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Biomedical subjects

J D Cohen

Publications and source records attributed to J D Cohen.

At least 127 records · Page 7Linked to original sources
PubMed1993

Arabidopsis thaliana auxotrophs reveal a tryptophan-independent biosynthetic pathway for indole-3-acetic acid.

We used tryptophan auxotrophs of the dicot Arabidopsis thaliana (wall cress) to determine whether tryptophan has the capacity to serve as a precursor to the auxin, indole-3-acetic acid (IAA). Quantitative gas chromatography-selected ion monitoring-mass spectrometry (GC-SIM-MS) revealed that the trp2-1 mutant, which is defective in the conversion of indole to tryptophan, accumulated amide- and ester-linked IAA at levels 38-fold and 19-fold, respectively, above those of the wild type. Tryptophan and free IAA were isolated from the trp2-1 mutant grown in the presence of [15N]anthranilate and [2H5]tryptophan, and the relative 15N and 2H5 enrichments of tryptophan and IAA were determined via GC-SIM-MS. The 15N enrichment of tryptophan, 13% +/- 4%, was less than the 15N enrichment of the IAA pool, 39% +/- 4%; therefore, IAA biosynthesis occurs via a tryptophan-independent pathway. The amount of 2H5 incorporated by the plant into IAA from tryptophan (9% +/- 4%) was low and only slightly above the level of spontaneous, nonenzymatic conversion of [2H5]tryptophan to [2H5]IAA. These results show that the dicot Arabidopsis is similar to the monocot Zea mays in that the major route of IAA biosynthesis does not occur through tryptophan.

Arabidopsis↗
PubMed1993

Functional topographic mapping of the cortical ribbon in human vision with conventional MRI scanners.

The human brain has anatomically distinct areas in which processing is laid out in space at the millimetre level with substantial variation across individuals. Activity occurs along a cortical ribbon 1.5-3 mm thick in response to specific stimuli. Here we report the first use of cortical ribbon analysis on humans using non-invasive functional magnetic resonance imaging techniques performed with a conventional 1.5 T MRI scanner. Changes in activation were detected using T2*-weighted, gradient echo imaging sequences. Subjects observed partial field, flashing checkerboard patterns (left-right, top-bottom, half rings, and wedges). Stimuli produced magnetic resonance signal changes in the 1-8% range, varying at the millimetre scale, which showed contralateral vertically reflected patterns of activation in the visual cortex. To compare the spatial topographies across subjects, computer algorithms were used to control for the subject-unique folding of cortex, providing a flattened cortical ribbon identifying four topographically distinct areas.

Brain Mapping↗
PubMed1993

Transformation of NIH/3T3 to anchorage independence by H-ras is accompanied by loss of suppressor activity.

Despite their familiar sensitivity to transformation by dominant-acting ras oncogenes, NIH/3T3 cells carry a ras suppressor. When tested by cell fusion they were able to suppress the anchorage-independent phenotype of both mouse and human cells transformed by activated H-ras or N-ras. This suppression occurred without a decrease in expression of the activated ras oncogene. Ras-transformed NIH/3T3 clones cured of their oncogene by benzamide treatment reverted to a nontransformed phenotype, but had lost the ability to suppress other ras transformants, indicating that their initial transformation was accompanied by suppressor loss. In hamster cells an active ras oncogene increased the rate of chromosome segregation by > 100-fold. These results suggest that in vitro transformation of NIH/3T3 cells by ras may be more similar to multistep in vivo tumor development than previously suspected, involving not only expression of an active oncogene but also loss of a suppressor activity, perhaps induced by the clastogenic oncogene.

3T3 Cells↗
PubMed1993

Hypertension in the elderly: age- and disease-related complications and therapeutic implications.

Effective treatment of hypertension in the elderly requires an understanding of both the progressive course of the disease and the impact of aging on the cardiovascular system, including physiological, genetic, lifestyle, and environmental factors. Review of the literature that has attempted to define the impact of an "aging process" on cardiovascular structure and function reveals a diversity of findings and interpretations. However, in general, normotensive elderly subjects exhibit the heart and vascular characteristics of "muted" hypertension, including many features of younger hypertensive patients: cardiac hypertrophy, diminution in resting left ventricular early diastolic filling rate, increased arterial stiffness and aortic impedance, diminution in the baroreceptor reflex, a diminished response to catecholamines and diminished renal blood flow, and an increase in peripheral vascular resistance (PVR). Treatment of elderly hypertensives is more challenging because of the greater likelihood of the presence of concomitant diseases, most importantly, coronary and peripheral atherosclerosis, renal dysfunction, and diabetes mellitus. Isolated systolic hypertension (ISH), the most common form of hypertension in the elderly, has also been clearly shown to be an important predictor of cardiovascular morbidity and mortality, including coronary artery disease, congestive heart failure, and stroke. Treatment of ISH has been shown to lower systolic pressure safely and effectively in the elderly. By reducing PVR, and possibly the arterial stiffness, and thus the early reflected pulse waves, vasodilators, including calcium antagonists, may lower these three components of arterial impedance, and hence lower the arterial load on the heart. The cardiac hypertrophy and reduced left ventricular filling rate associated with hypertension in older individuals can also be ameliorated, to some extent, by calcium channel blockers.

Aged↗
PubMed1993

Acute changes in glucose uptake after treatment: the effects of carmustine (BCNU) on human glioblastoma multiforme.

Sequential positron emission tomographic scans with [18F]-2-fluorodeoxyglucose (PET-FDG) were performed on 6 patients with glioblastoma multiforme who were treated with adjuvant BCNU. Scans were acquired before and 24 hours after BCNU. All patients had prior brain irradiation. Ratios between the maximal tumor FDG uptake and the contralateral white matter FDG uptake, the glucose uptake ratio, were determined. Percent changes in the glucose uptake ratio between the baseline scan and the 24 hour post-treatment scan were of prognostic significance. Patients with the largest percent changes in FDG uptake had the shortest survival. In contrast, neither the baseline glucose uptake ratio nor the visual tumor grade accurately predicted length of survival.

