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Biomedical subjects

C Myers

Publications and source records attributed to C Myers.

At least 37 records · Page 2Linked to original sources
PubMed1998

A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.

Adult↗
PubMed1998

Failure to detect intrauterine growth restriction following in utero exposure to MRI.

Echo planar imaging is a form of MRI with short image acquisition times, which permits in utero fetal imaging without motion artefacts. Echo planar imaging has been used to measure accurately fetal organ volume and to assess placental function. Two small animal studies have suggested the possibility of intrauterine growth restriction consequent upon MRI. We thus performed a prospective study of pregnancies in which fetuses were exposed to echo planar imaging, compared with a control group in which there was no in utero echo planar imaging exposure. There were no significant differences between the groups when maternal age, parity, proportion of smokers and proportion of Caucasian women were compared. Although the gestational age of delivery was lower in the echo planar imaging group, the proportion of women delivering prematurely was not significantly different. Although infant birthweights were significantly lower in the MRI group, the corrected birthweight for gestational age centiles (individualized birthweight ratio) was not significantly different between the two groups. In utero exposure to echo planar imaging thus did not have a marked effect on intrauterine fetal growth. A 10 year follow-up study of all infants imaged in utero is being performed.

Birth Weight↗
PubMed1998

Swimming upstream.

Explore the source record for details and available documents.

Costs and Cost Analysis↗
PubMed1998

The role of iron in doxorubicin-induced cardiomyopathy.

Doxorubicin participates in a wide range of free radical reactions. The drug can undergo one electron reduction to the corresponding semiquinone, leading the generation of superoxide and hydrogen peroxide. Additionally, the drug causes the disappearance of cardiac glutathione peroxidase, leaving the heart with no means of disposing of the hydrogen peroxide thus generated. Doxorubicin also is a powerful iron chelator and the resultant iron-drug complex is an efficient catalyst of the conversion of hydrogen peroxide to the highly reactive hydroxyl radical. Without the drug-iron complex, little or no cardiac production of hydroxyl radical occurs and heart damage does not occur.

Animals↗
PubMed1997

Using a performance improvement team to reinvent a mandatory education program.

BACKGROUND: To improve employee attendance at Annual Review Day, the day when all mandatory hospitalwide education requirements are presented. The Finley Hospital (Dubuque, Iowa) initiated a performance improvement team in March 1993. Data collected previous to 1993 indicated that the compliance goal of 90% was being met only with difficulty. PERFORMANCE IMPROVEMENT TEAM: Data indicated three main areas where improvements could be made-communication, enforcement, and curriculum. Recommendations of task forces, with team members as leaders, were implemented. Decisions were made to change Annual Review Day to a full-day format to include all mandatory education, make outcomes competency based, and maintain cost-effectiveness. TRIAL RUN AND EVALUATION: The one-year trial run began in 1994 with gradual changes in the program from a lecture and video format to an interactive game format. For example, at one point a crossword puzzle with information on infection control and bloodborne pathogens was added. The Jeopardy Game format, used to teach the principles of emergency preparedness, was added in June 1994. Full implementation of the curriculum, communication, and enforcement recommendations have resulted in 100% compliance. MAINTAINING THE GAIN: The performance improvement team has continued to monitor results and submit quarterly reports to the quality management department. All participants must complete and pass a competency-based test on the information covered; all 760 participants have passed. The curriculum task force continues to meet on a yearly basis to evaluate the ever-evolving format, analyze attendee evaluations, and consider annual changes to the format.

Accreditation↗
PubMed1997

Rigidone, a sesquiterpene o-quinone from the gorgonian Pseudopterogorgia rigida.

As part of a search for novel biologically active compounds in the Macrophage Scavenger Receptor (MSR) assay, the EtOAc extract of a gorgonian coral, Pseudopterogorgia rigida, was shown to be active. Bioassay-guided fractionation of the extract yielded curcuphenol, curcuhydroquinone, curcuquinone, and a novel o-quinone, rigidone (1). The structure and stereochemistry of 1 was determined by interpretation of spectral data and chemical transformation.

Animals↗
PubMed1997

Alterations in dopamine clearance and catechol-O-methyltransferase activity by dopamine infusions in children.

