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Biomedical subjects

M S Roberts

Publications and source records attributed to M S Roberts.

At least 145 records · Page 8Linked to original sources
PubMed1994

Disappearance kinetics of solutes from synovial fluid after intra-articular injection.

1. Five rheumatoid patients with a knee joint effusion participated in the study. An aqueous solution (0.1 to 0.2 ml) containing paracetamol, salicylate, diclofenac and [125I]-albumin was injected into a given joint to yield target concentrations of approximately 20 micrograms ml-1 for diclofenac, salicylate and paracetamol and 10(8) counts ml-1 for [125I]-albumin. 2. Paracetamol, salicylate and diclofenac were analysed in synovial fluid by h.p.l.c. [125I]-albumin was analysed using gamma counting. 3. The clearances (+/- s.d.) obtained for the solutes were [125I]-albumin (0.0053 +/- 0.0019 l h-1), diclofenac (0.0096 +/- 0.0061 l h-1), salicylate (0.024 +/- 0.022 l h-1) and paracetamol (0.055 +/- 0.041 l h-1). The corresponding fractions unbound of these solutes in synovial fluid were 0.0, < or = 0.01, 0.34 +/- 0.09 and 0.85 +/- 0.10, respectively. 4. Diffusion of unbound solute through the synovium is estimated to account for (+/- s.d.) 0.52 +/- 0.08, 0.87 +/- 0.06 and 0.99 +/- 0.01 of the total clearance of diclofenac, salicylate and paracetamol from the joint space, respectively. The remaining proportion of clearance is accounted for by efflux of solute bound to albumin. 5. An expression for the ratio of synovial fluid to total plasma concentrations after systemic administration was developed to include both diffusion of unbound solute and albumin flux. Most solutes appear to satisfy the conditions in which this expression reduces to the limiting case where the unbound concentration of the solute is identical in the synovial fluid and plasma under steady state conditions.

Acetaminophen↗
PubMed1994

Deep tissue penetration of bases and steroids after dermal application in rat.

The local deep tissue penetration of bases such as diazepam, antipyrine, iodoantipyrine, haloperidol and steroids such as hydrocortisone, fluocinolone acetonide, testosterone and progesterone after dermal application as aqueous solutions was studied in a rat model. The extent of local, as distinct from systemic delivery, for each solute was assessed by comparing the tissue concentrations obtained below a treated site with those in contralateral tissues. Local direct penetration was evident for all solutes below the applied site, although depth of penetration varied between individual solutes. A physiological pharmacokinetic model was employed to estimate local tissue concentrations of various compounds after dermal application.

Administration, Cutaneous↗
PubMed1994

Effect of perfusion flow rate on the tissue uptake of solutes after dermal application using the rat isolated perfused hindlimb preparation.

The rat perfused hindlimb preparation was investigated as a model to study the dermal clearance and tissue distribution of three solutes with differing physicochemical properties ([3H]water, [3H]diazepam, and [14C]lignocaine). The dermal clearance of each solute increased and the depth of tissue preparation decreased with increasing perfusion flow rate. The half-life for solute efflux from tissues into perfusate, and the peak times for amount of solute in tissue were in the order water > lignocaine > diazepam. Topical iontophoresis, which has previously been shown to achieve similar clearances from topical sites to those seen following passive dermal application, resulted in a clearance of lignocaine in the perfused hindlimb comparable with that obtained in the preparation following passive absorption through exposed dermis. The distribution of capillary blood flow in the perfused hindlimb was quantified using 51Cr-labelled 15-microns microspheres, with greater increases in flow found in deeper muscle tissues with increasing perfusion flow rate compared with superficial layers. Microsphere studies in anaesthetized rats also demonstrate slight differences in the distribution of flow within the hindlimb compared with the perfused preparation. We conclude that the rat perfused hindlimb preparation successfully combines many of the advantages of in-vitro and in-vivo methods and has potential for routine use in the study of solute dermal absorption kinetics.

Animals↗
PubMed1994

Lunar phases and psychiatric hospital admissions.

To assess the lunar hypothesis as predictive of mental health emergencies and antisocial behavior, the relation of the lunar hypothesis and the occurrence of psychiatric hospital admissions of developmentally disabled adults was examined. The full moon phase of the lunar cycle did not explain a higher rate of hospital admission and accounted for only .007% of the variance. A critique of the methodology in prior research led to the suggestion that more immediate stressors and environmental factors are more plausible contributing factors to hospital admission.

