Suspended judgment. Seeing through the double-masked design: a commentary.
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Antidepressive Agents↗
Biomedical subjects
S Fisher
Publications and source records attributed to S Fisher.
A meta-analysis of fluoxetine outcome in the treatment of depression.
A meta-analysis was conducted on all the double-blind, placebo-controlled efficacy trials of the antidepressant fluoxetine (Prozac). This drug has become the antidepressant most frequently prescribed by psychiatrists and has been hailed by the media as a "wonder drug." Results produced a relatively modest overall effect size that was no greater than effect sizes obtained by previous meta-analyses of tricyclic antidepressants. This study also examined the possibility that bias may have contaminated study outcome ratings. Because past studies suggest that the greater frequency of side effects in active drug groups unblinds study participants, we examined the relationship between study effect sizes and the percentage of patients reporting side effects. As predicted, both clinician and patient outcome ratings correlated significantly with the percentage of patients experiencing side effects. Questions are raised about the role of side effects in mediating drug outcome results.
Adult↗
Utility of laboratory screening in cocaine-exposed infants.
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Brain↗
Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog.
We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Veterans Affairs congestive heart failure antiarrhythmic trial. CHF STAT Investigators.
This is a prospective, double-blind, placebo-controlled trial to determine the effect of antiarrhythmic drug therapy on mortality in patients with congestive heart failure and ventricular arrhythmia. Patients will be assigned to receive either amiodarone or placebo. Eligible patients include those with ischemic and nonischemic congestive heart failure and with > or = 10 ventricular premature beats per hour. All patients must have shortness of breath with minimal exertion or paroxysmal nocturnal dyspnea, a left ventricular internal dimension (LVIDd) by echocardiogram of > or = 55 mm or a cardiothoracic ratio of > 0.5 and an ejection fraction of < or = 40%. All patients will receive vasodilator therapy, unless they find it intolerable. Patients will be entered into the study for 2.5 years and followed for an additional 2 years. Drug therapy will be continued for all patients throughout the entire study unless adverse reactions occur that necessitate individualized treatment. The expectation is that 674 patients will be entered into the study from 25 participating centers. This sample size will allow for the detection of a 33% decrease in 2-year mortality (20% vs 30%) in the treated patients compared with those in the placebo group, with a power of 0.90 and a 2-sided alpha level of 0.05. Intermittent Holter monitoring, radionuclide ventriculograms, pulmonary function tests, echocardiograms, and blood tests, including arterial blood gases, will be required for each patient.(ABSTRACT TRUNCATED AT 250 WORDS)
Amiodarone↗
Extracellular matrix 5: adhesive interactions in early mammalian embryogenesis, implantation, and placentation.
Normal morphogenesis and differentiation depend heavily on the coordination of cell-cell and cell-extracellular matrix interactions. During early mammalian development, the first cell lineages to be established are extraembryonic (trophoblast and extraembryonic endoderm), which are essential for satisfying the nutritional requirements of the developing embryo. This review emphasizes the importance of the cadherin family of cell-cell adhesion molecules and the integrin family of extracellular matrix receptors in mediating interactions between cells and their environment during early development. The review first discusses the critical role of cell-cell interactions in fertilization and early lineage decisions that occur during pre- and peri-implantation development in the mouse, using the calcium-dependent cell adhesion molecule E-cadherin as the primary example. The remainder of the review discusses the importance of cell-ECM interactions in the further morphogenesis and differentiation of the newly segregated lineages. The critical roles of integrins in differentiation, migration, and invasion of trophoblast in both mouse and human are emphasized.
Animals↗
How sound is the double-blind design for evaluating psychotropic drugs?
Sufficient data have accumulated to raise serious doubts about the integrity of the double-blind design that is presumed to shield psychotropic drug trials from bias and expectations. A major deficit in most drug trials has been the use of inert rather than active placebos. The deficiencies of the double-blind paradigm call for a questioning stance with respect to previous studies of psychotropic drug efficacy. Various possible ways of strengthening the double-blind paradigm are reviewed.
Clinical Trials as Topic↗
Social factors influencing performance of a foraging task for captive chimpanzees.
The performance of captive chimpanzees (Pan troglodytes) during a simulated foraging activity was compared to that reported for the foraging behavior of wild chimpanzees. The ability to find hidden fruit in a large outdoor play area was measured for 34 subjects housed in ten separate groups. Sex differences were apparent, with females searching for and finding significantly more fruit than males did. Chimpanzees of high and medium dominance rank found more fruit than those of low rank. Neither age nor stage of the female sexual cycle exerted an influence. The subjects became more proficient at finding fruit during the second block of trials. The results reflect possible influences of captivity on chimpanzee social behavior.
Animals↗
Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure.
