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Biomedical subjects

S Clarke

Publications and source records attributed to S Clarke.

At least 163 records · Page 9Linked to original sources
PubMed1997

Face recognition and postero-inferior hemispheric lesions.

Two patients with severe and lasting prosopagnosia were studied for visuo-cognitive functions and anatomo-clinical correlations. Both patients were deficient in recognizing familiar faces and items of previously well known categories (plants and fish for patient 1, mountains for patient 2). Patient 2, but not patient 1, was also deficient for matching of unknown faces. Patient 1, but not patient 2, was achromatopsic. Both patients had bilateral symmetrical lesions. Patient 1 had a lesion of the inferior occipito-temporal cortex, including inferior parts of early stage visual areas. Patient 2 had a lesion of the inferior temporal and fusiform gyri anterior to the early stage visual areas. When compared in Talairach space, the lesions of both patients had minimal overlap. Thus, severe and lasting prosopagnosia was associated with two almost exclusive lesion sites in the postero-inferior part of the hemispheres. Comparison between activation studies of face processing (by others) and our lesion study uncovered several paradoxes. Lesions of regions involved in a given task in normal subjects do not produce a deficit in this task, as shown here for gender discrimination and partially for face matching. Conversely, lesions of a region not specifically involved in a given task in normal subjects can produce a deficit in the task, as shown here for face identification.

Brain Diseases↗
PubMed1997

Molecular phylogenetics of a protein repair methyltransferase.

Protein-L-isoaspartyl (D-aspartyl) O-methyltransferase (E.C. 2.1.1.77) is a well-conserved and widely distributed protein repair enzyme that methylates isomerized or racemized aspartyl residues in age-damaged proteins. We exploited the availability of protein sequences from 10 diverse animal, plant and bacterial taxa to construct a phylogenetic tree and determine the rates of amino acid substitution for this enzyme. We used a likelihood ratio test to show that this enzyme fulfills the conditions for a molecular clock. We found that the rate of substitution is 0.39 amino acid substitutions per site per 10(9) years and remains relatively constant from bacteria to humans. We argue that this degree of sequence conservation may result from the functional constraints necessitated by the requirement to specifically recognize altered aspartyl but not normal aspartyl residues in proteins. Relative rate analysis of the Caenorhabditis elegans sequence suggests that the amino acid substitution rate in the nematode lineage may be higher than that in other lineages and that the divergence of nematodes may have been a more recent event than suggested by previous analysis.

Amino Acid Sequence↗
PubMed1997

Is there a role for video-assisted thoracoscopy in the staging of non-small cell lung cancer?

OBJECTIVE: To evaluate the role of video-assisted thoracoscopy (VAT) in the staging of non-small cell lung cancer (NSCLC). METHODS: In 30 patients (18 male, 12 female, median age 62 (50-78) years) VAT was used to assess the operability of NSCLC in cases where doubt existed after conventional staging investigations had been performed. RESULTS: VAT was used to assess direct tumour invasion of adjacent organs in 17 patients (mediastinal invasion in 14 and chest wall invasion in 3 patients). In 4 patients with limited respiratory reserve, VAT confirmed the need only for lobectomy prior to thoracotomy. Mediastinal lymph node biopsy was performed in 5 patients with significant (> 1.5 cm) lymphadenopathy on CT scan. VAT was also used to assess bilateral lesions in 4 patients with suspected synchronous tumours. Conversion to thoracotomy was necessary in 4 patients for technical reasons. Successful resection was possible in 17 of the remaining 26 cases, while unnecessary thoracotomy was avoided in 9 patients (30%) with unresectable or benign disease. In 4 patients deemed inoperable on CT scan, VAT staging enabled subsequent resection. CONCLUSIONS: Video-assisted thoracoscopy appears to have a complementary role in staging NSCLC when other methods are equivocal. It has the potential for increased sensitivity over conventional staging methods.

Aged↗
PubMed1997

Management of potentially violent detainees.

Most doctors and other health care workers have at some time received threats of violence, but the assessment of police detainees can be especially challenging and in a recent study of police surgeons, 18% had experienced physical violence. Aggression towards carers rarely erupts without warning and there is much that the examining doctor can do to minimize personal risk. This review offers a brief overview of current understanding about the causes of violence and offers guidance on the systematic assessment of risk and how to manage this within the setting of a clinical assessment of a detained individual.

Journal Article↗
PubMed1997

Use of radioiodine in the management of hyperthyroidism in the UK: development of guidelines.