Adolescent↗
PubMed1994

Toward a peer review process for medical decision analysis models.

This paper presents a framework for a peer review process for medical decision analysis models. This framework is based on the collective experience of the members of the Inter-PORT Decision Modeling work group, a team of decision analysis experts comprising members from each of the Patient Outcomes Research Teams (PORTs), sponsored by the Agency for Health Care Policy and Research. Important general principles of correct model structure include choice of model type, perspective of the analysis, choice of utility scheme and identification of strategies that should be included and events that should be modeled. In addition, a set of rules for correct decision model structure may help to identify common errors. Although not necessarily exhaustive, this scheme provides an approach by which a reviewer may judge the adequacy of a decision model presented for publication or as the basis for a health policy.

Decision Support Techniques↗
PubMed1994

Risk factors for invasive fungal infections complicating orthotopic liver transplantation.

Risk factors for invasive fungal infection in patients undergoing orthotopic liver transplantation were examined. Thirty-four of 168 transplants were complicated within 100 days after transplantation by documented invasive fungal infection (Candida species, 28 patients; mycelial fungi, 5; both Candida and Aspergillus species, 1). In the multivariate Cox proportional hazards model, three baseline and two posttransplant variables were independently significant risk factors for infection: level of creatinine (hazard ratio = 1.4), length of transplant operation (HR = 1.2), retransplantation (HR = 3.2), abdominal or intrathoracic reoperations (HR = 2.5), and cytomegalovirus infection (HR = 8.5). Four predictors (creatinine of > 3.0 mg/dL, operative time of > or = 11 h, retransplantation, and early colonization) assessable at the time of transplantation or shortly thereafter were incorporated into a simple predictive model for risk stratification. The risk of invasive fungal infection ranged from 1% in patients with no predictors to 67% in patients with two or more predictors. Strategies to prevent invasive fungal infections after liver transplantation should be targeted to these high-risk groups.

Adrenal Cortex Hormones↗
PubMed1994

Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are being administered increasingly by transdermal drug delivery for the treatment of local muscle inflammation. The human epidermal permeabilities of different NSAIDs (salicylic acid, diethylamine salicylate, indomethacin, naproxen, diclofenac and piroxicam) from aqueous solutions is dependent on the drug's lipophilicity. A parabolic relationship was observed when the logarithms of NSAID permeability coefficients were plotted against the logarithms of NSAID octanol-water partition coefficients (log P), the optimum log P being around 3. The local tissue concentrations of these drugs after dermal application in aqueous solutions were then determined in a rat model. The extent of local, as distinct from systemic delivery, for each NSAID was assessed by comparing the tissue concentrations obtained below a treated site to those in contralateral tissues. Local direct penetration was evident for all NSAIDs up to a depth of about 3 to 4 mm below the applied site, with distribution to deeper tissues being mainly through the systemic blood supply. A comparison of the predicted tissue concentrations of each NSAID after its application to human epidermis was then made by a convolution of the epidermal and underlying tissue concentration-time profiles. The estimated tissue concentrations after epidermal application of NSAIDs could be related to their maximal fluxes across epidermis from an applied vehicle.

Administration, Topical↗
PubMed1993

A quantitative assessment of limited joint mobility in patients with diabetes. Goniometric analysis of upper extremity passive range of motion.

