PubMed HealthSearch

Biomedical subjects

M R Alexander

Publications and source records attributed to M R Alexander.

At least 19 recordsLinked to original sources

The HOG pathway controls osmotic regulation of transcription via the stress response element (STRE) of the Saccharomyces cerevisiae CTT1 gene.

The HOG signal pathway of the yeast Saccharomyces cerevisiae is defined by the PBS2 and HOG1 genes encoding members of the MAP kinase kinase and of the MAP kinase family, respectively. Mutations in this pathway (deletions of PBS2 or HOG1, or point mutations in HOG1) almost completely abolish the induction of transcription by osmotic stress that is mediated by stress response elements (STREs). We have demonstrated previously that STREs also mediate induction of transcription by heat shock, nitrogen starvation and oxidative stress. This study shows that they are also activated by low external pH, sorbate, benzoate or ethanol stress. Induction by these other stress signals appears to be HOG pathway independent. HOG1-dependent osmotic induction of transcription of the CTT1 gene encoding the cytosolic catalase T occurs in the presence of a protein synthesis inhibitor and can be detected rapidly after an increase of tyrosine phosphorylation of Hog1p triggered by high osmolarity. Consistent with a role of STREs in the induction of stress resistance, a number of other stress protein genes (e.g. HSP104) are regulated like CTT1. Furthermore, catalase T was shown to be important for viability under severe osmotic stress, and heat shock was demonstrated to provide cross-protection against osmotic stress.

Adaptation, Physiological

Albumin utilization in a university hospital.

The inappropriate use of high-priced agents such as human serum albumin significantly contributes to the rising cost of medical care. A utilization review was conducted at the University of Michigan Hospital in order to identify the appropriateness of use of this agent. Criteria were developed and prescribing was retrospectively evaluated for 81 patients. Of the 935 units administered to these patients, 692 (74 percent) were judged to be inappropriate. This inappropriate use accounted for a projected annual expenditure of nearly $281,000. Interventions have previously demonstrated success in improving prescribing.

Drug Utilization

Penetration of cefotaxime into respiratory secretions.

The objective of this study was to quantitate cefotaxime and its active metabolite, desacetyl cefotaxime, in the distal airways and to compare these levels to concentrations in plasma. Respiratory secretions were obtained from the subsegmental level in 17 adult patients undergoing fiber-optic bronchoscopy within 2 h after receiving four doses of cefotaxime (2 g intravenously every 6 h). In 11 patients, cefotaxime levels measured by high-pressure liquid chromatography in bronchial secretions were below detectable limits (less than 0.5 mg/liter); however, levels of desacetyl cefotaxime exceeded 1.5 mg/liter in 9 of these 11 patients (range, 1.6 to 10 mg/liter). Concentrations of desacetyl cefotaxime in lung secretions (6.9 +/- 0.85 [standard error] mg/liter) was 77% of mean levels of desacetyl cefotaxime in plasma (8.9 +/- 1.26 mg/liter). In summary, concentrations of desacetyl cefotaxime in bronchial secretions are markedly higher than those of cefotaxime.

Adult

I.v. infusion devices: are they always justified?

Electronic infusion device (EID) use is increasing and contributes substantially to hospital costs, approximately $1,000,000 per year at the University of Michigan Hospitals. Only two studies have been conducted with the purpose of determining potential advantages of EID over less-expensive roller clamps. Neither clearly demonstrated that controllers are more beneficial than roller clamps. Pumps have not received this type of study. EID use should, therefore, be limited only to those situations in which they are decidedly advantageous.

Cost-Benefit Analysis

Therapy of chronic obstructive airways disease.

The most frequently employed measure in attempts to alleviate symptoms and improve the quality of life of patients with chronic obstructive airways disease (COAD) is to prescribe medications. However, COAD is largely an irreversible condition and no therapeutic intervention has been shown to be universally useful. Theophylline or corticosteroid are occasionally helpful but most patients will not benefit. Of the remaining options, only oxygen has been shown to be effective in selected patients and should be administered on a continuous basis. It is becoming increasingly evident that clinicians should be more discriminating when making therapeutic decisions for persons with COAD. Maintenance therapy with pharmacological agents should be entertained only after individually conducted therapeutic trials. Moreover, enormous costs can result from treating even a small fraction of the population estimated to have COAD.

