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Biomedical subjects

F M Williams

Publications and source records attributed to F M Williams.

At least 19 recordsLinked to original sources
PubMed2005

Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required.

Clinical Laboratory Techniques↗
PubMed2004

In vitro predictions of skin absorption of caffeine, testosterone, and benzoic acid: a multi-centre comparison study.

To obtain better insight into the robustness of in vitro percutaneous absorption methodology, the intra- and inter-laboratory variation in this type of study was investigated in 10 European laboratories. To this purpose, the in vitro absorption of three compounds through human skin (9 laboratories) and rat skin (1 laboratory) was determined. The test materials were benzoic acid, caffeine, and testosterone, representing a range of different physico-chemical properties. All laboratories performed their studies according to a detailed protocol in which all experimental details were described and each laboratory performed at least three independent experiments for each test chemical. All laboratories assigned the absorption of benzoic acid through human skin, the highest ranking of the three compounds (overall mean flux of 16.54+/-11.87 microg/cm(2)/h). The absorption of caffeine and testosterone through human skin was similar, having overall mean maximum absorption rates of 2.24+/-1.43 microg/cm(2)/h and 1.63+/-1.94 microg/cm(2)/h, respectively. In 7 out of 9 laboratories, the maximum absorption rates of caffeine were ranked higher than testosterone. No differences were observed between the mean absorption through human skin and the one rat study for benzoic acid and testosterone. For caffeine the maximum absorption rate and the total penetration through rat skin were clearly higher than the mean value for human skin. When evaluating all data, it appeared that no consistent relation existed between the diffusion cell type and the absorption of the test compounds. Skin thickness only slightly influenced the absorption of benzoic acid and caffeine. In contrast, the maximum absorption rate of testosterone was clearly higher in the laboratories using thin, dermatomed skin membranes. Testosterone is the most lipophilic compound and showed also a higher presence in the skin membrane after 24 h than the two other compounds. The results of this study indicate that the in vitro methodology for assessing skin absorption is relatively robust. A major effort was made to standardize the study performance, but, unlike in a formal validation study, not all variables were controlled. The variation observed may be largely attributed to human variability in dermal absorption and the skin source. For the most lipophilic compound, testosterone, skin thickness proved to be a critical variable.

Adolescent↗
PubMed2001

Peripheral cholinesterase inhibition by occupational chlorpyrifos exposure in Australian termiticide applicators.

Occupational exposure to organophosphorus insecticides (OPs), such as chlorpyrifos, may be monitored by the measurement of the activity of peripheral cholinesterase (ChE) enzymes, including erythrocyte acetylcholinesterase (EAChE) and serum cholinesterase (SChE). Lymphocyte neuropathy target esterase (NTE) is thought to have potential as a predictor of organophosphate-induced delayed neuropathy (OPIDN). This paper describes work performed in 39 Australian pest control operators (PCOs) exposed to a termiticide containing chlorpyrifos, and 34 unexposed control subjects. EAChE activities in PCOs did not differ from those of unexposed control workers. Mean NTE activity was slightly higher in PCOs than in controls and mean SChE was 52% of control activity. These results indicate that exposure of Australian PCOs to termiticides containing chlorpyrifos may be monitored using SChE but not EAChE or NTE, and that workers in this industry have sufficiently high OP exposure to significantly depress SChE activity. SChE inhibition of 70-80% may be associated with symptoms. Although no current symptoms were reported to be associated with occupational OP exposure, these workers may be at increased risk of acute effects following inadvertent spills or self-contamination due to their background level of exposure to OPs. While it is preferable to compare ChE enzyme activities between pre- and post-exposure periods to evaluate OP-related effects in individuals, in some cases there is an absence of pre-exposure data. The results of this study suggest that a screening value for SChE of 550 nmol/min/ml in a single blood sample may be useful to identify potentially OP-exposed individuals in the Australian population. Australian control subjects were similar with respect to EAChE, but displayed activities of NTE and SChE approximately 50 and 23% lower than an unexposed UK reference group. While these comparisons are presently speculative, they suggest that there may be differences in SChE and NTE activities in control populations of the two countries. The routine treatment of Australian homes with termiticides containing OPs, or differences in the availability and use of domestic OP-containing insecticides may explain these population differences. Further work is required to examine whether these differences are real, and if so their likely cause.