OBJECTIVE: The syndrome of limited joint mobility is a common but not widely recognized musculoskeletal complication of diabetes. The purpose of this study was to further characterize this syndrome using quantitative goniometric measures. METHODS: Cross-sectional analysis of a sample population was performed to establish the prevalence, location, and severity of limited joint mobility and to determine its relationship to extraarticular manifestations and complications of diabetes. Passive range of motion of both upper extremities was measured by goniometry in 70 adult patients with insulin-dependent diabetes mellitus and 70 nondiabetic controls who were group-matched for age, sex, and general activity level. Joint mobility was assessed by both individual joint motions and a composite scoring technique. RESULTS: Analysis of individual joints and composite scores revealed significant differences between dominant and nondominant extremities in both the control and the diabetic groups. Diabetic patients were generally less flexible than nondiabetic subjects throughout the arm, especially in shoulder and finger joints. In the full study population, multivariate analysis revealed that advanced age, male sex, and the presence of diabetes were associated with decreased passive range of motion for a majority of joints (P < 0.05). In the diabetes group, passive range of motion was significantly correlated (P < 0.05) with age, sex, duration of diabetes, and to a variable extent, glucose control, but was not correlated with the presence of clinically significant neuropathy, retinopathy, nephropathy, or peripheral vascular disease, with activity level, or with hand dominance. Stepwise regression analysis failed to identify single key joint motion(s) to serve as possible screening tests in predicting generalized limited joint mobility of the upper extremity. Finally, the effect of limb usage on range of motion in flexion may differ in diabetic and nondiabetic subjects. CONCLUSION: Limited joint mobility is a generalized phenomenon occurring throughout the upper extremities of many diabetic patients. It is significantly related to age, sex, and to a variable extent duration of diabetes and glucose control. It is not related to the standard complications of diabetes as defined in this study.

Adult↗
PubMed1993

Effects of murine leukemia viruses on the function of dendritic cells.

In asymptomatic human immunodeficiency virus-1 infection T cells respond normally to allogeneic dendritic cells (DC), but DC show reduced stimulatory capacity. By contrast in HTLV-1 infection no significant changes in allogeneic stimulation were seen but DC-stimulated activity of autologous T cells. In seeking animal models relevant to these diseases the effects of two murine leukemia retroviruses, Rauscher leukemia virus (RLV) and Moloney leukemia virus (MLV) on the function of dendritic cells and T cells in a primary mixed leucocyte reaction have been tested. Treatment by RLV in vitro suppressed the ability of DC to stimulate allogeneic T cells from healthy animals. MLV at the same concentration did not significantly affect the ability of DC to stimulate allogeneic T cells, but provoked considerable enhancement of the low level stimulation by DC in the syngeneic system. Similar results were obtained following in vivo exposure to viruses. Two pieces of evidence suggested that these effects were due to impairment of DC function and were not operating through infection of T cells. Firstly, exposure of T cells directly to virus in vitro and in vivo before stimulation with untreated allogeneic DC caused no significant alteration in T cell activity. Secondly, the impact of murine leukemia virus on DC function was not abrogated when infected DC were added to normal T cells and cultured in the presence of zidovudine. Treatment of DC by RLV caused a decrease of cluster formation with allogeneic T cells. No statistically significant influence of MLV was observed on cluster formation after 3-h of incubation in the allogeneic system. However, after 18-h incubation MLV-treated DC formed fewer clusters with T cells than untreated DC. At the same time a stimulatory effect of MLV on DC cluster formation with syngeneic T cells was found. Considerable decrease was found in major histocompatibility complex class II antigen and LFA-1 receptor expression on the DC surface in mice infected by RLV. MLV induced no significant changes. These mouse retroviruses can therefore cause changes in DC function similar to those already reported using human retroviruses and may provide models for studying their effects.

Animals↗
PubMed1993

Iontophoretic transdermal delivery of salicylic acid and lidocaine to local subcutaneous structures.

The depth of penetration of solutes into underlying tissues after transdermal iontophoresis has been evaluated with salicylic acid and lidocaine as model compounds. Concentrations of salicylic acid and lidocaine were measured in plasma and tissues below the donor electrode after iontophoresis in rats. The concentrations obtained were then compared with those obtained after passive delivery (without iontophoresis) of the drugs applied either to intact epidermis or to the exposed dermis (epidermis removed) of rats. Iontophoresis yielded high concentrations of lidocaine in each underlying tissue when compared with passive application to rat epidermis or dermis. Negligible concentrations of lidocaine in plasma were found for each mode of delivery. Similar concentrations of salicylic acid were found in each of the underlying tissues after delivery of salicylic acid either by iontophoresis through intact epidermis or after passive application to the exposed dermis. Negligible concentrations of salicylic acid in underlying tissues were obtained after passive application to intact epidermis. The plasma salicylic acid concentrations observed after both iontophoretic epidermal and passive dermal (epidermis removed) treatments were approximately the same as the tissue salicylic acid concentrations observed at approximately 3-4 mm below the application site. It is concluded that transdermal iontophoresis allows salicylic acid and lidocaine to be effectively delivered across the stratum corneum. Local direct deep tissue penetration of lidocaine is facilitated by iontophoresis. The concentrations of salicylic acid in deeper underlying tissues (> 3-4 mm) tend to be similar to the concentrations in plasma after either iontophoresis or passive dermal application, a result indicating that direct penetration of salicylic acid occurs only to a depth of 3-4 mm.

