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Biomedical subjects

R M Williamson

Publications and source records attributed to R M Williamson.

At least 19 recordsLinked to original sources
PubMed2002

Squamous cell carcinoma of the eyelids.

AIM: To review the clinical features, management, and outcomes of surgical treatment of eyelid squamous cell carcinoma (SCC). METHODS: A retrospective review of all eyelid SCCs treated between 1992 and 2001. RESULTS: 51 cases were identified in 50 patients. Patient ages ranged from 26 to 93 years, with a mean age of 65 years. 33 patients were male and 17 were female. The lesion was found on the lower lid in 31 cases, upper lid in five cases, lateral canthus in six cases, and medial canthus in nine cases. Perineural invasion was found in four patients, and orbital invasion in three patients. Recurrence occurred in one patient. Treatment was by complete excision with histological confirmation of clear margins. Exenteration was required in three patients. No patients developed lymph node or distant metastases. One patient, who declined treatment, died as a result of the tumour. Mean follow up was 31.1 months. CONCLUSIONS: Eyelid SCC is a relatively uncommon, but potentially fatal disease. However, if detected early and treated adequately, the prognosis is generally excellent. Treatment by complete excision with histological confirmation of tumour clearance is recommended. Perineural spread is an adverse prognostic sign, which may require postoperative radiotherapy. Orbital invasion is a rare complication but, if recognised early, can be treated effectively with exenteration. Because presentation varies and histological examination is required for accurate diagnosis, any suspicious lesion occurring on the eyelids should be excised or biopsied. All patients with eyelid SCC should be advised of the risk of recurrent or new tumours and encouraged to attend lifelong follow up. Prevention remains of prime importance in minimising the morbidity and mortality of these lesions.

Adult↗
PubMed2001

Stereocontrol of intramolecular Diels-Alder reactions: synthetic studies and transition structure modeling with c5-substituted 1,3,8-nonatrienes and nonadienynes.

An investigation into the endo/exo selectivity and pi-diastereofacial selectivity of ester-tethered intramolecular Diels-Alder reactions is reported. High levels of exo selectivity are realized with terminally substituted dienophiles, and high lk pi-diastereofacial selectivities are induced by the presence of a bulky dioxolanyl substituent at the allylic position of the tether. Precursors 19S, 20S, and 21S, readily prepared from glucose, provide densely functionalized bicyclic lactones of predictable stereochemistry in high yields in enantiomerically pure form upon thermolysis at 110 degrees C. B3LYP/6-31G(d) theory provides good descriptions of transition structures for these reactions and allows an understanding of the formation of the major cycloadducts.

Journal Article↗
PubMed1999

Evidence for overlapping substrate specificity between large neutral amino acid (LNAA) and dipeptide (hPEPT1) transporters for PD 158473, an NMDA antagonist.

PURPOSE: The objective of this research was to investigate the substrate specificity of large neutral amino acid carrier (LNAA) and di/tripeptide (hPEPT1) transporters with respect to PD 158473, an NMDA antagonist. METHODS: Cellular uptake studies were carried out using two types of Chinese Hamster Ovary (CHO). CHO-K1 cells represent the wild type with inherent large neutral amino acid (LNAA) activity. CHO-PEPT1 cells were generated by stable transfection of hPEPT1 gene into CHO cells. Therefore, these cells possess both LNAA activity and di/tripeptide transporter activities as a result of the transfection. Cellular uptake of PD 158473 was quantified using a HPLC method previously developed in our laboratory. RESULTS: The utility of the CHO-PEPT1 cell model was demonstrated by determining the uptake kinetics of Gly-Sar, a prototypical dipeptide transporter substrate. Uptake kinetics of PD 158473 displayed two carrier-mediated transport components in CHO-PEPT1 cells, while in CHO-K1 cells the relationship was consistent with classic one component Michaelis-Menten kinetics. These results confirmed the affinity of PD 158473 for both LNAA and di/tripeptide transporters. Further, results from inhibition experiments using these two cell types indicate that the high affinity-low capacity system was the LNAA carrier and the low affinity-high capacity carrier was the di/tripeptide transporter. CONCLUSIONS: This study demonstrates overlapping substrate specificity between LNAA carrier and di/tripeptide transporter (hPEPT1) for PD 158473, an amino acid analog. Establishing Structure Transport Relationship (STR) for this overlap will aid in a design strategy for increasing oral absorption or targeting specific drugs to selected tissues.

