Chemical modifications of deposited amyloid-beta peptides.
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Alzheimer Disease↗
Biomedical subjects
S Clarke
Publications and source records attributed to S Clarke.
Simultaneous EEG and EDA measures in adolescent attention deficit hyperactivity disorder.
Adolescent unmedicated ADHD males and age- and sex-matched normal control subjects were examined simultaneously using EEG and EDA measures in a resting eyes-open condition. ADHD adolescents showed increased absolute and relative Theta and Alpha1 activity, reduced relative Beta activity, reduced skin conductance level (SCL) and a reduced number of non-specific skin conductance responses (NS.SCRs) compared with the control subjects. Our findings indicate the continuation of increased slow wave activity in ADHD adolescents and the presence of a state of autonomic hypoarousal in this clinical group.
Adolescent↗
Informed consent and general surgeons' attitudes toward the use of pain medication in the acute abdomen.
To determine general surgeons' attitudes about the use of pain medications in the acute abdomen, a questionnaire was mailed to all practicing general surgeons in Iowa. The questionnaire sought to determine the frequency with which pain medications were administered either before informed consent was obtained or before the patient with an acute abdomen was examined, and, in cases when pain medications were withheld, the reasons for withholding. The response rate was 72% (131 of 182). Seven percent of patients with an acute abdomen received pain medications by a general surgeon before being seen and 22% received pain medication by another physician in the emergency department (ED). Fifty-three percent of general surgeons responded that they believe pain medications preclude a patient from signing a valid informed consent; 78% reported that concerns about informed consent enter into their decision to withhold pain medications. Sixty-seven percent agreed that pain medications interfere with diagnostic accuracy, and 82% consider diagnostic accuracy when deciding to withhold pain medication.
Abdomen, Acute↗
The effect of mannitol versus dimethyl thiourea at attenuating ischemia/reperfusion-induced injury to skeletal muscle.
OBJECTIVE: Mannitol is used as a treatment for skeletal muscle ischemia/reperfusion (I/R) injury in humans, despite the fact that its effectiveness in vivo is still disputed. The purpose of this study was to determine the efficacy of mannitol in attenuating I/R injury at the microcirculatory level. METHODS: The study was designed as an experimental study with male Wistar rats. The main outcome measures were intravital microscopy, which was used to measure capillary perfusion, capillary and venular red blood cell velocity (VRBC), and leukocyte-endothelial interactions in the extensor digitorum longus muscle of the rat hind limb before and after ischemia. In addition, tissue injury was assessed during reperfusion with the fluorescent vital dyes bisbenzimide and ethidium bromide. Dimethyl thiourea (DMTU), a highly effective therapeutic agent of experimental I/R injury, was used as a positive control. RESULTS: No-flow ischemia (2 hour) resulted in a 40% drop in capillary perfusion, a decline in capillary and venular VRBC, and increased leukocyte venular adherence and tissue infiltration. Tissue injury increased to a constant level during reperfusion. Mannitol attenuated capillary malperfusion during the first 60 minutes of reperfusion and prevented a decline in capillary VRBC. However, mannitol did not reduce tissue injury or leukocyte adherence and infiltration during reperfusion. By comparison, DMTU not only prevented the perfusion deficits and the increases in leukocyte venular adherence and tissue infiltration but significantly reduced the magnitude of tissue injury. CONCLUSION: Our findings suggest that mannitol may be of limited value for the prevention of early reperfusion-induced injury after no-flow ischemia in skeletal muscle. By comparison, DMTU was highly efficacious by not only reducing microvascular perfusion deficits but by also reducing leukocyte-endothelial cell interactions and the incidence of cellular injury.
Animals↗
Life threatening laryngeal toxicity following treatment with combined chemoradiotherapy for nasopharyngeal cancer: a case report with review of the literature.
