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Biomedical subjects

D Notterman

Publications and source records attributed to D Notterman.

8 recordsLinked to original sources
PubMed2000

Analysis of p53-regulated gene expression patterns using oligonucleotide arrays.

Oligonucleotide microarrays were employed to quantitate mRNA levels from a large number of genes regulated by the p53 transcription factor. Responses to DNA damage and to zinc-inducible p53 were compared for their transcription patterns in cell culture. A cluster analysis of these data demonstrates that genes induced by gamma radiation, UV radiation, and the zinc-induced p53 form distinct sets and subsets with a few genes in common to all these treatments. Cell type- or cell line-specific p53 responses were detected. When p53 proteins were induced with zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes fell into eight distinct classes, five different kinetics of induction, and three different kinetics of repression. In addition, low levels of p53 in a cell induced or repressed only a subset of genes observed at higher p53 levels. The results of this study demonstrate that the nature of the p53 response in diverse mRNA species depends on the levels of p53 protein in a cell, the type of inducing agent or event, and the cell type employed. Of 6000 genes examined for p53 regulatory responses, 107 induced and 54 repressed genes fell into categories of apoptosis and growth arrest, cytoskeletal functions, growth factors and their inhibitors, extracellular matrix, and adhesion genes.

Chlorides↗
PubMed1998

Prevention of mammalian DNA reduplication, following the release from the mitotic spindle checkpoint, requires p53 protein, but not p53-mediated transcriptional activity.

The tumor suppressor p53 has been identified as a component of a mitotic spindle checkpoint. When exposed to a spindle-disrupting drug such as nocodazole, fibroblasts derived from mice having wild-type p53 are blocked with a 4N content of DNA. Conversely, fibroblasts from p53-deficient mice become polyploid. To learn if transcriptional activation of downstream genes by p53 plays a role in this putative checkpoint, three cell lines were exposed to nocodazole. In one line, p53 protein is not expressed, while the other two cell lines over-express p53. In one of these two lines, the N-terminal transactivation domain is wild-type and in the second, this region contains a mutation that eliminates the ability of the protein to act as a transcription factor. Incubation with nocodazole of cells containing wild-type p53 results in accumulation of both 2N and 4N populations of cells. Under the same conditions, cells containing a transactivation-deficient mutant of p53 accumulate a 4N population of cells, but not a 2N population of cells. Cells entirely deficient in p53 protein become hyperdiploid, and display 8N to 16N DNA content. In all three cell lines, nocodazole elicited an initial increase in mitotic cells, but within 24 h the mitotic index returned to baseline. Expression patterns of cyclins B and D indicated that following entry into mitosis, the cells returned to a G1 state but with 4N DNA content. Subsequent re-duplication of DNA beyond 4N is prevented in cells containing either wild-type or transcriptionally inactive p53 protein. In cells entirely lacking p53 protein, DNA is re-duplicated (without an intervening mitosis) and the cells become hyperdiploid. These experiments indicate that p53 does not participate in the transient mitotic arrest that follows spindle disruption, but is essential to prevent subsequent reduplication of DNA and the resulting hyperdiploid state. This function is intact in a mutant that is transcriptionally inactive.

Amino Acid Substitution↗
PubMed1996

Respiratory and cardiac function in children after acute hypoxemic respiratory failure.

OBJECTIVE: To examine the pulmonary and cardiac function of children who survived an episode of acute hypoxemic respiratory failure. DESIGN: Descriptive cohort analysis. SETTING: Pediatric clinical research center of a university hospital. PATIENTS: Utilizing the criteria of PaO2 < 75 torr (< 10 kPa) with an FIO2 of > 0.5 while intubated, bilateral diffuse pulmonary infiltrates on chest radiograph, and exclusion of cardiogenic pulmonary edema, 147 patients were identified during the 6-yr period from July 1, 1986 to August 1, 1993. Fifty patients survived to discharge and 37 were alive at the time of follow-up. Fourteen patients were eventually entered into the study. INTERVENTIONS: The study patients were given a test battery consisting of a questionnaire specific for cardiopulmonary status, a physical examination, a chest radiograph, electrocardiography, echocardiography with detailed examination of the pulmonary circulation, pulse oximetry, complete blood count, and serum chemistries and pulmonary function testing with bronchoprovocation in selected patients. MEASUREMENTS AND MAIN RESULTS: The 14 follow-up patients were evaluated an average of 23 +/- 23 months (range 3 to 66) following intensive care unit discharge. No child reported a significant alteration in lifestyle or limitation of activities. Physical examinations were generally unremarkable. The room air oxyhemoglobin saturation was > or = 0.98 in all patients. Comparison of chest radiographs at the time of follow-up with those chest radiographs during the period of critical illness showed marked but not complete improvement in all. Electrocardiograms and echocardiograms showed new evidence of left ventricular hypertrophy in one child. The right ventricular preejection period to ejection time ratio was normal in all subjects. Eleven patients completed spirometry. Four patients were normal and the other patients had evidence of restrictive or obstructive disease either at baseline or after bronchoprovocation challenge. Ten children had lung volume measurements. Five children were normal, two showed increased volumes consistent with obstruction, and three showed decreased volumes indicative of restriction. Four of seven patients showed evidence of decreased diffusion capacity. Six of seven patients with evidence of abnormal pulmonary function had a positive response to bronchodilator administration. CONCLUSIONS: Although pediatric survivors of acute hypoxemic respiratory failure perceive neither a limitation in lifestyle nor chronic pulmonary morbidity, careful examination of the cardiopulmonary system demonstrates a significant number with abnormal chest radiographs and abnormalities in pulmonary function. These children require careful follow-up and may benefit from use of a bronchodilator.