Administration, Cutaneous↗
PubMed1993

Blood flow measurements in skin and underlying tissues by microsphere method: application to dermal pharmacokinetics of polar nonelectrolytes.

Blood flow rates to skin and underlying tissues in rats were determined by the radioactive microsphere technique. The dermal and local tissue clearance of two polar solutes, tritiated water and 14C-labeled sucrose, was assessed in anesthetized and sacrificed rats. The dermal clearance of tritiated water in the presence of viable dermal blood supply (6.17 +/- 1.41 mL/min/100 g) was similar in magnitude but more variable than the blood flow to skin estimated by the microsphere technique (5.18 +/- 0.25 mL/min/100 g). The dermal clearance of sucrose (1.66 +/- 0.32 mL/min/100 g) was approximately one quarter the dermal clearance for water, the difference corresponding to the free diffusion coefficients of the two solutes. The permeability coefficients of tritiated water in various tissues were estimated by both a pseudo-steady-state mass balance approach and numerical integration of differential equations (for dermis only) with a "series compartmental" model, from the tissue concentrations obtained in sacrificed rats. The estimates from numerical integration were comparable to those obtained by mass balance, confirming the general structure of the model. The observed tissue concentrations of tritiated water and sucrose in the anesthetized animal compared well with values predicted from the model.

Anesthesia↗
PubMed1993

Dermal and underlying tissue pharmacokinetics of salicylic acid after topical application.

The time course of salicylic acid at a dermal application site and in local underlying tissues below the site in rats was examined using a physiologically based pharmacokinetic model assuming first-order diffusional mass transfer between the dermis and underlying tissues. The concentrations of salicylic acid 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 salicylic acid was dominant only to a depth of 3-4 mm below the applied site for the first approximately 2 hr after application. The time course of salicylic acid in individual rats was modeled using known tissue blood flows and tissue-tissue clearances by (i) numerical integration and nonlinear regression of a series of differential equations representing events in individual tissues, and (ii) numerical integration and nonlinear regression of a single differential equation representation of the concentration-time course in an individual tissue with a polynomial representation of salicylate concentrations in other input tissues and an exponential representation of the input from the solution. Tissue-tissue clearances were deduced by both nonlinear regression and mass balance analysis (only for underlying dermis) using area-under-the-curves from salicylic acid tissue penetration data in anesthetized rats. The relative importance of direct penetration and blood supply in determining the concentrations of salicylic acid in deeper tissues was assessed by simulations in which either no direct penetration occurred or there was zero input from blood. Simulations confirm that direct penetration is only evident in the superficial tissues for approximately 2 hr. An attempt was also made to examine the dermal pharmacokinetics of salicylic acid using statistical moments.

Administration, Topical↗
PubMed1993

Physiological pharmacokinetics of solutes in the isolated perfused rat hindlimb: characterization of the physiology with changing perfusate flow, protein content, and temperature using statistical moment analysis.

Distribution of Evans Blue (EB), sucrose, and water into the isolated perfused rat hindlimb was studied under various conditions using the multiple indicator dilution (MID) technique. Statistical moment analysis of the outflow profiles for the EB, sucrose, and water were used to define the vascular, extravascular, and total water spaces, respectively. The varied perfusion conditions included albumin content (2, 4.7, and 7%), temperature (25, 37, and 42 C), perfusate flow rate (2, 4, 8, and 12 ml/min) and the presence/absence of red blood cells. The range of studies undertaken were chosen to represent the variety of conditions used in the preparation of both isolated animal and human limbs, the latter being particularly important in cytotoxic therapy for recurrent malignant melanoma. The distribution volumes of EB, sucrose, and water were dependent on the flow rate and the albumin content of perfusate. The normalized variances (CV2) of the markers were of the following order: sucrose (2.18) > water (1.58) > EB (0.68), indicating that some disequilibrium occurs during the capillary exchange of water and sucrose. It is suggested that a Krebs-Henseleit buffer containing 2% BSA is a suitable perfusate for most studies of the isolated rat hindlimb perfusion. The effect of albumin concentration manifests itself only at higher flows.

