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Biomedical subjects

M C Williams

Publications and source records attributed to M C Williams.

At least 19 recordsLinked to original sources
PubMed2006

The FEMA GRAS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavor ingredients.

This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential.

Alcohols↗
PubMed2006

Chronic vanadium poisoning in calves and its treatment with calcium disodium ethylenediaminetetraacetate.

Sixteen Friesland heifer calves aged between 96 and 157 days were removed from a dairy farm that had been polluted with vanadium and randomly allocated into two equal groups (n = 8). The objective of the trial was to determine whether calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA) could be used as a treatment for cattle running in environments high in background vanadium. The treatment group received 80 mg CaNa(2)EDTA per kg body weight intraperitonealy (i.p.) twice a week over a 10-week period. The control group received normal saline i.p. over the same period. During the trial calves were exposed to a daily intake of vanadium in the form of contaminated tef hay derived from the farm of origin. In addition, the total mixed ration was spiked with a further 20 mg V(2)O(5)/kg feed to compensate for possible on-farm inhalation exposure. A stochastic model was used to estimate daily intake of vanadium as a distribution function. The model estimated that the daily intake of vanadium varied between an absolute minimum of 33 mg/day to an absolute maximum of 124 mg/day. The average intake of vanadium was 71.8 mg per day per calf. Various chemical pathology parameters were measured throughout the trial as well as urine excretion rates of vanadium and lymphocyte stimulation counts. All calves were slaughtered and necropsied in cohorts of 4-6 animals at monthly intervals after completion of the trial and withdrawal of vanadium from the ration. Tissue concentrations of vanadium were determined and necropsy findings were noted. The study found that CaNa(2)EDTA appears to enhance the excretion of vanadium in calves, but could not prove that the treatment had a protective effect against vanadium exposure. Calves were able to tolerate the prolonged treatment with CaNa(2)EDTA without side-effects.

Animals↗
PubMed2005

Cryptococcus neoformans granuloma in the lung and spinal cord of a free-ranging cheetah (Acinonyx jubatus). A clinical report and literature review.

A 6-year-old, male, wild-born, free-ranging cheetah (Acinonyx jubatus) was evaluated for acute onset of progressive lameness in the right hind limb. Survey radiographs were unrewarding and myelography indicated an intramedullary compressive mass at the L3-L4 region. A fine needle aspirate of the lesion indicated the presence of Cryptococcus organisms. Necropsy confirmed the presence of granulomas (cryptococcoma) in the lung and the spinal cord (meningomyelitis) caused by Cryptococcus neoformans var. gattii. Cryptococcus neoformans is a yeast-like organism that is a potential pathogen to many species. Initial infection is thought to be of respiratory origin and then it commonly disseminates systemically from the nasal cavity or lungs to the skin, eyes and central nervous system in particular. The cheetah tested negative for both feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV), as have all the previously reported cheetah cases. C. neoformans is a non-contagious, opportunistic organism and is the most common systemic mycoses in domestic cats and the cheetah.

Acinonyx↗
PubMed2003

Investigation of the dependence of inferred interfacial tension on rotation rate in a spinning drop tensiometer.

The spinning drop tensiometer is widely used to study the interfacial properties of many systems. However, there have also been several reported limitations with the spinning drop tensiometer. In this paper, it is shown that there is a relationship between the measured interfacial tension and the rotation rate of the drop. A detailed investigation of this relationship is presented.

Journal Article↗
PubMed2003

Dynamics of low-energy helium vapor pulses.

We report results of experiments in which pulses of helium vapor are produced by a current pulse in a chromium film covered with superfluid helium at around 0.3 K. The pulses were detected by a titanium bolometer operating at 0.47 K. The shape of the detected signal is a strong function of the power of the initiating current pulse. For low powers the signal from a single current pulse also contains a single peak, but for higher powers, a single current pulse produces two and then at the highest powers, three peak signals. To analyze the origin of these phenomena we report results of hybrid gas-dynamics and hydrodynamics simulations, which demonstrate that the signals arise from shock waves formed in the vapor. The shock waves form due to the presence of a gradient in the small ambient background of helium vapor in the chamber and are extremely sensitive to the pulse power.

Journal Article↗
PubMed2001

Mechanism for nucleic acid chaperone activity of HIV-1 nucleocapsid protein revealed by single molecule stretching.