Australia↗
PubMed2000

Cytogenetic response without changes in peripheral cholinesterase enzymes following exposure to a sheep dip containing diazinon in vivo and in vitro.

Occupational exposure to organophosphorus insecticides (OPs), such as diazinon, may be monitored by the measurement of the activity of peripheral cholinesterase enzymes, including erythrocyte acetylcholinesterase (EAChE) and plasma or serum cholinesterase (plasma or serum ChE). Exposures have also been measured by the analysis of dialkyl phosphate metabolites of OPs in urine. The potential health risks associated with exposure, especially those of a neurological nature, may then be estimated, and appropriate measures to reduce or eliminate exposures can be implemented. There is evidence that some OP pesticides may have in vivo genotoxic effects, suggesting a possible link with cancer with long term or repeated heavy exposures. This paper describes work performed in 17 subjects with a single or two exposures to a sheep dip containing diazinon. Urine samples revealed OP metabolites dimethylphosphate (DMP), dimethylthiophosphate (DMTP), diethylphosphate (DEP) and diethylthiophosphate (DETP) in 37% of subjects at low levels which were not elevated after exposure. EAChE and plasma ChE were also unchanged before and after exposure, and were similar to those measured in unexposed control groups. Sister chromatid exchanges (SCE), a marker of chromosome damage, was significantly elevated in peripheral blood lymphocytes after exposure compared with before. SCE were unchanged in a group of non-occupationally exposed workers. In vitro studies with both authentic diazinon (98%) and diazinon in a sheep dip formulation (45%) showed increased SCE and decreased replicative indices, suggesting toxic and genotoxic effects of diazinon.

Acetylcholinesterase↗
PubMed2000

Electrophysiological and biochemical effects of single and multiple doses of the organophosphate diazinon in the mouse.

Diazinon is an organophosphorus compound (OP) widely used in pesticides. The relationship between dose of diazinon, inhibition of acetylcholinesterase, and effect on neuromuscular transmission has been studied in a mouse model. Inhibition of acetylcholinesterase activity occurred within 1 h, was maximal by 3 h and remained inhibited for at least 24 h. Blood, brain, diaphragm, and soleus acetylcholinesterase activities were differentially affected by diazinon. Brain and soleus activities were not affected by low doses. Multiple daily dosing of diazinon caused a cumulative decrease in acetylcholinesterase activity, although to a lesser extent in brain and soleus. Diazinon had no effect on the activity of neuropathy target esterase. Plasma and brain levels of diazinon peaked at 15 min after dosing and declined with a half-life of 2.5 h. Metabolic products of diazinon were cleared from the urine within 24 h. Increased miniature end-plate current half decay times occurred in a dose-dependent manner. Single doses of diazinon caused an increase in the jitter (variability of latencies) of evoked action potentials recorded in the diaphragm but did not affect end-plate potential (EPP) jitter. Multiple lower doses of diazinon caused an increase in EPP jitter after 28 days. This effect on nerve function was delayed and occurred when acetylcholinesterase activity had returned to control levels. The results indicate that diazinon produces long-term electrophysiological changes in neurotransmission following repeated dosing in the mouse. This has implications for the current use of diazinon; however, there is a need to further define the mechanism of this effect.

Acetylcholinesterase↗
PubMed2000

Mutations in the reduced-folate carrier affect protein localization and stability.