Although 131I therapy for hyperthyroidism has been in use for more than 50 years, there are wide variations in every aspect of its administration to patients. A recent survey of physicists and clinicians in the UK documented variations in workloads, responsibility for prescribing, and selection for treatment. Wide variations also were noted in terminology, radioiodine preparations, and activities and doses administered. There was a wide range of comments and reasons given by clinicians for their choice of regimen. The use of antithyroid drugs and beta-blockers before or after 131I therapy also was variable. As a result of these findings, a multidisciplinary group was convened to produce recommended guidelines for the administration of 131I in the UK. The implementation of these guidelines will require consensus among clinicians and this will require further evaluation.

Adrenergic beta-Antagonists↗
PubMed1997

Management of oral complications of disease-modifying drugs in rheumatoid arthritis.

Stomatitis is a troublesome adverse effect of disease-modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.

Aged↗
PubMed1997

Protein repair L-isoaspartyl methyltransferase in plants. Phylogenetic distribution and the accumulation of substrate proteins in aged barley seeds.

Protein L-isoaspartate (D-aspartate) O-methyltransferases (MTs; EC 2.1.1.77) can initiate the conversion of detrimental L-isoaspartyl residues in spontaneously damaged proteins to normal L-aspartyl residues. We detected this enzyme in 45 species from 23 families representing most of the divisions of the plant kingdom. MT activity is often localized in seeds, suggesting that it has a role in their maturation, quiescence, and germination. The relationship among MT activity, the accumulation of abnormal protein L-isoaspartyl residues, and seed viability was explored in barley (Hordeum vulgare cultivar Himalaya) seeds, which contain high levels of MT. Natural aging of barley seeds for 17 years resulted in a significant reduction in MT activity and in seed viability, coupled with increased levels of "unrepaired" L-isoaspartyl residues. In seeds heated to accelerate aging, we found no reduction of MT activity, but we did observe decreased seed viability and the accumulation of isoaspartyl residues. Among populations of accelerated aged seed, those possessing the highest levels of L-isoaspartyl-containing proteins had the lowest germination percentages. These results suggest that the MT present in seeds cannot efficiently repair all spontaneously damaged proteins containing altered aspartyl residues, and their accumulation during aging may contribute to the loss of seed viability.

Brassica↗
PubMed1997

RpoS- and OxyR-independent induction of HPI catalase at stationary phase in Escherichia coli and identification of rpoS mutations in common laboratory strains.

A rapid spectrophotometric assay to determine the activities of HPI and HPII catalases in Escherichia coli extracts has been developed. This assay is based upon the differential heat stabilities of the two enzymes and offers significant advantages over previous methods for quantitation of their activities. Measurement of catalase activities in extracts of various mutant strains confirmed the ability of this method to accurately distinguish the two activities. Contrary to previously published results, HPI catalase activity was observed to increase at stationary phase in strains lacking the stationary-phase sigma factor sigma(s) (RpoS). This increase was independent of OxyR and also occurred in a strain lacking the HPII structural gene, katE. These results suggest a potential novel pathway for HPI induction in response to increased oxidative stress in the absence of HPII. Measurement of HPII activity in strains carrying mutations in pcm (encoding the L-isoaspartyl protein methyltransferase) and surE led to the finding that these strains also have an amber mutation in rpoS; sequencing demonstrated the presence of this mutation in several commonly used laboratory strains of E. coli, including AB1157, W1485, and JC7623.

Acid Phosphatase↗
PubMed1997

D-aspartate content of erythrocyte membrane proteins is decreased in uremia: implications for the repair of damaged proteins.

The authors of this article have demonstrated that erythrocytes from patients affected by either chronic renal failure or ESRD, conditions associated with erythrocyte membrane disorders, show reduced levels of methyl esterified membrane proteins because of elevated S-adenosylhomocysteine concentration. The enzyme protein L-isospartyl (D-aspartyl) O-methyltransferase, responsible for the bulk of this methyl esterification, is implicated in the repair of proteins containing isomerized and racemized aspartyl residues, which arise from L-asparaginyl and L-aspartyl residues. The presence of these altered residues, spontaneously generated during protein aging, can adversely affect protein function. The amount of D- and L-aspartyl residues (and their isomerized derivatives) in erythrocyte membranes from hemodialysis patients was determined. The total level of D-aspartyl derivatives (D-Asx) actually was found to be lower than in controls. In contrast, neither the abundance of several other amino acids, nor of total non-Asx D-amino acids, differs between patients and controls. Mathematical simulation of relevant reactions supports the hypothesis that these effects reflect the lessening of the normal D-isoaspartyl residue accumulation that occurs as a side reaction in the methyltransferase-induced repair process. This evidence is the first that D-Asx content is influenced in vivo by L-isoaspartyl (D-aspartyl) O-methyltransferase activity and can be significantly altered in a disease where this activity is inhibited, thus representing a red flag in a disrupted circuit.

