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Biomedical subjects

M L Williams

Publications and source records attributed to M L Williams.

At least 91 records · Page 5Linked to original sources
PubMed1996

Epidermal barrier ontogenesis: maturation in serum-free media and acceleration by glucocorticoids and thyroid hormone but not selected growth factors.

Because the cutaneous permeability barrier develops late in gestation, prematurity may result in increased morbidity and mortality due to barrier incompetence. The purpose of the present study was to develop an in vitro model of barrier ontogenesis in order to identify those factors critical for fetal barrier formation. Skin explants from gestational day 17 fetal rats (term is 22 days) were incubated in hormone- and serum-free media. After 4 d in culture, a multi-layered stratum corneum (SC) developed that demonstrated a membrane pattern of fluorescence using the hydrophobic probe, nile red, and the deposition of mature lamellar unit structures throughout the SC interstices, ultrastructurally. Transepidermal water loss rates declined during explant culture such that after 4 d a competent barrier was present. Similarly, lanthanum permeation studies showed tracer penetration into all cell layers in 2-d explants, whereas it did not penetrate above the stratum granulosum in 4-d explants. Thus, the chronology of epidermal development in the explants precisely mirrored that observed in utero. Treatment with either 10 nM dexamethasone or 10 nM triiodothyronine accelerated SC development and barrier formation by 2 d. These results indicate that (i) the late events of fetal epidermal development progress in vitro under serum- and growth factor-free conditions, culminating in the formation of a functional barrier, and (ii) both dexamethasone and triiodothyronine accelerate barrier development.

Animals↗
PubMed1995

Neural computation of log likelihood in control of saccadic eye movements.

The latency between the appearance of a visual target and the start of the saccadic eye movement made to look at it varies from trial to trial to an extent that is inexplicable in terms of ordinary 'physiological' processes such as synaptic delays and conduction velocities. An alternative interpretation is that it represents the time needed to decide whether a target is in fact present: decision processes are necessarily stochastic, because they depend on extracting information from noisy sensory signals. In one such model, the presence of a target causes a signal in a decision unit to rise linearly at a rate r from its initial value s0 until it reaches a fixed threshold theta, when a saccade is initiated. One can regard this decision signal as a neural estimate of the log likelihood of the hypothesis that the target is present, the threshold being the significance criterion or likelihood level at which the target is presumed to be present. Experiments manipulating the prior probability of the target's appearing confirm this notion: the latency distribution then changes in the way expected if s0 simply reflects the prior log likelihood of the stimulus.

Humans↗
PubMed1995

Monitoring of exposure to air pollution.

This paper reviews recent advancements in methods of human exposure assessment to air pollutants. Instruments are becoming available for continuous recording of personal exposures, but their operating performance should be thoroughly assessed for accuracy, precision, interference, etc. Even after the method validation, it will be difficult and expensive to undertake continuous personal exposure monitoring in large study groups. The specification of exposures across a large population is probably best carried out using a combination of measurements and models. Detailed exposure measurements can be valuable in small-scale studies of exposure patterns, in pilot studies or to assess the validity of surrogate or proxy measures of exposure.

Air Pollutants↗
PubMed1995

Appropriate use of heparin. Empiric vs nomogram-based dosing.