The reduced-folate-carrier (rfc) gene has been shown to be functionally important for reduced-folate transport in mammalian cells. In the present paper we describe the identification of alterations in both alleles of the rfc gene in a mutant Chinese-hamster ovary cell line deficient in methotrexate transport. One allele of the rfc gene contains a point mutation resulting in a Gly(345)-->Arg substitution in the predicted amino acid sequence. In this case, a protein of similar size to the wild-type protein is produced, although it remains as an immature, core-glycosylated, form. The second allele contains a point mutation in the last base of intron 5 that results in the utilization of a cryptic splice site leading to a seven-base deletion in the mRNA. The use of an alternate splice site changes the reading frame to yield a truncated protein with 68 different C-terminal amino acids as compared with the wild-type. Both of these altered gene products were monitored by fusion with green fluorescent protein and found to be non-functional with an increased rate of turnover. The protein with the point mutation is trapped in the endoplasmic reticulum with subsequent degradation, whereas the product of the splice mutation is not membrane-associated and is partially degraded. Thus mutations in both alleles of the rfc gene in this resistant cell line account for the loss of reduced-folate transport. The observations made regarding the degradation of these mutant gene products also provide support for putative checkpoints in the endoplasmic reticulum.

Alleles↗
PubMed2000

Percutaneous absorption and metabolism of dinitrochlorobenzene in vitro.

Dinitrochlorobenzene (DNCB) absorption through mouse and rat dorsal skin, pig ear skin and human abdominal skin in vitro was determined, and local metabolism to the glutathione conjugate was related to glutathione transferase activities and glutathione status in the skin. Absorption studies were conducted using skin mounted in a flow-through diffusion cell with tissue culture medium as receptor fluid. DNCB applied to the surface of skin in acetone penetrated through 26-day-old rat skin better than through the skin of the other species investigated. The amounts of absorption through pig and human skin and conjugation formation were similar. In general, occlusion resulted in increased penetration of DNCB but no change in conjugation. Human skin showed the highest gluta-thione-S-transferase activity towards DNCB, followed by 26-day-old rat, pig, mouse and neonatal rat skin. Levels of glutathione were highest in mouse skin, followed by neonatal rat, 26-day-old rat, pig and human skin, with pig and human skin showing similar levels. These studies indicated that the glutathione level in skin was the determining factor influencing the degree of DNCB conjugation during percutaneous absorption, and this was greatly depleted during percutaneous penetration of DNCB.

Administration, Cutaneous↗
PubMed2000

Percutaneous penetration and dermal metabolism of triclosan (2,4, 4'-trichloro-2'-hydroxydiphenyl ether).

triclosan is widely used in many products that contact the skin of consumers. This study compares in vivo and in vitro skin absorption of triclosan and determines the potential of skin to metobolize it prior to entering the blood stream. After in vivo topical application of a 64.5mM alcoholic solution of [(3)H]triclosan to rat skin, 12% radioactivity was recovered in the faeces, 8% in the carcass 1% in the urine, 30% in the stratum corneum and 26% was rinsed from the skin surface at 24 hours after application. Free triclosan and the glucuronide and sulfate conjugates of triclosan were found in urine and faeces. triclosan penetrated rat skin more rapidly and extensively than human skin in vitro. 23% of the dose had penetrated completely through rat skin into the receptor fluid by 24 hours, whereas penetration through human skin was only 6.3% of the dose. Chromatographic analysis of the receptor solutions showed that triclosan was metabolized to the glucuronide, and to a lesser extent to the sulfate, during passage through the skin. triclosan glucuronide appeared rapidly in the receptor fluid whereas triclosan sulfate remained in the skin. Although the major site of metabolism was the liver, conjugation of triclosan in skin was also demonstrated in vitro and in vivo, particularly to the glucuronide conjugate which was more readily removed from the skin. The in vitro system provides a reasonable estimate of dermal absorption in vivo for the rat. Therefore by extrapolation of the comparative in vitro data for human and rat skin it is reasonable to deduce that dermal absorption in human of triclosan applied at the same dose is about one-third of that in the rat in vivo.

Administration, Cutaneous↗
PubMed2000

Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I).

Infection with human T-cell lymphotrophic virus-I (HTLV-I) is now a global epidemic, affecting 10 million to 20 million people. This virus has been linked to life-threatening, incurable diseases: adult T-cell leukemia/lymphoma (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The cumulative lifetime risk of developing these incurable diseases is approximately 5% in asymptomatic patients. For the emergency physician practicing among patients from high-risk groups, HTLV-I and its associated diseases are presenting an increasing challenge. This report describes its transmission, seroprevalence, treatment, and methods of controlling spread of this retrovirus. Coinfection with HTLV-I and HIV has been shown to accelerate the progression of acquired immune deficiency syndrome (AIDS).

