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Biomedical subjects

J L Cohen

Publications and source records attributed to J L Cohen.

At least 37 records · Page 2Linked to original sources
PubMed1999

The cutaneous porphyrias.

Deficiencies of 7 enzymes in the heme biosynthetic pathway result in the development of porphyrias. Two of the porphyrias, aminolevulinate dehydratase deficiency porphyria and acute intermittent porphyria do not have cutaneous findings. Cutaneous findings in the other porphyrias could be subdivided into acute phototoxicity and subacute phototoxicity. In addition, 2 of the porphyrias, hereditary coproporphyria and variegate porphyria have both cutaneous and neurovisceral findings. Now that chromosomal assignments for all the genes of the defective enzymes have been mode, prenatal diagnosis is possible for congenital erythropoietic porphyria, and in vitro gene therapy has been successfully performed for congenital erythropoietic porphyria and erythropoietic protoporphyria.

Dermatitis, Phototoxic↗
PubMed1999

Suicide gene-mediated modulation of graft-versus-host disease.

The development of suicide genes and progress in retroviral gene transfer to T-cells open new perspectives for the treatment of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) for leukemia and lymphoma. Indeed, suicide genes that metabolize inactive prodrugs into compounds toxic for dividing cells provide a powerful means for the pharmacogenetic control of T-cell reactivity. Here, we demonstrate the selective destruction of activated TK-transgenic T-cells in vivo and develop two new transgenic lines which should be useful for preclinical studies of suicide gene therapy strategies for GVHD.

Animals↗
PubMed1998

Deletional and mutational analyses of the human CD4 gene promoter: characterization of a minimal tissue-specific promoter.

In recent years, considerable interest has arisen in understanding the mechanisms of the CD4 gene transcriptional control which resulted in the identification of a promoter, enhancers and a silencer. While the murine CD4 gene promoter has been well studied, little is known about its human counterpart that we previously identified as a 1.1 kb region. Here, we show that the -170/+20 region represents a minimal tissue-specific promoter with a size compatible with its inclusion in viral vectors for gene therapy. In addition, mutational analyses provided evidence that this fragment contains three regions critical for transcriptional activity: an initiator-like sequence, an Ets consensus site and an ATF consensus site. The latter site is absent in the murine promoter, suggesting that some differences exist between the transcriptional control of the human and murine CD4 genes.

Animals↗
PubMed1998

Effects of practice setting on quality of lipid-lowering management in patients with coronary artery disease.

We undertook a study to determine whether there were differences in the quality of lipid management in patients with coronary artery disease (CAD) in 2 different practice settings (which represent different socioeconomic classes), and to determine the level of compliance with the National Cholesterol Education Program guidelines by academic physicians in managing patients with CAD. A retrospective cross-sectional study was performed using a systematic chart review of 270 medical records (131 from the cardiology clinic, 139 from the cardiology private practice) of patients with known CAD at an academic tertiary care center in New York City. The total proportion of patients with CAD having a lipid profile ordered in the clinic and private suite was 43%. Of these people, 22% had a low-density lipoprotein cholesterol (LDL) < or = 100 mg/dl and 54% had an LDL < or = 130 mg/dl (10% and 23% of the total population, respectively). The total proportion of patients taking lipid-lowering medications was 29%. When comparing the quality of treatment between the 2 settings, there were no statistically significant differences in the percentages of patients who had lipid profiles measured (40% clinic vs 47% private suite, p >0.10), in the percentage of patients with LDL < or = 130 mg/dl (50% clinic vs 57% private suite, p >0.10) or in the weighted percentage of patients taking lipid-lowering medications (29% clinic vs 48% private suite, p = 0.099). The performances of individual physicians, however, varied widely. The percentages of patients with lipid profiles measured by individual physicians ranged from 0% to 83%, while the percentages of patients on drug treatment by a physician ranged between 10% and 88%. These findings indicate that socioeconomic differences, represented by different practice settings, do not account for differences in the screening for, control of, or use of medications in managing hyperlipidemia. Rather, individual physicians are accountable for differences in lipid management.

Age Factors↗
PubMed1998

Three populations of mouse lymph node dendritic cells with different origins and dynamics.