Adrenal Cortex Hormones

Dipyridamole: a critical evaluation.

Dipyridamol is a vasodilator that is used primarily in clinical practice as an antiplatelet agent. It increases coronary blood flow and was originally introduced as an antianginal agent. An ability to prolong a shortened platelet survival has been used to justify its value in preventing thromboembolic complications. Conditions characterized by a reduction in platelet survival and where dipyridamole has been used include heart valve replacement, arterial grafting, cerebrovascular disorders, and disorders of peripheral circulation. The in vivo effect of dipyridamole on platelet aggregation has not been well defined and may depend on additional factors. Prostaglandins appear to have important roles in platelet homeostasis; their relationships to the action of dipyridamole are discussed. Dipyridamole usually is combined with aspirin for synergistic anti-aggregatory purposes. However, the nature of the interaction has not been elucidated and benefit from the addition of dipyridamole has not been demonstrated in clinical studies. A review of clinical studies using dipyridamole indicates that it currently has limited value.

Angina Pectoris

Theophylline in stable chronic airflow obstruction. A reappraisal.

Theophylline is commonly recommended for patients who have stable chronic airflow obstruction (CAO). Recent evidence confirms that serum theophylline concentrations between 10 and 20 mg/L may increase forced expiratory volume in 1 s (FEV1) and forced vital capacity in these patients. Exercise tolerance, however, and the classic respiratory symptoms of wheezing, breathlessness, cough, and sense of well-being do not improve. A reappraisal of the role of this medication in patients with stable CAO is therefore necessary; we recommend not prescribing this medication for all patients. Instead, the response of FEV1 after isoproterenol inhalation (0.15 mg) should be monitored. This simple test has good efficacy for predicting the response to oral theophylline therapy and could diminish the cost and unnecessary side effects of theophylline while benefiting those who will respond.

Administration, Oral

Therapeutic use of albumin: 2.

It has previously been shown that albumin costs in a Veterans Administration Hospital constituted a large portion of the pharmacy drug budget and that much albumin was prescribed inappropriately. Therefore, a program of education and use monitoring was instituted to improve understanding and prescribing of this product. Inappropriate use declined from 41% to 26% of total albumin units and, more dramatically, total cost of albumin used had decreased by 90% one year after this program was initiated. Projected yearly savings from decreased use was more than $85,000. These results demonstrate that such a program can promote more appropriate use of albumin and effect a cost savings for hospitals.

Albumins

Bronchial secretion concentrations of tobramycin.

The mean concentrations of tobramycin in bronchial secretions from patients with pneumonia were almost two times greater than secretions from patients free of lung infection. Mean tobramycin bronchial secretion to serum concentration ratios also were higher when obtained from infected lungs (0.66 versus 0.17) These data suggest that lung infection enhances the concentrations of tobramycin in bronchial secretions.

Aged

The efficacy of isoproterenol inhalation for predicting the response to orally administered theophylline in chronic obstructive pulmonary disease.

Orally administered theophylline is commonly prescribed for patients with chronic obstructive pulmonary disease (COPD). It would be advantageous to predict those patients who will or will not respond to this methylxanthine. Forty men with COPD received placebo and theophylline orally, each for 1 month in a double-blind, single cross-over fashion. The acute response of the forced expiratory volume in one second (FEV1) to isoproterenol inhalation (015 mg) during placebo therapy was determined. The subjective and objective responses after 1 month of therapeutic theophylline concentrations (15.1 +/- 4.2 microgram/ml), mean +/- SD) in these clinically stable subjects also were measured. The sensitivity and specificity of isoproterenol aerosolization for predicting an objective response to theophylline was 75 and 96%, respectively. We conclude that isoproterenol inhalation can predict the response to orally administered theophylline in patients with COPD.

Administration, Intranasal

[Volumetric correction of the maximal expiratory flow 25-75% in chronic obstructive bronchopneumopathies].