The nucleocapsid protein (NC) of HIV type 1 is a nucleic acid chaperone that facilitates the rearrangement of nucleic acids into conformations containing the maximum number of complementary base pairs. We use an optical tweezers instrument to stretch single DNA molecules from the helix to coil state at room temperature in the presence of NC and a mutant form (SSHS NC) that lacks the two zinc finger structures present in NC. Although both NC and SSHS NC facilitate annealing of complementary strands through electrostatic attraction, only NC destabilizes the helical form of DNA and reduces the cooperativity of the helix-coil transition. In particular, we find that the helix-coil transition free energy at room temperature is significantly reduced in the presence of NC. Thus, upon NC binding, it is likely that thermodynamic fluctuations cause continuous melting and reannealing of base pairs so that DNA strands are able to rapidly sample configurations to find the lowest energy state. The reduced cooperativity allows these fluctuations to occur in the middle of complex double-stranded structures. The reduced stability and cooperativity, coupled with the electrostatic attraction generated by the high charge density of NC, is responsible for the nucleic acid chaperone activity of this protein.

DNA, Viral↗
PubMed2001

Effect of pH on the overstretching transition of double-stranded DNA: evidence of force-induced DNA melting.

When a single molecule of double-stranded DNA is stretched beyond its B-form contour length, the measured force shows a highly cooperative overstretching transition. We have investigated the source of this transition by altering helix stability with solution pH. As solution pH was increased from pH 6.0 to pH 10.6 in 250 mM NaCl, the overstretching transition force decreased from 67.0 +/- 0.8 pN to 56.2 +/- 0.8 pN, whereas the transition width remained nearly constant. As the pH was lowered from pH 6.0 to pH 3.1, the overstretching force decreased from 67.0 +/- 0.8 pN to 47.0 +/- 1.0 pN, but the transition width increased from 3.0 +/- 0.6 pN to 16.0 +/- 3 pN. These results quantitatively agree with a model that asserts that DNA strand dissociation, or melting, occurs during the overstretching transition.

Biophysical Phenomena↗
PubMed2001

Entropy and heat capacity of DNA melting from temperature dependence of single molecule stretching.

When a single molecule of double-stranded DNA is stretched beyond its B-form contour length, the measured force shows a highly cooperative overstretching transition. We have measured the force at which this transition occurs as a function of temperature. To do this, single molecules of DNA were captured between two polystyrene beads in an optical tweezers apparatus. As the temperature of the solution surrounding a captured molecule was increased from 11 degrees C to 52 degrees C in 500 mM NaCl, the overstretching transition force decreased from 69 pN to 50 pN. This reduction is attributed to a decrease in the stability of the DNA double helix with increasing temperature. These results quantitatively agree with a model that asserts that DNA melting occurs during the overstretching transition. With this model, the data may be analyzed to obtain the change in the melting entropy DeltaS of DNA with temperature. The observed nonlinear temperature dependence of DeltaS is a result of the positive change in heat capacity of DNA upon melting, which we determine from our stretching measurements to be DeltaC(p) = 60 +/- 10 cal/mol K bp, in agreement with calorimetric measurements.

Calorimetry↗
PubMed2001

Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase.

The mitochondrial enzyme 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) plays an important role in calcium homeostasis by catalyzing synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D(3), in the kidney. However, enzyme activity assays indicate that 1 alpha-hydroxylase is also expressed in a variety of extrarenal tissues; recent cloning of cDNAs for 1 alpha-hydroxylase in different species suggests that a similar gene product is found at both renal and extrarenal sites. Using specific complementary ribonucleic acid probes and antisera to 1 alpha-hydroxylase, we have previously reported the distribution of messenger ribonucleic acid and protein for the enzyme along the mouse and human nephron. Here we describe further immunohistochemical and Western blot analyses that detail for the first time the extrarenal distribution of 1 alpha-hydroxylase in both normal and diseased tissues. Specific staining for 1 alpha-hydroxylase was detected in skin (basal keratinocytes, hair follicles), lymph nodes (granulomata), colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex), and placenta (decidual and trophoblastic cells). Further studies using psoriatic skin highlighted overexpression of 1 alpha-hydroxylase throughout the dysregulated stratum spinosum. Increased expression of skin 1alpha-hydroxylase was also associated with sarcoidosis. In lymph nodes and skin from these patients 1 alpha-hydroxylase expression was observed in cells positive for the surface antigen CD68 (macrophages). The data presented here confirm the presence of protein for 1 alpha-hydroxylase in several extrarenal tissues, such as skin, placenta, and lymph nodes. The function of this enzyme at novel extrarenal sites, such as adrenal medulla, brain, pancreas, and colon, remains to be determined. However, the discrete patterns of staining in these tissues emphasizes a possible role for 1 alpha-hydroxylase as an intracrine modulator of vitamin D function in peripheral tissues.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2001

Bone marrow-derived cells as progenitors of lung alveolar epithelium.

