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Biomedical subjects

M S Roberts

Publications and source records attributed to M S Roberts.

At least 127 records · Page 7Linked to original sources
PubMed1995

Influence of physicochemical parameters and perfusate flow rate on the distribution of solutes in the isolated perfused rat hindlimb determined by the impulse-response technique.

The relationship between solute distribution, physicochemical properties, and tissue physiology was determined by the impulse-response (IR) technique and statistical moment analysis in the isolated perfused rat hindlimb. The concentration of bovine serum albumin (BSA; 2, 4.7, and 7%, w/v), perfusate flow rate (4 and 8 mL/min), and solute physicochemical properties (lipophilicity, P, fraction unbound to protein, fu; fraction ionized, fi; and molecular weight MW) were varied to better understand the underlying determinants of solute distribution. An apparent low availability was found for a number of the solutes as a consequence of tissue sequestration. This low availability precludes the estimation of an apparent volume of distribution (V) for these solutes. The V of solute and tissue (skin, fat, and muscle) blood flow increased with perfusion flow rate (p < 0.01). The unbound distribution volume (Vu) of basic solutes was significantly linear with respect to P. Multiple linear regression analysis showed that the distribution volume of solute in tissue was significantly related to fu (p < 0.01), but not improved by including relationships to P, MW, and fi. Data obtained with this IR technique yield results consistent with in vivo studies in terms of the importance of fu as a determinant of V. This work has shown that the estimations of solute V by the IR technique in a single-pass preparation are unreliable for solutes with a low availability due to apparent solute sequestration into tissue. The parameter V may also be affected by changes in the perfused limb physiology associated with the perfusion conditions used. The Vs for lidocaine and diazepam vary with fu in accordance with deductions based on the results of steady-state studies.

Adrenergic beta-Antagonists↗
PubMed1995

The log-linear relationship between sexual isolation and sequence divergence in Bacillus transformation is robust.

The relationship between sexual isolation and sequence divergence in Bacillus transformation was previously shown to be log linear. In the present study, we have shown that this relationship is robust with respect to naturally occurring genetic variation among recipient strains of Bacillus subtilis and B. mojavensis. Naturally occurring restriction endonuclease activity was shown not to affect this relationship. Also, seven out of eight recombination mutants tested for their sensitivity to sequence divergence have shown the same relationship between sequence divergence and sexual isolation; a mutant for recH was more sensitive to sequence divergence, suggesting that the product of this gene may be involved in resolution of mismatches in heterogamic transformation. We have also shown that the relationship between sexual isolation and sequence divergence is robust with respect to variation in the conditions of transformation, including variation in the length of donor DNA, the concentration of donor DNA, and intracellular competition between donor-derived and recipient-derived DNA. The robustness of the relationship between sexual isolation and sequence divergence among naturally occurring strains and across transformation conditions allows us to predict the eventual outcome of sequence divergence among B. subtilis and its closest relatives.

Bacillus↗
PubMed1995

Prediction of cathodal iontophoretic transport of various anions across excised skin from different vehicles using conductivity measurements.

Solute concentration, buffer concentration, applied pH and buffer constituents affect the cathodal iontophoresis of salicylate, benzoate and butyrate across excised skin. Experiments were conducted in which the iontophoretic flux of salicylate was measured across excised human skin with variations in salicylate concentration, donor solution pH, buffer concentrations and buffer consitutents. The conductivity of these solutes and of solutions described in studies on the iontophoresis of benzoate and butyrate were then measured. The observed variations in salicylate, benzoate and butyrate fluxes across a range of conditions were found to be related to the ratio of specific conductance of the solutes in deionized distilled water to that in the buffer solution containing the solutes. The present results suggest that conductivity of solutes in vehicle solutions is one means of predicting the iontophoretic flux of solutes from different vehicle compositions.

Biological Transport↗
PubMed1995

Percutaneous absorption of salicylates from some commercially available topical products containing methyl salicylate or salicylate salts in rats.

Studies to determine the extent of local tissue penetration of topically applied, commercially available salicylate esters and salts were conducted in male Wistar rats. The salicylate concentration in plasma, tissues underlying the site of drug application, and similar tissues on the contralateral (control) side were measured. The plasma and tissue salicylate levels suggest that direct penetration of salicylate was predominant to the top muscle level on the treated site. Results also suggest that the drugs were first absorbed into the bloodstream and subsequently distributed to both the deeper tissues on the treated site and the contralateral tissues. The topical application of formulations of ester methyl salicylate and salts triethanolamine salicylate and diethylamine salicylate containing comparable salicylate concentrations yielded similar salicylate concentrations in the various tissues. The salicylate concentrations in the deeper tissues approached concentrations observed in the contralateral tissues suggesting that salicylate present in these tissues was due to the systemic blood supply.