Nasopharyngeal carcinoma is a rare cancer in Western society, however there is a higher incidence in Asian. Chinese and African populations. A significant number of Asians reside in Australia, and consequently patients with nasopharyngeal carcinoma are an increasing clinical problem. Radiotherapy has been the predominant treatment in the past, but more recently multi-modality treatments have been utilised. The results of an Intergroup trial, coordinated by the Southwest Oncology Group (SWOG) demonstrated markedly superior progression free and overall survival for combined chemoradiotherapy compared to radiotherapy alone. At three years progression free survival was 24% for the radiotherapy arm and 69% for the chemoradiotherapy group (P < 0.001), and three-year survival was 47% for the radiotherapy arm compared with 78% for the combined arm (P = 0.005). There was minimum toxicity reported for either of the arms and no treatment related deaths. Based on these survival data the administration of concomitant cisplatin and radiotherapy has become standard of care for nasopharyngeal carcinoma in the USA. Our institution has also adopted a similar combined therapy protocol for patients with stage III and IV nasopharyngeal cancer and good performance status. The patients treated at our institution have experienced significant side effects. We describe the case of a woman so treated with this protocol who subsequently developed severe life threatening laryngeal necrosis.
Antineoplastic Agents↗
Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia.
We report a patient with Philadelphia (Ph)-positive, BCR-ABL rearrangement positive, chronic myeloid leukemia (CML) with a prolonged chronic phase of 24 years who was first prescribed alpha-2 interferon 22 years after initial diagnosis. This therapy was tolerated poorly on account of thrombocytopenia, but an eventual major cytogenetic response was followed soon afterwards by transformation to terminal acute myeloid leukemia (AML). Cytogenetic studies indicated that the transformed myeloblasts were karyotypically normal and Ph negative. Although polymerase chain reaction (PCR) analysis of total leukemic mRNA remained BCR-ABL positive, other molecular studies, including Southern blotting and fluorescent in situ hybridization (FISH) analyses, showed that myeloblasts were BCR-ABL rearrangement negative. PCR-based clonality studies using an X-chromosome-linked restriction fragment polymorphism within the phosphoglycerate kinase gene (PGK1) further showed that the Ph-negative blast cells had a different clonal origin from the Ph-positive clone of chronic phase. We suggest that cases of underlying Ph-negative leukemic transformation in Ph-positive CML warrant further study and should be considered for trial of intensive remission induction therapy as appropriate for acute leukemia.
Acute Disease↗
Thalamic projections of the fusiform gyrus in man.
Previous retrograde degeneration studies have shown that human extrastriate visual cortex receives projections from the pulvinar, but their precise topographical organization remained unknown. We report on the distribution of thalamic projections originating in the fusiform gyrus, as studied with the Nauta method for anterogradely degenerating axons, in a case of right fusiform gyrus infarction. Ipsilaterally to the lesion, high density of afferents was found in the inferior pulvinar nucleus and a low density in the medial pulvinar nucleus as well as in the postero-inferior part of the reticular nucleus; no degenerating fibres were found in the lateral geniculate body. Degenerating axons were completely absent in the contralateral thalamus. Thus, there is a precise topographic relationship between parts of the extrastriate cortex and the pulvinar, suggesting segregated thalamocortical pathways for different parts of the extrastriate cortex. As in nonhuman primates, the human inferior temporal cortex has no direct output to the lateral geniculate body.
Aged↗
Opioid analgesia: new information from gene knockout studies.
The cloning of opioid peptides and receptors has led to the development of knockout mice deficient in a gene encoding for each peptide and each receptor. The major advantage of the knockout approach is the complete selectivity that the removal of a protein encoded for by a gene provides. These knockout animals are adding to our knowledge of the physiology, pathophysiology and pharmacology of opioid systems. In addition, they are providing real impact in addressing the long-standing debates over receptor subtype heterogeneity and functional cooperativity between receptor subtypes.
Journal Article↗
Development of in vitro assays for the detection of botulinum toxins in foods.
Currently the only accepted method for the detection of botulinum neurotoxin in contaminated samples is the mouse bioassay. Although highly sensitive this test has a number of drawbacks: it is expensive to perform, lacks specificity and involves the use of animals. With increasing resistance to such animal tests there is a need to replace the bioassay with a reliable in vitro test. Over the past six years it has been demonstrated that all the botulinum neurotoxins act intracellularly as highly specific zinc endoproteases, cleaving proteins involved in the control of secretion of neurotransmitters. In the work described, this enzymatic activity has been utilised in assay formats for the detection in foods of neurotoxin of the serotypes involved in food-borne outbreaks in man. These assays have been shown to have a greater sensitivity, speed and specificity than the mouse bioassay. It is envisaged that such assays will prove realistic alternatives to animal-based tests.
