Biomedical subjects

D J Goldstein

Publications and source records attributed to D J Goldstein.

At least 55 records · Page 3Linked to original sources

PubMed1997

Inhaled nitric oxide is not a negative inotropic agent in a porcine model of pulmonary hypertension.

BACKGROUND: Reports of pulmonary edema complicating inhaled nitric oxide therapy in patients with chronic heart failure and pulmonary hypertension have raised the concern that inhaled nitric oxide may have negative inotropic effects. METHODS AND RESULTS: We investigated the effect of multiple doses of inhaled nitric oxide (20, 40 and 80 ppm) on left ventricular contractile state in 10 open-chest pigs. Pressure-volume loops were generated during transient preload reduction to determine the end-systolic pressure-volume relationship and the stroke work-end-diastolic volume relation. Inhaled nitric oxide had no effect on systemic vascular resistance, cardiac output, end-systolic pressure volume relationship or stroke work-end-diastolic volume relation under normal conditions. After induction of pulmonary hypertension (intravenous thromboxane A2 analog), inhalation of nitric oxide (80 ppm) resulted in a reduction in pulmonary vascular resistance (mean +/- standard error of the mean) from 10.4 +/- 3 to 6.5 +/- 2 Wood units (p < 0.001) and in pulmonary artery pressure from 44 +/- 4 to 33 +/- 4 mm Hg (p < 0.05). Left ventricular end-diastolic volume rose from 53 +/- 9 ml to 57 +/- 10 ml (p = 0.02). No statistically significant change in cardiac output or systemic vascular resistance was observed. Inhaled nitric oxide had no effect on end-systolic pressure-volume relationship or stroke work-end-diastolic volume relation. CONCLUSIONS: In a porcine model of pulmonary hypertension, inhaled nitric oxide does not impair left ventricular contractile function. Therefore the cause of pulmonary edema observed in some patients receiving inhaled nitric oxide is not due to a negative inotropic action of this therapy.

Administration, Inhalation↗

PubMed1997

Systolic ventricular interaction in normal and diseased explanted human hearts.

OBJECTIVE: The purpose of this study was to quantify the magnitude of interaction between the right and left ventricles in conditions of heart failure. METHODS: Human hearts were taken from transplant recipients diagnosed with diluted cardiomyopathy at the time of transplantation and were restored to beating condition with use of an isolated perfusion circuit. Left ventricular-right ventricular interaction was determined by ramping volume in the left ventricle while holding right ventricular volume constant. Right ventricular pressure gain was plotted against left ventricular pressure and the slope of the linear regression determined the left ventricular-right ventricular interaction. A similar procedure was used to determine right ventricular-left ventricular interaction. Two normal hearts were obtained from transplant donors not suitable for cardiac donation to serve as control hearts. RESULTS: Mean left ventricular-right ventricular interaction was 0.22 in the hearts with dilated cardiomyopathy compared with 0.06 in the control hearts. Mean right ventricular-left ventricular interaction was 0.14 in the hearts with dilated cardiomyopathy compared with 0.09 in the control hearts. A marked increase in left ventricular-right ventricular interaction was noted in the hearts with dilated cardiomyopathy compared with control hearts. Although observed values of right ventricular-left ventricular interaction also correspond to previously published results, no significant increase was observed in the dilated cardiomyopathy condition. CONCLUSIONS: These studies confirm previously published values for systolic ventricular interaction obtained with animal models and demonstrate a marked increase in the dependence of the right ventricle on left ventricular function to maintain systolic pressure generation during conditions of dilated cardiomyopathy.

Cardiomyopathy, Dilated↗

PubMed1997

Effects of first-trimester fluoxetine exposure on the newborn.

OBJECTIVE: To determine whether first-trimester exposure to fluoxetine, a selective serotonin reuptake inhibitor commonly used to treat depression and obsessive-compulsive disorders, is associated with increased frequency of fetal malformations. METHODS: We evaluated outcomes of all pregnancies identified prospectively with confirmed first-trimester fluoxetine exposure contained in the Eli Lilly and Company worldwide fluoxetine pregnancy registry. These outcomes were compared with historic reports of newborn surveys. RESULTS: Outcomes were available for 796 pregnancies, 37 from fluoxetine clinical trials and 759 from spontaneous reports. Spontaneous abortions were reported in 110 of the 796 (13.8%) pregnancies. Of the remaining 686, malformations, deformations, and disruptions, including those identified after the perinatal period, were reported in 34 (5.0%). No consistent or recurring pattern of abnormalities was observed. CONCLUSION: Based on comparison with historic reports of newborn surveys, it is unlikely that maternal fluoxetine use during the first trimester of pregnancy results in increased risk of fetal malformations.