OBJECTIVE: To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine. DESIGN: The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function. SETTING: A 16-bed pediatric intensive care unit serving both medical and surgical patients. PATIENTS: The study was performed using 14 dopamine-treated and five untreated control patients. Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female. All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease. Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score. INTERVENTIONS: All treated patients received dopamine as a continuous intravenous infusion. Infusion rates were determined by caregivers and ranged from 3.0 to 20 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity. Measured rates of dopamine infusion (3.0 to 18.3 micrograms/kg/min) were consistently less than the nominal rates (3.0 to 20.0 micrograms/kg/min) of infusion (p < .0001) due in part to calculations based on the hydrochloride salt rather than dopamine base. At similar steady-state infusion rates, plasma dopamine concentrations varied over a four-fold range, with steady-state concentrations at even the lowest infusion rate exceeding endogenous concentrations by at least ten-fold. Variations in steady-state plasma dopamine concentration reflected large age-associated variations in dopamine clearance, which was found to be saturable at concentrations of > 200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age. COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of > 100 ng/mL. CONCLUSIONS: These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates. While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine.

Catechol O-Methyltransferase↗
PubMed1997

Fluid resuscitation.

Contention over fluid resuscitation is not new. The issues however have changed considerably. The crystalloid/colloid debate has largely reached a stalemate with little to define clear differences between the two especially early in traumatic shock when increased capillary permeability is a minor issue. Blood, despite its difficulties and its cost is now safer than ever before and we will have to wait a number of years before routine use of blood substitutes becomes possible. Hypertonic saline and hypertonic saline dextran solutions used as an early bolus of 4-6 ml/kg and in conjunction with isotonic crystalloids and blood appear to be the new resuscitation fluids of first choice for haemorrhagic shock and there will be a progressive swing towards these fluids over the next 5 years. Application of the principles of minimal volume or delayed resuscitation requires the reconsideration of many entrenched attitudes and expectations present in the traditional management of haemorrhagic shock. Currently there is hard evidence to support its use only in ruptured AAA and penetrating truncal trauma but the application of the principles should be much more widespread. Minimal volume resuscitation emphasizes the need for urgent investigation and definitive management of uncontrollable haemorrhage reserving the early use of fluid resuscitation to maintain life only, until the integrity of the vascular circuit has been verified or restored. Thus it is the timing rather than the quantity of fluid which is the underlying issue. The questions which these new models of haemorrhage raise and the reconsideration of the physiology of haemorrhagic shock must be our focus. It would be foolish to replace the long-held dogma of aggressive fluid resuscitation in all situations with the new dogma of minimal volume resuscitation in all situations. Instead we must walk the tightrope attempting to understand the likely physiological mechanisms of our patients at an individual level. Fluid resuscitation has necessarily become more complex as the potential to do harm has been more clearly demonstrated. The use of resuscitation fluids must now receive as much care and consideration as is currently given to the prescription of potent drugs, weighing the potential benefits of a course of action against its possible side effects. Much research is required to clarify and refine the data on fluid resuscitation but there is little doubt that the conceptual changes which underlie this work on haemorrhagic shock offer the most exciting advances in fluid resuscitation seen in the past 30 years.

Animals↗
PubMed1996

The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB.

Opportunistic infections, such as aspergillosis, are among the most serious complications suffered by immunocompromised patients. Aspergillus fumigatus and other pathogenic fungi synthesize a toxic epipolythiodioxopiperazine metabolite called gliotoxin. Gliotoxin exhibits profound immunosuppressive activity in vivo. It induces apoptosis in thymocytes, splenocytes, and mesenteric lymph node cells and can selectively deplete bone marrow of mature lymphocytes. The molecular mechanism by which gliotoxin exerts these effects remains unknown. Here, we report that nanomolar concentrations of gliotoxin inhibited the activation of transcription factor NF-kappaB in response to a variety of stimuli in T and B cells. The effect of gliotoxin was specific because, at the same concentrations, the toxin did not affect activation of the transcription factor NF-AT or of interferon-responsive signal transducers and activators of transcription. Likewise, the activity of the constitutively DNA-binding transcription factors Oct-1 and cyclic AMP response element binding protein (CREB), as well as the activation of protein tyrosine kinases p56lck and p59fyn, was not altered by gliotoxin. Very high concentrations of gliotoxin prevented NF-kappaB DNA binding in vitro. However, in intact cells, inhibition of NF-kappaB did not occur at the level of DNA binding; rather, the toxin appeared to prevent degradation of IkappaB-alpha, NF-kappaB's inhibitory subunit. Our data raise the possibility that the immunosuppression observed during aspergillosis results in part from gliotoxin-mediated NF-kappaB inhibition.

Cells, Cultured↗
PubMed1996

Effect of different infusion regimens on colonic motility and efficacy of colostomy irrigation.