After inhalation of a bronchodilator aerosol, indices of airway obstruction usually improve whereas the forced expiratory flow between 25 and 75% (FEF25-75%) of the forced vital capacity (FVC) commonly remains the same or may decrease. This is due to the fact that the FEF25-75% after bronchodilatation is measured at lower absolute lung volumes with subsequently less elastic recoil pressure. A goal of this study was to analyze this test after volume adjusting so that the flows before and after a bronchodilator are compared at equal volumes (isovolume). Thirty-seven men with chronic obstructive pulmonary disease (COPD) performed maximal forced expiratory maneuvers before and 15 minutes after isoproterenol (0.15 mg) inhalation. The mean value of isovolume (0.56 +/- .30 1. sec-1) was significantly greater (p less than 0.001) than the FEF25-75% recorded before (0.45 +/- .26 1. sec-1) and after (0.50 +/- .27 1. sec-1, p less than 0.01) bronchodilator inhalation. The FVC was improved in 18 patients but only 6 (33%) had an improved conventional FEF25-75%. On the other hand, isovolume FEF improved in 12 (66%) patients. Isovolume FEF also improved twice as frequently as conventional FEF25-75% in those demonstrating an improvement in forced expiratory volume in the first second (FEV1). Furthermore, when the conventional FEF25-75% demonstrated no improvement after isoproterenol inhalation, isovolume improved in 8/26 (31%) of these patients. Our results suggest that volume adjusting the FEF25-75% after isoproterenol inhalation increases its sensitivity for detecting acute bronchodilation in patients with COPD, and that this methods appears practical in routine pulmonary function testing.

Forced Expiratory Flow Rates

Isoproterenol challenge during placebo and oral theophylline therapy in chronic obstructive pulmonary disease.

Because it is common to perform a bronchodilator challenge while a patient continues oral methylxanthines, we wanted to determine if this procedure might be misleading for subsequent therapy. Thirty-eight men with a long smoking history and a clinical diagnosis of chronic obstructive pulmonary disease (COPD) were given placebo and oral theophylline (each for one month) in a double-blind, single-crossover manner. Pulmonary functional tests were performed before and after isoproterenol nebulization on the final day of each 4-wk period. There were significantly larger increases in FVC (p less than 0.001) and FEV1 (p less than 0.01) after isoproterenol challenge when receiving placebo than when receiving theophylline. According to the intermountain Area rating criteria, only the results after isoproterenol challenge during placebo therapy would indicate improvement. These results suggested that isoproterenol inhalation challenge be performed after methylxanthines have been discontinued if used to predict which patients with COPD may respond to oral theophylline therapy.

Bronchial Provocation Tests

Therapeutic use of thrombolytic agents.

The use of thrombolytic agents for clotting disorders as compared with standard anticoagulant therapy is reviewed. The resolution rates of pulmonary emboli (PE) were examined in a comparison of streptokinase, urokinase, and heparin therapy in several studies. The effectiveness of streptokinase therapy was compared to heparin treatment of deep vein thrombosis (DVT) as well. In addition, studies on the use of thrombolytic agents for acute myocardial infarction (AMI) are reviewed. Clinical studies show that although streptokinase and urokinase promote more rapid resolution of PE and DVT (as determined by perfusion lung scans, angiography, and venography), superiority over conventional treatment has not been established. The disadvantages include greater cost and more frequent bleeding episodes than anticoagulant therapy. The studies of thrombolytic agents for AMI did not find significant beneficial effects on the mortality rates. It is recommended that thrombolytic agents not be used routinely for the treatment of PE, DVT, or AMI.

Angiography

Treatment of chronic obstructive pulmonary disease with orally administered theophylline. A double-blind, controlled study.

Theophylline is commonly prescribed for chronic obstructive pulmonary disease (COPD), although controlled studies do not exist to support this use. We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind, crossover manner. Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period. Theophylline therapy produced small, but significant, increases over placebo in mean values. However, only the forced expiratory volume in 1 s was "improved," according to published criteria. There were no significant differences in subjective effects between treatment periods. Six patients were identified as "responders"; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization. Theophylline therapy is not beneficial to most COPD patients, and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy.

Administration, Oral