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Biomedical subjects

M L Williams

Publications and source records attributed to M L Williams.

At least 19 recordsLinked to original sources
PubMed2005

Identification and characterization of a two-component hemolysin from Edwardsiella ictaluri.

The channel catfish pathogen Edwardsiella ictaluri possesses hemolysin activity, and strains that are adapted for growth in fish tend to have greater hemolysin activity than strains that are adapted for in vitro growth conditions. To investigate its potential role in virulence, an isogenic hemolysin mutant strain of E. ictaluri R4383 was constructed by transposon mutagenesis. Sequencing of the chromosomal insertion site identified two genes, designated eihA and eihB, that encode proteins with homology to the Serratia family of two-component hemolysins. EihB is similar to the secretion/activation proteins from this family, and EihA is similar to the cytolysin proteins from this family. Bacterial challenge in channel catfish fingerlings did not show a significant difference in virulence between the wild type E. ictaluri strain and the hemolysin deficient E. ictaluri mutant strain.

Animals↗
PubMed2005

Heroin and HIV risk in Dar es Salaam, Tanzania: youth hangouts, mageto and injecting practices.

HIV risk through needle sharing is now an emerging phenomenon in Africa. This article describes the practices that heroin users are producing as they establish the rules and organization surrounding their drug use. Their practices and interactions reveal the ways that they become initiated into its use, how they progress to injecting, and the important role of local neighbourhood hangouts in facilitating this process. Their practices, interactions and narratives also provide insights into what may be the most appropriate HIV-prevention interventions. Semi-structured interviews were conducted during the months of February and July 2003 with 51 male and female injectors residing in 8 neighbourhoods in the Dar es Salaam, Tanzania. Interviews were content coded and codes were collapsed into emergent themes around hangout places, initiation of heroin use, and progression to injecting. Interviews reveal that Dar es Salaam injectors begin smoking heroin in hangout areas with their friends, either because of peer pressure, desire, or trickery. One hangout place in particular, referred to as the 'geto' (ghetto) is the main place where the organization and rules governing heroin use are produced. Three main types of heroin 'ghettoes' are operating in Dar es Salaam. As users build a tolerance for the drug they move along a continuum of practices until they begin to inject. Injecting heroin is a comparatively recent practice in Africa and coincides with: (1) Tanzania transitioning to becoming a heroin consuming community; (2) the growing importance of youth culture; (3) the technical innovation of injecting practices and the introduction and ease of use of white heroin; and (4) heroin smokers, sniffers, and inhalers perceived need to escalate their use through a more effective and satisfying form of heroin ingestion.

Female↗
PubMed2004

Psychosocial factors associated with adherence to antiretroviral medications in a sample of HIV-positive African American drug users.

The purpose of the study was to investigate factors affecting antiretroviral adherence among African American drug users, specifically to identify associations between self-reported adherence levels and psychosocial measures selected with guidance from the Transactional Model of Stress and Coping (TMSC). The study was conducted using data collected from 137 HIV-positive African American drug users who were receiving antiretroviral medications at the time they were interviewed. Bivariate associations were investigated using correlational analyses and variables showing a significant correlation with adherence were entered into a multivariate regression model. The multivariate model showed only perceived efficacy of antiretrovirals and one measure of perceived barriers, simply forgetting to take medications, were independently related to adherence. These preliminary findings suggest that theoretical approaches to understanding antiretroviral adherence must address a range of variables, including but not limited to behavioural practices, cognitive appraisals, affective responses and social support. Further studies using the complete TMSC are recommended.

Adult↗
PubMed2004

The relationship between a urinary cachectic factor and weight loss in advanced cancer patients.

A 24K glycoprotein, the proteolysis-inducing factor (PIF), has been identified in mice and humans with cancer cachexia. Clinical cross-sectional studies found an association between the presence of PIF in urine and tumors of patients and weight loss. For the first time, we report results from a longitudinal study establishing the relationship between a urinary PIF pattern and persistent weight loss. Over time, cancer patients positive for the PIF pattern experienced weight loss, whereas those with a negative test gained weight.

