Biomedical subjects
K Wilson
Publications and source records attributed to K Wilson.
The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy.
BACKGROUND: 5-HT3 antagonists are effective in reducing the acute nausea and vomiting caused by cancer chemotherapy. However, it is not clear whether continuing these agents beyond twenty four hours is useful in controlling emesis on days two to seven after chemotherapy. PATIENTS AND METHODS: Four hundred seven patients receiving moderately emetogenic chemotherapy who had been given dexamethasone 8 mg i.v. and either ondansetron 32 mg i.v. or dolasetron 2.4 mg/kg i.v. were randomized to continue either an oral form of their 5-HT3 antagonist (ondansetron 8 mg b.i.d. or dolasetron 200 mg daily) plus dexamethasone 8 mg p.o. daily or dexamethasone alone for days two to seven. Endpoints assessed by self-report were: 1) complete control (no vomiting, no rescue medications, no missing data) of emesis; 2) nausea severity; and 3) quality-of-life as measured by the EORTC QLQ-C30. RESULTS: Continuation of 5-HT3 antagonists improved slightly, but not significantly, the complete control rate (47% vs. 41%: P = 0.24 one-sided) after chemotherapy. However, mean nausea severity was significantly (P = 0.015 one sided) reduced (by 3 mm on a 10 cm scale) on the combined arm. Minimal differences in quality of life were observed. CONCLUSION: The benefit of continuing 5-HT3 antagonists beyond 24 hours is modest and the merits of routine use in these circumstances debatable.
Ds elements on all five Arabidopsis chromosomes and assessment of their utility for transposon tagging.
The maize transposons Activator (Ac) and Dissociation (Ds) tend to transpose to sites close to their original position and can be efficiently used to transposon-tag genetically linked genes. To facilitate this approach, we describe the locations of seven T-DNAs carrying Ds elements, including at least one on each of the five chromosomes. For five of these T-DNAs, we have confirmed that the Ds element transposes preferentially to genetically linked sites. A large-scale transposon-tagging experiment was performed by activating Ds from eight chromosomal locations that included at least one on each of the five chromosomes. These experiments produced a total of 1132 F3 families that were predicted to carry around 870 independent Ds insertions. In these populations, 33 independently isolated mutants that were visibly different from wild-type were identified. Twenty-nine of these mutants were studied genetically, and 14 were not tagged with Ds because the element could be separated from the mutation by recombination. The remaining 15 mutations were possibly tagged because the transposon and the mutation were not separated by recombination. These experiments provide tools for transposon-tagging on each chromosome, and indicate that approximately 50% of identified mutations are likely to be tagged, thereby enabling cloning of the affected genes.
K-ras oncogene activation in atypical alveolar hyperplasias of the human lung.
Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. A common genetic alteration in lung adenocarcinomas is mutational activation of K-ras. To determine the timing of K-ras activation, we evaluated formalin-fixed and paraffin-embedded tissue samples of 41 AAHs and their paired lung neoplasms from 28 patients for codon 12 point mutations of the K-ras oncogene. K-ras codon 12 mutations were detected using PCR followed by allele-specific oligonucleotide hybridization. Mutations were found in 16 (39%) of the 41 AAHs, 8 (42%) of the 18 adenocarcinomas, and none (0%) of the 5 lung neoplasms that were not adenocarcinomas. Of the 18 patients with both an AAH and a synchronous lung adenocarcinoma, 6 had K-ras mutation in the adenocarcinoma but not in the AAH, 6 had mutations in the AAH but not in the adenocarcinoma, 4 did not harbor mutations in either the AAH or the adenocarcinoma, and 2 had mutations in both their AAH and their synchronous adenocarcinoma. In just 1 of the 18 patients was the same K-ras mutation present in the AAHs and adenocarcinoma of the patient. The detection of independent activating point mutations in a cancer-causing gene points to the neoplastic nature of AAH and suggests that glandular neoplasms of the lung arise from a background of field cancerization.
Back pain in osteoarthritis of the knee.
