Biomedical subjects
M Green
Publications and source records attributed to M Green.
On making a difference.
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Occurrence of IgA and IgG antibodies to select peptides representing human papillomavirus type 16 among cervical cancer cases and controls.
We used an enzyme-linked immunosorbent assay to test sera from 186 cases of invasive cervical cancer and 172 age-matched controls for IgG and IgA antibodies to an human papillomavirus 16 E7 peptide and to peptide 245, representing an epitope in E2. Cases had significantly higher mean absorbance values than controls for both immunoglobulin isotypes to E7 and elevated mean values for IgG to peptide 245. Since absorbances were not normally distributed we analyzed cervical cancer risk for seropositive and seronegative women. Of the traditional cervical cancer risk factors, cigarette smoking, educational level, number of pregnancies, time interval since last Papanicolaou smear, and age at first intercourse influenced the distribution of seropositivity to some of the viral antigens. Adjusting for these variables, the odds ratios of cervical cancer associated with IgG to E7 was 5.28 [95% confidence (95% CI) = 2.4-11.6] and that with IgA to E7 was 2.67 (95% CI = 1.3-5.3). IgG to peptide 245 was less strongly associated, odds ratio 1.68 (95% CI = 1.2-3.3), and IgA to peptide 245 was not significantly associated with disease. These findings suggest that antibodies to E7 are markers for invasive cervical cancer. However, seropositivity correlated poorly with clinical state, survival, or the presence of human papillomavirus DNA in the cancer tissue.
The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion.
Expression of the glucose-regulated proteins (GRPs), GRP78 and GRP94, is induced by a variety of stress conditions including treatment of cells with tunicamycin or the calcium ionophore A23187. The stimulus for induction of these resident endoplasmic reticulum (ER) proteins appears to be accumulation of misfolded or underglycosylated protein within the ER. We have studied the induction of mRNAs encoding two other resident ER proteins, ERp72 and protein disulfide isomerase (PDI), during the stress response in Chinese hamster ovary cells. ERp72 shares amino acid sequence homology with PDI within the presumed catalytic active sites. ERp72 mRNA and, to a lesser degree, PDI mRNA were induced by treatment of Chinese hamster ovary cells with tunicamycin or A23187. These results identify ERp72 as a member of the GRP family. Stable high level overproduction of ERp72 or PDI from recombinant expression vectors did not alter the constitutive or induced expression of other GRPs. High level overexpression resulted in secretion of the overproduced protein specifically but not other resident ER proteins. This suggests that the ER retention mechanism is mediated by more specific interactions than just KDEL sequence recognition.
Physician reporting of adverse drug reactions. Results of the Rhode Island Adverse Drug Reaction Reporting Project.
The Food and Drug Administration, Rockville, Md, contracted with the Rhode Island Department of Health, Providence, to conduct a project to increase reporting of suspected adverse drug reactions through physician education. Voluntary reporting, an important part of postmarketing surveillance that signals potential problems with marketed drugs, historically has been underused by physicians. After 2 years, there was a more than 17-fold increase in reports submitted directly from Rhode Island compared with the yearly average before initiation of the project. Increases in the total numbers of reports were paralleled by significant increases in the numbers of reports of severe reactions. Similar increases were not experienced nationally. Physicians in Rhode Island were surveyed before and 2 years after interventions began to determine changes in knowledge and attitudes about reporting of adverse drug reactions. Significant gains in knowledge and positive attitudes toward the reporting system occurred. We conclude that physicians can be stimulated to increase their reporting of suspected reactions, thereby improving the viability of the federal reporting system.
Internal combustion and health.
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Antibodies to human papillomavirus type 16 in patients with cervical neoplasia.
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Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration.
A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.
Making better decisions: construction of clinical scoring systems by the Spiegelhalter-Knill-Jones approach.