Adult↗
PubMed2003

Deterministic photon transport calculations in general geometry for external beam radiation therapy.

A deterministic method is described for performing three-dimensional (3D) photon transport calculations of a LINAC head and phantom/patient geometry to obtain dose distributions for therapy planning. The space, energy, and directional-dependent photon flux density is obtained by numerically solving the Boltzmann equation in general 3D geometry using the method of characteristics. The deterministic transport calculations use similar ray tracing routines as found in Monte Carlo (MC) codes. A special treatment is developed to better represent the impact of scattering from accelerator head components. Equations are presented for computing the water kerma distribution due to the uncollided and collided photon flux density field in the patient region. Kerma results obtained from the deterministic computation are compared to Monte Carlo values for a variety of source spectra and field sizes. The agreement for kerma values in the beam is usually within the MC uncertainties. It is concluded that the deterministic method is a rigorous, first-principles approach that could provide a superior alternative to Monte Carlo calculations for some types of problems. However additional development is needed to provide capability for 3D electron transport calculations.

Algorithms↗
PubMed2003

High-density EEG mapping during general anaesthesia with xenon and propofol: a pilot study.

Anaesthetic-induced spatial inhomogeneities of the electrencephalogram(EEG) using "high density" electrode mapping have not previously been reported. We measured the scalp EEG with a dense electrode (128-channel) montage during the course of light general anaesthesia with xenon and then propofol in normal human subjects. EEG was measured during induction and recovery of general anaesthesia in five normal subjects, and we obtained analysable data from three of these subjects. EEG topographies were plotted on a realistic head surface. Scalp fields were spatially de-blurred using a realistic head model and projected onto an averaged cortical surface Both xenon and propofol elicited large increases in midline frontal theta-band EEG power. Propofol reliably elicited orbitofrontal delta activity. Xenon, but not propofol, caused large increases in delta over the posterior cortex. Increased gamma power was observed for both anaesthetic agents at midline electrodes over the posterior cortex, but not anteriorly. Anaesthesia-induced delta and theta waves were differentially distributed along the anterior-posterior axis of the brain in a manner that corresponds well to the anatomy of putative neuronal generators. The distribution of anaesthetic-induced changes in fast gamma-band power seems to reflect functional differences between the posterior and anterior aspects of the cerebral cortex. These preliminary observations were consistent within our small sample, indicating that larger studies of anaesthetic effects using high-density recordings are warranted.

Adult↗
PubMed2002

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Aging↗
PubMed2002

Deterministic calculations of photon spectra for clinical accelerator targets.

A method is proposed to compute photon energy spectra produced in clinical electron accelerator targets, based on the deterministic solution of the Boltzmann equation for coupled electron-photon transport in one-dimensional (1-D) slab geometry. It is shown that the deterministic method gives similar results as Monte Carlo calculations over the angular range of interest for therapy applications. Relative energy spectra computed by deterministic and 3-D Monte Carlo methods, respectively, are compared for several realistic target materials and different electron beams, and are found to give similar photon energy distributions and mean energies. The deterministic calculations typically require 1-2 mins of execution time on a Sun Workstation, compared to 2-36 h for the Monte Carlo runs.

Computers↗
PubMed2001

Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children.

