Biomedical subjects
M L Williams
Publications and source records attributed to M L Williams.
Analysis of a petrol plume over England: 18-19 January 1997.
OBJECTIVES: About 7000 tonnes of unleaded petrol were discharged into the English Channel after a tanker collision off Ostend on Saturday 18 January 1997. The petrol evaporated and the vapour plume was carried across the central part of England to Wales, resulting in reports of unidentified odours, and irritation of the eyes, skin, and upper respiratory tract. This work uses this incident to show how marine and atmospheric dispersion modelling together with routine air quality monitoring can assist in identifying hazards to the population at risk from chemical incidents. METHODS: Public health surveillance and results from environmental sampling were compared with the behaviour of the plume as predicted by computer modelling. RESULTS: The predicted plume path and dispersion were shown to correlate well with the results from surveillance and environmental analysis. CONCLUSIONS: There is a need for public health professionals to interact with medical toxicologists, atmospheric and marine scientists and engineers, and other environmental experts in managing events of this nature.
Auditory recall and response to command during recovery from propofol anaesthesia.
Most studies of awareness under general anaesthesia use the ability to respond to a verbal command as the primary measure of consciousness. The aim of this pilot study was to discover whether it was possible for subjects recovering from a propofol general anaesthetic to experience conscious awareness without the capability of responding to verbal command. Ten healthy volunteers received an intravenous propofol infusion (1500 mg/hr) until they were no longer conscious. The infusion was then stopped and they were given verbal commands interspersed with random numbers from a recorded tape until they were able to respond appropriately. Seven of the subjects were able to remember numbers corresponding to times 10 to 40 seconds before they responded to verbal command. In none of these subjects was there recall of the number 30 minutes later. We concluded that there is an ability to have conscious awareness of auditory input without necessarily being able to demonstrate this by responding to verbal command.
Drug use, AIDS knowledge, and HIV risk behaviors of Cuban-, Mexican-, and Puerto-Rican-born drug injectors who are recent entrants into the United States.
To date, relatively little research attention has been devoted to the HIV-risky behaviors of persons who are newly arrived in the United States and who use drugs. Data gathered from street-recruited injection drug users (IDUs) recruited in 10 United States cities who were born in Mexico, Cuba, and Puerto Rico and who are recent entrants into the United States suggest that, in comparison to US-born IDUs, Mexican-born subjects are at elevated risk for acquiring and transmitting HIV as a result of sharing needles with friends and running partners; sharing drug injection implements such as cookers, cotton, and rinse water; frequent injection in HIV-risky settings; use of unsterilized needles; and relatively frequent trading of sex for drugs or money. Puerto-Rican-born IDUs were found to inject drugs relatively frequently, and to do so relatively often in high-risk settings in which sterile injecting equipment and cleaning materials often are scarce. These data also show generally lower levels of AIDS knowledge among the in-migrant IDUs than among US-born IDUs. Respondents from each nationality group most often cited television as the source of their most useful and reliable AIDS information, but also tended to regard community outreach workers as a significant source of reliable AIDS and needle cleaning information. The high levels of involvement in HIV-risky behaviors, deficits in knowledge concerning the means of HIV transmission, and relative ease of mobility of the at-risk (for HIV) individuals examined here indicate a need for a comprehensive public health prevention initiative to limit the future spread of HIV. At a minimum, such an undertaking would do well to incorporate group-specific, culturally appropriate behavioral interventions as well as an information campaign.
Hair shaft defects visualized after detergent extraction.
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Cyclophosphamide versus ifosfamide: to use ifosfamide or not to use, that is the three-dimensional question.
Ifosfamide and cyclophosphamide are alkylating agents that are extensively used in the clinical treatment of cancer. However, the continued use of ifosfamide has been questioned with the suggestion that cyclophosphamide be used exclusively. One response to this proposal is based upon the fact that both cyclophosphamide and isfosfamide are chiral and are administered as racemic (50:50) mixtures of the two isomers. Studies of the clinical pharmacology, metabolism and disposition of these agents indicate that stereochemistry plays a minor role in the efficacy and toxicity of cyclophosphamide but is a major factor in neurotoxicity associated with ifosfamide administration. Studies have demonstrated that the use of a single ifosfamide enantiomer, (R)-ifosfamide would retain the unique antitumor efficacy of this agent, while eliminating the major source of the observed ifosfamide-associated neurotoxicity, (S)-ifosfamide.