Disease Outbreaks↗
PubMed2000

Systemic endothelial cell markers in primary antiphospholipid syndrome.

The pathogenic mechanism underlying the prothrombotic tendency of Hughes' or antiphospholipid syndrome (APS) has not been elucidated. Numerous procoagulant mechanisms have been tested including platelet activation, monocyte tissue factor (TF) expression and endothelial cell (EC) activation. There is some evidence for the latter from studies on cultured human umbilical vein endothelial cells (HUVEC). Incubation with antiphospholipid antibodies (aPL) induces EC activation in vitro. We investigated whether there was evidence of EC perturbation in vivo using enzyme-linked immunosorbant assays (ELISAs) for soluble markers of EC dysfunction. Serum and plasma were collected from controls and patients with primary APS and ELISAs performed to quantify soluble vascular cell adhesion molecule (sVCAM), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), endothelin-1 (ET-1), von Willebrand factor (vWF) and soluble tissue factor (sTF). In addition, soluble p-selectin (p-selectin) and vascular endothelial growth factor (VEGF) were measured: the former as a marker of platelet activation, the latter as a potential mediator of TF expression. No significant differences in the levels of blood-borne soluble markers were detected between the patient and control groups except for VEGF and sTF, patients having significantly higher levels of VEGF and sTF than controls (p <0.05). These results suggest plasma soluble tissue factor and VEGF may play a role in the pathogenesis of thrombosis in APS, although the cell of origin of these molecules remains unclear.

Adult↗
PubMed1999

The role of metabolism in determining susceptibility to parathion toxicity in man.

Human liver microsomes (n = 16) activated parathion (O, O, diethyl O-p-nitrophenyl phosphorothioate, 20 and 200 microM) to paraoxon at a rate of 23.3-199.3 and 18.7-310.3 pmol/min per mg protein, respectively. p-Nitrophenol, was also formed, at 321.1-769.2 and 406.2-778.3 pmol/min per mg protein. This represented a 16-fold and 2-fold range in capacity to activate and detoxify parathion, respectively. Parathion was activated with an apparent Km of 9-16 microM (n = 3). The activation of parathion (200 microM) was positively correlated with nifedipine oxidation, indicating the involvement of CYP3A. Correlations were not significant with ethoxyresorufin-O-dealkylation (CYP1A1/2), pentoxyresorufin-O-dealkylation (CYP2B6), p-nitrophenol hydroxylation (CYP2E1), paraoxon hydrolysis (A-esterase) or phenylvalerate hydrolysis (B-esterase). Paraoxon formation from parathion was markedly reduced by CYP3A inhibitors. Experiments with EDTA indicated that A-esterase was not functionally important at low levels of paraoxon. Human P450s 3A4 and 3A5 expressed microsomes were the most efficient at biotransforming parathion to paraoxon, although P450s 1A1, 2B6 and 2C8 also catalysed the reaction. This study has determined wide interindividual variations in capacity to metabolise parathion, mainly by CYP3A, which may influence its manifest toxicity.

Cytochrome P-450 Enzyme System↗
PubMed1999

Biomechanical performance of orthopedic gloves.

The purpose of this study was to compare the biomechanical performance of commercially available orthopedic gloves to that of a single surgical glove, as well as a double glove system. The orthopedic gloves were found to be thicker than the single surgical glove. This increased thickness of the orthopedic glove was associated with a greater resistance to glove puncture. The thickest orthopedic gloves also had reduced tactile sensitivity when compared to the single surgical glove. In addition, the glove donning forces and glove hydration rates varied considerably. These latter biomechanical performance parameters were not significantly related to glove thickness. The double glove systems tested in this study had similar performance characteristics in regard to many of the orthopedic gloves. The glove donning forces for the double glove systems were the lowest of the gloves tested. In addition, the double glove systems displayed the greatest resistance to glove hydration of the gloves tested. Their performance in the glove hydration tests and the force required to don the double glove systems were much more desirable than any of the orthopedic gloves. The results of this study indicate that the double glove systems may provide a desirable alternative to the use of the single orthopedic gloves.