Patients with a giant congenital melanocytic nevus can develop melanotic tumors characterized by central nervous system involvement, termed leptomeningeal melanocytosis or neurocutaneous melanosis. Although symptomatic neurocutaneous melanosis is rare, we previously reported distinct magnetic resonance (MR) findings of T1 shortening, strongly suggestive of neurocutaneous melanosis, in 30 percent (6 of 20) of children with giant congenital melanocytic nevi who presented initially without neurological symptoms. The purpose of this study was to determine the incidence of neurocutaneous melanosis in high-risk patients and its long-term clinical significance. Magnetic resonance imaging was recommended for all 46 patients with "at-risk" giant congenital melanocytic nevi involving the skin overlying the dorsal spine or scalp. The clinical histories and follow-up of these patients were evaluated by retrospective chart review. Forty-two underwent MR imaging of the brain and 11 underwent additional MR scanning of the spinal cord. Abnormalities were identified in 14 of 43 MR studies, and 23 percent (n = 10) had T1 shortening indicative of melanotic rests within the brain or meninges. None had associated masses or leptomeningeal thickening. The most common areas of involvement in these 10 included the amygdala (n = 8), cerebellum (n = 5), and pons (n = 3). In the group of 11 patients with spinal MR scans, a tethered spinal cord was demonstrated in one. Additional abnormalities were detected by MR scanning, including a middle cranial fossa arachnoid cyst, a Chiari type I malformation, and a crescentic enhancement that subsequently resolved. Clinical follow-up averaging 5 years (range, 2 to 8 years) revealed that only one of the 46 patients evaluated developed neurological symptoms, manifested as developmental delay, hypotonia, and questionable seizures but no other signs of neurocutaneous melanosis. No patient has developed a cutaneous or central nervous system melanoma. Magnetic resonance findings of neurocutaneous melanosis are relatively common, even in asymptomatic children with giant congenital melanocytic nevi. Although these findings suggest an increased lifetime risk of central nervous system melanoma, they do not signify the eventual development of symptomatic neurocutaneous melanosis during childhood.

Brain↗
PubMed2001

Cutaneous manifestations of maternal engraftment in patients with severe combined immunodeficiency: a clinicopathologic study.

SCID is a heterogeneous group of disorders characterized by defective T cell and B cell function. Eczematous and morbilliform eruptions are common, and graft-versus-host disease (GVHD) due to maternal engraftment has been documented. We sought to better characterize SCID-related cutaneous disease observed prior to BMT and to compare the eruption to conventional GVHD. Medical records of 51 patients with SCID treated between 1982 and 1999 were reviewed. Ten of 51 (20%) had rash and evidence of maternal engraftment prior to BMT (study group). Eleven of 51 (22%) had no rash or evidence of engraftment pre-BMT but developed GVHD following transplant (control group). Skin biopsies were available for review for 8/10 of the study group and for 8/11 of the control group. Cutaneous findings consisted of a scaling, erythematous maculopapular eruption spread widely over the trunk and extremities, with near-erythroderma in some patients. Microscopically, biopsies from the study group differed significantly from controls. Key differences included parakeratosis (P < or = 0.01), psoriasiform hyperplasia (P < or = 0.04) and spongiosis (P < or = 0.04). The dermatopathologic findings of transplacental GVHD differ from the pattern of post-transplant GVHD. A 'psoriasiform-lichenoid-spongiotic' pattern with necrotic keratinocytes should trigger consideration of SCID and maternal engraftment in the dermatopathologic evaluation of eruptions of infancy.

Bone Marrow Transplantation↗
PubMed2001

Pathogenesis of the permeability barrier abnormality in epidermolytic hyperkeratosis.