BACKGROUND: A study involving two groups of patients with cardiovascular disease was conducted to compare empiric (clinician-directed) heparin therapy with therapy based on a nomogram-determined dosage. The comparison was based on (1) the average weight-referenced infusion rate yielding a therapeutic activated partial thromboplastin time (APTT) and (2) the time required to reach a therapeutic APTT (55 to 95 seconds) after empiric or nomogram-based heparin therapy was initiated. METHODS: Data were collected for patients admitted to the cardiology service at a university health science center in two phases: phase 1 (April 1 through June 30, 1992), involving 95 patients receiving heparin therapy, with 88 patients included in the data analysis, and phase 2 (March 11 through June 11, 1993), involving 156 patients receiving heparin therapy, with 45 patients receiving nomogram-guided therapy included in the data analysis. RESULTS: In phase 1, 66 patients (75.0%) achieved a therapeutic APTT some time during their heparin therapy, with an average time to therapeutic APTT of 20.7 + 19.1 hours. Regression analysis demonstrated a statistically significant relationship between the heparin infusion rate at the time of the patient's first therapeutic APTT and the patient's total body weight (r2 = .3043). An initial infusion rate based on total body weight (13 U/kg per hour) was therefore used as the basis for the nomogram in phase 2. In phase 2, 41 patients (91.1%) achieved a therapeutic APTT at some time during their heparin therapy, with an average time to therapeutic APTT of 13.1 + 11.9 hours, statistically significantly shorter than that in phase 1. A greater proportion of patients in phase 2 compared with patients in phase 1 reached the therapeutic range within 12 hours (62.2% vs 34.1%) and within 24 hours (77.8% vs 54.5%). CONCLUSIONS: Use of a weight-based nomogram to determine the initial and maintenance heparin infusion rates was associated with a higher percentage of patients admitted to the cardiology service reaching the targeted therapeutic APTT range at a time earlier in the course of therapy compared with empiric dosing.

Adult↗
PubMed1995

Cutaneous lipid synthesis during late fetal development in the rat.

Lipid synthesis in fetal skin may be important both for the development of a mature epidermal permeability barrier and for growth. In these studies, we measured cutaneous cholesterol, sphingolipid and fatty acid synthesis during the critical period of epidermal barrier development in fetal rats to determine whether barrier function influences synthetic rates. In addition, the activities of HMG CoA reductase, serine palmitoyl transferase and acetyl coenzyme A carboxylase were evaluated. In whole skin, synthesis of cholesterol, ceramide, sphingomyelin and fatty acid decreased from day 17 to day 21 of gestation, as did the activity of HMG CoA reductase, serine palmitoyl transferase and acetyl coenzyme A carboxylase. In both the epidermis and dermis, a decrease in cholesterol, ceramide, sphingomyelin and fatty acid synthesis was measured over days 19-21 of gestation. Epidermal HMG CoA reductase activity also decreased over this same time period. In summary, epidermal and dermal synthetic rates and enzyme activity were highest early in gestation when the barrier was least competent and decreased as competence was achieved. Since other studies with mature animals have revealed that epidermal synthetic rates and enzyme activity are highest when barrier disruption is maximal, enhanced epidermal lipid synthesis precedes the establishment of a competent barrier in both fetal and mature rodents.

Animals↗
PubMed1995

Differential utilization of linoleic and arachidonic acid by cultured human keratinocytes.

The essential fatty acid, linoleic acid (LA), is required for the epidermal barrier and LA is also the precursor fatty acid for arachidonic acid (AA). Both fatty acids are imported from systemic sources, because AA is also not synthesized in the epidermis. The present studies were undertaken to compare the uptake and incorporation into cellular lipid of these fatty acids and to determine whether they compete with one another in these processes in relation to keratinocyte differentiation. The incorporation of [14C]LA and/or [14C]AA into phospholipids and triglycerides was examined in keratinocytes cultured under submerged and lifted conditions. In submerged (less well-differentiated) cultures, more LA was incorporated into phospholipids than AA, while AA was incorporated into triglycerides to a greater extent. When given together, neither fatty acid influenced the total and/or relative uptake and lipid distribution of the other. Compared to submerged cultures, the uptake of LA increased 2-fold in lifted (differentiated) cultures, while the uptake of AA was unchanged. Lifting increased the proportion of AA incorporated into phospholipids, but did not alter the distribution of LA among phospholipids or triglycerides. These data suggest that the essential fatty acids, LA and AA, which are destined for different metabolic roles within the keratinocyte do not compete with one another during their uptake and distribution among cellular lipid species. Furthermore, as keratinocytes differentiate in culture, their increased requirement for LA for the synthesis of barrier lipids may be achieved through the preferentially enhanced uptake and lipid incorporation.

3T3 Cells↗
PubMed1995

Sweet's syndrome leading to acquired cutis laxa (Marshall's syndrome) in an infant with alpha 1-antitrypsin deficiency.

