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Biomedical subjects

J D Cohen

Publications and source records attributed to J D Cohen.

At least 73 records · Page 4Linked to original sources
PubMed1998

The Philadelphia chromosome as a secondary change in leukemia: three case reports and an overview of the literature.

Three cases of acute nonlymphocytic leukemia with a Philadelphia chromosome (Ph) as a secondary abnormality are reported. The Ph was late-appearing in one patient and appeared as an additional anomaly in the other two patients. Fluorescence in situ hybridization studies of the first patient identified the presence of a minor BCR/ABL rearrangement. The findings of these cases support the conclusion that the Ph plays a role not only in leukemogenesis, but also in disease progression. An overview of the literature dealing with similar cases is also presented.

Adolescent↗
PubMed1998

Comparison of the fixed combination of enalapril/diltiazem ER and their monotherapies in stage 1 to 3 essential hypertension.

The safety and efficacy of two fixed dose combinations of enalapril and diltiazem extended release formation (ER) (E/D) were compared with their monotherapies and placebo in patients with stage 1 to 3 hypertension. The trial design was a multicenter, randomized, double blind, placebo controlled, parallel group, 12 week treatment phase, followed by a 36 week, open label phase. A total of 891 patients with sitting diastolic blood pressure (SiDBP) between 95 and 115 mm Hg were randomly assigned to enalapril 5 mg, diltiazem ER 120 mg, diltiazem ER 180 mg, enalapril 5 mg/diltiazem ER 120 mg (E5/D120), enalapril 5 mg/ diltiazem ER 180 mg (E5/D180), or placebo. In the open label phase, 562 patients received the fixed combination, titrated as needed to control SiDBP < 90 mm Hg. Efficacy was determined with trough (24 +/- 2 h postdose) sitting blood pressure measurements at week 12 and at the end of the open label part of the study. Safety was evaluated based on patient symptoms, clinical laboratories, and electrocardiograms (ECG). E5/D120 and E5/D180 significantly reduced trough SiDBP (-7.6 and -8.3 mm Hg, respectively; P < .05) versus their monotherapies. E5/D120 and E5/D180 significantly reduced trough sitting systolic blood pressure (-7.9 and -9.0, respectively; P < .05) versus both diltiazem ER monotherapies. All active treatments significantly decreased SiDBP and SiSBP versus placebo. E/D effectively lowered SiDBP and SiSBP during the open label extension. No significant difference was seen among treatment groups for the overall incidence of adverse events. The most common drug related adverse events were headache, edema/swelling, dizziness, asthenia/fatigue, cough, rash, and impotence. The event frequency for the combinations were similar to those seen with the monotherapies. Fixed combinations of E/D were generally well tolerated, with an increased blood pressure lowering effect as compared with the individual components in patients with stage I to III hypertension.

Adult↗
PubMed1998

Dual inhibition of human rhinovirus 2A and 3C proteases by homophthalimides.

The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 microM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.

Colorimetry↗
PubMed1998

Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives.

Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (> or = 5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [< or = 88 mmol/d Na+] and high salt [>190 mmol/d Na+] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7+/-107.5 mmol/d urinary Na+) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1+/-50.8 mmol/d Na+); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, -3.6/-1.6 mmHg; white, -6.2/-3.9 mmHg; Hispanic, -8.1/-5.3 mm Hg) than did enalapril-treated patients (black, -9.0/-5.3 mm Hg; white, -11.8/-7.0 mm Hg; Hispanic, -11.1/-5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

Adult↗
PubMed1998

Functional hypofrontality and working memory dysfunction in schizophrenia.

OBJECTIVE: Hypofrontality is a common but not invariable finding in schizophrenia. Inconsistencies in the literature may reflect, in part, the fact that abnormal physiological responses in the prefrontal cortex are best identified under conditions that place well-specified functional demands on this region. METHOD: The authors studied eight patients with schizophrenia and eight matched comparison subjects using [(15)O]H2O positron emission tomography and the "N-back" task, which activates the prefrontal cortex as a function of working memory load in normal subjects. RESULTS: Under low-working-memory-load conditions, the accuracy of both groups in the N-back task was equal, but when the memory load increased, the patients' performance deteriorated more than did that of the comparison subjects. The regional cerebral blood flow response to increased working memory load was significantly reduced in the patients' right dorsolateral prefrontal cortex. CONCLUSIONS: These results confirm the importance of using tasks that tap specific cognitive functions, linked to specific neural systems, in studies of brain-behavior relationships in schizophrenia. Hypofrontality is reliably demonstrated in schizophrenia during tasks that engage working memory functions of the prefrontal cortex.