Animals↗
Development of an in vitro bioassay for Clostridium botulinum type B neurotoxin in foods that is more sensitive than the mouse bioassay.
A novel, in vitro bioassay for detection of the botulinum type B neurotoxin in a range of media was developed. The assay is amplified by the enzymic activity of the neurotoxin's light chain and includes the following three stages: first, a small, monoclonal antibody-based immunoaffinity column captures the toxin; second, a peptide substrate is cleaved by using the endopeptidase activity of the type B neurotoxin; and finally, a modified enzyme-linked immunoassay system detects the peptide cleavage products. The assay is highly specific for type B neurotoxin and is capable of detecting type B toxin at a concentration of 5 pg ml(-1) (0.5 mouse 50% lethal dose ml(-1)) in approximately 5 h. The format of the test was found to be suitable for detecting botulinum type B toxin in a range of foodstuffs with a sensitivity that exceeds the sensitivity of the mouse assay. Using highly specific monoclonal antibodies as the capture phase, we found that the endopeptidase assay was capable of differentiating between the type B neurotoxins produced by proteolytic and nonproteolytic strains of Clostridium botulinum type B.
Animals↗
Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia.
Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other systemic effects of PPARalpha activators.
Animals↗
Validity of the heart rate deflection point as a predictor of lactate threshold during running.
During an incremental run test, some researchers consistently observe a heart rate (HR) deflection at higher speeds, but others do not. The present study was designed to investigate whether differences in test protocols could explain the discrepancy. Additionally, we sought to determine whether the HR deflection point accurately predicts lactate threshold (LT). Eight trained runners performed four tests each: 1) a treadmill test for maximal O(2) uptake, 2) a Conconi test on a 400-m track with speeds increasing approximately 0.5 km/h every 200 m, 3) a continuous treadmill run with speeds increasing 0.5 km/h every minute, and 4) a continuous LT treadmill test in which 3-min stages were used. All subjects demonstrated an HR deflection on the track, but only one-half of the subjects showed an HR deflection on the treadmill. On the track the shortening of stages with increasing speeds contributed to a loss of linearity in the speed-HR relationship. Additionally, the HR deflection point overestimated the LT when a continuous treadmill LT protocol was used. In conclusion, the HR deflection point was not an accurate predictor of LT in the present study.
Adult↗
Assignment of the protein L-isoaspartate (D-aspartate) O-methyltransferase gene (PCMT1) to human chromosome bands 6q24-->q25 with radiation hybrid mapping.
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Animals↗
Vinblastine pharmacokinetics in patients with non-small cell lung cancer given cisplatin.
The pharmacokinetics of vinblastine were studied in 16 patients with non-small cell lung cancer after a bolus intravenous dose of 3 mg/m2 given before or after cisplatin (100 mg/m2). Venous blood was collected at 0, 10, and 36 hr for analysis by radioimmunoassay. The mean plasma vinblastine concentration at 10 hr was similar when vinblastine was given before (4.8 ng/ml; 95% CI, 3.2-6.3) or after cisplatin (4.9 ng/ml; 95% CI, 2.7-7.1). Plasma vinblastine concentrations in patients given cisplatin were higher than previously reported in patients given vinblastine alone. Patients with plasma vinblastine concentrations less than 2.75 ng/ml at 10 hr experienced less severe neutropenia (37% fall in neutrophil count; 95% CI, 18-55) than those with levels greater than 2.75 ng/ml (69% fall in neutrophil count; 95% CI, 62-77). In conclusion, the pharmacokinetics of vinblastine predict the severity of neutropenia and may be altered when given in conjunction with cisplatin.
Aged↗
Novel assays for the detection of botulinum toxins in foods.
