Direct testing for low-density lipoprotein cholesterol.
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Adult↗
Biomedical subjects
J D Cohen
Publications and source records attributed to J D Cohen.
Cytotoxic interactions of tumor necrosis factor, melphalan and 41.8 degrees C hyperthermia.
Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests dramatic clinical responses in sarcoma and malignant melanoma. To extrapolate these results to clinical 41.8 degrees C whole-body hyperthermia (WBH) and systemic therapy, we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was TNF preceding 41.8 degrees C hyperthermia by 48 h, and L-PAM given simultaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a super-additive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L-PAM had super-additive interactions with TNF followed by hyperthermia. Relative to therapeutic index, we studied WBH, L-PAM and TNF in non-tumor bearing mice. The optimal trimodality sequence did not result in increased normal tissue toxicity compared to L-PAM alone. The concentrations and sequencing of TNF and L-PAM studied are consistent with clinical application to WBH.
Animals↗
Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold.
The typical functional magnetic resonance (fMRI) study presents a formidable problem of multiple statistical comparisons (i.e., > 10,000 in a 128 x 128 image). To protect against false positives, investigators have typically relied on decreasing the per pixel false positive probability. This approach incurs an inevitable loss of power to detect statistically significant activity. An alternative approach, which relies on the assumption that areas of true neural activity will tend to stimulate signal changes over contiguous pixels, is presented. If one knows the probability distribution of such cluster sizes as a function of per pixel false positive probability, one can use cluster-size thresholds independently to reject false positives. Both Monte Carlo simulations and fMRI studies of human subjects have been used to verify that this approach can improve statistical power by as much as fivefold over techniques that rely solely on adjusting per pixel false positive probabilities.
Brain↗
The effect of potassium supplementation in persons with a high-normal blood pressure. Results from phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.
We conducted a randomized, double-blind, placebo-controlled trial of oral potassium chloride supplementation (60 mmol/d) in 353 men and women with an initial average diastolic blood pressure between 80 and 89 mm Hg. In the active (n = 178) compared to the placebo (n = 175) treatment group, the urinary potassium level was significantly (p < 0.001) increased by an average of 44.0 and 42.3 mmol/24 h following 3 and 6 months of therapy, respectively. Compared to placebo, active treatment was associated with a small (mean = 1.8 mm Hg) but significant (p = 0.04) reduction in diastolic blood pressure following 3 months of therapy. Following 6 months, however, this apparent treatment effect had virtually disappeared (mean reduction in diastolic blood pressure = 0.3 mm Hg). There was no significant effect of potassium supplementation on systolic blood pressure at either follow-up visit. There was a significant, independent, dose-response relationship between change in both 24-hour urinary potassium excretion and urinary sodium-potassium ratio and the corresponding change in diastolic blood pressure (-1.49 mm Hg for the highest versus the lowest quartile of change in urinary potassium excretion.
Administration, Oral↗
Lack of blood pressure effect with calcium and magnesium supplementation in adults with high-normal blood pressure. Results from Phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.
Phase I of the Trials of Hypertension Prevention (TOHP) was a randomized, multicenter investigation that included double-blind, placebo-controlled testing of calcium and magnesium supplementation among 698 healthy adults (10.5% blacks and 31% women) aged 30 to 54 years with high-normal diastolic blood pressure (DBP) (80 to 89 mm Hg). Very high compliance (94 to 96% by pill counts) with daily doses of 1 g of calcium (carbonate), 360 mg of magnesium (diglycine), or placebos was corroborated for the active supplements by significant net increases in all urine and serum compliance measures in white men and for urine compliance measures in white women. Overall, neither calcium nor magnesium produced significant changes in blood pressure at 3 and 6 months. Analyses stratified by baseline intakes of calcium, magnesium, sodium, or initial blood pressures also showed no effect of supplementation. These analyses suggested that calcium supplementation may have resulted in a DBP decrease in white women and that response modifiers in this subgroup might have included lower initial urinary calcium levels, urinary sodium levels, or lower body mass index. However, overall analyses indicated that calcium and magnesium supplements are unlikely to lower blood pressure in adults with high-normal DBP. The subgroup analyses, useful to formulate hypotheses, raise the possibility of a benefit to white women, which requires testing in future trials.
Administration, Oral↗
Design of a multicenter trial to evaluate long-term life-style intervention in adults with high-normal blood pressure levels. Trials of Hypertension Prevention (phase II). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.