Biological Transport, Active↗
PubMed1993

Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia.

Thymidine kills cells by depleting dCTP stores. The present experiments tested whether deoxycytidine, by replenishing dCTP pools, could prevent thymidine cytotoxicity and thymidine's enhancement of carboplatin killing in two human T-cell acute leukemia cell lines. MOLT3 and JM cells were exposed to combinations of thymidine, deoxycytidine, and carboplatin and then assessed for survival, the magnitude of thymidine-carboplatin chemosensitization, and changes in deoxyribonucleoside triphosphate pools. For both cell lines, deoxycytidine (up to 144.5 micrograms/ml x 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100-1000 micrograms/ml x 24 h) and thymidine-carboplatin sensitization (up to 60 micrograms carboplatin/ml during the last hour of thymidine). This contrasts with complete protection in prior studies using other cell types. Thymidine alone markedly increased dTTP and dGTP pools and decreased dCTP; dATP pools underwent a sharp decline which has not been observed before in any cell line. In subsequent studies 0.0336-137.3 micrograms deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 micrograms thymidine/ml. Together, deoxycytidine and deoxyadenosine completely prevented thymidine-carboplatin sensitization even though dATP and dCTP pools were not entirely returned to normal. These findings are discussed in regard to the unusual sensitivity of T-cell malignancies to thymidine toxicity, mechanisms of cytotoxicity and chemosensitization by thymidine, and the possibility of thymidine selectively sensitizing T-cell malignancies to killing by alkylating agents.

Carboplatin↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

Phase I clinical trial of carboplatin and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial. PATIENTS AND METHODS: Thirty assessable patients with cancer refractory to conventional therapy were treated. During induction therapy, patients received WBH alone in week 1, WBH plus carboplatin in week 2, and carboplatin alone in week 5. Carboplatin dose was escalated (three patients per group) as follows: 100, 150, 200, 250, 300, 350, 400, 480, and 575 mg/m2; three additional patients were entered at 480 mg/m2. Carboplatin was administered at target temperature. RESULTS: Comparisons of the mean/median WBC and platelet nadirs for carboplatin alone and carboplatin plus WBH demonstrated no enhancing effect by WBH. Toxicities including nausea and/or vomiting, as well as myelosuppression, were within acceptable limits, allowing for escalation to a dose of 575 mg/m2; three of three patients at this dose level experienced grade 4 myelosuppression with no associated infection or bleeding. No renal toxicity was observed. Analysis of platinum in plasma ultrafiltrate and urine showed only slight effects of WBH on the pharmacokinetics and renal excretion of platinum. Responses included the following: lung--minor response (200 mg/m2); gastrointestinal neuroendocrine--complete response (CR) (400 mg/m2); pancreatic--partial response (PR) (480 mg/m2); small bowel--PR (575 mg/m2); ovarian--CR, two patients (575 mg/m2), with marker data suggesting WBH enhancement of carboplatin cytotoxicity. Another three patients experienced clinical improvement after WBH plus carboplatin, but progression with carboplatin alone (lung, 400 mg/m2; gastrointestinal neuroendocrine, 480 mg/m2; melanoma, 480 mg/m2). CONCLUSION: We conclude that carboplatin with WBH is well tolerated even at conventional carboplatin doses. Clinical results are consistent with preclinical predictions of an increased therapeutic index for this combination, which encourages future clinical studies.

Adult↗
PubMed1993

Response of "benign" metastasizing leiomyoma to progestin withdrawal. Case report.

We report a rare case of a benign metastasizing leiomyoma in which progestin therapy permitted or promoted pulmonary metastases, but progestin withdrawal induced a marked tumor regression. The significance of these observations is discussed relative to the estrogen and progesterone receptor positivity of this patient's tumor.

Female↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

Context, cortex, and dopamine: a connectionist approach to behavior and biology in schizophrenia.

Connectionist models are used to explore the relationship between cognitive deficits and biological abnormalities in schizophrenia. Schizophrenic deficits in tasks that tap attention and language processing are reviewed, as are biological disturbances involving prefrontal cortex and the mesocortical dopamine system. Three computer models are then presented that simulate normal and schizophrenic performance in the Stroop task, the continuous performance test, and a lexical disambiguation task. They demonstrate that a disturbance in the internal representation of contextual information can provide a common explanation for schizophrenic deficits in several attention- and language-related tasks. The models also show that these behavioral deficits may arise from a disturbance in a model parameter (gain) corresponding to the neuromodulatory effects of dopamine, in a model component corresponding to the function of prefrontal cortex.

Computer Simulation↗
PubMed1992

Auxin Biosynthesis during Seed Germination in Phaseolus vulgaris.

The relative roles of de novo biosynthesis of indoleacetic acid (IAA) and IAA conjugates stored in mature seeds (Phaseolus vulgaris L.) in supplying auxin to germinating bean seedlings were studied. Using (2)H oxide and 2,4,5,6,7-[(2)H]l-tryptophan as tracers of IAA synthesis, we have shown that de novo biosynthesis of IAA, primarily from tryptophan, is an important source of auxin for young bean seedlings. New synthesis of IAA was detected as early as the second day of germination, at which time the seedlings began to accumulate fresh weight intensively and the total content of free IAA began to increase steadily. IAA conjugates that accumulate in large amounts in cotyledons of mature seeds may thus be considered to be only one of the possible sources of IAA required for the growth of bean seedlings.

Journal Article↗