Currently the only accepted method for the detection of botulinum neurotoxin in contaminated samples is the mouse bio-assay. Although highly sensitive this test has a number of drawbacks: it is expensive to perform, lacks specificity and involves the use of animals. With increasing resistance to such animal tests there is a need to replace the bio-assay with a reliable in vitro test. Over the past six years it has been demonstrated that all the botulinum neurotoxins act intracellularly as highly specific zinc endoproteases, cleaving proteins involved in the control of secretion of neurotransmitters. In the work described, this enzymatic activity has been utilised in assay formats for the detection in foods of neurotoxin from the serotypes involved in food-borne outbreaks in man. These assays have been shown to have a greater sensitivity, speed and specificity than the mouse bio-assay. It is envisaged that such assays will prove realistic alternatives to animal based tests.
Animals↗
delta-N-methylarginine is a novel posttranslational modification of arginine residues in yeast proteins.
We have found a novel modification of protein arginine residues in the yeast Saccharomyces cerevisiae. Intact yeast cells lacking RMT1, the gene encoding the protein omega-NG-arginine methyltransferase, were labeled with the methyl donor S-adenosyl-L-[methyl-3H]methionine. The protein fraction was acid-hydrolyzed to free amino acids, which were then fractionated on a high resolution sulfonated polystyrene cation exchange column at pH 5.27 and 55 degreesC. In the absence of the omega-NG, NG-[3H]dimethylarginine product of the RMT1 methyltransferase, we were able to detect a previously obscured 3H-methylated species that migrated in the region of methylated arginine derivatives. The [3H]methyl group(s) of this unknown species were not volatilized by treatment with 2 M NaOH at 55 degreesC for up to 48 h, suggesting that they were not modifications of the terminal omega-guanidino nitrogen atoms. However, this base treatment did result in the formation of a new 3H-methylated derivative that co-chromatographed with delta-N-methylornithine on high resolution cation exchange chromatography, on reverse phase high pressure liquid chromatography, and on thin layer chromatography. From these data, we suggest that the identity of the original unknown methylated residue is delta-N-monomethylarginine. The presence of this methylated residue in yeast cells defines a novel type of protein modification reaction in eukaryotes.
Arginine↗
Distinct short-term memory systems for sound content and sound localization.
Short-term memory for sound content and sound localization was investigated in normal subjects using the same/different comparison of two sound stimuli separated by an interval. Auditory or visual interference tasks requiring recognition or spatial judgements were introduced in the interval. Auditory interference tasks reduced memory for sound content and sound location in a specific way. Memory for sound content was significantly more reduced by auditory recognition than by auditory spatial interference task. Visual interference tasks reduced significantly memory for sound location but not for sound content. These results suggest that (i) short-term memory for sound content and that for sound location involve partially distinct processing; and (ii) auditory spatial functions are more closely linked to visual functions than auditory recognition.
Acoustic Stimulation↗
A highly active protein repair enzyme from an extreme thermophile: the L-isoaspartyl methyltransferase from Thermotoga maritima.
We show that the open reading frame in the Thermotoga maritima genome tentatively identified as the pcm gene (R. V. Swanson et al., J. Bacteriol. 178, 484-489, 1996) does indeed encode a protein L-isoaspartate (D-aspartate) O-methyltransferase (EC 2.1.1.77) and that this protein repair enzyme displays several novel features. We expressed the 317 amino acid pcm gene product of this thermophilic bacterium in Escherichia coli as a fusion protein with an N-terminal 20 residue hexa-histidine-containing sequence. This protein contains a C-terminal domain of approximately 100 residues not previously seen in this enzyme from various prokaryotic or eukaryotic species and which does not have sequence similarity to any other entry in the GenBank databases. The C-terminal region appears to be required for enzymatic function as no activity is detected in two recombinant constructs lacking this domain. Sedimentation equilibrium analysis indicated that the enzyme is monomeric in solution. The Km values for measured for peptide and protein substrates were found to be intermediate between those of the high-affinity human enzyme and those of the lower-affinity wheat, nematode, and E. coli enzymes. The enzyme was extremely heat stable, with no loss of activity after 60 min at 100 degreesC. Enzyme activity was observed at temperatures as high as 93 degreesC with an optimal activity of 164 nmol/min/mg protein at 85 degreesC. This activity is approximately 18-fold higher than the maximal activities of mesophilic homologs at 37 degreesC. These data suggest that the Thermotoga enzyme has unique features for initiating repair in damaged proteins containing L-isoaspartyl residues at elevated temperatures.
Amino Acid Sequence↗