Phase II of the Trials of Hypertension Prevention (TOHP) is a multicenter, randomized trial sponsored by the National Heart, Lung, and Blood Institute designed to test whether weight loss alone, sodium reduction alone, or the combination of weight loss and sodium reduction will decrease diastolic (DBP) and systolic blood pressure (SBP) as well as the incidence of hypertension (DBP > or = 90 mm Hg, SBP > or = 140 mm Hg, and/or use of antihypertensive medications) in subjects with high-normal DBP (83 to 89 mm Hg) and SBP less than 140 mm Hg at entry. These interventions were chosen for longer-term testing with end points including hypertension prevention as well as blood pressure (BP) change based on their demonstrated short-term efficacy in reducing BP in phase I of TOHP. The phase II study population is comprised of 2382 participants (1566 men and 816 women) who are 110 to 165% of desirable body weight, allocated at random to the four treatment arms using a 2 x 2 factorial design. The trial has 80% power to detect an overall treatment effect on DBP of 1.2 mm Hg for weight loss or sodium reduction and a difference of 1.6 mm Hg between the combined intervention and placebo groups. BP observers are blinded to participant treatment assignments. Participants will be followed for 3 to 4 years. This trial may have important public policy implications concerning the ability of life-style modifications to reduce BP and prevent the development of hypertension over the long term, thereby avoiding the need for drug therapy which while effective is costly and may have side effects.
Adult↗
Baseline characteristics of participants in phase II of the Trials of Hypertension Prevention (TOHP II). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.
Phase II of the Trials of Hypertension Prevention (TOHP II) is a multicenter, controlled clinical trial designed to test whether weight loss, a reduced sodium intake, or a combination of weight loss and a reduced sodium intake will lower blood pressure (BP) and prevent the occurrence of hypertension. The study population consists of middle-aged, moderately overweight individuals with a diastolic BP between 83 and 89 mm Hg. Of the 2382 randomized participants, 816 (34%) are female and 494 (21%) are from a racial or ethnic minority background. At baseline, mean dietary intakes of sodium, based on measurements of 24-hour urinary excretion, were 199 mmol/d in men and 154 mmol/d in women. The average body mass index was 30.9 kg/m2. Across the four randomized groups, there was no substantial imbalance in the distribution of baseline variables; however, the mean age in the four groups was slightly but significantly different (range: 43.2 to 44.2 years, P = 0.02). A comparison of baseline characteristics of TOHP II participants with those of participants in three other primary prevention trials reveals a high level of mean dietary sodium intake in each study. Data reported in this article indicate that any subsequent differences in BP among the randomized groups are unlikely to result from maldistribution of known confounding variables at baseline. Finally, because of the high prevalence of overweight and excessive sodium intake in the United States, results from TOHP II should be broadly applicable to the general population.
Adult↗
An anatomically constrained neural network model of fear conditioning.
Conditioning of fear reactions to an auditory conditioned stimulus (CS) paired with a footshock unconditioned stimulus (US) involves CS transmission to the amygdala from the auditory thalamus, the auditory cortex, or both. This article presents a simple neural network model of this neural system. The model consists of modules of mutually inhibitory nonlinear units representing the different relevant anatomical structures of the thalamo-amygdala and thalamo-corticoamygdala circuitry. Frequency-specific changes produced by fear conditioning were studied at the behavioral level (stimulus generalization) and the single-unit level (receptive fields). The findings mirror effects observed in conditioning studies of animals. This computational model provides an initial grounding for explorations of how emotional information and behavior are related to anatomical and physiological observations.
Acoustic Stimulation↗
A new technological approach to radiant heat whole body hyperthermia.
A new methodology for administering radiant heat whole body hyperthermia (WBH) in humans is described. The technology utilized circulates hot water in a cylinder constructed from copper tubing; the design incorporates a counter current distribution system to maintain thermal constancy. The tubing is coated with a temperature resistant high emissivity finish. Other features include a humidification system to eliminate evaporative heat losses. Data accrued from initial evaluation of this apparatus with a canine model shows that there was no detectable WBH-related hematological, biochemical or physiological toxicity. The perceived advantages of this WBH-system are discussed.
Animals↗
Massive pulmonary embolism and tourniquet deflation.
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Female↗
The effect of fish oil on blood pressure and high-density lipoprotein-cholesterol levels in phase I of the Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative Research Group.