OBJECTIVE: To compare patients with knee osteoarthritis (OA) who have and do not have back pain, and evaluate the prevalence, characteristics, and consequences of back pain among knee OA patients. METHODS: During a 3-year period, consecutive patients attending an outpatient rheumatology clinic were evaluated for the presence of back pain, and 368 were found to have OA of the knee. Clinical status was evaluated by the Clinical Health Assessment Questionnaire, radiographs, and joint examinations. RESULTS: Back pain was present in 54.6% of patients with OA of the knee. Almost every clinical status measure was worse among those reporting back pain, including Health Assessment Questionnaire (HAQ) disability, pain, global severity, fatigue, and psychological status. Back pain was more common in women and the obese, but was not associated with age, marital status, formal education, smoking history, or knee radiographic scores. In multivariate analyses the strongest correlates of back pain in knee OA patients were anxiety, night pain, HAQ disability, and global severity. CONCLUSION: Back pain is prevalent among OA clinic patients, more common than in rheumatoid arthritis or population studies, is linked to body mass index, and is associated with clinically significant increases in pain and other measures of clinical distress.
A double-blind randomized placebo-controlled trial of sibutramine.
Sibutramine is a beta-phenethylamine which blocks reuptake of norepinephrine and serotonin. In this clinical study, a group of 173 patients were randomized to treatment with sibutramine at doses of 1, 5, 10, 15, 20 or 30 mg/d and were compared with placebo in a 24-week double-blind trial. There was a dose-dependent reduction in body weight, with doses of 10, 15, 20 and 30 mg being significantly greater than placebo. Weight loss was still continuing in the highest three doses at the end of the study. When drugs were discontinued patients regained weight, as expected. Side effects were generally mild and were most evident in the group treated with the highest dose. These studies suggest that sibutramine may be a valuable new drug for treatment of obesity.
Cytochrome c3 from Desulfovibrio gigas: crystal structure at 1.8 A resolution and evidence for a specific calcium-binding site.
Crystals of the tetraheme cytochrome c3 from sulfate-reducing bacteria Desulfovibrio gigas (Dg) (MW 13 kDa, 111 residues, four heme groups) were obtained and X-ray diffraction data collected to 1.8 A resolution. The structure was solved by the method of molecular replacement and the resulting model refined to a conventional R-factor of 14.9%. The three-dimensional structure shows many similarities to other known crystal structures of tetraheme c3 cytochromes, but it also shows some remarkable differences. In particular, the location of the aromatic residues around the heme groups, which may play a fundamental role in the electron transfer processes of the molecule, are well conserved in the cases of hemes I, III, and IV. However, heme II has an aromatic environment that is completely different to that found in other related cytochromes c3. Another unusual feature is the presence of a Ca2+ ion coordinated by oxygen atoms supplied by the protein within a loop near the N-terminus. It is speculated that this loop may be stabilized by the presence of this Ca2+ ion, may contribute to heme-redox perturbation, and might even be involved in the specificity of recognition with its redox partner.
Fluorescence decay of tryptophans in serine proteinases from microorganisms: relation to X-ray models.
Fluorescence decay kinetics of indole groups in five proteinases from microorganisms are reported. The data show differences between the excited state lifetimes of the tryptophans located in identical positions in the polypeptide chains of the closely related proteinases mesentericopeptidase and subtilisin Novo. The lifetime of the single Trp 113 in subtilisins DY and Carlsberg are identical. The microenvironments of this residue in the four subtilisins are identical and probably its fluorescence is quenched in these proteins. The crystallographic models of the enzymes investigated were analysed in the region of the tryptophyl residues and provide an explanation for the observed emission properties.
pH dependence of the catalytic activity of a subtilisin-like proteinase.
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Three dimensional structure of the antibiotic bacitracin A complexed to two different subtilisin proteases: novel mode of enzyme inhibition.
The three dimensional crystal structures of thermitase-bacitracin (TMTBAC), Savinase- bacitracin (SAVBAC) and Savinase-zinc/bacitracin (SAVBAC/ZN) have been determined by X-ray diffraction to 2.2 angstroms, 2.2 angstroms and 1.95 angstroms resolution, respectively. The multifunctional dodecapeptide bacitracin A secreted by Bacillus licheniformis is well known as an antibiotic against gram-positive bacteria but also as an inhibitor for different proteases. The bacteriocidal activity requires the presence of divalent metal cations such as zinc or nickel. It also could be shown that bacitracin A is bound to subtilisin in the Bacillus licheniformis. This complex is stable throughout the purification by chromatography. Therefore the subtilisin proteases thermitase and Savinase were used for cocrystallization with bacitracin A and zinc/bacitracin A. The complexes are formed from two enzyme molecules and two bacitracin A molecules. All three complexes show the same novel mode of enzyme inhibition. Each bacitracin A chain binds non-covalently to two protease molecules: to the catalytic side of one and to the substrate recognition side of the second protease molecule. In that way the two bacitracin A molecules link two subtilisin molecules together to form a dimer. Despite this common feature we found some important differences in the conformations of bacitracin A in the three complex structures which were analysed and described in detail in this paper. An examination of the solvent structure of the complexes shows water molecules in the region around the bacitracin A molecules are not conserved and play a different role in the stabilization of the bacitracin A conformation.