Functional Laterality↗
PubMed1998

Selective pharmacological activation of limbic structures in human volunteers: a positron emission tomography study.

Using a pharmacological probe, procaine hydrochloride, the authors elicited consistent and selective activation of anterior limbic and paralimbic structures in normal human volunteers as documented by H215O positron emission tomography. This activation was associated with a range of emotional, somatic, and visceral experiences, often similar to those experienced during the aura of temporal lobe epilepsy. Several subjects also experienced panic attacks. This study confirms that selective anterior limbic/paralimbic activity in normal human volunteers evokes many emotional phenomena as well as common "ill-defined" symptoms observed in clinical conditions. The present combination of procaine challenge and neuroimaging provides a noninvasive procedure to probe the contribution of different anterior limbic and paralimbic structures to normal human emotions and to neuropsychiatric disorders.

Adult↗
PubMed1998

Massive spontaneous hemothorax as a presenting sign of aneurysmal rupture of the internal thoracic artery. A case report.

Massive spontaneous hemothorax is a very uncommon, life-threatening situation. Acute dissection and ruptured aorta can be one of the differential diagnoses, but usually the clinical feature is completely different, and very few patients have survived this event and received medical attention. Among other causes of spontaneous bleeding, some are extremely rare, demanding precise diagnosis and judicial and immediate intervention. We describe a patient who presented with a massive hemothorax. There was no immediately apparent cause. Emergent angiography revealed active bleeding from an extremely unusual source: aneurysmal dilatation of the internal thoracic artery.

Adult↗
PubMed1997

There are no racial, age, sex, or weight differences in the effect of salt on blood pressure in salt-sensitive hypertensive patients.

BACKGROUND: This report is part of a larger, multicenter, placebo-controlled study designed to test the effects of low and high salt intake on the antihypertensive action of enalapril maleate or isradipine in salt-sensitive, hypertensive patients. OBJECTIVE: To present our findings with respect to the effects of race, age, sex, and weight on the blood pressure response to low and high salt intake in salt-sensitive hypertensive patients before randomization into the larger study. PATIENTS AND METHODS: After 3 week (weeks -9 to -6) of ad lib salt intake (100-200 mmol/d of sodium), 1916 patients whose sitting diastolic blood pressure was between 95 and 115 mm Hg entered a 3-week period (week -6 to -3) of low salt intake (50-80 mmol/d of sodium) and then a 3-week period (week -3 to 0) of high salt intake (200-250 mmol/d of sodium). Of the 1916 patients, 624 were identified as being sensitive to salt by demonstrating an increase in sitting diastolic blood pressure of equal to or more than 5 mm Hg from the low to high salt intake. Of these patients, 367 were white, 156 were black, 92 were Hispanic, 8 were Asian, and 1 was American Indian. Also, 315 were men and 309, women; 351 were 55 years or younger and 273 were older than 55 years; and 195 had a body mass index of 27 or less and 429 had a body mass index higher than 27. RESULTS: The sitting blood pressure decreased with salt restriction and increased with salt load in all groups of patients (P < .001). There were no statistically significant differences in the blood pressure changes to salt changes by race, age, sex, and weight. CONCLUSIONS: This large, multicenter study did not demonstrate any statistically significant effect of race, age, sex, and weight on blood pressure response to salt changes in salt-sensitive hypertensive patients.

Aging↗
PubMed1997

Heart rate adjustment of exercise-induced ST-segment depression identifies men who benefit from a risk factor reduction program.

BACKGROUND: Whether subjects identified as being at increased risk of coronary heart disease (CHD) death by heart rate adjustment of exercise-induced ST-segment depression will benefit from therapy aimed at reducing risk factors has not been examined. METHODS AND RESULTS: Exercise ECGs were performed in 11,880 men from the Usual Care (UC) and Special Intervention (SI) groups of the Multiple Risk Factor Intervention Trial. UC men were referred to customary sources of care in the community; SI men received counseling on smoking cessation and dietary reduction of cholesterol, and stepped-care therapy for hypertension. An abnormal ST-segment response to exercise was defined according to standard criteria as > or = 100 microV of additional horizontal or downsloping ST-segment depression and by an ST-segment/heart rate (ST/HR) index >1.60 microV/bpm. After 7 years of follow-up, CHD mortality was significantly lower in SI than UC men with an abnormal ST/HR index (2.4%, 19/786 versus 5.3%, 39/729, P=.005) but was comparable in SI and UC men with a normal ST/HR index (1.6%, 84/5154 versus 1.3%, 70/5211, P=NS). Risk reduction in SI men with an abnormal ST/HR index was independent of age and other cardiac risk factors. In contrast, there was no significant difference in CHD death rate between the smaller groups of SI and UC men with an abnormal test by standard criteria (3.6%, 7/192 versus 2.7%, 5/186, P=NS). CONCLUSIONS: An abnormal ST/HR index identifies men in whom therapy aimed at reducing CHD risk factors reduces the risk of CHD death by 61%. These findings support the application of heart rate adjustment of ST depression for screening of asymptomatic subjects at increased risk of CHD to identify those who will benefit most from risk factor-reduction programs.