Acute Disease↗
PubMed1995

Length/serum creatinine ratio does not predict measured creatinine clearance in critically ill children.

OBJECTIVE: Information regarding renal function is important in critically ill children to adjust the dosage of drugs that are eliminated by the kidneys. Methods for estimating glomerular filtration rate (GFR) based on age and serum creatinine level have shown good agreement with measured creatinine clearance (CLCR) in children without critical illness but have not been examined in critically ill children. METHODS: CLCR (24 hours) was measured (CLCR-measured) in 100 individuals (aged 5.6 years [range, 0.1 to 20.8 years]) admitted to a pediatric intensive care unit. Urine was collected by indwelling bladder catheters. Serum levels were determined. CLCR was calculated (CLCR-measured) according to the standard formula. GFR was estimated (CL-estimated) according to a published method, in which GFR is based on serum creatinine levels, patient length, and a constant that varies with the age and sex of the child. For each patient, the percentage difference between methods was calculated as the difference between the methods divided by the average obtained by the two methods and expressed as a percentage. Bias was calculated as the absolute value of the percentage difference. RESULTS: CLCR-measured and CL-estimated were significantly correlated (CLCR-measured = 0.57 CL-estimated + 16.8; r = 0.68; p < 0.001). However, CL-estimated was greater than CLCR-measured in 84 patients. The difference ranged from -230 to +123 ml/min/1.73 m2 (mean -25.9 ml/min/1.73 m2 [95% confidence interval, -18.1 to 33.7 ml/min/1.73 m2]). The mean percentage difference between the methods was also large (-38.1% [95% confidence interval, -47.1% to 29.2%]) and ranged from -153.2% to 102.1%. The mean bias was 45.2% (95% confidence interval, 37.7% to 52.8%). In 36 of 100 patients the discrepancy between the two methods was greater than 50%. Adjusting for weight percentile, as a proxy for abnormal muscle mass, did not improve the model. CONCLUSION: A method to estimate GFR in children that is based on age and sex, but not critical illness, does not correspond with measured 24-hour CLCR. Use of this method to adjust dosage of drugs eliminated by the kidney might result in significant overdosage in most critically ill children.

Adolescent↗
PubMed1994

Atrial natriuretic peptide response to postural change and medication in familial dysautonomia.

Circulating atrial natriuretic peptide (ANP) was assayed before and after postural change and exercise in 54 patients with familial dysautonomia (FD) and 20 controls. ANP levels were compared with blood pressure, heart rate, plasma catecholamines and parameters of renal function. Compared with controls supine FD subjects had elevated blood pressures, heart rates and ANP levels (39 +/- 4 pg/ml vs. 23 +/- 3 pg/ml, p < 0.01). With the erect posture and exercise in FD subjects, blood pressure fell below control values, with ANP lowered. In FD subjects, blood pressure was correlated with ANP levels when supine and when erect and with heart rate post exercise. In controls, ANP levels did not correlate with other parameters. In FD patients on metoclopramide, supine and erect blood pressure and ANP levels were higher. FD subjects treated with fludrocortisone, had elevated supine and erect noradrenaline (p < 0.05 and p = 0.06); and those on diazepam had lower erect and post exercise noradrenaline (p < 0.05), but ANP levels were similar. In conclusion, sympathetic denervation may increase FD patients' responsiveness to other regulators of cardiovascular integrity, such as ANP. In addition, circulating ANP and catecholamines in FD subjects appear to be influenced by commonly used medications, such as metoclopramide.

Adolescent↗
PubMed1991

Pediatric interhospital critical care transport: consensus of a national leadership conference.

As pediatric interhospital critical care transport has evolved toward a distinct discipline, practitioners in this field have recognized the need for guidelines for transport program development and patient care. At a gathering of medical directors of pediatric transport programs, the following topics were discussed: team composition and transport staffing, training requirements for pediatric and nonpediatric transport teams, goals and design of a transport data base, and medical-legal issues, including the responsibilities of the referring and receiving institutions. Consensus recommendations were made for the major issues in each of these areas. Several questions were raised which may be answered by multiinstitutional studies.

Child↗