An approach to seizure detection using an artificial neural network (ANN).
We have developed an EEG seizure detector based on an artificial neural network. The input layer of the ANN has 31 nodes quantifying the amplitude, slope, curvature, rhythmicity, and frequency components of EEG in a 2 sec epoch. The hidden layer has 30 nodes and the output layer has 8 nodes representing various patterns of EEG activity (e.g. seizure, muscle, noise, normal). The value of the output node representing seizure activity is averaged over 3 consecutive epochs and a seizure is declared when that average exceeds 0.65. Among 78 randomly selected files from 50 patients not in the original training set, the detector declared at least one seizure in 76% of 34 files containing seizures. It declared no seizures in 93% of 44 files not containing seizures. Four false detections during 4.1 h of recording yielded a false detection rate of 1.0/h. The detector can continuously process 40 channels of EEG with a 33 MHz 486 CPU. Although this method is still in its early stages of development, our results represent proof of the principle that ANN could be utilized to provide a practical approach for automatic, on-line, seizure detection.
Body image, maternal fetal attachment, and breast feeding.
The aim of this study is to make a preliminary examination of the relationship between body satisfaction, maternal fetal attachment, and breast or bottle feeding plans in pregnancy. Thirty eight women between 32 and 38 weeks pregnant were examined by means of the Maternal Foetal Attachment Scale, the Eating Disorders Examination, and the Body Satisfaction Scale. Women intending to breast feed were more satisfied with their shape. Women intending to breast feed had higher levels of maternal fetal attachment. Body shape dissatisfaction and low maternal fetal attachment may account for why some women choose to bottle feed.
Stem-completion priming in Alzheimer's disease: the importance of target word articulation.
Stem-completion priming performance in patients with Alzheimer's type dementia (DAT) was explored in three experiments in which both the standard repetition priming effect and a novel indirect form of priming, cohort priming, were measured. In the first experiment, in which study stimuli were words, both priming effects were found to be markedly attenuated in the DAT group. In the second experiment, the study stimuli were specially constructed nonwords, and it was found that cohort priming was present at normal levels in the DAT group. In a third experiment we tested the specific hypothesis that the requirement to overtly articulate target stimuli during the study phase was critical for the appearance of normal cohort priming in the DAT group in Experiment 2, and also for the normal levels of repetition priming which have been reported in some published studies. Two encoding conditions were compared, one in which subjects simply had to read aloud the target words and a second in which subjects were required to make evaluative (pleasantness) ratings for each of the target words (identical to that used in Experiment 1). Stem-completion priming performance following the latter condition was significantly attenuated in the DAT group relative to a healthy control group, but following the "read aloud" encoding condition, normal levels of repetition and cohort priming were observed. It is suggested that the most fruitful approach to understanding the performance of DAT subjects on lexical repetition priming tasks will involve a detailed analysis of language functions and how they interact with other, possibly mnemonic, processes in the generation of primed responses.
Rifampicin antibiotic impregnation of the St. Jude Medical mechanical valve sewing ring: a weapon against endocarditis.
The Dacron sewing ring material of the St. Jude Medical mechanical heart valve (St. Jude Medical, Inc., St. Paul, Minn.) was passively impregnated with rifampicin (60 mg/ml) both in its unsealed state and after sealing by the methods of preclotting in blood, autoclaving in blood, and autoclaving in 20% albumin. Antistaphylococcal activity in the Dacron material was assessed immediately after rifampicin impregnation and at regular periods up to 5 days after implantation into the goat aorta. When the Dacron material had been sealed by autoclaving in blood and autoclaving in 20% albumin significant retention of antistaphylococcal activity was found after 5 days in vivo. Best results were obtained with the use of autoclaved blood (p < 0.05). We also compared these results with those obtained from impregnating commercially available gelatin-sealed (Gelseal) and collagen-sealed (Hemashield) Dacron material with rifampicin. Although antistaphylococcal activity was equivalent immediately after rifampicin impregnation, after 4 days in vivo the activity was negligible in Gelseal material (p < 0.05) and could not be demonstrated in Hemashield material. Rifampicin impregnation of the intact St. Jude Medical mechanical valve sewing ring may have an application in the prevention of prosthetic valve endocarditis and a clinical protocol is suggested.