We assessed the capacity of plastic-adherent cultured bone marrow cells to serve as precursors of differentiated parenchymal cells of the lung. By intravenously delivering lacZ-labeled cells into wild-type recipient mice after bleomycin-induced lung injury, we detected marrow-derived cells engrafted in recipient lung parenchyma as cells with the morphological and molecular phenotype of type I pneumocytes of the alveolar epithelium. At no time after marrow cell injection, did we detect any engraftment as type II pneumocytes. In addition, we found that cultured and fresh aspirates of bone marrow cells can express the type I pneumocyte markers, T1alpha and aquaporin-5. These observations challenge the current belief that adult alveolar type I epithelial cells invariably arise from local precursor cells and raise the possibility of using injected marrow-derived cells for therapy of lung diseases characterized by extensive alveolar damage.

Animals↗
PubMed2000

Cytosine methylation of an Sp1 site contributes to organ-specific and cell-specific regulation of expression of the lung epithelial gene t1alpha.

Several recent observations have suggested that cytosine methylation has a role in the in vivo transcriptional regulation of cell-specific genes in normal cells. We hypothesized that methylation regulates T1alpha, a gene expressed primarily in lung in adult rodents. In fetuses T1alpha is expressed in several organs, including the entire nervous system, but during development its expression is progressively restricted to lung alveolar type I epithelial cells, some osteoblasts and choroid plexus. Here we report that T1alpha is methylated at a key Sp1 site in the proximal promoter in cells and organs, including brain, where no gene expression is detectable. Conversely, in T1alpha-expressing cells, these sites are not methylated. In embryonic brain T1alpha is unmethylated and expressed; in adult brain the gene is methylated and not expressed. In lung epithelial cell lines, methylation of the T1alpha promoter in vitro decreases expression by approx. 50% (the maximum suppression being 100%). Analysis of mutated promoter constructs indicates that a single Sp1 site in the proximal promoter provides all or most of the methylation-sensitive gene silencing. We conclude that, in addition to regulation by transcription factors, cytosine methylation has a role in the complex expression patterns of this gene in intact animals and primary cells.

Animals↗
PubMed2000

Role of nitric oxide in a toxin-induced model of haemolytic uraemic syndrome.

The role of nitric oxide in the pathogenesis of glomerular thrombotic microangiopathy was explored using an established rat model in which ricin with or without lipopolysaccharide induced glomerular thrombosis. Ricin alone caused a small rise in the plasma concentration of nitric oxide (control 9.2+/-0.7 microM, ricin 23.3+/-6.3 microM at 7 h). This increase occurred after the development of glomerular thrombosis. Nitric oxide synthase (NOS) activity in the kidney showed no significant change from control values (control 5.66+/-2.7 pmol/min per ml homogenate, ricin 7.52+/-1.8 pmol/min per ml homogenate, total activity). When ricin and lipopolysaccharide were administered together, calcium-independent NOS activity increased whereas calcium-dependent activity decreased (1.22+/-2.6 pmol/min per ml homogenate). The increase in calcium-independent NOS activity correlated with a high plasma concentration of interleukin-1beta in the ricin plus lipopolysaccharide group (4,036.83+/-1,001.5 pg/ml). These data indicate that thrombus formation in a rat model of haemolytic uraemic syndrome is independent of the effects of nitric oxide.

Animals↗
PubMed2000

Histologic chorioamnionitis is associated with fetal growth restriction in term and preterm infants.

OBJECTIVE: Our aim was to evaluate associations between chorioamnionitis and fetal growth restriction in infants enrolled in the Collaborative Perinatal Project. STUDY DESIGN: A total of 2579 nonanomalous, singleton infants delivered at 28 to 44 weeks' gestation with chorioamnionitis were matched 1:3 for ethnicity, gestational age, parity, and maternal cigarette use (all of which were correlated with both chorioamnionitis and markers of fetal growth restriction) with 7732 control infants. Moderate or marked leukocytic infiltrates of the placenta defined chorioamnionitis. Birth weight, length, head circumference, weight/length ratio, ponderal index, and birth weight/head circumference ratio in the lowest 5th percentile were markers of fetal growth restriction. Placental weight and the birth weight/placental weight ratio were also evaluated. RESULTS: Compared with data on matched control infants, histologic chorioamnionitis was associated with all markers of fetal growth restriction and with low birth weight/placental weight ratios (odds ratios, 1.3-1.7). The strongest associations were found at 28 to 32 weeks' gestation (odds ratios, 2.2-11). Attributable risks for several markers of fetal growth restriction exceeded 50% in infants born at <33 weeks' gestation. CONCLUSION: Histologic chorioamnionitis is associated with multiple markers of fetal growth restriction, with stronger associations noted in prematurity.

Adult↗
PubMed2000

Aquaporin-5 expression, but not other peripheral lung marker genes, is reduced in PTH/PTHrP receptor null mutant fetal mice.

Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor are important developmental regulators of cell growth and differentiation in some organs. In lung, both the peptide and the receptor are expressed early in development and in alveolar cells in adults. In adult alveolar cells, PTHrP appears to promote the alveolar type II cell phenotype in vitro. Mice carrying null mutations in genes for either receptor or ligand die at birth of respiratory failure. To determine if absence of the PTH/PTHrP receptor alters morphogenesis or cellular differentiation of the distal lung, we analyzed the morphology and gene expression patterns in PTH/PTHrP receptor null mutant mice right before birth and compared them with wild-type and heterozygous null littermates. Using semiquantitative Northern blots, we observed that messenger RNA (mRNA) for aquaporin-5, the type I cell-specific water channel, was markedly decreased. The abundance of other marker mRNAs for type I and type II cell phenotypes, including T1alpha, surfactant proteins, and others, was unaltered. Gross morphology and lung pattern, assessed by in situ hybridization for surfactant protein C, were normal. We conclude therefore that, although signaling through this receptor may influence expression of specific lung genes, it does not play a major role in the general regulation of lung development and growth.

Animals↗
PubMed2000

Fetal abdominal circumference measurements of 35 and 38 cm as predictors of macrosomia. A risk factor for shoulder dystocia.

OBJECTIVE: To determine if ultrasound measurements of fetal abdominal circumference (AC) can be used to predict macrosomic infants. STUDY DESIGN: Using a computer database, 1,996 women at > or = 36 weeks' gestation, delivering a singleton infant and having an ultrasound examination within one week of delivery were studied. Fetal AC was evaluated to determine if it was useful in predicting the birth of a macrosomic infant, > 4,000 or > 4,500 g. RESULTS: AC predicted infants > 4,500 g better than those > 4,000 g. Almost all macrosomic infants > 4,500 g had an AC of > or = 35 cm (68/69, or 99%), but many nonmacrosomic infants were also in this group (683). AC of > or = 38 cm occurred in 99 infants, and 37 of the 69 (53.6%) weighing > 4,500 g were identified. Most infants (78%) with AC > or = 38 cm weighed > 4,000 g. CONCLUSION: Fetal AC was very helpful in identifying potential macrosomic infants. If AC was < 35 cm, the risk of infant birth weights > 4,500 g was < 1%. If AC was > or = 38 cm, the risk was 37% (37/99), and > 50% of these infants were identified (37/69, or 53.6%).

Abdomen↗
PubMed2000

Developmental changes in California Card Sorting Test performance.

The purpose of the present study was to determine 1) if performance on the California Card Sorting Test (CCST) follows the same developmental gradient as other measures of concept formation and 2) whether the components of concept formation tapped by the CCST are developmentally dissociable. Participants were 68 children and young adults in four age-based groups: 7 to 9 years (n = 13); 10 to 12 years (n = 16); 17 to 19 (n = 20); and, 20 to 22 years (n = 19). All were of average or higher measured intelligence and screened for neurological, psychiatric, reading and attentional disorder. The findings of the present study suggest that like many other concept formation tasks, CCST performance approximates adult levels by age 10. Further, the different components of concept formation measured by the CCST are dissociable in the youngest children with the development of concept recognition preceding sorting ability.

Journal Article↗
PubMed1999

1.3 kilobases of the lung type I cell T1alpha gene promoter mimics endogenous gene expression patterns during development but lacks sequences to enhance expression in perinatal and adult lung.

The T1alpha gene is one of few markers for the type I cell phenotype in the adult mammalian lung. Type I cells form a large, thin epithelial layer that facilitates gas exchange and transport of fluids between the air spaces and capillaries. The T1alpha gene has a complex pattern of developmental expression in lung and brain; in vitro studies indicate that expression is regulated in part by thyroid transcription factor 1, forkhead proteins, and Sp1/Sp3 proteins. To explore the mechanisms that confine T1alpha expression in intact adult animals to alveolar type I and choroid plexus epithelial cells, we generated mice bearing a 1.3-kb T1alpha promoter-chloramphenicol acetyltransferase (CAT) gene. In situ hybridization and RNase protection assays show that the 1.3-kb promoter confers a pattern of CAT expression that largely matches the endogenous T1alpha in embryos and mid-term fetuses in lung and central nervous system. However, the 1.3-kb promoter lacks elements important for perinatal up-regulation of T1alpha in the lung and maintenance of that expression in the adult lung and brain. The final adult pattern of T1alpha expression may be directed by elements outside the 1.3-kb fragment, perhaps those 5' to the 1.3-kb fragment as we show herein, or in 3' and intronic regions. Dev Dyn 1999;215:319-331.

Animals↗