A RIA for human brain natriuretic peptide (BNP) was developed. Both BNP and atrial natriuretic peptide (ANP) were extracted from human plasma with Vycor glass powder (71% recovery for BNP). The assay had a minimum detection limit of 0.45 fmol/tube and an IC50 of 9 fmol/tube. The within-assay coefficients of variation were 11.4% at 4 pmol/L and 3.2% at 22 pmol/L, and the between-assay coefficient of variation was 11% at 24 pmol/L. There was no significant loss of immunoreactive (IR)-BNP in plasma samples stored at -80 C for 4 weeks. Low rates of labeled BNP and IR-BNP degradation occurred in EDTA plasma incubated at 37 C. The mean venous plasma IR-BNP (6.3 +/- 0.3 pmol/L) in normal subjects (n = 48) was significantly lower than plasma ANP (8.4 +/- 0.6 pmol/L). In contrast to ANP, IR-BNP did not increase when normotensive or hypertensive subjects changed from erect to supine posture. Markedly elevated levels were found in patients with congestive heart failure (mean IR-BNP, 87 +/- 11 pmol/L; ANP, 87 +/- 12 pmol/L; n = 35), recent myocardial infarction (mean IR-BNP, 60 +/- 9 pmol/L; ANP, 33 +/- 6 pmol/L; n = 7), and chronic renal failure. High pressure liquid chromatography of plasma extracts from heart failure subjects revealed both high (mol wt, 10,000) and low (mol wt, 4,000) mol wt IR-BNP. High mol wt BNP was the major component (mean ratio, 1.9:1) and was linearly correlated with low mol wt BNP (r = 0.99). HPLC of plasma extracts from three normal subjects receiving constant infusions of human BNP (2 pmol/kg.min) showed a single major peak eluting in the position of hBNP-32, with no evidence of high mol wt material. These results show that whereas marked elevations in BNP occur in circulatory disorders, a major (> 50%) and consistent contribution to immunoreactivity is due to precursor forms. Further, compared to ANP, there is no IR-BNP response to supine posture in normal and hypertensive subjects.
Adult↗
Prescription for quality primary care. Interview by Sandy Marron.
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Delivery of Health Care↗
Postmarketing surveillance by patient self-monitoring: trazodone versus fluoxetine.
This article presents incidence estimates and relative risks for a number of adverse clinical events reported by outpatients being treated with either trazodone or fluoxetine. Data were collected via an innovative method of patient self-monitoring. Many of the suggested differences between the two drugs are quite consistent with expected adverse drug reactions documented in both the package insert data for outpatients and with reports in the literature. Findings not so readily anticipated for trazodone, however, include higher relative frequencies for muscle weakness or soreness, skin swelling, and urinary complaints compared with fluoxetine; for fluoxetine, data are presented indicating a higher incidence of various psychologic/psychiatric adverse clinical events, including delusions and hallucinations, aggression, and suicidal ideation. Other possible interpretations of the results are discussed.
Adult↗
Congestive heart failure: survival trial of antiarrhythmic therapy (CHF STAT). The CHF STAT Investigators.
This study is a prospective, double-masked, randomized, clinical trial to determine the effect of anti-arrhythmic drug therapy on mortality in patients with congestive heart failure and ventricular arrhythmia. Patients will be assigned to receive either amiodarone or placebo. Eligible patients include those with ischemic and nonischemic congestive heart failure (New York Heart Association class III or VI) and with 10 or more ventricular premature beats per hour. All patients must have shortness of breath with minimal exertion or paroxysmal nocturnal dyspnea, a left ventricular internal dimension (LVIDd) by echocardiogram of 55 mm or greater (> or = 55 mm) or a CT ratio of greater than 0.5, and an ejection fraction of 40% of less. Patients will be entered into the study for 2.5 years and followed for an additional 2 years. Drug therapy will be continued for all patients throughout the entire study unless adverse reactions occur that necessitate individualized treatment. The expectation is that 674 patients are to be entered into the study from 25 participating centers. This sample size will allow for the detection of a 33% decrease in 2-year mortality (20% vs. 30%) in the treated patients as compared to those in the placebo group with a power of 0.90 and a two-sided alpha level of 0.05. Intermittent Holter monitoring, radionuclide ventriculograms, pulmonary function tests, echocardiograms, and blood tests, including arterial blood gases, will be required for each patient. The study analysis will address differences in total mortality, cardiac mortality, and sudden cardiac death between patients receiving anti-arrhythmic drug therapy and those receiving placebo. Other factors to be examined include the effects of antiarrhythmic therapy on suppression of arrhythmias, on ejection fraction, and relation of ischemic events to mortality.
Amiodarone↗
A meta-analysis of antidepressant outcome under "blinder" conditions.
A meta-analysis of 22 studies of antidepressant outcome assessed the level of medication effects under conditions thought to be less subject to clinician bias than those in the typical double-blind drug trial. Studies were included only if, in addition to a newer antidepressant group, they also contained both standard antidepressant and placebo control groups. Effect sizes were quite modest and approximately one half to one quarter the size of those previously reported under more transparent conditions. Effect sizes that were based on clinician outcome ratings were significantly larger than those that were based on patient ratings. Patient ratings revealed no advantage for antidepressants beyond the placebo effect. Effect sizes were unrelated to sample sex ratios, patient age, inpatient or outpatient status, dosage level, and treatment duration. Findings highlight the fragility of the antidepressant effect.