Biocompatible Materials↗
PubMed1999

Failure of a new double glove hole detection system in the Emergency Department.

The purpose of this study was to evaluate the performance of a new double glove hole detection system in the Emergency Department. First, the frequency of holes in both gloves of the double glove hole detection system was determined using a watertight test method. Second, the frequency of glove puncture was determined first by searching for the optical color change that occurs with the ingress of fluid in the double glove hole detection system. These same gloves were then removed and also checked for holes by the watertight test method. After removal from the package, no holes were detected in the two gloves of the system using the watertight test method. In 50 consecutive patients, there was no color change in the inner glove indicating glove puncture. When these same gloves were then tested with the watertight test method, 14 of the 50 double glove hole detection systems failed; all 14 outer gloves were punctured, and three of the inner gloves had holes without demonstrable injury to the skin. This double glove hole detection system is not a reliable system to detect holes in relatively dry clinical settings because the ingress of fluid by capillary action between the gloves is necessary to cause a color change in the inner glove that signals the presence of a hole.

Arthroplasty↗
PubMed1999

Biomechanical performance of examination gloves.

The purpose of this study was to compare the biomechanical performance of new powder-free commercially available synthetic examination gloves to that of commercially available powder-free latex examination gloves. The synthetic gloves were significantly thinner than the latex gloves. Despite the decreased thickness, all three nitrile gloves, as well as the polyvinyl chloride glove, exhibited a greater resistance to glove puncture. The glove donning forces varied considerably among all gloves, and wet donning forces were greater than dry donning forces. Under dry conditions, the donning forces for the synthetic gloves were less than or equal to the forces for the latex gloves. Because of their increased puncture resistance and similar donning forces, synthetic gloves are a safe alternative to latex examination gloves.

Biomechanical Phenomena↗
PubMed1999

Integrity of powder-free examination gloves to bacteriophage penetration.

The purpose of this study was to compare the resistance to viral penetration of powder-free synthetic examination gloves with powder-free latex examination gloves commonly used in hospitals. Because these gloves had no holes, this study examined viral penetration through a membrane. Using a standard bacteriophage penetration model, no bacteriophage penetration was detected through the membrane for any of the gloves tested. The new powder-free nitrile and polyvinyl chloride synthetic examination gloves provided comparable resistance to viral penetration as did the powder-free latex examination gloves.

Bacteria↗
PubMed1999

Biomechanical performance of latex and non-latex double-glove systems.

The purpose of this study was to evaluate ten commercially available latex, powder-free surgical gloves and four commercially available non-latex, powder-free surgical gloves using standardized, reproducible biomechanical parameters that included glove thickness, puncture resistance, and glove donning force. For all gloves tested, with one exception (Neolontrade mark PF), puncture resistance increased for double-gloves as compared to single-gloves. In addition, single-glove thickness was not a reliable determinant of puncture resistance for either latex or non-latex gloves. For the latex gloves, the Ultrafree double and single-gloves exhibited the highest puncture resistance. The glove donning forces for the Biogeltrade mark M and Biogel Sensortrade mark single-gloves were the lowest. In contrast, the Biogel Revealtrade mark and Encoretrade mark Ultra-Thick exhibited the lowest double-glove donning forces. On the basis of these performance tests of latex gloves, the surgeon should consider the Biogel Reveal as well as the Ultrafree gloves for their latex double-glove system. For the non-latex gloves, the Pure Advantage Nitriletrade mark glove had the highest puncture resistance for one layer and two layers of glove material. The thin Pure Advantage Nitrile glove was the most resistant to glove puncture. The Pure Advantage Nitrile glove had low glove donning forces for both single-glove donning configurations and double-glove donning configurations. Consequently, we recommend the Pure Advantage Nitrile glove as the powder-free, non-latex, double-glove system.

Biomechanical Phenomena↗