Administration, Topical↗
PubMed1995

Availability and mean transit times of phenol and its metabolites in the isolated perfused rat liver: normal and retrograde studies using tracer concentrations of phenol.

Phenolic compounds are frequently detoxified by the formation of sulphate and glucuronic acid conjugates in the liver. These conjugates are formed in the hepatocytes and then either transported into the bile or back into the blood. In this study, we examined the transport kinetics of phenol and its metabolites in the isolated perfused rat liver by monitoring the outflow profiles of these compounds after a bolus input in a single pass preparation. Phenol was almost exclusively metabolized to phenyl sulphate (97%) at the trace concentrations used, with the amount of phenol and metabolites excreted into the bile being minimal (3.5%). The metabolite formed was rapidly transported back into the perfusate, with mean transit times of 17.4 and 12.3 s anterograde and 24.9 and 24.2 s retrograde at flow rates of 15 and 30 mL min-1 respectively, which were intermediate between those of Evans blue and water. The outflow concentration-time profile for phenyl sulphate formation was unaffected by the addition of another organic anion (bromosulphophthalein). The effect of enzyme zonation on outflow concentration-time profiles was also investigated using retrograde perfusions. The transit time ratios for generated metabolite to water for anterograde perfusions (0.6) was found to be more than twice that for retrograde perfusions (0.23) at 15 mL min-1 and approximately 1.6 times greater at 30 mL min-1, being 0.58 and 0.37 respectively. The relative ratios obtained are consistent with previous findings that normalized variance of solutes in the retrograde perfusions is greater than that for anterograde perfusions.

Animals↗
PubMed1995

Nuclear localization of v-Abl leads to complex formation with cyclic AMP response element (CRE)-binding protein and transactivation through CRE motifs.

Deregulated expression of v-abl and BCR/abl genes has been associated with myeloproliferative syndromes and myelodysplasia, both of which can progress to acute leukemia. These studies identify the localization of the oncogenic form of the abl gene product encoded by the Abelson murine leukemia virus in the nuclei of myeloid cells and the association of the v-Abl protein with the transcriptional regulator cyclic AMP response element-binding protein (CREB). We have mapped the specific domains within each of the proteins responsible for this interaction. We have shown that complex formation is a prerequisite for transcriptional potentiation of CREB. Transient overexpression of the homologous cellular protein c-Abl also results in the activation of promoters containing an intact CRE. These observations identify a novel function for v-Abl, that of a transcriptional activator that physically interacts with a transcription factor.

Base Sequence↗
PubMed1994

Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial.

OBJECTIVE: To assess the effect of an individualized treatment regimen on the intensity and duration of medication treatment for alcohol withdrawal. DESIGN: A randomized double-blind, controlled trial. SETTING: An inpatient detoxification unit in a Veterans Affairs medical center. PATIENTS: One hundred one patients admitted for the treatment of alcohol withdrawal who could give informed consent and had no history of seizures or medication use that might alter the clinical course of withdrawal. INTERVENTION: Patients were randomized to either a standard course of chlordiazepoxide four times daily with additional medication as needed (fixed-schedule therapy) or to a treatment regimen that provided chlordiazepoxide only in response to the development of the signs and symptoms of alcohol withdrawal (symptom-triggered therapy). The need for administration of "as-needed" medication was determined using a validated measure of the severity of alcohol withdrawal. MAIN OUTCOME MEASURES: Duration of medication treatment and total chlordiazepoxide administered. RESULTS: The median duration of treatment in the symptom-triggered group was 9 hours, compared with 68 hours in the fixed-schedule group (P < .001). The symptom-triggered group received 100 mg of chlordiazepoxide, and the fixed-schedule group received 425 mg (P < .001). There were no significant differences in the severity of withdrawal during treatment or in the incidence of seizures or delirium tremens. CONCLUSIONS: Symptom-triggered therapy individualizes treatment, decreases both treatment duration and the amount of benzodiazepine used, and is as efficacious as standard fixed-schedule therapy for alcohol withdrawal.

Adult↗
PubMed1994

Role of conductivity in iontophoresis. 2. Anodal iontophoretic transport of phenylethylamine and sodium across excised human skin.