Abnormalities, Drug-Induced↗

PubMed1997

Rupture of a nonaneurysmal atherosclerotic infrarenal aorta.

We report a case of spontaneous rupture of a nonaneurysmal infrarenal aorta through an area of atherosclerotic thinning. Close follow-up, aggressive antihypertensive therapy, and serial imaging of asymptomatic patients with documented aortic ulceration is warranted. In symptomatic patients, surgical intervention should be undertaken so that transmural aortic rupture can be averted.

Aged↗

PubMed1997

Dexfenfluramine.

Explore the source record for details and available documents.

Appetite Depressants↗

PubMed1997

Adenovirus-mediated transduction of ribozymes abrogates HER-2/neu and pleiotrophin expression and inhibits tumor cell proliferation.

The combination of specific gene targeting technologies with efficient gene delivery systems could provide the means to evaluate the concept of anticancer strategies designed to block expression of potentially rate-limiting tumor promoting factors. Here, we constructed adenoviruses expressing hammerhead-ribozymes targeted to two of these factors, the tyrosine kinase receptor HER-2/neu or the growth factor pleiotrophin (PTN). Adenovirus-mediated transduction of either HER-2/neu- or PTN-targeted ribozymes depleted the respective RNAs and inhibited protein expression significantly in three different human cancer cell lines. This resulted in almost complete abrogation of HER-2/neu- or PTN-dependent cancer-cell proliferation, thus demonstrating the feasibility of this approach as a future cancer gene therapy.

Adenoviridae↗

PubMed1997

Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study.

Lanepitant is a high-affinity, selective neurokinin-1 receptor (NK-1) and is effective in the dural inflammation model of acute migraine. Lanepitant 30, 80, and 240 mg given orally was evaluated in a double-blind, placebo-controlled crossover study to determine its effect in reducing migraine pain and severity of associated symptoms. Outpatients treated four migraine headaches of moderate or severe pain intensity with study drug according to a randomization schedule. They recorded their pain intensity and severity of migraine-associated symptoms at 30, 60, 90, and 120 min. Although 53 patients were randomly allocated to a treatment sequence, only 40 patients completed all treatments. There was no statistically significant difference in improvement in migraine pain at any time for any of the treatments. Additionally, there was no change in severity of migraine-associated symptoms associated with lanepitant therapy. No adverse events could be attributed to lanepitant. Lanepitant was ineffective orally in treating acute migraine in this trial. This may be due to poor bioavailability during a migraine attack. Alternatively, the neurogenic inflammation hypothesis may not apply to migraine.

Acute Disease↗

PubMed1997

Fluoxetine in medically stable, depressed geriatric patients: effects on weight.

This study assessed the effect of fluoxetine 20 mg/day on weight loss in older patients treated for major depression in a multicenter, double-blind placebo-controlled, 6-week clinical trial. Thirty U.S. outpatient clinics affiliated with psychiatric programs participated in the study that involved 671 medically stable outpatients at least 60 years old who had normal cognition and met DSM-III-R criteria for major depression. Weight was recorded at weekly visits. As a measure of adiposity, patients were categorized into two groups, high and low/normal body mass index (BMI) groups. Analyses were done for each group. The high BMI group, but not the low/normal BMI group, had a statistically greater proportion of fluoxetine-treated patients who lost at least 5% of their baseline weight. Overall mean weight change for the fluoxetine-treated patients was about 1% compared with essentially no change for placebo-treated patients. Only one patients, who was treated with fluoxetine and in the low/normal BMI group, discontinued from the study because of weight loss. Although 5% weight loss occurred in more fluoxetine-treated than placebo-treated patients, most of the patients who lost weight had higher adiposity at baseline. There was not a statistically significant difference in the proportion of fluoxetine-treated and placebo-treated patients in the low/normal group who had at least 5% weight loss. Medically relevant weight loss in older patients treated with fluoxetine was uncommon.

Aged↗

PubMed1997

Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994.

OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.

Blindness↗

PubMed1997

Is aprotinin indicated for reoperative valvular surgery?

BACKGROUND AND AIMS OF THE STUDY: While the hemostatic effect of aprotinin for patients undergoing reoperative coronary bypass is well established, it remains unclear whether these effects extend to patients undergoing reoperative valvular surgery. METHODS: We examined our experience with 85 consecutive patients undergoing isolated reoperative valvular surgery with and without use of perioperative aprotinin in order to investigate differences in perioperative blood use, blood loss, bleeding complications, mortality and incidence of myocardial injury. RESULTS: Aprotinin recipients benefited from a significant reduction in bleeding complications, and a decrease in perioperative and in-hospital mortalities as compared with untreated patients. Anaphylactic reactions and clinically significant thromboembolic events were not observed. There was no difference in the incidence of renal dysfunction or myocardial injury among aprotinin-treated and untreated groups. CONCLUSIONS: Our results indicate that aprotinin therapy can be safely administered to patients undergoing reoperative valvular surgery. No increased incidence of anaphylactic reactions, renal dysfunction or perioperative myocardial injury was noted. The observed reductions in bleeding complications and perioperative and in-hospital mortality strongly warrant the evaluation of aprotinin for reoperative valvular surgery in a prospective fashion.