Barrier function of neonatal skin.
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Transglutaminase 1 expression in a patient with features of harlequin ichthyosis: case report.
Harlequin ichthyosis (HI) is a life-threatening disorder characterized clinically by massive generalized hyperkeratosis and ultrastructurally by an absence of lamellar bodies. However, infants who survive the perinatal period develop a phenotype resembling the nonbullous ichthyosiform erythrodermic (CIE) form of autosomal recessive ichthyosis. We studied a child with a severe hyperkeratotic skin disorder present at birth that developed into a CIE-like phenotype. Electron microscopy demonstrated an absence of lamellar bodies consistent with HI. Abnormalities of filaggrin and involucrin expression by immunostaining were evident. However, transglutaminase 1 (TGase1) was expressed in the epidermis in a pattern consistent with other diseases that involve epidermal acanthosis. Analysis of patient keratinocytes grown in vitro demonstrated expression of normal amounts of TGase1 mRNA and full length TGase1 protein, as well as normal levels of transglutaminase enzymatic activity.
Ontogeny of the epidermal permeability barrier.
A competent permeability barrier must be present by the end of gestation to allow for life in a terrestrial environment. Indeed, early preterm infants display serious complications of skin immaturity. Yet, regardless of their degree of prematurity, all infants quickly develop a competent barrier. To learn more about the mechanisms and regulation of barrier ontogeny, we have utilized late-gestation fetal rodents. In 19-21 d fetal rats, we showed that barrier competence is accompanied by both enhanced epidermal development and formation of extracellular lamellar membranes in the stratum corneum. The identical sequence and time-course occurs when fetal rat skin is cultured in a serum-free medium. Glucocorticoids, thyroid hormone (T3), and estrogen accelerate, while androgens delay barrier formation both in utero and in the in vitro system, explaining the poorer outcome of premature males versus females. But neither T3 nor glucocorticoids are absolutely required for barrier development. Lifting fetal skin cultures to an air-medium interface also accelerates barrier formation, explaining the rapid emergence of barrier competence in very premature infants. PPARalpha and FXR activators, which, like T3, heterodimerize with the nuclear receptor, RXR, also accelerate barrier development in vitro. Finally, not only the nuclear receptor family, but also Ca++ could regulate key events late in barrier development.
Abnormal transglutaminase 1 expression pattern in a subset of patients with erythrodermic autosomal recessive ichthyosis.
An autosomal recessive ichthyosis characterized by collodian membrane at birth followed by generalized skin redness and fine, light-colored scales has been termed nonbullous congenital ichthyosiform erythroderma (CIE). CIE has often been classified together with the other major form of recessive ichthyosis without internal organ involvement, lamellar ichthyosis, which is characterized by minimal erythema and a coarser, darker scale pattern. Recently, autosomal recessive ichthyosis has been associated with keratinocyte transglutaminase (TGase1) defects in some patients. This group of diseases, however, is genetically heterogeneous and TGase1 abnormalities in CIE have not been clearly described. Therefore we examined TGase1 expression in five patients with CIE and three with classic lamellar ichthyosis. Although lamellar ichthyosis patients displayed no TGase1 expression, an abnormal intracellular accumulation of TGase1 was observed in four of five CIE patients. This finding was specific and was not observed in other skin disorders characterized by erythema and abnormal cornification, including erythrodermic psoriasis, atopic dermatitis, epidermolytic hyperkeratosis, and Netherton's syndrome. CIE keratinocytes with abnormal TGase1 localization expressed full-length TGase1 mRNA and protein but demonstrated transglutaminase activity intermediate between normal and the minimal activity seen in lamellar ichthyosis patient cells. The abnormal TGase1 expression pattern and CIE clinical features were recapitulated in epidermis regenerated in vivo on immune deficient mice from CIE patient keratinocytes. These studies describe a specific abnormality in TGase1 intrinsic to keratinocytes in a subset of CIE patients and suggest that this abnormality may be involved in the disordered epidermal differentiation seen in this disorder.
Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha.
Peroxisome proliferator activated receptors (PPAR) belong to the superfamily of nuclear hormone receptors that heterodimerize with the retinoid X receptor and regulate transcription of several genes involved in lipid metabolism and adipocyte differentiation. Because of the role of 1,25-dihydroxyvitamin D3 and retinoic acid working through similar receptors (the vitamin D receptor and retinoic acid receptor, respectively) on keratinocyte differentiation, we have examined the effects of activators of PPARalpha on keratinocyte differentiation. The rate of cornified envelope formation was increased 3-fold in keratinocytes maintained in low calcium (0.03 mM) and incubated in the presence of clofibric acid, a potent PPARalpha activator. Involucrin, a cornified envelope precursor, and the cross-linking enzyme transglutaminase, were increased at both the message level (2-7-fold) and the protein level (4-12-fold) by clofibric acid. Furthermore, physiologic doses of the fatty acids oleic acid, linoleic acid, and eicosatetraynoic acid, which are also activators of PPARalpha, also induced involucrin and transglutaminase protein and mRNA. In contrast, the PPARgammaligand prostaglandin J2 had no effect on protein or mRNA levels of involucrin or transglutaminase. Levels of involucrin and transglutaminase mRNA and protein were induced by clofibric acid in keratinocytes incubated in 1.2 mM calcium, a concentration which by itself induces keratinocyte differentiation. Finally, PPARalpha activators inhibit DNA synthesis. This study demonstrates that PPARalpha activators, including putative endogenous ligands such as fatty acids, induce differentiation and inhibit proliferation in keratinocytes, and suggests a regulatory role for the PPARalpha in epidermal homeostasis.
Formation of the epidermal calcium gradient coincides with key milestones of barrier ontogenesis in the rodent.
The epidermal permeability barrier forms late in gestation, coincident with decreased lipid synthesis, increased lipid processing, and development of a mature, multi-layered stratum corneum. Prior studies have shown that changes in the epidermal Ca++ gradient in vivo regulate lamellar body secretion and lipid synthesis, and modulations in extracellular Ca++ in vitro also regulate keratinocyte differentiation. We asked here whether a Ca++ gradient forms in fetal epidermis in utero, and whether its emergence correlates with key developmental milestones of barrier formation and stratum corneum development. Using either ion precipitation or proton induced X-ray emission analysis of fetal mouse and rat skin, we showed that a Ca++ gradient is not present at gestational days 16-18, prior to barrier formation, and that a gradient forms coincident with the emergence of barrier competence (day 19, mouse; day 20, rat) prior to birth. These results are consistent with a role for Ca++ in the regulation of key metabolic events leading to barrier formation. Whether the calcium gradient is formed actively or passively remains to be determined.
Ligands and activators of nuclear hormone receptors regulate epidermal differentiation during fetal rat skin development.