BACKGROUND: Marshall's syndrome is a rare pediatric skin disease that is characterized by acquired, localized neutrophilic dermatitis (Sweet's disease), followed by loss of elastic tissue in the dermis and cutis laxa. The cause of this syndrome is unknown. alpha 1-Antitrypsin (alpha 1-AT) deficiency is a codominantly inherited disorder of alpha 1-AT, the major serum antiprotease active against a number of serine-type proteases. OBSERVATIONS: The first patient with classic Marshall's syndrome who had coexisting alpha 1-AT deficiency and a review of other cases of Marshall's syndrome are presented, and pathogenic mechanisms are discussed. CONCLUSIONS: A deficiency of alpha 1-AT may allow proteases such as neutrophil elastase to destroy dermal elastin and, thus, produce cutis laxa in Marshall's syndrome. Other cases of acquired cutis laxa should be screened for alpha 1-AT deficiency to further evaluate this association and to enable patients and their families to be counseled about possible systemic complications of alpha 1-AT deficiency.

Cutis Laxa↗
PubMed1994

Evidence for a novel keratinocyte fatty acid uptake mechanism with preference for linoleic acid: comparison of oleic and linoleic acid uptake by cultured human keratinocytes, fibroblasts and a human hepatoma cell line.

Keratinocytes require the essential fatty acid (FA), linoleic acid (LA), for the synthesis of stratum corneum membrane lipids. A plasma membrane-FA binding protein (PM-FABP), is postulated to mediate cellular FA-uptake in hepatocytes and several other tissues, but the mechanism whereby exogenous FA are taken up by keratinocytes has not been investigated. This study examines the uptake of LA and oleic acid (non-essential) in cultured human keratinocytes, in comparison to dermal fibroblasts and the human hepatoma cell line, HepG2. As previously reported for hepatocytes, FA-uptake in keratinocytes was curvilinear, with an initial (30 s) rapid cellular influx. The initial uptake component was temperature dependent, exhibited saturable kinetics and was significantly inhibited by pretreatment with trypsin. In contrast, fibroblast FA-uptake lacked an initial rapid uptake component, was relatively temperature insensitive, and was not inhibited by trypsin. Keratinocytes differed from both hepatocytes and fibroblasts by more rapid uptake of LA in comparison to oleic acid during the initial influx phase. Moreover, FA-uptake in keratinocytes was not inhibited by preincubation with a anti-rat liver PM-FABP antibody. These data provide evidence for a PM-FA transporter in keratinocytes that is distinct from the hepatic PM-FABP. The apparent preference of the putative keratinocyte FA transporter for LA may function to ensure epidermal capture of sufficient LA for barrier lipid synthesis.

Adult↗
PubMed1994

X-linked dominant ichthyosis with peroxisomal deficiency. An ultrastructural and ultracytochemical study of the Conradi-Hünermann syndrome and its murine homologue, the bare patches mouse.

BACKGROUND AND DESIGN: The bare patches (Bpa) mouse expresses an X-dominant disorder that may be homologous to the Conradi-Hünermann (CH) syndrome in man; ie, both express ichthyosis, cataracts, and skeletal defects. To confirm their homology, we compared the light and electron microscopy of involved (I) vs uninvolved (U) skin from an infant with CH syndrome to Bpa mice during and after resolution of the scaling disorder. The peroxisomal content of Bpa and CH skin was evaluated by diaminobenzidine (DAB) ultracytochemistry (Bpa only) and by assessment of catalase (Bpa only) and dihydroxyacetone phosphate-acyltransferase (DHAP-AT) activities in cultured I vs U fibroblasts. RESULTS: Both CH and Bpa I epidermis exhibited psoriasiform features. In addition, ultrastructurally both exhibited the following: (1) vacuolated lamellar bodies, (2) dilatation of intercellular spaces by vesicular structures and amorphous debris, and (3) abnormal mitochondria. Stratum corneum interstices were filled with vesicular structures, and no lamellar unit structures were evident using ruthenium tetroxide postfixation. Peroxisomes were poorly stained by DAB in I Bpa epidermis and dermis during the eruptive phase. Moreover, catalase and DHAP-AT activities in cultured I Bpa fibroblasts were decreased to 40% and 30% of U Bpa levels, respectively; DHAP-AT activity in cultured I CH fibroblasts was also reduced (60% of U CH). With resolution of the scaling disorder, the ultrastructural and ultracytochemical features of I and U Bpa skin became indistinguishable. CONCLUSIONS: These studies provide evidence for a self-resolving defect involving multiple organelles, including lamellar bodies, peroxisomes, and mitochondria in the I skin of CH syndrome and the Bpa mouse.