Adult↗
PubMed1997

Assessment-based intervention for severe behavior problems in a natural family context.

Functional assessments and assessment-based interventions were conducted with a boy with disabilities and severe problem behavior in the context of two family routines: using the bathroom in the family home and dining in a fast-food restaurant. A multiple baseline design demonstrated the effectiveness of the intervention package as implemented by the boy's mother in the two routines. The results provide a systematic replication and extension of behavior-analytic interventions in natural family contexts.

Behavior Therapy↗
PubMed1996

Phantom face: conscious correlate of neural reorganization after removal of primary sensory neurones.

A patient in whom mandibular and maxillary parts of right trigeminal ganglion were removed experienced referred sensations after stimulation of the right hand and right forehead. She described them either as parallel to the perception at the actual stimulation site or as coming uniquely from a (non-existent) stimulation of denervated territory. The latter occurred in 6-19% of stimulations performed on the right forehead and on digits 1, 3 and 4 of the right hand. Thumb stimulations were localized on the right side of the face, stimulations of right forehead, middle and ring fingers more precisely on right cheek. Referred sensations were present on postoperative day 7 and had a more real-like quality than 5 days later.

Brain Mapping↗
PubMed1996

Structure of the human gene encoding the protein repair L-isoaspartyl (D-aspartyl) O-methyltransferase.

The protein L-isoaspartyl/D-aspartyl O-methyltransferase (EC 2.1.1.77) catalyzes the first step in the repair of proteins damaged in the aging process by isomerization or racemization reactions at aspartyl and asparaginyl residues. A single gene has been localized to human chromosome 6 and multiple transcripts arising through alternative splicing have been identified. Restriction enzyme mapping, subcloning, and DNA sequence analysis of three overlapping clones from a human genomic library in bacteriophage P1 indicate that the gene spans approximately 60 kb and is composed of 8 exons interrupted by 7 introns. Analysis of intron/exon splice junctions reveals that all of the donor and acceptor splice sites are in agreement with the mammalian consensus splicing sequence. Determination of transcription initiation sites by primer extension analysis of poly(A)+ mRNA from human brain identifies multiple start sites, with a major site 159 nucleotides upstream from the ATG start codon. Sequence analysis of the 5'-untranslated region demonstrates several potential cis-acting DNA elements including SP1, ETF, AP1, AP2, ARE, XRE, CREB, MED-1, and half-palindromic ERE motifs. The promoter of this methyltransferase gene lacks an identifiable TATA box but is characterized by a CpG island which begins approximately 723 nucleotides upstream of the major transcriptional start site and extends through exon 1 and into the first intron. These features are characteristic of housekeeping genes and are consistent with the wide tissue distribution observed for this methyltransferase activity.

Base Sequence↗
PubMed1996

Rapid mapping of genomic P1 clones: the mouse L-isoaspartyl/D-aspartyl methyltransferase gene.

We report the mapping of the gene for the murine protein-L-isoaspartate (D-aspartate) O-methyltransferase (EC 2.1.1. 77) from a 129 mouse strain. This gene encodes an enzyme present in all tissues that can catalyze the first step of a repair reaction in which age-damaged proteins containing abnormal l-isoaspartyl (or d-aspartyl) residues can be converted to forms containing normal l-aspartyl residues. We first mapped the restriction sites from a genomic P1 clone using a rapid method generally applicable to all bacteriophage P1 clones containing large DNA inserts. We show that a single pulsed-field electrophoresis blot can be used to map an entire 89-kb P1 clone insert for eight restriction endonucleases with an error of no more than 2% of the length of the fragment, or 1 kb at the middle of the insert. In this method, we combine complete restriction endonuclease digestion at rare sites within the P1 vector with partial restriction endonuclease digestion within the insert. After size separation by pulsed-field gel electrophoresis and blotting, the fragments are detected by Southern hybridization with probes to the vector. This method is potentially useful for restriction mapping other large DNA clones such as artificial chromosomes. We then determined the positions of the exons of the methyltransferase gene by restriction mapping of long PCR fragments. The previously unidentified exon 8, which encodes the -DEL C-terminus of the more acidic isozyme II, was sequenced and mapped 5. 3 kb from the end of exon 7.