Adult↗
PubMed1997

Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.

CONTEXT: Heart failure is often preceded by isolated systolic hypertension, but the effectiveness of antihypertensive treatment in preventing heart failure is not known. OBJECTIVE: To assess the effect of diuretic-based antihypertensive stepped-care treatment on the occurrence of heart failure in older persons with isolated systolic hypertension. DESIGN: Analysis of data from a multicenter, randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS: A total of 4736 persons aged 60 years and older with systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure below 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP). INTERVENTION: Stepped-care antihypertensive drug therapy, in which the step 1 drug is chlorthalidone (12.5-25 mg) or matching placebo, and the step 2 drug is atenolol (25-50 mg) or matching placebo. MAIN OUTCOME MEASURES: Fatal and nonfatal heart failure. RESULTS: During an average of 4.5 years of follow-up, fatal or nonfatal heart failure occurred in 55 of 2365 patients randomized to active therapy and 105 of the 2371 patients randomized to placebo (relative risk [RR], 0.51; 95% confidence interval [CI], 0.37-0.71; P<.001; number needed to treat to prevent 1 event [NNT], 48). Among patients with a history of or electrocardiographic evidence of prior myocardial infarction (MI), the RR was 0.19 (95% CI, 0.06-0.53; P=.002; NNT, 15). Older patients, men, and those with higher systolic blood pressure or a history of or electrocardiographic evidence of MI at baseline had higher risk of developing heart failure. CONCLUSION: In older persons with isolated systolic hypertension, stepped-care treatment based on low-dose chlorthalidone exerted a strong protective effect in preventing heart failure. Among patients with prior MI, an 80% risk reduction was observed.

Aged↗
PubMed1997

Deoxycytidine in human plasma: potential for protecting leukemic cells during chemotherapy.

Degradation of DNA produces deoxycytidine. Metabolism of deoxycytidine to dCTP inhibits phosphorylation of cytosine arabinoside (araC), fludarabine (FaraA) and 2-chlorodeoxyadenosine (CdA) by deoxycytidine kinase. This study measured plasma deoxycytidine in healthy adults and two leukemia patients and then determined how clinically relevant deoxycytidine levels would affect drug toxicity in human leukemia and lymphoma cells. Deoxycytidine was well below 0.05 microM in ten healthy persons. In the leukemia patients it was <0.05 and 0.44 microM before chemotherapy, rising to 10.3 and 5.5 microM during treatment. A broad range of clinically relevant deoxycytidine levels were high enough to profoundly decrease araC, FaraA and CdA toxicity in MOLT3, CA46 and HL60 leukemia/lymphoma cells and to change dCTP, DNA synthesis and drug incorporation into DNA in a manner consistent with prior mechanistic studies. Varying deoxycytidine levels could be an important factor influencing leukemia therapy.

Adult↗
PubMed1997

Brain regions responsive to novelty in the absence of awareness.

Brain regions responsive to novelty, without awareness, were mapped in humans by positron emission tomography. Participants performed a simple reaction-time task in which all stimuli were equally likely but, unknown to them, followed a complex sequence. Measures of behavioral performance indicated that participants learned the sequences even though they were unaware of the existence of any order. Once the participants were trained, a subtle and unperceived change in the nature of the sequence resulted in increased blood flow in a network comprising the left premotor area, left anterior cingulate, and right ventral striatum. Blood flow decreases were observed in the right dorsolateral prefrontal and parietal areas. The time course of these changes suggests that the ventral striatum is responsive to novel information, and the right prefrontal area is associated with the maintenance of contextual information, and both processes can occur without awareness.

Adult↗
PubMed1997

Resonance Raman spectroscopic studies of cellobiose dehydrogenase from Phanerochaete chrysosporium.