Because a protective barrier is essential for life, the development of the epidermis and stratum corneum must be completed prior to birth. The epidermal permeability barrier is comprised of corneocytes embedded in a lipid enriched matrix. Recent studies from our laboratory, using an explant model of fetal rat skin development that closely parallels in utero development, have shown that hormones and other activators of members of the nuclear receptor family regulate permeability barrier ontogenesis by stimulating lipid metabolism and the formation of the extracellular lipid lamellae. Using this model we sought to determine whether these hormones and nuclear activators also regulate keratinocyte differentiation during fetal development. Profilaggrin/filaggrin and loricrin expression, assessed by in situ hybridization and by immunohistochemistry, were progressively increased during epidermal ontogenesis. Whereas profilaggrin/filaggrin and loricrin were not expressed at day 17 of gestation, by day 19 both were present in the upper layers of the epidermis and both became still more abundant by day 21. These developmental changes also occurred in fetal skin explants cultured in vitro for 4 d, although the expression levels did not appear as robust as in utero. Whereas neither profilaggrin/filaggrin nor loricrin were expressed in control explants cultured for 2 d, they were seen in explants treated with either thyroid hormone, glucocorticoids, or estrogens. In contrast, dihydrotestosterone treatment delayed the expression of profilaggrin/filaggrin and loricrin. Moreover, both clofibrate, a peroxisome proliferator-activated receptor-alpha ligand, and juvenile hormone III, a farnesoid X-activated receptor activator, markedly accelerated fetal epidermal differentiation, stimulating both profilaggrin/filaggrin and loricrin expression. Our results demonstrate that several hormones and activators of nuclear hormone receptors regulate epidermal differentiation during fetal development, affecting key constituents of both keratohyalin granules and the cornified envelope. Thus, a variety of ligands/activators of nuclear receptors accelerate not only permeability barrier ontogenesis, but also the expression of structural proteins essential for stratum corneum formation.
Glucocorticoid deficiency delays stratum corneum maturation in the fetal mouse.
The stratum corneum (SC) matures during late gestation in man and other mammals. Using the fetal rat as an experimental model, we have previously shown that glucocorticoids given in pharmacologic doses accelerate fetal SC maturation and barrier formation. To determine whether glucocorticoids are required for normal SC maturation, we examined the epidermal morphology of glucocorticoid-deficient (C-) murine pups, derived from matings of mice homozygous for null mutations of the corticotropin-releasing hormone alleles. In control pups on day 17.5 of gestation (term is 19.5 d), a multilayered SC was present and neutral lipid deposition in a membrane pattern was observed using Nile red fluorescence histochemistry. Ultrastructurally, mature lamellar unit structures predominate in the SC intercellular domains. In contrast, in C-pups only a single layer of SC was evident on day 17.5, and secreted lamellar material was not organized into mature lamellar structures. Furthermore, the expression of structural proteins necessary for cornified envelope formation, involucrin, loricrin, and filaggrin, and the activity of the lipid synthetic enzymes beta-glucocerebrosidase and steroid sulfatase, markers of barrier maturation, were reduced in day 17.5 C-pups. C-pups derived from pregnancies supplemented with physiologic amounts of cortisone, however, display normal SC ultrastructure on day 17.5 of gestation. Furthermore, at birth, both control and C-pups exhibit a multilayered SC replete with mature lamellar membrane structures. These data demonstrate that fetal glucocorticoid deficiency delays SC maturation, and suggests that normal levels of glucocorticoids are not absolutely required for SC development.
Recessive x-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality.
Cholesterol sulfate is a multifunctional sterol metabolite, produced in large amounts in squamous keratinizing epithelia. Because patients with recessive x-linked ichthyosis display not only a 10-fold increase in cholesterol sulfate, but also a 50% reduction in cholesterol, we assessed here whether cholesterol sulfate accumulation and/or cholesterol deficiency produce abnormal barrier function in recessive x-linked ichthyosis. Patients with recessive x-linked ichthyosis display both an abnormal barrier under basal conditions, and a delay in barrier recovery after acute perturbation, which correlate with minor abnormalities in membrane structure and extensive lamellar-phase separation. Moreover, both the functional and the structural abnormalities were corrected by topical cholesterol. Yet, topical cholesterol sulfate produced both a barrier abnormality in intact skin and extracellular abnormalities in isolated stratum corneum, effects largely reversed by coapplications of cholesterol. Together, these results suggest that cholesterol sulfate accumulation rather than cholesterol deficiency is responsible for the barrier abnormality. Despite the apparent importance of cholesterol sulfate-to-cholesterol processing for normal barrier homeostasis, neither steroid sulfatase activity nor mRNA levels are upregulated following acute perturbations. These results demonstrate both a potential role for cholesterol sulfate-to-cholesterol processing in normal permeability barrier homeostasis, and that basal levels of steroid sulfatase are sufficient to accommodate acute insults to the permeability barrier.