OBJECTIVE: To study the effects of moderate doses of fish oil on blood pressure and high-density lipoprotein (HDL)-cholesterol. METHODS: The participants were 350 normotensive men and women aged 30-54 years who were enrolled from seven academic medical centers in phase I of the Trials of Hypertension Prevention. They were randomly assigned to receive placebo or 6 g purified fish oil once a day, which supplied 3 g n-3 polyunsaturated fatty acids for 6 months. RESULTS: Baseline blood pressure was (mean +/- SD) 123 +/- 9/81 +/- 5 mmHg. The mean differences in the blood pressure changes between the fish oil and placebo groups were not statistically significant. There was no tendency for fish oil to reduce blood pressure more in subjects with baseline blood pressures in the upper versus the lower quartile (132/87 versus 114/75 mmHg), low habitual fish consumption (0.4 versus 2.9 times a week) or low baseline plasma levels of n-3 fatty acids. Fish oil increased HDL2-cholesterol significantly compared with the placebo group. Subgroup analysis showed this effect to be significant in the women but not in the men. Increases in serum phospholipid n-3 fatty acids were significantly correlated with increases in HDL2-cholesterol and decreases in systolic blood pressure. CONCLUSION: Moderate amounts of fish oil (6 g/day) are unlikely to lower blood pressure in normotensive persons, but may increase HDL2-cholesterol, particularly in women.
Adult↗
Short report: the effect of fish oil on blood pressure and high-density lipoprotein-cholesterol levels in phase I of the Trials of Hypertension Prevention.
OBJECTIVE: To study the effects of moderate doses of fish oil on blood pressure and high-density lipoprotein (HDL)-cholesterol. METHODS: The participants were 350 normotensive men and women aged 30-54 years who were enrolled from seven academic medical centers in phase I of the Trials of Hypertension Prevention. They were randomly assigned to receive placebo or 6 g purified fish oil once a day, which supplied 3 g n-3 polyunsaturated fatty acids for 6 months. RESULTS: Baseline blood pressure was (mean +/- SD) 123 +/- 9/81 +/- 5 mmHg. The mean differences in the blood pressure changes between the fish oil and placebo groups were not statistically significant. There was no tendency for fish oil to reduce blood pressure more in subjects with baseline blood pressure in the upper versus the lower quartile (132/87 versus 114/75 mmHg), low habitual fish consumption (0.4 versus 2.9 times a week) or low baseline plasma levels of n-3 fatty acids. Fish oil increased HDL2-cholesterol significantly compared with the placebo group. Subgroup analysis showed this effect to be significant in the women but not in the men. Increases in serum phospholipid n-3 fatty acids were significantly correlated with increases in HDL2-cholesterol and decreases in systolic blood pressure. CONCLUSION: Moderate amounts of fish oil (6 g/day) are unlikely to lower blood pressure in normotensive persons, but may increase HDL2-cholesterol, particularly in women.
Adult↗
Cytokine induction in humans by 41.8 degrees C whole-body hyperthermia.
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Cytokines↗
A theory of dopamine function and its role in cognitive deficits in schizophrenia.
In spite of extensive research on the biological and behavioral correlates of dopamine (DA) function, little is known about the mechanisms by which DA may produce the cognitive deficits observed in schizophrenia. Neural network simulation models offer a framework for exploring how DA effects at the physiological level may influence behavior. We focus on findings suggesting that DA modulates neuronal activity by enhancing the ability of neurons to transmit signals and reduce distortion by noise. These phenomena can be captured in simulations by increasing the gain of individual units of a network. When gain is increased diffusely, improvement in signal detection performance of such a network parallels the improvement in performance of human subjects receiving DA agonists. Furthermore, decreasing gain in a network module supporting a memory function analogous to that of prefrontal cortex results in deterioration of performance equivalent to that of schizophrenic subjects. A test of predictions made by such networks about the performance of schizophrenic patients in a new variant of the Continuous Performance Test is discussed. Preliminary data are consistent with predictions and support the account of schizophrenic cognitive deficits in terms of the theory of DA function suggested by the models.
Antipsychotic Agents↗
Identification of a benzyladenine disaccharide conjugate produced during shoot organogenesis in Petunia leaf explants.
Prior studies of benzyladenine (BA) metabolism in Petunia hybrida Vilm. leaf explants during shoot organogenesis revealed the presence of an abundant unidentified BA conjugate. The BA conjugate, compound C, made up to 39% of the total pool of BA conjugates in two Petunia lines and was associated with an increased shoot organogenic response when compared with a third Petunia line that did not produce any compound C. Structural analysis of compound C utilizing fast atom bombardment mass spectrometry, two methods of carbohydrate analysis, ultraviolet absorption spectra, and Fourier transform infrared spectra identified it as a new cytokinin conjugate, 6-benzylamino-9-[O-glucopyranosyl-(1-->3)-ribofuranosyl]-purine. Based on our prior biological studies and the similarity of this compound to related cytokinin conjugates, this disaccharide cytokinin conjugate may be part of the interconvertible pool of cytokinins active in Petunia shoot organogenesis.