A study was carried out assessing the practical use of a simple system of scoring information which can help in making a diagnosis or establishing a prognosis in an individual patient. The system was introduced in 1984 for use in gastroenterology, but it can be employed in a wide range of medical and surgical settings. This series was concerned with predicting postoperative respiratory complications in a group of elderly surgical patients. The system combines elements from Baye's theorem and logistic regression, though no mathematical knowledge is required to apply it in clinical practice. The method by which results are presented is easy to understand, yet at the same time more complex ideas such as conflict of evidence and doubt may be embraced if the clinician so desires.
ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase.
We have cloned, sequenced, and expressed full length cDNA clones encoding two abundant, luminal endoplasmic reticulum proteins (ERp), ERp59/PDI and ERp72. ERp59/PDI has been identified as the microsomal enzyme protein disulfide isomerase (PDI). An analysis of the amino acid sequence of ERp72 showed that it shared sequence identity with ERp59/PDI at three discrete regions, having three copies of the sequences that are thought to be the CGHC-containing active sites of ERp59/PDI. Thus, ERp72 appears to be a newly described member of the family of CGHC-containing proteins. ERp59/PDI has the sequence KDEL at its COOH terminus while ERp72 has the related sequence KEEL. Removal of the KDEL of ERp59/PDI or the KEEL of ERp72 by in vitro mutagenesis techniques and subsequent analysis of the mutants in transient expression assays, showed that both sequences are endoplasmic reticulum retention signals for their respective proteins. The most dramatic difference in secretion between the wild type and the mutant forms of the protein was seen in the case of ERp72.
Phase II trial of etoposide and cisplatin for refractory small cell lung cancer: a Cancer and Leukemia Group B Study.
A phase II trial of etoposide and cisplatin for patients with previously treated small cell lung cancer was carried out by CALGB from June 1983 to May 1984. Thirty-five evaluable patients who had failed one prior chemotherapy regimen were treated with etoposide 80 mg/m2 and cisplatin 20 mg/m2 days 1-5 every 3 weeks. Objective responses were seen in 7 patients (20%) with 1 complete response and 6 partial responses. The median duration of response was 5.1 months. Fifteen patients (43%) had stable disease. Overall survival was 49% at 6 months and 14% at 1 year. The median survival was 6 months. Toxicity was mainly hematologic with severe and life-threatening leukopenia and thrombocytopenia seen in 71% and 66% of patients, respectively. Two treatment-related deaths caused by infection were seen. This cooperative group study fails to confirm the high response rates previously reported in institutional pilot studies.
Esorubicin (deoxydoxorubicin) has low grade activity in malignant melanoma. Results of an Eastern Cooperative Oncology Group study (EST 2685).
In this phase II trial, twenty patients with advanced, measurable melanoma from ECOG institutions were treated with esorubicin 30 mg/m2 iv every three weeks. Doses were escalated or reduced based on nadir counts. The dose limiting toxicity was leukopenia with no significant thrombocytopenia or anemia. Other toxicities were mild. One patient had skin necrosis with extravasation. Two patients with soft tissue disease had partial remissions and were treated with 9 and 17 courses. One patient was stable for 8 courses. No cardiac toxicity was seen in three patients receiving more than 150 mg/m2. The response rate was 10% (90% CI = 2 to 30%). Low level activity was seen, but it is unlikely that this drug has sufficient activity to warrant further development in melanoma.
Clinical cardiotoxicity of esorubicin (4'-deoxydoxorubicin,DxDx): prospective studies with serial gated heart scans and reports of selected cases. A Cancer and Leukemia Group B report.
