linked to original sources
PubMed2002

Sound transmission in the lung as a function of lung volume.

We were interested in how the transmission of sound through the lung was affected by varying air content in intact humans as a method of monitoring tissue properties noninvasively. To study this, we developed a method of measuring transthoracic sound transit time accurately. We introduced a "coded" sound at the mouth and measured the transit time at multiple microphones placed over the chest wall by using a 16-channel lung sound analyzer (Stethographics). We used a microphone placed over the neck near the trachea as our reference and utilized cross-correlation analysis to calculate the transit times. The use of the coded sound, composed of a mix of frequencies from 130 to 150 Hz, greatly reduced the ambiguity of the cross-correlation function. The measured transit time varied from 1 ms at the central locations to 5 ms at the lung bases. Our results also indicated that transit time at all locations decreased with increasing lung volume. We found that these results can be described in terms of a model in which sound transmission through the lung is treated as a combination of free-space propagation through the trachea and a propagation through a two-phase system in the parenchyma.

Acoustics↗
PubMed2001

Specific targeting, biodistribution, and lack of immunogenicity of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma: results of a phase I trial.

PURPOSE: KM871 is a chimeric monoclonal antibody against the ganglioside antigen GD3, which is highly expressed on melanoma cells. We conducted an open-label, dose escalation phase I trial of KM871 in patients with metastatic melanoma. PATIENTS AND METHODS: Seventeen patients were entered onto one of five dose levels (1, 5, 10, 20, and 40 mg/m2). Patients received three infusions of KM871 at 2-week intervals, with the first infusion of KM871 trace-labeled with indium-111 (111In) to enable assessment of biodistribution in vivo. Biopsies of metastatic melanoma sites were performed on days 7 to 10. RESULTS: Fifteen of 17 patients completed a cycle of three infusions of KM871. No dose-limiting toxicity was observed during the trial; the maximum-tolerated dose was therefore not reached. Three patients (at the 1-, 5-, and 40-mg/m2 dose levels) developed pain and/or erythema at tumor sites consistent with an inflammatory response. No normal tissue uptake of 111In-KM871 was observed, and tumor uptake of 111In-KM871 was observed in all lesions greater than 1.5 cm (tumor biopsy 111KM871 uptake results: range, 0.001% to 0.026% injected dose/g). The ratio of maximum tumor to normal tissue was 15:1. Pharmacokinetic analysis revealed a 111In-KM871 terminal half-life of 7.68 +/- 2.94 days. One patient had a clinical partial response that lasted 11 months. There was no serologic evidence of human antichimeric antibody in any patient, including one patient who received 16 infusions over a 12-month period. CONCLUSION: This study is the first to demonstrate the biodistribution and specific targeting of an anti-GD3 antibody to metastatic melanoma in patients. The long half-life and lack of immunogenicity of KM871 makes this antibody an attractive potential therapy for patients with metastatic melanoma.

Adult↗
PubMed2001

Timing of antiretroviral therapy. Use of Markov modeling and decision analysis to evaluate the long-term implications of therapy.

BACKGROUND: The timing of initiation of antiretroviral therapy is controversial. Current guidelines are heavily based on the principle of 'hit early, hit hard', although the long-term implications of this approach are unknown. METHODS: Using Markov modeling and decision analysis we modeled the virologic outcomes over 10 years in a hypothetical population of 10 000 HIV-infected patients in which therapy (with the possibility of three sequential regimens before the development of multidrug-resistant virus) is started immediately versus starting progressively at rates of 5, 10, 15, 20 or 30% of the original population each year. The model used inputs from available clinical trial data: virologic success rate and durability of the response of the first and subsequent regimens. We performed one-way and two-way sensitivity analysis to evaluate changes in the input variables. RESULTS: If therapy is started immediately in all patients, by 10 years 57% would be undetectable, but 38% would have detectable multidrug-resistant virus. In contrast, the population as a whole would have had better virologic outcomes if one waited before starting treatment at any progression rate; for example, initiating therapy in 10% of the subjects per year results in 64% of patients being undetectable and 24% with multidrug-resistant virus. Two-way sensitivity analysis demonstrates that immediate initiation should be at least 15 to 20% better than delayed antiretroviral therapy to justify immediate initiation of therapy over a wide range of success rates of the delayed start. CONCLUSION: Our analysis, utilizing optimistic outcomes based on short-term clinical trials, provides a theoretical basis for questioning the current aggressive early use of therapy and should help prompt studies that look at when and how to start antiretroviral therapy.