Adenine↗
Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group.
OBJECTIVE: To evaluate the contribution of mild to moderate hypertension to progressive loss of renal function by analysis of renal function data from the Multiple Risk Factor Intervention Trial. DESIGN: The cohort of men with mild to moderate hypertension (baseline diastolic blood pressure > or = 90 mm Hg), randomized to a special intervention (SI) group or usual care (UC) group, were examined for change in renal function based on individual reciprocal creatinine slopes over an average of 7 years' follow-up as the outcome measure. Contribution of blood pressure control during follow-up, age, race, and blood pressure at entry were assessed. PARTICIPANTS: The cohort of 5524 (463 black, 5061 nonblack) hypertensive men receiving no therapy at entry provided the data for the present analysis. RESULTS: Blood pressure control was similar for black and white participants, but significant decline in reciprocal creatinine slope was found for black men (mean slope, -0.0090 +/- 0.0013 dL/mg/y) compared with white men (+0.0018 +/- 0.0004 dL/mg/y) (P < .001 for difference between blacks and whites). Decline in renal function was also greater among individuals with elevated systolic (P < .001) as well as diastolic blood pressure (P < .001), and older individuals (P < .001). No difference between the SI and UC groups was seen in reciprocal creatinine slopes, but in both groups combined, treatment that maintained diastolic blood pressure below an average value of 95 mm Hg was associated with stable or improving renal function, whereas participants whose blood pressure remained 95 mm Hg or greater continued to decline at -0.0013 +/- 0.0009 dL/mg/y (P = .007 for difference). Separate examination of the subset of black men (n = 463) failed to show such a difference. CONCLUSIONS: Effective blood pressure control was associated with stable or improving renal function in nonblacks but not in blacks. These findings emphasize the importance of blood pressure control to maintain adequate renal function in hypertensive white men and raise important questions about the relationship of pressure reduction and renal function change in blacks.
Adult↗
Abnormal electrocardiograms and cardiovascular risk: role of silent myocardial ischemia. Evidence from MRFIT.
The Multiple Risk Factor Intervention Trial (MRFIT) was designed as a primary prevention study to test the effect of multifactorial intervention on long-term outcome in men with a combination of risk factors that placed them in the top 10-15 percentiles of risk for coronary artery disease. Of the 12,866 patients in this study, the 3,600 men (about 28%) with abnormalities in the baseline electrocardiogram were prospectively identified. They were expected to be at increased risk for coronary events compared with those without electrocardiographic abnormalities. Analysis of cumulative mortality data following antihypertensive regimens that included high dosages of diuretics revealed an association between electrocardiographic abnormalities at rest and diuretic treatment that related to adverse outcome. When the dosages of the diuretic were lowered, this trend was reversed. It is proposed that diuretic-related hypokalemia may predispose patients who may have silent myocardial ischemia to potentially fatal arrhythmias and that use of potassium-sparing antihypertensive regimens be considered in high-risk hypertensive patients.
Adult↗
Outcome of urgent percutaneous transluminal coronary angioplasty in acute myocardial infarction: comparison of single-vessel versus multivessel coronary artery disease.
Despite recent clinical trials of percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction, specific groups of patients that may benefit from adjunctive or alternative therapy have yet to be adequately characterized. The in-hospital outcome of 151 consecutive patients treated for acute myocardial infarction with urgent PTCA of the infarct-related artery was studied to identify a subgroup of patients at high risk. Patients were divided into two groups based on the angiographic presence of either single-vessel (n = 86) or multivessel (n = 65) coronary artery disease. Despite PTCA of only the infarct-related artery and similar baseline clinical characteristics such as age, peak serum creatine kinase concentration, left ventricular ejection fraction, and time from the onset of chest pain to arrival at the hospital, the group with multivessel disease had a lower rate of successful angioplasty (75% vs 92%, p < 0.005), with higher incidences of persistent total occlusion of the infarct-related artery (14% vs 3%, p < 0.02) and procedural complications during PTCA (28% vs 13%, p < or = 0.02), and were more likely to have multiple complications (12% vs 1%, p < 0.004). In addition, the group with multivessel disease had a higher rate of urgent (< or = 24 hours) coronary artery bypass graft surgery (13% vs 2%, p < 0.05) and a trend toward a higher in-hospital mortality rate (6% vs 1%, p < or = 0.17). By stepwise logistic regression, only the presence of single-vessel versus multivessel disease was predictive of PTCA success (p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