Epidermolytic hyperkeratosis is a dominantly inherited ichthyosis, frequently associated with mutations in keratin 1 or 10 that result in disruption of the keratin filament cytoskeleton leading to keratinocyte fragility. In addition to blistering and a severe disorder of cornification, patients typically display an abnormality in permeability barrier function. The nature and pathogenesis of the barrier abnormality in epidermolytic hyperkeratosis are unknown, however. We assessed here, first, baseline transepidermal water loss and barrier recovery kinetics in patients with epidermolytic hyperkeratosis. Whereas baseline transepidermal water loss rates were elevated by approximately 3-fold, recovery rates were faster in epidermolytic hyperkeratosis than in age-matched controls. Electron microscopy showed no defect in either the cornified envelope or the adjacent cornified-bound lipid envelope, i.e., a corneocyte scaffold abnormality does not explain the barrier abnormality. Using the water-soluble tracer, colloidal lanthanum, there was no evidence of tracer accumulation in corneocytes, despite the fragility of nucleated keratinocytes. Instead, tracer, which was excluded in normal skin, moved through the extracellular stratum corneum domains. Increasing intercellular permeability correlated with decreased quantities and defective organization of extracellular lamellar bilayers. The decreased lamellar material, in turn, could be attributed to incompletely secreted lamellar bodies within granular cells, demonstrable not only by several morphologic findings, but also by decreased delivery of a lamellar body content marker, acid lipase, to the stratum corneum interstices. Yet, after acute barrier disruption a rapid release of preformed lamellar body contents was observed together with increased organelle contents in the extracellular spaces, accounting for the accelerated recovery kinetics in epidermolytic hyperkeratosis. Accelerated recovery, in turn, correlated with a restoration in calcium in outer stratum granulosum cells in epidermolytic hyperkeratosis after barrier disruption. Thus, the baseline permeability barrier abnormality in epidermolytic hyperkeratosis can be attributed to abnormal lamellar body secretion, rather than to corneocyte fragility or an abnormal cornified envelope/cornified-bound lipid envelope scaffold, a defect that can be overcome by external applications of stimuli for barrier repair.

Adolescent↗
PubMed2001

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Adolescent↗
PubMed2001

Comparison of changes in electroencephalographic measures during induction of general anaesthesia: influence of the gamma frequency band and electromyogram signal.

Recent research has shown that high-frequency, gamma-band electroencephalographic (EEG) oscillations (40-60 Hz) may be an important marker of the conscious state. We compared the ability of the bispectral index (BIS) to distinguish the awake and anaesthetized states during the induction of general anaesthesia with: (i) components of the BIS (BetaRatio, SynchFastSlow); (ii) a new EEG variable--the median frequency of the first time derivative of the EEG signal (SE50d); and (iii) the SE50d derived from an EEG signal that has had the frequencies above 30 Hz removed (SE50d(30Hz)). Two groups of subjects were studied: (i) nine volunteers undergoing a short propofol infusion until loss of response to verbal command, and (ii) 84 patients undergoing routine anaesthesia for a variety of surgical procedures. In the volunteer group, the changes in the BetaRatio and SE50d were comparable with changes in the BIS. The changes in the SE50d(30Hz) were less consistent. In the patient group, the BIS components were equivalent to the BIS in separating the awake from the surgically anaesthetized states (area under receiver operating curve: BIS 0.95, SE50d 0.95, BetaRatio 0.96). Using the submental electromyogram (EMG) signal to estimate the frontalis EMG (30-47 Hz) signal, the changes in EMG signal were, on average, about one-tenth the magnitude of the EEG. We conclude that: (i) there exist simpler derived EEG variables that are similar in accuracy to the BIS; (ii) it is important to avoid filtering out the EEG frequencies above 30 Hz; and (iii) in most patients the confounding effects of the frontalis EMG on the EEG are minimal.

Adult↗
PubMed2001

Gender differences in the processes of change for condom use: patterns across stages of change in crack cocaine users.

Interventions to increase condom use in crack users have had mixed results. For interventions to achieve greater success, the mechanisms of behavior change in this population need to be understood. One mechanism, the processes of change, was examined across stages of change for condom use. Results from the analysis of variance for males and females revealed that stage of change was associated with different levels of three experiential processes: consciousness raising, social liberation and self-reevaluation. However, these analyses found that male and females seem to have different patterns of behavioral process use. Specifically, females in the preparation stage were different from those in precontemplation, whereas this difference was not pronounced in males. In general, people had high levels of experimental processes in every stage of change. The patterns of behavior process use mimicked patterns found for other behaviors with a linear increase across the stages of change. This may indicate that for maintaining condom use, more emotional and behavioral activities are required throughout the process of acquisition and maintenance than are necessary for other health-related activities. Implications of this research are that interventions for increasing condom use in drug users may target behavioral steps differently for males and females.

Adult↗
PubMed2001

Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D.