Physical growth, infant nutrition, breastfeeding, and general nutrition.
A constant in the practice of general pediatrics is an emphasis on infant nutrition and monitoring of growth. These topics are the focus of this issue's "Office pediatrics" section. Much of the new research and publication concerning nutrition in childhood in the past year continues to focus on breastfeeding-its short-term and long-term benefits and strategies to increase the number of women who successfully nurse their infants. The documentation of breastfeeding's benefits is becoming increasingly strong, even in developed countries such as the United States. At the same time, the many weaknesses in the health care system's support of this important health-promoting behavior continue to be documented. Separate from breastfeeding per se, additional articles examining the state of nutrition among children in the United States show that despite our relative affluence, malnutrition remains prevalent. The poor and the chronically ill appear particularly vulnerable to inadequate nutrition and should remain a focus of our efforts at nutritional monitoring and support.
A Dissociation insertion causes a semidominant mutation that increases expression of TINY, an Arabidopsis gene related to APETALA2.
A novel transposon-tagging strategy designed to recover dominant gain-of-function alleles was performed with Arabidopsis by using a Dissociation element with a cauliflower mosaic virus 35S promoter transcribing outward over one terminus. Lines containing transposed copies of this transposon were screened for mutants, and a semidominant mutation affecting plant height, hypocotyl elongation, and fertility was recovered. The pleiotropic effects of this mutation appear to result from a general reduction in cell expansion, and some of the effects are similar to those caused by supplying exogenous ethylene or cytokinin to wild-type seedlings. In addition, the arrangement of cells in some organs such as the etiolated hypocotyl, is disorganized. The mutation was called tiny, and the affected gene was cloned by first using transposon sequences to isolate the mutant allele. The predicted protein product of the TINY gene shows strong homology with the DNA binding domain of a recently identified class of plant transcription factors. This domain, called the APETALA2 domain, was initially identified as a duplicated region within the APETALA2 gene of Arabidopsis and then as a conserved region between APETALA2 and the ethylene responsive element binding proteins of tobacco. In the mutant allele, the Dissociation element is inserted in the untranslated leader of the TINY gene, 36 bp from the ATG, and the mutant contains a novel transcript that initiates from the cauliflower mosaic virus 35S promoter within the transposon. This transcript is present in greater abundance than the wild-type TINY transcript; therefore, the semidominant tiny mutation most likely results from increased, or ectopic, expression of the gene.
Carbazate as a glycine bioisostere in restricticin.
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Inhibition of dexamethasone-induced cytoskeletal changes in cultured human trabecular meshwork cells by tetrahydrocortisol.
PURPOSE: To determine the cellular mechanism of action of the intraocular pressure (IOP) lowering steroid tetrahydrocortisol (THF). METHODS: Tetrahydrocortisol was evaluated for glucocorticoid antagonist activity using in vitro and in vivo assays. Systemically administered THF was evaluated for its ability to inhibit dexamethasone-induced body weight loss and systemic hypertension in rats. In vitro receptor antagonism was tested using the supernatant fraction of IM9 cells as the source of soluble glucocorticoid receptor in 3H-dexamethasone displacement binding assays. In addition, six different primary human trabecular meshwork (TM) cell lines were cultured for 0 to 14 days in the absence or presence of dexamethasone (10(-7) M) and/or THF (10(-6) to 10(-8) M). The effects of these steroids on the TM cytoskeleton were determined by epifluorescent microscopy and by transmission electron microscopy. RESULTS: Tetrahydrocortisol was unable to inhibit the dexamethasone (DEX)-induced systemic hypertension and decrease in body mass in rats and was unable to displace 3H-DEX from the soluble human glucocorticoid receptor. However, THF inhibited the DEX-induced formation of cross-linked actin networks in cultured human TM cells in a progressive and dose-dependent manner (IC50 = 5.7 x 10(-7) M). Dexamethasone caused changes in the TM cell microtubules that were reversed partially by concomitant treatment with THF. Tetrahydrocortisol alone appeared to increase microfilament bundling in TM cells. CONCLUSIONS: Tetrahydrocortisol was not a glucocorticoid antagonist at the level of the classical glucocorticoid receptor and did not appear to antagonize systemically mediated glucocorticoid activity in the rat. Tetrahydrocortisol inhibited DEX-induced changes in the TM microfilaments and microtubules. These results may explain partially the IOP lowering activity of THF because glucocorticoid-mediated changes in the TM cytoskeleton have been proposed to be involved in the generation of ocular hypertension.