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Biomedical subjects

J D Cohen

Publications and source records attributed to J D Cohen.

At least 109 records · Page 6Linked to original sources
PubMed1996

Quantification of free plus conjugated indoleacetic acid in arabidopsis requires correction for the nonenzymatic conversion of indolic nitriles.

The genetic advantages to the use of Arabidopsis thaliana mutants for the study of auxin metabolism previously have been partially offset by the complexity of indolic metabolism in this plant and by the lack of proper methods. To address some of these problems, we developed isotopic labeling methods to determine amounts and examine the metabolism of indolic compounds in Arabidopsis. Isolation and indentification of endogenous indole-3-acetonitrile (IAN; a possible precursor of the auxin indole-3-acetic acid [IAA]) was carried out under mild conditions, thus proving its natural occurrence. We describe here the synthesis of 13C1-labeled IAN and its utility in the gas chromatography-mass spectrometry quantification of endogenous IAN levels. We also quantified the nonenzymatic conversion of IAN to IAA under conditions used to hydrolyze IAA conjugates. 13C1-Labeled IAN was used to assess the contribution of IAN to measured IAA following hydrolysis of IAA conjugates. We studied the stability and breakdown of the indolic glucosinolate glucobrassicin, which is known to be present in Arabidopsis. This is potentially an important concern when using Arabidopsis for studies of indolic biochemistry, since the levels of indolic auxins and auxin precursors are well below the levels of the indolic glucosinolates. We found that under conditions of extraction and base hydrolysis, formation of IAA from glucobrassicin was negligible.

Arabidopsis↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Activation of prefrontal cortex in children during a nonspatial working memory task with functional MRI.

Functional magnetic resonance imaging (fMRI) was used to examine the pattern of activity of prefrontal cortex in prepubertal children during performance of a nonspatial working memory task. The children observed sequences of letters and responded whenever a letter repeated with exactly one nonidentical letter intervening. In a comparison task, subjects monitored similar sequences of letters for any occurrence of a single, prespecified target letter. Location of activation closely approximated that observed in a recent fMRI study with adults using exactly the same task. Activation of the inferior and middle frontal gyri was reliably observed within individual subjects during performance of the working memory task relative to the comparison task. Activation increased and decreased with a time course that was highly consistent with the task manipulations and correlated with behavioral performance. To our knowledge, this study is one of the first to demonstrate the applicability of fMRI to a normative developmental population. Issues of age dependence of the hemodynamic responses of fMRI are discussed.

Adult↗
PubMed1995

Interference and facilitation effects during selective attention: an H215O PET study of Stroop task performance.

To investigate the functional anatomy of interference and facilitation during selective attention, we studied 15 normal subjects using the H215O positron emission tomography technique and a computer presented single-trial Stroop task for cognitive activation. Increases in regional cerebral blood flow (rCBF) were observed in a network of structures that have been previously associated with selective attention, including the anterior cingulate gyrus, the frontal polar cortex, the inferior parietal lobule, and the thalamus, as well as the lingual gyrus. Furthermore rCBF decreases (compared to control states) were observed in lateral extra-striate cortex. rCBF changes in prefrontal and extra-striate regions varied with differences in the need to modulate the influence of word and color information while subjects responded to either incongruent or congruent Stroop stimuli. These results indicate the utility of Stroop procedures for investigating the functional anatomy of selective attention. Given recent interest regarding the role of the anterior cingulate gyrus in the pathophysiology of neuropsychiatric disorders, our results also suggest that the Stroop task can serve as a reliable neurobehavioral probe for this region. The significance of these results for understanding processing mechanisms underlying selective attention is discussed within the framework of a parallel distributed processing model of Stroop task performance.

Adult↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.