Acyltransferases↗
PubMed1994

Giant congenital melanocytic nevi: brain magnetic resonance findings in neurologically asymptomatic children.

BACKGROUND: Patients with giant or multiple congenital melanocytic nevi occasionally have leptomeningeal melanocytosis, also called neurocutaneous melanosis (NCM). Patients with symptomatic NCM usually have signs or symptoms of increased intracranial pressure and have a poor prognosis. Magnetic resonance (MR) imaging is sensitive in detecting melanin; several recent reports have described the MR findings in neurocutaneous melanosis. OBJECTIVE: The aim of this study is to review the brain MR findings and their potential significance in a group of neurologically asymptomatic children with giant congenital melanocytic nevi at risk for the development of NCM. METHODS: Retrospective review of patient charts and MR studies was performed. RESULTS: Nine of the 20 patients evaluated had MR abnormalities: six had focal areas of high signal on T1-weighted images, strongly suggestive of melanosis, in one or multiple areas of the brain including the temporal lobes, cerebellum, pons, and medulla. One had a middle cranial fossa arachnoid cyst; another had a Chiari type I malformation of the brain. In one patient a crescentic enhancement over the right parietal region, probably from perinatal trauma, was absent on repeat MR 6 months later. In no case was thickening of the leptomeninges or spinal abnormalities noted. CONCLUSIONS: NCM may be much more common than previously suspected in patients with giant congenital melanocytic nevi. The most common finding on MR appears to be T1 shortening in the cerebellum, temporal lobes, pons, and medulla, rather than evidence of leptomeningeal thickening. These findings may have implications for management of patients with giant CMN.

Brain↗
PubMed1994

Interindividual variation in the isomerization of 4-hydroxytamoxifen by human liver microsomes: involvement of cytochromes P450.

Tamoxifen and its metabolite 4-hydroxytamoxifen can both exist as geometrical isomers. Trans-tamoxifen is an oestrogen receptor antagonist and is used for the treatment of breast cancer. Trans-4-hydroxytamoxifen is 100 times more anti-oestrogenic than trans-tamoxifen. The cis isomers of tamoxifen and 4-hydroxytamoxifen are oestrogenic and weakly anti-oestrogenic or oestrogenic respectively. Both isomers of 4-hydroxytamoxifen have been detected in breast tumours of patients treated with trans-tamoxifen and it has been proposed that enzymatic isomerization of 4-hydroxytamoxifen occurs in vivo, resulting in resistance to tamoxifen therapy. We have investigated the isomerization of 4-hydroxytamoxifen by human liver microsomes and whether it is mediated by cytochromes P450. Microsomes from five of the 12 livers examined catalysed the interconversion of trans- and cis-4-hydroxytamoxifen (0.52 microM) when incubated for 40 min with an NADPH-generating system. Between 51 and 64% conversion of trans-4-hydroxytamoxifen was observed. Cis-4-hydroxytamoxifen was also converted to trans-4-hydroxytamoxifen (range 22-27%). Incubations with control, heat-treated microsomes resulted in approximately 1% isomerization of trans-4-hydroxytamoxifen. The extent of isomerization of trans- to cis-4-hydroxytamoxifen observed in microsomes from the other seven livers (range 2-8%) did not greatly exceed that seen in heat-inactivated microsomes. Enzymatic isomerization required NADPH and was inhibited by SKF 525A and ketoconazole, indicating the involvement of cytochromes P450. Enzymatic isomerization of trans-tamoxifen and trans-droloxifene (the 3-hydroxy synthetic analogue of tamoxifen) was not observed. These findings may have implications for the safe and effective use of tamoxifen.

Adult↗