The anodal iontophoretic transdermal delivery of a model cation, phenylethylamine (PEA), across excised human skin was investigated to define the role of conductivity in iontophoresis. The ratio of the specific conductance of PEA in deionized-distilled water to that of the solution applied in the donor compartment (buffer+PEA) was employed to assess the relationship between the flux of PEA and the conductivity. The flux of PEA was linearly related to the ratio of specific conductance at 5 and 20 mM PEA for a variety of experimental conditions. A curvilinear relationship was observed at 1 mM PEA concentration, particularly when the conductivity of the donor solution was low. It is therefore hypothesized that a threshold conductivity in solution exists above which a linear relationship between iontophoretic flux and specific conductance is observed. The present study confirms that conductivity of an ion in a solution provides a simple means of estimating the competitive transport between solute and other ions during transdermal iontophoresis.

Buffers↗
PubMed1994

Dermal and underlying tissue pharmacokinetics of lidocaine after topical application.

The deep-tissue penetration of lidocaine below a dermally applied site was quantified in a rat model. The concentrations of lidocaine in tissues below the applied site were measured and compared with plasma concentrations and concentrations in similar tissues on the contralateral side. The direct penetration of lidocaine was predominant for the first 2 h up to a depth of about 1 cm below the applied site. A physiologically based pharmacokinetic model based on apparent tissue-tissue clearances and local blood flow to tissues is presented which adequately describes the concentration-time profiles of lidocaine in underlying tissues after dermal application. The apparent tissue-tissue clearances were estimated by nonlinear regression assuming first-order diffusional mass transfer of lidocaine between the various tissue compartments below the applied site in anesthetized rats. Tissue levels of lidocaine were estimated using simulations from the model with and without direct penetration and tissue blood supply. Dermal microcirculation is not a perfect sink for lidocaine.

Administration, Topical↗
PubMed1994

Effects of vasoconstriction on dermal pharmacokinetics and local tissue distribution of compounds.

The effects of the local vasoconstrictor phenylephrine on the dermal absorption kinetics and local tissue distribution of compounds were investigated in rats. Phenylephrine (0.0025% -0.1%) and tracer quantities of salicylic acid, lidocaine, and water were applied in an aqueous solution to the exposed rat dermis. The disappearance of salicylic acid from the solution into the rat dermis and its appearance in blood, local underlying tissues, and similar tissues on the contralateral side was quantified. The clearance of salicylic acid into the dermis decreased and the concentrations of salicylic acid in underlying tissues increased with an increase in phenylephrine concentration (up to 0.01%). The concentrations of salicylic acid in plasma and contralateral issues decreased with increasing phenylephrine concentrations. At higher phenylephrine concentrations, no significant increase in local tissue concentrations of salicylic acid was observed. The effects of phenylephrine on local tissue levels of lidocaine and tritiated water paralleled those found for salicylic acid. The concentration-depth profiles for solutes in underlying tissues with variable blood flows were described by a compartment-in-series pharmacokinetic model in which each tissue's blood flows to and from a central compartment were incorporated. The values predicted under varying degrees of vasoconstriction were found to compare well with the experimentally determined concentrations of salicylic acid, lidocaine, and water in issues below a dermal application site, in the presence of phenylephrine. Phenylephrine can significantly increase quantities of solutes delivered to local tissues after dermal application, the observed effects being due to the vasoconstrictive properties of phenylephrine. Blood flow changes in skin can have profound effects on dermal pharmacokinetics and relative processes of local and systemic solute distribution.

Animals↗
PubMed1994

Screening for vitamin B12 deficiency in psychiatric patients.

Psychiatric patients are frequently screened for vitamin B12 deficiency in the absence of hematologic or other neurologic findings. To determine the yield of this practice, 162 psychiatric inpatients were screened for vitamin B12 deficiency. Ten patients had initial low serum vitamin B12 levels, but only two had definite B12 deficiency on further evaluation. Three patients who had initially low B12 levels had normal levels subsequently during outpatient follow-up. When low serum vitamin B12 levels are discovered in psychiatric patients without hematologic or neurologic findings, a diagnosis of B12 deficiency should not be presumed without further evaluation. Key words: screening: psychiatric patients; vitamin B12.

Adolescent↗
PubMed1994

A genetic and molecular analysis of the 46C chromosomal region surrounding the FMRFamide neuropeptide gene in Drosophila melanogaster.