Lipids that are synthesized de novo in the epidermis, including fatty acids, oxysterols, 1,25-dihydroxyvitamin D(3), and farnesol, can regulate the differentiation of normal human keratinocytes (NHK). Cholesterol sulfate (CS), an epidermal lipid that is produced in the upper nucleated layers of the epidermis coincident with terminal differentiation, has been shown to play a role in the regulation of the late stages of keratinocyte differentiation, including formation of the cornified envelope. In the present study, we determined i) whether CS regulates involucrin (INV), an early keratinocyte differentiation marker, and ii) the mechanism by which CS regulates differentiation. mRNA and protein levels of INV, a precursor protein of the cornified envelope, increased 2- to 3-fold in NHK incubated in the presence of CS. In contrast, cholesterol had no effect on INV protein or mRNA levels. Transcriptional regulation was assessed in NHK transfected with INV promoter-luciferase constructs. CS increased luciferase reporter activity approximately 2- to 3-fold in NHK transfected with a 3.7-kb INV promoter construct. Deletional analysis revealed a CS-responsive region of the INV promoter located between bp --2452 and --1880. A 5-base pair (bp) mutation of the AP-1 site (bp --2117 to --2111) within this responsive region abolished CS responsiveness, suggesting a role for the AP-1 complex in the regulation of INV transcription by CS. Electrophoretic mobility shift analysis demonstrated increased binding of nuclear extracts isolated from CS-treated NHK to AP-1 DNA as compared with vehicle-treated controls. Incubation of the nuclear extract with the appropriate antibodies showed that the AP-1 DNA-binding complex contained Fra-1, Fra-2, and Jun D. Western blots demonstrated that CS treatment increased the levels of Fra-1, Fra-2, and Jun D, and Northern analyses revealed that CS increased mRNA levels for these same AP-1 factors. These data indicate that CS, an endogenous lipid synthesized by keratinocytes, regulates the early stages of keratinocyte differentiation, and may do so through its ability to modulate levels of AP-1 proteins. -- Hanley, K., L. Wood, D. C. Ng, S. S. He, P. Lau, A. Moser, P. M. Elias, D. D. Bikle, M. L. Williams, and K. R. Feingold. Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D. J. Lipid Res. 2001. 42: 390--398.

Binding Sites↗
PubMed2001

Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels.

Curcumin prevents colon cancer in rodent models. It inhibits lipid peroxidation and cyclooxygenase-2 (COX-2) expression and induces glutathione S-transferase (GST) enzymes. We tested the hypothesis that 14 days of dietary curcumin (2%) affects biomarkers relevant to cancer chemoprevention in the rat. Levels of inducible COX-2, as reflected by prostaglandin E(2) production by blood leukocytes, were measured ex vivo. Total GST activity and adducts of malondialdehyde with DNA (M(1)G), which reflect endogenous lipid peroxidation, were measured in colon mucosa, liver, and blood leukocytes. Curcumin and its metabolites were analyzed by high-performance liquid chromatography in plasma, and its pharmacokinetics were compared following a diet containing 2% curcumin versus intragastric (i.g.) administration of curcumin suspended in an amphiphilic solvent. The curcumin diet did not alter any of the markers in the blood but increased hepatic GST by 16% and decreased colon M(1)G levels by 36% when compared with controls. Administration of carbon tetrachloride during the treatment period increased colon M(1)G levels, and this increase was prevented by dietary curcumin. Dietary curcumin yielded low drug levels in the plasma, between 0 and 12 nM, whereas tissue concentrations of curcumin in liver and colon mucosa were 0.1--0.9 nmol/g and 0.2--1.8 micromol/g, respectively. In comparison with dietary administration, suspended curcumin given i.g. resulted in more curcumin in the plasma but much less in the colon mucosa. The results show that curcumin mixed with the diet achieves drug levels in the colon and liver sufficient to explain the pharmacological activities observed and suggest that this mode of administration may be preferable for the chemoprevention of colon cancer.

Animals↗