Antidepressive Agents↗
Hypnotizability and recovery from cardiac surgery.
We studied 32 coronary bypass patients to examine the effect of hypnosis on recovery from surgery. The patients were assessed for hypnotizability with the Hypnotic Induction Profile (HIP) and assigned to experimental groups with a random stratification procedure to equate for differences in hypnotizability, age, and severity of illness. We taught patients in groups one and two formal hypnosis with different treatment strategies; patients in group three were not taught formal hypnosis or a treatment strategy. Scores on the HIP were significant predictors of recovery, independent of experimental treatment with formal hypnosis. Patients who scored "Midrange" stabilized more quickly in the intensive care unit (ICU) than those who scored "High" or "Low" (p = < .05). Patients who scored "High" had more labile blood pressure in the ICU compared to the "Midrange" and "Lows" (p = < .05). Measured hypnotizability was associated with the recovery sequence from surgery.
Coronary Artery Bypass↗
Role of FFA-glucose cycle in glucoregulation during exercise in total absence of insulin.
Muscle contraction in vitro increases glucose uptake (GU), independent of insulin, but in vivo, the exercise-induced increase in GU is impaired in insulin-deficient diabetic dogs. We wished to determine whether, in vivo, suppression of the free fatty acid (FFA)-glucose cycle with methylpalmoxirate (MP, inhibitor of FFA oxidation) alone or combined with propranolol (PRO, beta-blocker) could improve GU during exercise in the absence of insulin. We performed four groups of exercise experiments (6 km/h, 10% slope) in depancreatized insulin-deprived dogs: 1) control (n = 6); 2) MP treated (5 oral doses of 10 mg/kg, twice daily, n = 6); 3) treated with MP+octanoate (OCT; oxidation unaffected by MP, 27 mumol.kg-1.min-1 iv during exercise; n = 5); and 4) MP+PRO treated (5 micrograms.kg-1.min-1 iv during exercise, n = 6). MP abolished ketosis (inhibition of hepatic FFA oxidation), decreased basal glucose production (GP), and increased metabolic clearance of glucose (MCR). During exercise, MP attenuated the increment in GP (P < 0.01), which was reversed by OCT. MP did not affect the exercise-induced increase in GU and MCR. With MP+PRO, FFAs decreased and lactate did not rise during exercise. GP was not further suppressed, but GU and MCR were increased (P < 0.01) to 89 and 31% of normal, respectively. In insulin-deprived depancreatized dogs, glucose cycling was increased to a greater extent than GP, as in type II diabetes. By the end of exercise, glucose cycling increased (P < 0.05), but to a similar extent as GP.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison of three depression rating scales.
We directly compared scores on the self-rated Beck Depression Inventory with two other common rating scales that assess a wider range of psychopathology, including depression, the self-rated Symptom Check List-90--R (SCL-90--R), and the clinician-rated Brief Psychiatric Rating Scale for 71 inpatients who suffered from depression (n = 50) and other disorders. All measures of depression showed robust correlations among themselves. The self-rated scales correlated better between themselves than with the clinician-rated scale. Since the SCL-90--R assesses depression as well as the Beck inventories, is also a self-report instrument, yet provides a richer description of psychopathology with little extra effort, it may have some advantage over the latter.
Adult↗
Tuberculous osteomyelitis of the skull in an Ethiopian immigrant child.
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Child↗
18F-2-deoxy-2-fluoro-D-glucose uptake into human tumor xenografts. Feasibility studies for cancer imaging with positron-emission tomography.
The positron-emitting glucose analogue 18F-2-fluoro-2-deoxy-d-glucose (FDG) was evaluated for its accretion into the following subcutaneous human tumor xenografts in nude mice: B-cell lymphoma (Namalwa or Raji), ovarian carcinoma (HTB77), colon cancer (SW948), choriocarcinoma (BEWO), bladder cancer (UM-UC-2), renal cell carcinoma (UM-RC-3), neuroblastoma (Mey), melanoma (HTB63), and small cell lung carcinoma (NCI69). Two hours postinjection, tumor uptakes ranged from 0.027 (colon cancer) to 0.125% kg injected dose/g (melanoma); and was greater than 0.085 in the Namalwa lymphomas and the renal cell carcinomas. Tumor-blood ratios of up to 23:1 were seen 2 hours postinjection (melanoma) with a mean tumor-blood ratio for all tumors of 12.3 +/- 1.8. Uptake in the other tumors was intermediate. When evaluated, tumor uptake was slightly greater at 1 than at 2 hours postinjection, although target-background ratios were generally higher at 2 hours postinjection. This compound, FDG, may have broad applicability as a tracer for positron-emission tomographic imaging of many human malignancies.
Animals↗