We have analyzed the FMRFamide neuropeptide gene region of Drosophila melanogaster. This gene maps to the 46C region of chromosome 2R; this interval previously was not well characterized. For this genetic and molecular analysis, we have used X-ray mutagenesis, EMS mutagenesis, and the recently reported local P element transposition method. We identified four overlapping deletions, two of which have proximal breakpoints that define a 50-60-kb region surrounding the FMRFamide gene in 46C. To this small region, we mapped three lethal complementation groups; 10 additional lethal complementation groups were mapped to more distal regions of 46CD. One of these groups corresponds to even-skipped, the other 12 are previously unidentified. Using various lines of evidence we excluded the possibility that FMRFamide corresponds to any of the three lethal complementation groups mapping to its immediate 50-60-kb vicinity. The positions of two of the three lethal complementation groups were identified with P elements using a local transposition scheme. The third lethal complementation group was excluded as being FMRFamide mutants by sequence analysis and by immunocytochemistry with proFMRFamide precursor-specific antibodies. This analysis has (1) provided a genetic map of the 46CD chromosomal region and a detailed molecular map of a portion of the 46C region and (2) provided additional evidence of the utility of local transposition for targeting nearby genes.

Animals↗
PubMed1994

On constructing the disorder of hysteria.

The concept of hysteria is traced from Hippocrates, where it was though to be caused by a wandering uterus, through Galen and up to Freud. Throughout the history of medicine from the early Greeks up to the end of the nineteenth century, the definition and diagnosis of hysteria had a function similar to that found in the persecution of witchcraft: it sought to eradicate the outbursts of nonconforming and emotionally threatening conduct of women. At the beginning of the twentieth century, however, the category virtually disappears from psychiatric nosologies.

Attitude to Health↗
PubMed1994

Dendritic cells persistently stimulate antibody responses to HIV in seropositive individuals.

OBJECTIVES: B-cell hyperactivity and hypergammaglobulinaemia with high levels of HIV-1-specific antibody occur during HIV-1 infection. We investigated the role played by antigen-presenting cells (APC) in the ongoing production of antibody. METHODS: Adherent monocytes and non-adherent low density dendritic cells were enriched from peripheral blood of patients at different stages of HIV-1 infection (Centers for Disease Control and Prevention categories II, III and IV) and from control subjects at high or low risk of HIV infection. Different concentrations of lymphocytes were cultured in 20 ml hanging drops in the presence or absence of autologous dendritic cells or monocytes. Antibodies to p24 and gp120 were assessed by enzyme-linked immunosorbent assay. RESULTS: Lymphocytes taken from asymptomatic HIV-1-seropositive subjects and depleted of APC produced low or moderate levels of antibody to gp120 or p24 in vitro. However, adding back autologous dendritic cells significantly enhanced antibody production, although fewer samples showed responses to p24 than to gp120. Less antibody production was stimulated using cells from patients with persistent generalized lymphadenopathy, or if monocytes rather than dendritic cells were added back. Little or no antibody was produced by cells from patients with AIDS and no antibody was detected in cultures of cells from seronegative individuals with low or high risk for infection. CONCLUSIONS: The evidence suggests that ongoing humoral responses to HIV-1 are fuelled by dendritic cells. Thus, the dominance of humoral over cell-mediated responses in HIV-1 infection may depend upon signalling via dendritic cells. Changes in signalling by dendritic cells could be central to the immunologic features of HIV-1 infection.

Antibody Formation↗
PubMed1994

Melphalan uptake, hyperthermic synergism and drug resistance in a human cell culture model for the isolated limb perfusion of melanoma.

Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines; (b) prolonging the treatment time beyond 1 h had little additional toxicity; and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines; pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan; (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours; and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.

Chemotherapy, Cancer, Regional Perfusion↗
PubMed1994

Bacillus mojavensis sp. nov., distinguishable from Bacillus subtilis by sexual isolation, divergence in DNA sequence, and differences in fatty acid composition.

A number of Bacillus strains isolated from desert soil samples were shown to belong to a previously unidentified species, for which we propose the name Bacillus mojavensis. The type strain is RO-H-1 (= NRRL B-14698). On the basis of restriction digest data, B. mojavensis is most closely related to Bacillus amyloliquefaciens, Bacillus atrophaeus, and Bacillus subtilis. So far, B. mojavensis can be distinguished from B. subtilis only by differences in whole-cell fatty acid composition, divergence in DNA sequence, and resistance to genetic transformation between taxa (in addition to reduced genome relatedness values). Sequence divergence and sexual isolation may prove to be more useful than metabolic characteristics for delimiting cryptic Bacillus species.

Bacillus↗