Anti-HIV Agents↗
PubMed2001

Morphine and clonidine activate different K+ channels on rat amygdala neurons.

In cell-attached patch-clamp recordings from freshly dissociated neurons of the rat amygdalohippocampal area, clonidine principally activated a 95-pS (picosiemens) inwardly rectifying K+-permeable channel, whereas morphine acting at mu-opioid receptors activated a different 130-pS channel. Clonidine's effects were largely antagonized by the alpha(2)-adrenoceptor antagonist idazoxan, but were poorly mimicked by agmatine. These results partially contradict the prevailing hypothesis that alpha(2) and opioid receptors act through the same ion channel transduction pathways.

Adrenergic alpha-Antagonists↗
PubMed2001

Virologic and CD4 cell response to zidovudine or zidovudine and lamivudine following didanosine treatment of human immunodeficiency virus infection.

To optimize nucleoside reverse transcriptase inhibitor (nRTI) antiretroviral therapy, 137 subjects who had been treated with didanosine monotherapy for more than 3 years in the AIDS Clinical Trials Group (ACTG) 175 study were randomized to zidovudine and didanosine (dual therapy) or zidovudine, didanosine, and lamivudine (triple therapy). Evaluation of early (8 week) change in HIV plasma RNA demonstrated that addition of lamivudine and zidovudine provided significantly greater virologic suppression compared to the addition of zidovudine alone (mean decrease of 1.27 vs. 0.74 log(10) copies/ml, n = 108, p = 0.007). Both dual and triple therapy provided significant long-term decreases (from study entry to mean at Weeks 40 and 48) in HIV plasma RNA: 0.62 and 0.86 log(10) copies/ml, respectively (n = 110). However, the difference between treatments was not significant (p = 0.16). At 48 weeks, 26% of subjects starting study treatment had <500 copies/ml of plasma HIV RNA. The CD4 count response was greater at 4 weeks for triple versus dual therapy: a mean increase of 51 vs. 12 CD4 cells/ml(3) (n = 126, p = 0.039). The difference at Weeks 40 and 48 was not significant (a 22 cell increase vs. a 1 cell decrease, n = 129, p = 0.41). Zidovudine and didanosine treatment, with or without lamivudine, was well tolerated and only 2 of 137 (1.5%) of study participants developed an AIDS-defining event over 48 weeks.

Adult↗
PubMed2001

A Val193Met mutation in GPIIIa results in a GPIIb/IIIa receptor with a constitutively high affinity for a small ligand.

We have identified a patient designated as (GTa) with Glanzmann's Thrombasthenia (GT) diagnosed on the basis of a prolonged bleeding time and failure of the patient's platelets to aggregate. The number of glycoprotein (GP)IIb/IIIa receptors on the platelet surface was 37% of normal and those receptors displayed a defect in soluble fibrinogen binding. Nevertheless, GTa platelets showed increased adhesion to solid-phase fibrinogen and binding affinity for the RGD-mimetic (3)H-SC52012, a non-peptide GPIIb/IIIa antagonist. Dithiothreitol (DTT) and ADP enhanced the affinity for [(3)H]-SC52012 in normal platelets, but had little effect in GTa platelets. These findings suggested that GTa platelets were locked in an altered affinity state. Genetic analysis showed that GTa was a compound heterozygote for the GPIIIa gene. One allele showed a deletion at the 3' end of exon 3 resulting in a premature stop codon. The second GPIIIa allele had a G to A transition at nucleotide 577, resulting in a Val193Met substitution. HEK 293T cells transfected with mutant GPIIb/IIIaV193M bound [(3)H]-SC52012 with a higher affinity than wild-type GPIIb/IIIa, and this was not increased by DTT. The mutant receptor distinguishes between platelet adhesion and aggregation, and demonstrates the phenotype that may be expected when platelet aggregation alone is inhibited.

Adenosine Diphosphate↗
PubMed2001

Effect of experience of severe stroke on subjective valuations of quality of life after stroke.