The colonic motility response and short-term clinical effectiveness of colonic irrigation was studied in five patients with an end-colostomy, each of whom was studied on up to six occasions, using volumes of 500 and 1500 ml water infused under gravity and over a period of 2.5 and 5 min with a pump. The median baseline colonic luminal pressure was 14 cmH2O and rose to 42 cmH2O with a 500-ml infusion, and to 74 cmH2O with a 1500-ml infusion. Irrigation induced high-pressure (over 200 cmH2O) propagated waves which caused the efflux of colonic contents. These were more numerous after a 1500- than a 500-ml infusion (median 4.5 versus 2.0 respectively). There was no difference between the two volumes infused in the incidence of colostomy break-through before subsequent irrigation. Colostomy irrigation with 500-1500 ml water appears to produce intracolonic pressure rises that are safe. These volumes can be infused rapidly under gravity alone.

Aged↗
PubMed1996

Interactions of the CelS binding ligand with various receptor domains of the Clostridium thermocellum cellulosomal scaffolding protein, CipA.

The Clostridium thermocellum cellulosomal scaffolding protein, CipA, acts as an anchor on the cellulose surface for the various catalytic subunits of the cellulosome, a large extracellular cellulase complex. CipA contains nine repeated domains that serve as receptors for the cellulosomal catalytic subunits, each of which carries a conserved, duplicated ligand sequence (DS). Four representative CipA receptor domains with sequence dissimilarity were cloned and expressed in Escherichia coli. The interaction of these cloned receptor domains with the duplicated ligand sequence of CelS (expressed as a thioredoxin fusion protein, TRX-DSCelS), was studied by nondenaturing polyacrylamide gel electrophoresis. TRX-DSCelS formed a stable complex with each of the four receptor domains, indicating that CelS, the most abundant cellulosomal catalytic subunit, binds nonselectively to all of the CipA receptors. Conversely, the duplicated sequence of CipA (in the form of TRX-DSCipA), which is homologous to that of CelS, did not bind to any of the receptors under the experimental conditions.

Bacterial Proteins↗
PubMed1996

An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes.

We have isolated and analyzed human CTCF cDNA clones and show here that the ubiquitously expressed 11-zinc-finger factor CTCF is an exceptionally highly conserved protein displaying 93% identity between avian and human amino acid sequences. It binds specifically to regulatory sequences in the promoter-proximal regions of chicken, mouse, and human c-myc oncogenes. CTCF contains two transcription repressor domains transferable to a heterologous DNA binding domain. One CTCF binding site, conserved in mouse and human c-myc genes, is found immediately downstream of the major P2 promoter at a sequence which maps precisely within the region of RNA polymerase II pausing and release. Gel shift assays of nuclear extracts from mouse and human cells show that CTCF is the predominant factor binding to this sequence. Mutational analysis of the P2-proximal CTCF binding site and transient-cotransfection experiments demonstrate that CTCF is a transcriptional repressor of the human c-myc gene. Although there is 100% sequence identity in the DNA binding domains of the avian and human CTCF proteins, the regulatory sequences recognized by CTCF in chicken and human c-myc promoters are clearly diverged. Mutating the contact nucleotides confirms that CTCF binding to the human c-myc P2 promoter requires a number of unique contact DNA bases that are absent in the chicken c-myc CTCF binding site. Moreover, proteolytic-protection assays indicate that several more CTCF Zn fingers are involved in contacting the human CTCF binding site than the chicken site. Gel shift assays utilizing successively deleted Zn finger domains indicate that CTCF Zn fingers 2 to 7 are involved in binding to the chicken c-myc promoter, while fingers 3 to 11 mediate CTCF binding to the human promoter. This flexibility in Zn finger usage reveals CTCF to be a unique "multivalent" transcriptional factor and provides the first feasible explanation of how certain homologous genes (i.e., c-myc) of different vertebrate species are regulated by the same factor and maintain similar expression patterns despite significant promoter sequence divergence.

Amino Acid Sequence↗
PubMed1995

Minimally raised end colostomy.

The traditional maturation of the mucocutaneous junction of an end colostomy often leads to a stoma with no significant projection above the skin. We describe a simple method which allows a small spout to be easily created. This technique has been used in 30 patients and is believed to diminish leakage. A raised stoma is easier for the patient to see and Stoma care nurses prefer them.

Colostomy↗
PubMed1995

From laminin to lamin: regulation of tissue-specific gene expression by the ECM.

Mammary epithelial cells need a laminin-rich extracellular matrix (ECM) to achieve a functionally differentiated phenotype that includes secretion of milk-specific proteins such as beta-casein. There is good evidence that ECM-induced expression of beta-casein involves an 'ECM-response element' in the promoter of the casein gene that is activated by integrin-mediated signalling. This article proposes that ECM-induced structural changes in the cytoskeleton, histone organization and the nuclear matrix contribute to this tissue-specific gene expression.

Journal Article↗