Animals↗
PubMed1996

The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase.

The TIS21 immediate-early gene and leukemia-associated BTG1 gene encode proteins with similar sequences. Two-hybrid analysis identified a protein that interacts with TIS21 and BTG1. Sequence motifs associated with S-adenosyl-L-methionine binding suggested this protein might have methyltransferase activity. A glutathione S-transferase (GST) fusion of the putative methyltransferase modifies arginine residues, in appropriate protein substrates, to form NG-monomethyl and NG,NG-dimethylarginine (asymmetric). We term the protein- arginine N-methyltransferase (EC 2.1.1.23) gene "PRMT1, " for protein-arginine methyltransferase 1. GST-TIS21 and GST-BTG1 fusion proteins qualitatively and quantitatively modulate endogenous PRMT1 activity, using control and hypomethylated RAT1 cell extracts as methyl-accepting substrates. PRMT1 message appears ubiquitous, and is constitutive in mitogen-stimulated cells. Modulation of PRMT1 activity by transiently expressed regulatory subunits may be an additional mode of signal transduction following ligand stimulation.

Amino Acid Sequence↗
PubMed1996

Problem peanuts.

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Anaphylaxis↗
PubMed1996

The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae.

We have identified the major enzymatic activity responsible for the S-adenosyl-L-methionine-dependent methylation of arginine residues (EC 2.1.1.23) in proteins of the yeast Saccharomyces cerevisiae. The RMT1 (protein-arginine methyltransferase), formerly ODP1, gene product encodes a 348-residue polypeptide of 39.8 kDa that catalyzes both the NG-mono- and NG, NG-asymmetric dimethylation of arginine residues in a variety of endogenous yeast polypeptides. A yeast strain in which the chromosomal RMT1 gene was disrupted is viable, but the level of NG,NG-[3H]dimethylarginine residues detected in intact cells incubated with S-adenosyl-L-[methyl-3H]methionine is reduced to less than 15% of the levels found in the parent strain, while the NG-[3H]monomethylarginine content is reduced to less than 30%. We show that soluble extract from parent cell, but not from mutant rmt1 cells, catalyzes the in vitro methylation of endogenous polypeptides of 55, 41, 38, 34, and 30 kDa. The hypomethylated form of these five polypeptides, as well as that of several others, can be mono- and asymmetrically dimethylated by incubating the mutant rmt1 extract with a purified, bacterially produced, glutathione S-transferase-RMT1 fusion protein and S-adenosyl-L-[methyl-3H]methionine. This glutathione S-transferase-RMT1 fusion protein is also able to methylate a number of mammalian polypeptides including histones, recombinant heterogeneous ribonucleoprotein A1, cytochrome c, and myoglobin, but cannot methylate myelin basic protein. RMT1 appears to be a yeast homolog of a recently characterized mammalian protein-arginine methyltransferase whose activity may be modulated by mitotic stimulation of cells.

Amino Acid Sequence↗
PubMed1996

The human lysozyme promoter directs reporter gene expression to activated myelomonocytic cells in transgenic mice.

The 5' region of the human lysozyme gene from -3500 to +25 was fused to a chloramphenicol acetyltransferase (CAT) reporter gene and three transgenic founder mice were obtained. All three transgenic lines showed the same pattern of CAT enzyme expression in adult mouse tissues that was consistent with the targeting of elicited, activated macrophages in tissues and developing and elicited granulocytes. In normal mice high CAT enzyme activity was found in the spleen, lung, and thymus, tissues rich in phagocytically active cells, but not in many other tissues, such as the gut and muscle, which contain resident macrophages. Cultured resident peritoneal macrophages and cells elicited 18 hr (granulocytes) and 4 days (macrophages) after injection of sterile thioglycollate broth expressed CAT activity. Bacillus Calmette-Guérin infection of transgenic mice resulted in CAT enzyme expression in the liver, which contained macrophage-rich granulomas, whereas the liver of uninfected mice did not have any detectable CAT enzyme activity. Although the Paneth cells of the small intestine in both human and mouse produce lysozyme, the CAT gene, under the control of the human lysozyme promoter, was not expressed in the mouse small intestine. These results indicate that the human lysozyme promoter region may be used to direct expression of genes to activated mouse myeloid cells.

Animals↗