Previous work suggests that the quality of life associated with severe disability after stroke is rated very poorly by members of the public, often as being worse than death. Other evidence suggests that experience of illness alters perceptions of its severity. This was tested for severe stroke. Eleven patients with severely disabling stroke, but able to complete a standard gamble interview, 22 age and sex matched controls, and 20 health professionals participated. A standard gamble interview was carried out to determine the quality of life (utility) associated with three hypothetical scenarios representing mild, moderate, and severe stroke, and current health. A sample was retested for reliability, and comparisons were made with other measures of health status. All three subject groups showed wide variation in the utilities they attached to each of the scenarios. The control subjects' valuations were lower than those of either patients or staff members, especially for moderate stroke (median 0.30, 0.73, and 0.68 respectively). There were weak to moderate correlations between utilities and other measures of health status including the Barthel index (r=0.51) and Rivermead mobility score (r=0.24). Test retest-reliability was modest (reliability coefficient 0.75), but indicators of the internal validity of the results were good. In conclusion, it cannot be assumed that general population valuations are valid for patient groups. In clinical practice it is unsafe to make any assumption about subjective quality of life after stroke, due to the wide range of valuations given, although many people rate severe and moderate stroke at least as bad as death.

Aged↗
PubMed2001

Creatine transporter protein content, localization, and gene expression in rat skeletal muscle.

The present study examined the gene expression and cellular localization of the creatine transporter (CreaT) protein in rat skeletal muscle. Soleus (SOL) and red (RG) and white gastrocnemius (WG) muscles were analyzed for CreaT mRNA, CreaT protein, and total creatine (TCr) content. Cellular location of the CreaT protein was visualized with immunohistochemical analysis of muscle cross sections. TCr was higher (P < or = 0.05) in WG than in both RG and SOL, and was higher in RG than in SOL. Total CreaT protein content was greater (P < or = 0.05) in SOL and RG than in WG. Two bands (55 and 70 kDa) of the CreaT protein were found in all muscle types. Both the 55-kDa (CreaT-55) and the 70-kDa (CreaT-70) bands were present in greater (P < or = 0.05) amounts in SOL and RG than in WG. SOL and RG had a greater amount (P < or = 0.05) of CreaT-55 than CreaT-70. Immunohistochemical analysis revealed that the CreaT was mainly associated with the sarcolemmal membrane in all muscle types. CreaT mRNA expression per microgram of total RNA was similar across the three muscle types. These data indicate that rat SOL and RG have an enhanced potential to transport Cr compared with WG, despite a higher TCr in the latter.

Animals↗
PubMed2000

Some compartmental models of the root: steady-state behavior.

Plots of the pressure difference (DeltaP) applied to plant roots vs. the resulting volume flow rate (Q(v)) often exhibit an anomalous offset that has been difficult to explain. The present analysis suggests that solute build-up in two- and three-compartment models of the root cannot account for this offset. The Ginsburg-Newman three-compartment model explains the offset in terms of differing reflection coefficients for the membranes bounding the intermediate compartment. This model appears more promising, but it predicts a minimum in the plot of xylem-sap osmotic pressure vs. Q(v)which is not observed in practice. Fiscus hypothesized that an internal asymmetric distribution of non-mobile solutes is responsible for the offset. In the present study, this hypothesis is incorporated into a four-compartment model of the root that is conceptually related to the three-compartment model of Miller. But according to the four-compartment model, the asymmetric solute distribution does not arise because of solvent drag. Rather the anomalous offset is associated with a concentration gradient of photoassimilates (the non-mobile solutes) that exists in the absence of volume flow, and which drives the diffusive transport of these solutes from the stele to the cortex via endodermal plasmodesmata. This model is consistent with the existence of radial symplastic osmotic-pressure gradients, and it appears to have greater explanatory power than the Ginsburg-Newman model. In particular, it suggests explanations for diurnal variations in DeltaP-Q(v)curves, as well as the effects of changing external solute concentrations. It also shows how the overall root reflection coefficient can be less than unity, even when the cell membranes are effectively ideally semipermeable, and there is negligible extracellular transport of water and solutes. The model makes a number of experimentally testable predictions.

Biological Transport↗
PubMed2000

Altered gating of opiate receptor-modulated K+ channels on amygdala neurons of morphine-dependent rats.

The molecular mechanism of tolerance to opiate drugs is poorly understood. We have used single-channel patch-clamp recordings to study opiate receptor effects on dissociated neurons from rat amygdala, a limbic region implicated in addiction processes. A 130-pS inwardly rectifying K(+)-preferring cation channel was activated by mu opioid receptors in a membrane-delimited manner. After chronic treatment of the rats with morphine, channel gating changed markedly, with an approximately 100-fold decrease in open probability at a given morphine concentration. The change in channel gating correlated both in time course and in dose of morphine treatment with the development of functional opiate dependence and appeared to arise at a step after G-protein activation and before channel permeation by K(+). This decreased receptor-channel coupling appears to be large enough to account quantitatively for opiate tolerance and may represent one of the mechanisms through which tolerance occurs.

Amygdala↗