Esorubicin (4'-deoxydoxorubicin, DxDx) has undergone extensive Phase II investigation for the treatment of cancer. Based on in vitro and animal data, esorubicin may possess less myocardial toxicity when compared to doxorubicin. One hundred thirty-six patients with histologically or cytologically documented non-small cell lung cancer or advanced breast cancer were enrolled in two concurrent CALGB clinical trials using esorubicin at a dose of 30 mg/m2 administered intravenously every 21 days. No patient had previously received an anthracycline agent or had evidence of severe cardiovascular disease. Cardiotoxicity was observed in eleven patients. Four patients developed symptoms of congestive heart failure and three asymptomatic patients had a significant fall in left ventricular ejection fraction (LVEF) as measured by gated pool heart scan. Four patients had cardiac signs or symptoms of indeterminate relationship to esorubicin therapy. Of 44 patients receiving more than four cycles of therapy, 36 patients (82%) had serial gated pool heart scans permitting assessment of subclinical myocardial toxicity. A 5% drop in LVEF was observed following approximately 240 mg/m2 esorubicin; a 10% drop was observed after approximately 480 mg/m2. If further clinical studies are undertaken with esorubicin, investigators are advised to monitor cardiac function frequently once the cumulative esorubicin dose exceeds 240 mg/m2. If congestive failure appears during therapy, prompt cessation of esorubicin and institution of inotropic agents may provide effective palliation. Normal myocardial function may be restored within several months.
Good tolerance of weekly oral idarubicin: (4-demethoxydaunorubicin): a phase I study with pharmacology.
Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly x 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m2 weekly x 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 +/- 0.3 h and a beta half-life of 39 +/- 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules.
The duration, nature and recurrence rate of brief depressions.
1. It has been shown in placebo controlled studies of prophylactic treatment of suicidal behaviour in patients not suffering from major depression that brief episodes of depression predict further suicidal behaviour. 2. In a prospective follow up study of patients with a history of repeated suicidal behaviour it appears that almost all suffered recurrent episodes of brief depression, mainly of moderate to severe intensity. Two thirds of the episodes lasted between two and four days. The recurrences were frequent, irregular, and apparently unpredictable. 3. The episodes were distinguishable from major depression only by the short duration.
Plasma-level response relationships with fluoxetine and zimelidine.
The results of pharmacokinetic studies of two recent 5-HT uptake inhibitors, zimelidine and fluoxetine, have pointed to the inadequacy of open-dose rising studies for establishing the most appropriate dose of new antidepressants. High plasma concentrations of the active metabolites, norzimelidine and norfluoxetine, were associated with a poorer therapeutic response in patients suffering from major depression. High drug plasma concentrations are also associated with increased side effects. Large fixed-dose placebo controlled studies with fluoxetine have confirmed the findings of the small pharmacokinetic study that lower doses are more effective. Fixed-dose pharmacokinetic studies are recommended as part of the program to establish the best dose of new antidepressants.
Absent or minimal cerebrospinal fluid abnormalities in Haemophilus influenzae meningitis.
A case of Haemophilus influenzae type b (Hib) meningitis in which the diagnosis and treatment were delayed because of normal cerebrospinal fluid analysis is presented. A retrospective review was conducted at two children's hospitals to determine the frequency and clinical characteristics of patients with Hib meningitis whose spinal fluid had a normal total white blood cell count, normal chemistries, and negative Gram stain, but subsequent growth of Hib in culture. Of 379 cases of Hib meningitis, two had completely normal CSF, and two had CSF containing small numbers of polymorphonuclear cells as the sole abnormality. In three of the four cases, the duration of symptoms was less than 24 hours, and appropriate therapy was significantly delayed because of benign-appearing CSF. Normal CSF cell counts, chemistries, and Gram stain do not exclude the possibility of bacterial meningitis, and one should remain suspicious when a child has clinical findings suggesting meningitis.
Biochemical fingerprints of Legionella spp. by the BIOLOG system: presumptive identification of clinical and environmental isolates.
Six Legionella strains were characterized with the BIOLOG identification system. A specific metabolic pattern for the six Legionella strains was observed after 24 h. Several positive reactions were detected intermittently in all six strains tested. The possible application of the BIOLOG system for identification of Legionella spp. from environmental or clinical samples is discussed.