We have identified three distinct populations of mouse lymph node dendritic cells (DC) that differ in their capacity to uptake Ag delivered by different routes, and in their dynamics. The "I-DCs" are large cells that resemble the interdigitating cells and have a mature phenotype and a slow turnover. They derive from the regional tissues. The "sm-DCs" and "sI-DCs" are smaller (hence s-DC), have a more immature phenotype and a rapid turnover. The sI-DC phenotype, including CD8alpha expression suggests a lymphoid-related origin. The sI-DC population is expanded 100-fold after an in vivo flt3 ligand treatment. The sm-DC phenotype suggests a myeloid-related origin. Interestingly, sm-DCs can acquire i.v. injected macromolecules in less than 30 min after injection. They may, therefore, play an important role in the immune response against blood Ags.

Animals↗
PubMed1998

Safety and efficacy of closed-loop arbutamine stress echocardiography for detection of coronary artery disease. International Arbutamine Study Group.

Closed-loop arbutamine stress echocardiography has been shown to be safe and effective for detecting coronary artery disease (CAD) using a standardized infusion protocol and centralized core laboratory analyses. However, the accuracy of arbutamine stress echocardiography using local test interpretation has not been previously tested in a large population. The present study reports the safety, sensitivity, and specificity of arbutamine stress echocardiography in a multicenter trial allowing user-defined, nonstandardized protocols and local test interpretation. In all, 1,070 patients underwent arbutamine stress testing at 81 sites. Heart rate increased from 73 +/- 13 to 124 +/- 15 beats/min, systolic blood pressure from 144 +/- 24 to 174 +/- 25 mm Hg, and pressure rate product x 10(3) from 10.5 +/- 2.8 to 19.6 +/- 3.9. Among 1,070 patients, there were only 2 (0.2%) significant adverse events related to arbutamine, both of which resolved completely with appropriate therapy. There were no incidents of ventricular fibrillation, sustained ventricular tachycardia, or death related to testing. Among 242 patients who underwent arbutamine stress echocardiography and diagnostic coronary angiography within 12 weeks, sensitivity and specificity for detection of CAD were 71% (95% confidence interval 64% to 77%) and 67% (95% confidence interval 52% to 80%), respectively. Closed-loop arbutamine stress echocardiography is a safe and effective method for evaluating CAD in clinical practice.

Adult↗
PubMed1998

Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents in patients with suboptimal echocardiograms.

OBJECTIVES: This study was performed to compare the safety and efficacy of intravenous 2% dodecafluoropentane (DDFP) emulsion (EchoGen) with that of active control (sonicated human albumin [Albunex]) for left ventricular (LV) cavity opacification in adult patients with a suboptimal echocardiogram. BACKGROUND: The development of new fluorocarbon-based echocardiographic contrast agents such as DDFP has allowed opacification of the left ventricle after peripheral venous injection. We hypothesized that DDFP was clinically superior to the Food and Drug Administration-approved active control. METHODS: This was a Phase III, multicenter, single-blind, active controlled trial. Sequential intravenous injections of active control and DDFP were given 30 min apart to 254 patients with a suboptimal echocardiogram, defined as one in which the endocardial borders were not visible in at least two segments in either the apical two- or four-chamber views. Studies were interpreted in blinded manner by two readers and the investigators. RESULTS: Full or intermediate LV cavity opacification was more frequently observed after DDFP than after active control (78% vs. 31% for reader A; 69% vs. 34% for reader B; 83% vs. 55% for the investigators, p < 0.0001). LV cavity opacification scores were higher with DDFP (2.0 to 2.5 vs. 1.1 to 1.5, p < 0.0001). Endocardial border delineation was improved by DDFP in 88% of patients versus 45% with active control (p < 0.001). Similar improvement was seen for duration of contrast effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to affect patient management. There was no difference between agents in the number of patients with adverse events attributed to the test agent (9% for DDFP vs. 6% for active control, p = 0.92). CONCLUSIONS: This Phase III multicenter trial demonstrates that DDFP is superior to sonicated human albumin for LV cavity opacification, endocardial border definition, duration of effect, salvage of suboptimal echocardiograms, diagnostic confidence and potential to influence patient management. The two agents had similar safety profiles.

Adult↗
PubMed1998

Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial.