The acceptability of a computer HIV/AIDS risk assessment to not-in-treatment drug users.
The purpose of this paper is to report the results of a study assessing the acceptability of a computer HIV risk assessment instrument administered to not-in-treatment drug users. The study asked three questions related to acceptability: (1) are drug users comfortable responding to HIV risk questions using the computer assessment; (2) do drug users feel that they possess the requisite skill to respond to questions using a computer; and (3) do drug users believe that the responses they provide using the computer assessment will remain private and confidential. This study differs from other assessments of the acceptability of computer assisted data collection in that the population of interest has only limited education and interaction with computers. Furthermore, the study was implemented under field conditions. To conduct the study, an existing HIV risk assessment instrument was adapted for use with the computer. Only slight modifications were made to the content of the instrument. To facilitate data collection with this population, audio enhancement and touch screen were used. Three scales measuring comfort, skill and perceived privacy were developed. Results of analysis showed that drug users are comfortable responding to an HIV risk assessment using computer assisted interviewing. Drug users also perceived that they possessed the requisite skill to successfully complete the interview. And, study participants reported that they believed that their responses using the computer interview would remain private and confidential. Only minor differences in scale scores based on sociodemographic characteristics were found among study participants. Implications of the findings are discussed.
Moles and melanoma.
The melanoma epidemic in adults is well documented, and there is now evidence that the incidence of malignant melanoma in teenagers is increasing. Risk factors for melanoma are recognizable in children and include congenital nevi, numerous common nevi, and atypical nevi. Large congenital nevi overlying the head or spine also carry risk for central nervous system involvement, which, if symptomatic, carries a grave prognosis. Laser therapy has recently been advocated for small congenital nevi but often yields only temporary improvement. Adjuvant therapy with interferon alfa-2b holds promise for patients with metastatic melanoma. Melanoma risk is also linked to sun sensitivity and childhood exposures, and sunscreen use has been promoted for prevention of skin cancer. Because many sunscreens offer protection from ultraviolet (UV) B but not UVA, spectra that may be involved in melanoma induction, pediatricians should counsel their families to practice a full program of sun protection that includes sun avoidance and protective clothing and eyeware in addition to sunscreens.
Interactive MR imaging-guided biopsy and aspiration with a modified clinical C-arm system.
OBJECTIVE: This investigation was performed to test the hypotheses that interactive guidance of MR image acquisition during needle-directed procedures using a clinical 0.2-T C-arm open MR imaging system integrated with a frameless optically linked stereotaxy system is feasible, and that procedure times can be sufficiently short to be well tolerated by the patient. SUBJECTS AND METHODS: One hundred six MR-guided procedures were performed in 86 patients (ranging in age from 5 months to 88 years) using a clinical C-arm imaging system supplemented with an in-room RF-shielded liquid crystal display monitor, a frameless stereotaxy system, rapid gradient-echo sequences for needle guidance, and MR-compatible monitoring and surgical lighting equipment. We performed 50 biopsies and aspirations of the head and neck in 37 patients, 23 biopsies of musculoskeletal lesions in 22 patients, 16 biopsies of abdominal sites in 10 patients, six biopsies of the thoracolumbar spine or sacrum in six patients, and 11 shoulder joint injections for MR arthrography in 11 patients, in addition to 38 MR arthrographic injections on the same imaging system described in a previous report. Tissue sampling included fine-needle aspiration (n = 90) and cutting needle core biopsy (n = 41). Thirty-five patients underwent both procedures. Procedures were evaluated for success of needle placement, procedure time, and complications. RESULTS: Needle placement was successful in all cases, and no complications occurred. Tissue was sufficient for pathologic diagnosis for all but eight patients. Passes per patient averaged 2.1. For fine-needle aspiration, instrument time averaged 7 min 42 sec per pass, cutting needle core biopsy averaged 6 min 24 sec, and shoulder injection averaged 8 min. CONCLUSION: MR imaging guidance for needle procedures on a clinical 0.2-T C-arm system with supplemental interventional accessories is feasible, with relatively rapid needle placement.