Amino Acid Transport Systems↗
PubMed1998

Coprological methods for the diagnosis of Anoplocephala perfoliata infection of the horse.

OBJECTIVE: To compare the sensitivities of three coprological techniques for the diagnosis of Anoplocephala perfoliata infection in horses and to assess the value of the methods for diagnosis of horses at risk of clinical cestodiasis. DESIGN: Faecal samples were collected from necropsied horses with or without A perfoliata infection and examined using one sedimentation and two different flotation methods. The coprological results were compared with worm counts performed at necropsy of the horses and the degree of mucosal damage. In addition, the efficiency of recovery of A perfoliata eggs from faeces was tested. RESULTS: The overall sensitivities of the methods ranged from 22.5 to 37.5%, and the capacity of the methods to diagnose infection increased with the intensity of infection. A simple flotation method achieved a better sensitivity (37.5%) at all intensities of infection compared with the other two methods (22.5 to 25%). That method was also more sensitive in detecting eggs in 'negative' faecal samples spiked with known numbers of A perfoliata eggs. CONCLUSION: The results indicated that, despite the low sensitivities of present methods, faecal flotation is likely to be of value in detecting horses at risk of clinical disease.

Animals↗
PubMed1997

The distribution of Anoplocephala perfoliata in the intestine of the horse and associated pathological changes.

The intestinal tracts of 130 horses were examined for infection with Anoplocephala perfoliata at necropsy. Fifty horses (38.5%) harboured the tapeworm, and the site of attachment of each worm was recorded using predetermined anatomical landmarks. The worms were attached in four regions of the gastrointestinal tract: 17% of the worms were found at the ileocaecal junction, 81% on the caecal wall, 1.7% in the terminal ileum and 0.2% in the ventral colon. The severity of lesions produced at the sites of attachment was related to the number of worms attached. Due to the small area of the ileocaecal junction, worms at this site were attached in close proximity, resulting in more severe lesions. The major features of the lesions included ulceration, diphtheritic membranes and thickening of the mucosa, submucosa and lamina propria. There was an increase in the number of eosinophils and a decrease in the number of lymphocytes present at the sites of lesions.

Animals↗
PubMed1997

Large intestinal lymphocytic phlebitis and venulitis in chronic ulcerative colitis.

Colonic vasculitis is seen in Crohn's disease and as a component of primary systemic vasculitis. It has rarely been described in chronic ulcerative colitis. Here we report a case of ulcerative colitis with prominent transmural lymphocytic phlebitis and venulitis. Although this is, to our knowledge, the first description of such an association, its recognition is important if confusion with other entities is to be avoided. The etiology of the vascular changes is unclear but they may be a secondary phenomenon induced by antigens, toxins or cytokines draining from the inflamed mucosa.

Chronic Disease↗
PubMed1995

Potent, orally active, competitive N-methyl-D-aspartate (NMDA) receptor antagonists are substrates for a neutral amino acid uptake system in Chinese hamster ovary cells.

A series of enantiomerically pure (phosphonomethyl)-substituted phenylalanine derivatives related to SDZ EAB 515 (1) were prepared as competitive N-methyl-D-aspartate (NMDA) receptor antagonists. Unlike most known competitive NMDA antagonists, analogs in this series with the S-configuration are potent NMDA antagonists whereas analogs with the unnatural R-configuration are weak NMDA antagonists, as determined by receptor binding experiments and their anticonvulsant action in mice. Examination in a previously reported competitive NMDA pharmacophore model revealed that receptor affinity can be explained partially by a cavity that accommodates the biphenyl ring of 1, while the biphenyl ring of the R-enantiomer 2 extends into a disallowed steric region. We proposed that analogs with the natural S-configuration and a large hydrophobic moiety would have an advantage in vivo over analogs with an R-configuration by being able to use a neutral amino acid uptake system to enhance both peripheral adsorption and transport into the brain. Examination in a system L neutral amino acid transport carrier assay shows that 1 competes with L-Phe for transport in an apparent competitive and stereospecific manner (estimated Ki = 50 microM). The 1- and 2-naphthyl derivatives 3a,3b were found to be among the most potent, competitive NMDA antagonists yet discovered, being ca. 15-fold more potent than 1 in vitro and in vivo, with a long duration of action. The title compound 3a had potent oral activity in MES (ED50 = 5.0 mg/kg). 3a also retains its ability to compete, albeit more weakly than 1 (estimated Ki = 200 microM), for L-Phe uptake to CHO cells. In this series, analogs with the R-configuration are not substrates for the system L neutral amino acid transport carrier. These results provide evidence that central nervous system active agents can be designed as substrates of a neutral amino acid transporter as a means to enhance penetration of the blood-brain barrier.