OBJECTIVES: The echocardiographic contrast-enhancing effects and safety profile of ALBUNEX (a suspension of air-filled albumin microspheres) were compared with the new contrast agent OPTISON (formerly FS069: a suspension of albumin microspheres containing the gas perfluoropropane) in 203 patients with inadequate noncontrast echocardiograms. BACKGROUND: The efficacy of ALBUNEX has been limited by its short duration of action. By using perfluoropropane instead of air within the microsphere, its duration of action is increased. METHODS: Each patient received ALBUNEX (0.8 and 0.22 mL/kg) and OPTISON (0.2, 0.5, 3.0, and 5.0 mL) on separate days a minimum of 48 hours apart. Echocardiograms were evaluated for increase in left ventricular (LV) endocardial border length, degree of LV opacification, number of LV endocardial border segments visualized, conversion from a nondiagnostic to a diagnostic echocardiogram, and duration of contrast enhancement. A thorough safety evaluation was conducted. RESULTS: Compared with ALBUNEX, OPTISON more significantly improved every measure of contrast enhancement. OPTISON increased well-visualized LV endocardial border length by 6.0+/-5.1, 6.9+/-5.4, 7.5+/-4.7, and 7.6+/-4.8 cm, respectively, for each of the four doses, compared with only 2.2+/-4.5 and 3.4+/-4.6 cm, respectively, for the two ALBUNEX doses (p < 0.001). 100% LV opacification was achieved in 61%, 73%, 87%, and 87% of the patients with the four doses of OPTISON, but in only 16% and 36% of the patients with the two ALBUNEX doses (p < 0.001). Conversion of nondiagnostic to diagnostic echocardiograms with contrast occurred in 74% of patients with the optimal dose of OPTISON (3.0 mL) compared with only 26% with the optimal dose of ALBUNEX (0.22 mL/kg) (p < 0.001). The duration of contrast effect was also significantly greater with OPTISON than with ALBUNEX. In a subset of patients with potentially poor transpulmonary transit of contrast (patients with chronic lung disease or dilated cardiomyopathy), OPTISON more significantly improved the same measures of contrast enhancement compared with ALBUNEX and did so to the same extent as in the overall population. Side effects were similar and transient with the two agents. CONCLUSION: OPTISON appears to be a safe, well-tolerated echocardiographic contrast agent that is superior to ALBUNEX.

Albumins↗
PubMed1998

Fertile homozygous transgenic mice expressing a functional truncated herpes simplex thymidine kinase delta TK gene.

Dividing cells expressing the Herpes simplex type 1 thymidine kinase (TK) can be killed upon ganciclovir treatment. Likewise, conditional cell knock-out can be obtained in transgenic mice expressing a TK gene placed under the control of tissue-specific regulatory sequences. Such animals provide powerful experimental systems for assessing the functional role of specific cell populations through their time-controlled ablation. However, whatever the regulatory sequences used, a leaky toxic overexpression of TK in testis renders male TK-transgenic mice sterile and prevents the generation of homozygous TK-expressing animals. To solve this problem, we designed a truncated TK variant (delta TK) not expressed in the testis. We generated transgenic mice expressing delta TK under the control of lymphocyte-specific regulatory sequences derived from the CD4 gene. The delta TK protein expressed in T-lymphocytes allowed the conditional ablation of activated T-cells in vitro and in vivo. Importantly, for one transgenic line we could generate fertile homozygous mice harboring a functional delta TK transgene. delta TK should thus dramatically facilitate the development of transgenic mice expressing a conditional suicide gene.

Animals↗
PubMed1998

Hir proteins are required for position-dependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I.

Chromatin assembly factor I (CAF-I) is a three-subunit histone-binding complex conserved from the yeast Saccharomyces cerevisiae to humans. Yeast cells lacking CAF-I (cacDelta mutants) have defects in heterochromatic gene silencing. In this study, we showed that deletion of HIR genes, which regulate histone gene expression, synergistically reduced gene silencing at telomeres and at the HM loci in cacDelta mutants, although hirDelta mutants had no silencing defects when CAF-I was intact. Therefore, Hir proteins are required for an alternative silencing pathway that becomes important in the absence of CAF-I. Because Hir proteins regulate expression of histone genes, we tested the effects of histone gene deletion and overexpression on telomeric silencing and found that alterations in histone H3 and H4 levels or in core histone stoichiometry reduced silencing in cacDelta mutants but not in wild-type cells. We therefore propose that Hir proteins contribute to silencing indirectly via regulation of histone synthesis. However, deletion of combinations of CAC and HIR genes also affected the growth rate and in some cases caused partial temperature sensitivity, suggesting that global aspects of chromosome function may be affected by the loss of members of both gene families.

Amino Acid Sequence↗
PubMed1998

Pain control following elective gastrointestinal surgery: is epidural anesthesia warranted?