Protein C replacement therapy with a monoclonal antibody purified, virus inactivated protein C concentrate was carried out in nine infants (three male, six female) with severe congenital protein C deficiency and life-threatening purpura fulminans and/or thrombosis associated with disseminated intravascular coagulation (DIC). Eight infants were homozygous for protein C deficiency; one was a compound heterozygote. The treatment period varied from 22 days to three years. The half-life of protein C was found to be as short as two to three hours during activation of the coagulation system, increasing to approximately ten hours after stabilization. During the acute phase, protein C levels of 0.10 to 0.25 IU/mL were associated with elevated markers of coagulation activation indicating DIC, while protein C levels greater than 0.25 were associated with normalization of coagulation markers. No product-related side effects were reported. Episodes of bleeding or purpura recurred in all patients who were switched to oral anticoagulant therapy, necessitating reinstatement of protein C replacement therapy, either as needed to control symptoms, or on a long-term prophylactic schedule, alone or in addition to oral anticoagulation. Home treatment with protein C concentrate allowed a near-normal life-style for patients who otherwise would be hospitalized for long periods of time.

Antibodies, Monoclonal↗
PubMed1995

A new 1-aminocyclopropane-1-carboxylic acid-conjugating activity in tomato fruit.

A new conjugate, 1-(gamma-L-glutamylamino)cyclopropane-1-carboxylic acid (GACC), of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) is identified. The only previously identified conjugate of ACC is 1-(malonylamino)cyclopropane-1-carboxylic acid (MACC). GACC, not MACC, was the major conjugate formed by crude protein extracts of tomato (Lycopersicon esculentum Mill cv Ailsa Craig) fruit pericarp and seeds incubated with [14C]ACC. GACC was resolved from [14C]ACC and [14C]MACC by reversed-phase C18 thin-layer chromatography and subsequently detected and quantified using a radioisotope-imaging system. Proteins precipitated from crude extracts failed to catalyze formation of GACC unless the supernatant was added back. Reduced glutathione, but not other reducing agents, replaced the crude supernatant. When [35S-cysteine]glutathione and [3H-2-glycine]glutathione were used as substrates, neither radiolabeled glycine nor cysteine from the glutathione tripeptide was incorporated into GACC. Oxidized glutathione, S-substituted glutathione, and di- and tripeptides having an N-terminal gamma-L-glutamic acid, but lacking cysteine and glycine, also served as substrates for GACC formation. Peptides lacking the N-terminal gamma-L-glutamic acid did not serve as substrates. Acid hydrolysis of GACC yielded ACC, suggesting that GACC is an amide-linked conjugate of ACC. Taken together, these results indicate that GACC is 1-(gamma-glutamylamino)cyclopropane-1-carboxylic acid and that its formation is catalyzed by a gamma-glutamyltranspeptidase. Gas chromatography-mass spectrometry analysis of the N-acetyl dimethyl ester of GACC confirmed this structure.

Acyltransferases↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1993

Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST).

OBJECTIVE: To test the hypothesis that in survivors of myocardial infarction, the suppression of ventricular premature depolarizations improves survival free of cardiac arrest and arrhythmic death. DESIGN: International, prospective, multicenter, randomized, placebo-controlled trial. SETTING: University and community hospitals. PATIENTS: A total of 3549 patients with myocardial infarction and left ventricular dysfunction. INTERVENTION: Administration of encainide, flecainide, moricizine, or placebo to suppress ventricular premature depolarizations. MAIN OUTCOME MEASURES: Overall survival and survival free of cardiac arrest or arrhythmic death were compared in patients randomized to long-term, active antiarrhythmic drug therapy vs corresponding placebo, using the stratified log rank statistic. RESULTS: At 1 year from the time of randomization to blinded therapy, 95% of placebo-treated patients vs 90% of active drug-treated patients remained alive (P = .0006). Similarly, at 1 year, 96% of placebo-treated patients vs 93% of active drug-treated patients remained free of cardiac arrest or arrhythmic death (P = .003). CONCLUSIONS: The suppression of asymptomatic or mildly symptomatic ventricular arrhythmias after myocardial infarction does not improve survival and can increase mortality. Treatment strategies designed solely to suppress these arrhythmias should no longer be followed.

Aged↗