2-Amino-5-phosphonovalerate↗
PubMed1995

Information theory analysis of the relationship between primary sequence structure and ligand recognition among a class of facilitated transporters.

Determining how specificity for a given ligand occurs among sequence and structurally related transporters is a fundamental problem in elucidating facilitated transport. It is likely that the specificity of a transporter for a ligand is defined by the primary amino acid sequence, and that different ligand specificities among highly related proteins are associated with variations in the amino acid sequence. To assist studies on the potential relationships between protein structure and ligand specificity, information theory was used to assign a measure that quantitates the importance of amino acid choice at individual sites in protein sequences based upon their variability. The approach allows for the transformation of a collection of multiply aligned sequences into a profile that provides a quantitative assessment of the relative frequencies of chemically similar residues at each site. Profiles generated from particular groups of proteins can be directly compared to profiles generated for other groups. These comparisons allow unique differences in the utilization of amino acids at individual sites to be identified as differences in information distribution. The approach was applied to the problem of identifying sites of the dopamine transporter which may play a role in distinguishing its ligand specificity and function from those of a related population of transporters for amino acid and amino-acid-like ligands. Several sites were identified that appear highly likely to distinguish the dopamine transporter from related proteins. Many of the sites identified were also found to be associated with predicted variations in local secondary and tertiary structure between the two classes of proteins.

Animals↗
PubMed1993

Membrane association of leucyl-tRNA synthetase during leucine starvation in Escherichia coli.

The influence of leucine starvation on the subcellular location of leucyl-tRNA synthetase in Escherichia coli was examined in a leucine auxotrophic strain by sucrose density sedimentation analysis. Analysis of the subcellular distribution of leucyl-tRNA synthetase activity revealed that during unrestricted growth, the leucine synthetase enzyme activity was found to be localized in the soluble protein fraction of the gradient. However, during restricted growth on low levels of leucine, leucyl-tRNA synthetase activity was localized in the cytoplasmic membrane fraction of the gradient. The transition from soluble to membrane-association of the enzyme also occurred following inhibition of protein synthesis by treatment of cells with chloramphenicol. These results collectively suggest that leucyl-tRNA synthetase may be recruited to the cytoplasmic membrane in response to shortages of leucine or perturbation of protein synthesis.

Cell Compartmentation↗
PubMed1993

Detection of fundamental principles and a level of order for large-scale gene clustering on the Escherichia coli chromosome.

The Escherichia coli K-12 genetic map was divided into intervals of equal length to count the number of genes per interval. Plots of genes per interval at four sets of interval lengths revealed large-scale clustering of genes with the major clusters occurring at regularly spaced distances apart. Major gene cluster properties were analyzed at a scale of 100 intervals wherein each interval corresponded to a genetic map unit length of 1 min. In any major gene cluster, the highest gene concentration was observed at or near the midpoint interval, and the number of genes per interval was found to decline exponentially as a function of the linear distance from the midpoint or interval of peak gene concentration of that cluster. An autocorrelation analysis of gene content in first-neighbor intervals throughout the chromosome revealed an ordered first-neighbor relationship in comparison to 2,000 randomized interval versions of the chromosome. Attempts to simulate gene placement by a Gaussian model did not produce large-scale gene clustering in any way comparable to that observed on the chromosome. We propose that major gene clusters formed from smaller gene clusters, and the contemporary chromosome formed from fusion of homologous or heterologous major gene clusters.

Chromosome Mapping↗
PubMed1993

Ethionine-induced atrophy of rat pancreas involves apoptosis of acinar cells.