Fifty-nine patients undergoing elective major gastrointestinal surgery were entered into a prospective, randomized trial between January 1993 and July 1994 comparing the effectiveness, side effects, and hospital costs of postoperative epidural anesthesia (Group 1, n = 29) and intramuscular narcotic injections (Group 2, n = 30). Epidural catheters were inserted by a team that supervised catheter care and infusion rates in the postoperative period. The nonepidural group received intramuscular injections on a regular basis. Patients filled out visual analog scales to measure levels of pain ( 1 = minimal, 10 = maximal) every eight hours. Patient activity, bowel, and urinary function were recorded by the nursing staff. Control of pain (as measured by the daily average visual analog score) was more effective in Group 1 (P < .001) on postoperative days 1-3 (1.3 vs 3.6 on day 1, 0.7 vs 2.6 on day 2, 0.9 vs 3 on day 3). There was no significant difference in mean values between groups 1 and 2 with respect to first ambulation on the hospital ward, onset of liquid diet, intake of solid food, first spontaneous voiding, first bowel movement, length of hospitalization, or charge of hospitalization ($13,439 +/- 7,452 vs $11,821 +/- 6,630). We conclude that epidural anesthesia significantly lessens incisional pain following major elective lower gastrointestinal surgery when compared to analgesic injections alone. However, while not statistically significant, the overall charge was increased by 14% in the epidural group. This finding should be examined in light of the relatively low pain level in patients receiving narcotic injections alone.

Adult↗
PubMed1998

Erythema multiforme associated with contact dermatitis to poison ivy: three cases and a review of the literature.

Erythema multiforme (EM) is a hypersensitivity reaction that occurs mainly after exposure to certain medications or in the setting of infection, most commonly that due to herpes simplex virus. Rare cases of EM have been reported after allergic contact dermatitis due to various substances. There has been one case in the literature of EM following Rhus contact dermatitis. We report three patients who developed EM after allergic contact dermatitis due to poison ivy. In all three patients, targetoid lesions developed primarily on the palms and soles, either after a brief course of prednisone or during its taper. Two of the patients have had more than one episode of EM after poison ivy dermatitis. Although EM has been described after allergic contact dermatitis due to a variety of antigens (nickel being the most common), there is only one report in the literature of EM following Rhus contact dermatitis. Given the prevalence of allergic contact dermatitis due to poison ivy, this may be an under-reported complication.

Adolescent↗
PubMed1997

Position-dependent variegation of a CD4 minigene with targeted expression to mature CD4+ T cells.

The CD4 gene follows a complex and highly regulated pattern of expression throughout T cell development. This expression is governed by different regulatory elements that have been partly identified, including a promoter, a proximal enhancer, and a silencer. Here we show that a CD4 minigene comprising a combination of these elements is specifically expressed in mature CD4+ T cells of transgenic mice, but not in CD4+CD8+ double positive thymocytes. The proportion of transgene-expressing CD4+ T cells was constant within a given transgenic line, but varied greatly from one line to another. We demonstrate that this pattern of expression is due to integration of the transgene within or in the vicinity of centromeric heterochromatin. This position-effect variegation demonstrated with a short CD4 transgene has not been observed with larger ones containing additional regulatory sequences, suggesting that the CD4 gene contains a locus control region. Such position-dependent effects must be taken into consideration when developing transgenic models or gene transfer vectors because they can result in the absence of transgene expression in a subpopulation of target cells. Finally, the combination of the CD4 gene silencer, proximal enhancer, and promoter provides an interesting tool to selectively express genes of interest in mature CD4+ T cells of transgenic mice and for the development of gene therapy vectors.

Animals↗
PubMed1997

Prevention of graft-versus-host disease in mice using a suicide gene expressed in T lymphocytes.

Alloreactive T cells present in a bone marrow transplant are responsible for graft-versus-host disease (GVHD), but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-versus-leukemia effect. We developed a therapeutic strategy against GVHD based on the selective destruction of these alloreactive T cells, while preserving a competent T-cell pool of donor origin. We generated transgenic mice expressing in their T lymphocytes the Herpes simplex type 1 thymidine kinase (TK) suicide gene that allows the destruction of dividing T cells by a ganciclovir treatment. T cells expressing the TK transgene were used to generate GVHD in irradiated bone marrow grafted mice. We show that a short 7-day ganciclovir treatment, initiated at the time of bone marrow transplantation, efficiently prevented GVHD in mice receiving TK-expressing T cells. These mice were healthy and had a normal survival. They maintained a T-cell pool of donor origin that responded normally to in vitro stimulation with mitogens or third party alloantigens, but were tolerant to recipient alloantigens. Our experimental system provides the proof of concept for a therapeutic strategy of GVHD prevention using genetically engineered T cells.