Cellobiose dehydrogenase (CDH), an extracellular hemoflavoenzyme produced by cellulose-degrading cultures of Phanerochaete chrysosporium, oxidizes cellobiose to cellobionolactone. The enzyme contains one 6-coordinate, low-spin b-type heme and one FAD cofactor per monomeric protein. In this work, resonance Raman (RR) spectra are reported for the oxidized, reduced, and deflavo forms of CDH as well as the individual flavin and heme domains of the enzyme obtained by peptide proteolysis. The RR spectra of the flavin and heme groups of CDH were assigned by comparison to the spectra of other hemoflavoenzymes and model compounds. Proteolytic cleavage of the CDH domains had only a minimal spectroscopic effect on the vibrational modes of the heme and FAD cofactors. Excitation of the oxidized CDH holoenzyme at 413 or 442 nm resulted in photoreduction of the heme. However, the same excitation wavelength used on the deflavo form of the enzyme or on the heme domain alone did not cause photoreduction, indicating that photoinitiated electron transfer requires the FAD cofactor. These observations suggest an enzymatic mechanism whereby reducing equivalents obtained from the oxidation of cellobiose are transferred from the FAD to the heme. A similar mechanism has been proposed for flavocytochrome b2 of Saccharomyces cerevisiae which oxidizes lactate to pyruvate (A. Desbois et al., 1989, Biochemistry 28, 8011-8022).

Basidiomycota↗
PubMed1997

Temporal dynamics of brain activation during a working memory task.

Working memory is responsible for the short-term storage and online manipulation of information necessary for higher cognitive functions, such as language, planning and problem-solving. Traditionally, working memory has been divided into two types of processes: executive control (governing the encoding manipulation and retrieval of information in working memory) and active maintenance (keeping information available 'online'). It has also been proposed that these two types of processes may be subserved by distinct cortical structures, with the prefrontal cortex housing the executive control processes, and more posterior regions housing the content-specific buffers (for example verbal versus visuospatial) responsible for active maintenance. However, studies in non-human primates suggest that dorsolateral regions of the prefrontal cortex may also be involved in active maintenance. We have used functional magnetic resonance imaging to examine brain activation in human subjects during performance of a working memory task. We used the temporal resolution of this technique to examine the dynamics of regional activation, and to show that prefrontal cortex along with parietal cortex appears to play a role in active maintenance.

Adult↗
PubMed1997

A population-based approach to cholesterol control.

The large proportion of the population who have only modest or moderate hypercholesterolemia will experience more coronary events than the smaller percentage of people who are at higher risk from more extreme elevations of serum cholesterol. The high-risk individual strategy for prevention of coronary heart disease (CHD) can result in impressive declines in cholesterol, but the benefits will be concentrated at the upper end of the population distribution. On the other hand, a population strategy for coronary disease prevention will achieve a much more modest reduction of cholesterol, but these changes will be over the entire distribution and will reduce the risk of the much larger proportion of people with average cholesterol levels who otherwise would likely go untreated. In light of the fact that epidemiologic studies and long-term clinical trials predict that a 10% reduction in serum cholesterol will result in a 30% reduction in coronary events, the population strategy has the potential for an enormous impact in reducing CHD, which, despite our great success over the past two decades, still remains the number one killer in the United States.

Cholesterol↗
PubMed1997

Estimating test-retest reliability in functional MR imaging. II: Application to motor and cognitive activation studies.

Functional magnetic resonance imaging (fMRI) using blood oxygenation contrast has rapidly spread into many application areas. In this paper, a new statistical model is used to evaluate the reliability of fMRI activation in a finger opposition motor paradigm for both within-session and between-session data and in a working memory paradigm for between-session data. A slice prescription procedure for between-session reproducibility is introduced. Estimates are made for the probabilities of correctly and falsely classifying voxels as active or inactive and receiver operator characteristic curves are generated. In the motor paradigm, estimated between-session reliability was found to be somewhat reduced relative to within-session reliability; however, this includes additional sources of variation and may not reflect intrinsically lower reliability. After matching false-positive classification probabilities, between-session reliability was found to be nearly identical for both motor and cognitive activation paradigms.

Brain↗
PubMed1997

A parametric study of prefrontal cortex involvement in human working memory.

Although recent neuroimaging studies suggest that prefrontal cortex (PFC) is involved in working memory (WM), the relationship between PFC activity and memory load has not yet been well-described in humans. Here we use functional magnetic resonance imaging (fMRI) to probe PFC activity during a sequential letter task in which memory load was varied in an incremental fashion. In all nine subjects studied, dorsolateral and left inferior regions of PFC were identified that exhibited a linear relationship between activity and WM load. Furthermore, these same regions were independently identified through direct correlations of the fMRI signal with a behavioral measure that indexes WM function during task performance. A second experiment, using whole-brain imaging techniques, both replicated these findings and identified additional brain regions showing a linear relationship with load, suggesting a distributed circuit that participates with PFC in subserving WM. Taken together, these results provide a "dose-response curve" describing the involvement of both PFC and related brain regions in WM function, and highlight the benefits of using graded, parametric designs in neuroimaging research.

Adolescent↗