Animals↗
PubMed1993

Cell type-specific transcriptional regulation of the Drosophila FMRFamide neuropeptide gene.

We have used lacZ reporter gene constructs to study the promoter/enhancer regions of the Drosophila FMRFamide neuropeptide gene in germ line transformants. FMRFamide is normally expressed in approximately 60 diverse neurons of the larval CNS that represent approximately 15 distinct cell types. An 8 kb FMRFamide DNA fragment (including 5 kb of 5' upstream sequence) was sufficient to direct a pattern of lacZ expression that mimicked nearly all spatial aspects of the normal pattern. This result indicates that the cell-specific regulation of FMRFamide expression is largely generated by transcriptional mechanisms. Reporter gene expression was lost from selected cell types when smaller fragments were tested, suggesting that multiple control regions are included in the FMRFamide promoter. One region (a 300 bp fragment from -476 to -162) acted as an enhancer for 1 of the approximately 15 FMRFamide-positive cell types, the OL2 neurons. These results suggest that, in the mature nervous system, the complex pattern of FMRFamide neuropeptide gene expression derives from the activity of discrete, cell type-specific enhancers that are independently regulated.

Animals↗
PubMed1993

Pathway and kinetics of prednisolone metabolism in the human placenta.

Prednisolone is metabolized in the perfused human placental lobule to prednisone, 20 alpha-dihydroprednisone, 20 beta-dihydroprednisone and 20 beta-dihydroprednisolone. The pathway of metabolite formation was defined in perfusions of placental lobules using prednisone and 20 beta-dihydroprednisone separately as substrates and with prednisolone co-perfused with glycyrrhetinic acid, a potent inhibitor of the 11-oxidase component of the 11 beta-hydroxysteroid dehydrogenase enzyme system. The pattern of metabolites identified from 6 h samples indicated a reversible formation of prednisone from prednisolone, the production of the 20 alpha- and 20 beta-dihydro metabolites of prednisone from prednisone, the formation of 20 beta-dihydroprednisolone from 20 beta-dihydroprednisone only and no direct formation of 20 beta-dihydroprednisolone from prednisolone. Kinetic analysis at two substrate concentrations confirmed that the formation of three of the four steroid metabolites followed first order kinetics. In perfusions with an initial prednisolone concentration of 1 microgram/ml (n = 4) or 100 ng/ml (n = 3), the rate constants obtained were (mean +/- SD, maternal compartment, h-1): prednisone, 1.97 +/- 0.49 and 2.25 +/- 0.15, P > 0.1; 20 alpha-dihydroprednisone, 0.0006 +/- 0.0004 and 0.0017 +/- 0.0006, P < 0.1; 20 beta-dihydroprednisone, 0.15 +/- 0.022 and 0.15 +/- 0.0077, P > 0.1. In contrast, the rate constant for formation of 20 beta-dihydroprednisolone at an initial prednisolone concentration of 100 ng/ml (0.083 +/- 0.0095 h-1) was significantly (P < 0.01) greater than the corresponding rate constant at the higher initial prednisolone concentration (0.039 +/- 0.015 h-1). A significant increase (P < 0.05) was observed for the formation of 20 beta-dihydroprednisolone at the end of 6 h perfusions at the lower initial substrate concentration (11.2 +/- 1.9%) compared with the 1 microgram/ml concentration (6.0 +/- 2.5%).

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

The effect of DNA sequence divergence on sexual isolation in Bacillus.

We have investigated the relationship between sexual isolation and DNA sequence divergence in the transformation (at locus rpoB) of a naturally competent strain of Bacillus subtilis. Using both genomic DNA and a PCR-amplified segment of gene rpoB as donor, we found that the extent of sexual isolation at locus rpoB was closely predicted, over three orders of magnitude, as a log-linear function of sequence divergence at that locus. Because sexual isolation between a recipient and any potential donor may be determined as a general mathematical function of sequence divergence, transformation is perhaps the only sexual system, in either the prokaryotic or the eukaryotic world, in which sexual isolation can be predicted for a pair of species without having to perform the cross. These observations suggest the possibility of a general approach to the indirect prediction of sexual isolation in bacteria recombining principally by natural transformation.

Bacillus↗