Animals↗
PubMed1997

Mesenteric angiography for lower gastrointestinal hemorrhage: are there predictors for a positive study?

PURPOSE: Selective mesenteric angiography is an expensive, invasive, diagnostic, and therapeutic tool for lower gastrointestinal hemorrhage. Some institutions have required a positive nuclear medicine bleeding scan before angiography. We have attempted to determine if this is a valid screening test for mesenteric angiography. Are there any other factors to predict which patients are actively bleeding and who will benefit from angiography? METHODS: All cases of mesenteric angiography for hemorrhage performed during a 12-year period were reviewed. RESULTS: A total of 131 angiograms were performed during a 12-year period with 45 patients demonstrating active bleeding; 54 patients had a bleeding scan before angiography. A positive bleeding scan did not increase the percentage of positive angiograms. A history of prior gastrointestinal bleeding, transfusions, orthostatic hypotension, or tachycardia were not predictors for a positive angiogram. DISCUSSION: This study could not identify any single useful predictor that will increase the likelihood of obtaining a positive angiogram. Nuclear medicine scans should not be used routinely as a screening test for angiography.

Aged↗
PubMed1997

Ruptured visceral artery aneurysms.

Visceral artery aneurysms are uncommon lesions that are rarely identified in the absence of symptoms. Between February 1972 and April 1992, nine patients (5 men and 4 women) with rupture of visceral artery aneurysms were treated. The average age was 62 years old (range 39 to 86 years old). The arteries involved were the splenic (4), the common hepatic (2), the left hepatic (1), the celiac (1), and the superior mesenteric (SMA) (1). No ruptured renal artery aneurysm was identified. Six patients presented with abdominal distension, pain, and hemodynamic instability. Three patients had recurrent gastrointestinal bleeding with erosion into the duodenum, the common bile duct or the pancreatic duct. All three had unnecessary gastrointestinal operations despite preoperative (2 patients) or intraoperative (1 patient) identification of a visceral artery aneurysm. One patient with an SMA aneurysm had ligation and bypass. Three patients with splenic artery aneurysms had splenectomy. The remaining five patients had either ligation or resection without arterial reconstruction. No end-organ dysfunction was identified. There was one death (11%) due to the SMA aneurysm. Pathological findings in four patients were cystic medial necrosis, diffuse deficiency of the internal elastic lamina, fibromuscular dysplasia, and atherosclerosis, respectively. The remainder were thought to be due to atherosclerosis on gross examination. Rupture of visceral artery aneurysms occurs infrequently and can be treated by simple ligation in most cases. Recognition that rupture of splanchnic arterial aneurysms into adjacent viscera can cause recurrent gastrointestinal bleeding may prevent both substantial delays in diagnosis and inappropriate therapy.

Aged↗
PubMed1997

Influence of local delivery of the protein tyrosine kinase receptor inhibitor tyrphostin-47 on smooth-muscle cell proliferation in a rat carotid balloon-injury model.

Smooth-muscle cell proliferation in response to arterial injury represents an important etiologic factor in restenosis after angioplasty. Tyrphostin-47, a protein tyrosine kinase inhibitor, inhibits smooth-muscle cell proliferation in vitro. In this study tyrphostin-47 was incorporated into matrixes to determine whether prolonged local delivery would result in a reduction of neointimal proliferation after arterial injury in a rat carotid balloon-injury model. A polymer matrix (polylactic polyglycolic acid copolymer and pluronic gel F-127, mean matrix weight 7.83 +/- 0.39 mg) was loaded with tyrphostin-47 (25% w/w). Release studies demonstrated delivery of 11% of the incorporated drug over a 21-day release period. In cell culture, tyrphostin-47 released from the polymer matrix produced a reduction in smooth-muscle cell proliferation (p < 0.0007). Balloon denudation injury of the left common carotid artery of 34 animals was performed. In 12 animals, polymer matrixes containing tyrphostin-47 were wrapped around the injured arteries to provide prolonged drug delivery (estimated dosage 28 micrograms/kg/24 hr); in 10 animals a polymer matrix without tyrphostin-47 was implanted; and in 12 animals only balloon injury was performed. The mean neointimal cross-sectional areas, luminal areas, and intima/media ratios were not significantly different among animals receiving local treatment with tyrphostin-47, sham polymer after injury, or balloon injury without polymer implantation. We conclude that despite inhibition of smooth-muscle cell proliferation by tyrphostin-47 in vitro, sustained local delivery of this tyrosine kinase inhibitor does not result in a reduction of neointimal proliferation in the rat carotid injury model.

Animals↗