The mechanism of acinar cell loss occurring during ethionine-induced atrophy of the pancreas was investigated. Rats were given a standard diet, a protein-depletion diet (PDD), or a PDD with low- (0.04 g/kg body wt; LDE) or high- (0.4 g/kg; HDE) dose ethionine administered intraperitoneally daily for 10 days. Changes were most extensive in the animals given a PDD and HDE: After 10 days, pancreatic weight was reduced by 72%, and most of the acinar cells had disappeared. Prior to their deletion, these cells showed cytoplasmic vacuolation and enhanced autophagy. The main mechanism involved in their deletion was apoptosis, the apoptotic bodies being phagocytosed and degraded by adjacent acinar cells and intraepithelial macrophages. In contrast, necrosis of acinar cells was rare. Interstitial inflammation and apoptosis of capillary endothelial cells were also observed. In animals given a PDD and LDE, enhanced apoptosis occurred later and was more limited in extent, and additional manifestations of cell injury were not evident. As in other circumstances where glandular atrophy is effected by apoptosis, the basic tissue architecture was preserved, thus explaining the known capacity for the pancreas to regenerate after ethionine is discontinued.

Animals↗
PubMed1992

Premature termination of in vivo transcription of a gene encoding a branched-chain amino acid transport protein in Escherichia coli.

Previous studies have suggested that control of expression of genes of the LIV-I permease system for the high-affinity transport of branched-chain amino acids in Escherichia coli involves modulation in the frequency of mRNA elongation. Mutation of the Rho transcription termination factor and shortages of charged leucyl-tRNA have been shown to alter LIV-I transport activity. Rho-dependent transcription termination regulated by shortages of charged leucyl-tRNA at sites preceding structural genes has been proposed to account for their role in regulation of LIV-I transport. Transcription of the livJ-binding protein gene, encoding one of the periplasmic components of the LIV-I system, was analyzed in vivo with strains which lack repression of the LIV-I genes and harbor a temperature-sensitive allele for either leucyl-tRNA synthetase or Rho factor. Analysis of mRNA synthesis by DNA-RNA hybridization in the various mutant strains indicated that both shortages of leucyl-tRNA caused by inactivation of the temperature-sensitive leucyl-tRNA synthetase and inactivation of the Rho factor were associated with increased synthesis of livJ mRNA. Nuclease protection and gel electrophoresis studies detected prematurely terminated transcripts corresponding in size to the leader region of livJ mRNA. Accumulations of these short transcripts were suppressed in strains harboring temperature-sensitive alleles for either leucyl-tRNA synthetase or Rho factor. These results provide support for the hypothesis that expression of livJ involves Rho-dependent transcription termination in which antitermination is associated with the intracellular availability of aminoacyl leucyl-tRNA.

Amino Acids, Branched-Chain↗
PubMed1990

Sequence and structural similarities between the leucine-specific binding protein and leucyl-tRNA synthetase of Escherichia coli.

A role for the leucyl-tRNA synthetase (EC 6.1.1.4) has been established for regulating the transport of leucine across the inner membrane of Escherichia coli by the leucine, isoleucine, valine (LIV-I) transport system. This transport system is mediated by interactions of periplasmic binding proteins with a complex of membrane-associated proteins, and transcription of the high-affinity branched-chain amino acid transport system genes is repressed by growth of E. coli on high levels of leucine. We now report results from sequence comparisons and structural modeling studies, which indicate that the leucine-specific binding protein, one of the periplasmic components of the LIV-I transport system, contains a 121-residue stretch, representing 36% of the mature protein, which displays both sequence and structural similarities to a region within the putative nucleotide-binding domain of leucyl-tRNA synthetase. Early fusion events between ancestral genes for the leucine-specific binding protein and leucyl-tRNA synthetase could account for the similarity and suggest that processes of aminoacylation and transport for leucine in E. coli may be performed by evolutionarily interrelated proteins.

Amino Acid Sequence↗
PubMed1987

Common evolutionary origin of the ilvGMEDA attenuation locus and tRNA(1Leu) in Escherichia coli.

Published sequences of transcripts from ilvGMEDA leader regions of several enteric bacteria were compared with published sequences of the tRNAs from Escherichia coli. The analyses revealed homology between the ilvGMEDA leader peptide-coding region and tRNA(1Leu) in E. coli, Salmonella typhimurium, and Klebsiella aerogenes, whereas homology was not present in Serratia marcescens and Edwardsiella tarda.

Biological Evolution↗