Adolescent↗

PubMed1997

p53-independent expression of p21waf1/cip1 in preinvasive and invasive squamous neoplasms of the uterine cervix.

Although mutations of the p53 gene are the most common genetic alteration in human tumors, they are relatively rare in cervical carcinomas, possibly because human papillomaviruses of the oncogenic type encode for an oncoprotein that leads to the ubiquitin-mediated destruction of p53. An important mediator of p53-induced cell-cycle arrest is p21waf1/cip1, and although several studies evaluated invasive and preinvasive cervical lesions for p53 expression, none has studied expression of this important downstream effector. We examined normal cervical squamous epithelium, squamous cell carcinomas, and a range of preinvasive cervical lesions for expression of p53, p21waf1/cip1, and the proliferation-associated antigen, Ki-67, by immunohistochemical analysis. p53 expression was absent in normal squamous epithelium and all dysplasias regardless of severity, consistent with the presence of predominantly wild-type p53. Invasive carcinomas were mostly negative but contained occasional small nests of cells immunoreactive for p53. p21waf1/cip1, on the other hand, was expressed in all normal squamous epithelium and all preinvasive and invasive lesions. In normal squamous epithelium, the basal and immediate parabasal layers were negative, with the early differentiating layers positive. Expression was increased in dysplasias compared with normal squamous epithelium, both in number of immunoreactive nuclei and intensity of staining. The highest expression was seen in high-grade dysplasias and invasive carcinomas. Ki-67 expression also increased with increasing severity of the lesion, but p21waf1/cip1 and Ki-67 seemed to be expressed in different cells, a fact that was confirmed by double immunohistochemical staining for these two proteins on the same sections. This paradoxical increase in p21waf1/cip1 expression and mutually exclusive expression might be related to the role of p21waf1/cip1 in differentiation.

Adult↗

PubMed1997

Treatment of cardiac tumors by orthotopic cardiac transplantation.

Primary soft tissue tumors of the heart usually cannot be excised with adequate margins. Orthotopic heart transplantation (OHT) could allow complete resection of cardiac tumors and has been performed in selected patients. However, most are not transplanted because of the high risk of tumor recurrence or metastasis and the possible enhancement of tumor growth by immunosuppressive drugs. Six patients with soft tissue cardiac tumors have been transplanted at the Columbia Presbyterian Medical Center: one paraganglionoma and one fibroma (both benign), and four malignant primary sarcomas. In all cases, there was no preoperative evidence of metastasis. In all but one case, the tumor was completely resected with adequate margins at the time of transplantation. One sarcoma patient who had not received preoperative or postoperative chemotherapy died suddenly 2.6 months after operation with no evidence of tumor. One patient is alive at 38 months with diffuse metastatic disease; two patients were treated preoperatively with intensive doxorubicin-based chemotherapy (one of whom also received postoperative external-beam radiotherapy to a positive surgical margin) and are tumor free 16 and 6 months after transplantation. Our experience compares favorably with the worldwide results of OHT for cardiac tumors (an additional 13 patients).

Adult↗

PubMed1996

Carcinoma of the lung after heart transplantation.

We have recently noted an unexpected high incidence of lung cancer in our population of cardiac allograft recipients. We conducted a retrospective review of cardiac transplantation at our institution to investigate the incidence, clinical course, and outcome of patients who developed lung cancer following heart transplantation. Nine patients--each with a history of smoking at 30 pack-years--developed lung cancer following heart transplantation, for an incidence of 1.56% of patients at risk. Eight of the patients were male > or = 50 years of age, representing 3.3% of the male transplant recipients in this age group. The interval from transplantation to diagnosis clustered around 3-5 years after transplantation, but in two instances (22%), a neoplasm was discovered within 6 months of transplantation. Almost half of the cancers were discovered incidentally, despite routine radiographic surveillance. Seven of 9 (78%) patients had stage IV disease at presentation. Median survival after diagnosis was 3 months, and five of the seven patients who died survived less than 4 months after diagnosis. We conclude that cardiac transplant recipients are at increased risk for development of lung cancer. Patients with a moderate to heavy smoking history might well be advised to undergo chest CT scanning in an aggressive search for occult lung cancer before cardiac transplantation is considered further. Finally, despite frequent radiologic examinations, these lung cancers are often diagnosed incidentally, are far advanced at the time of diagnosis, are not surgically resectable, and are poorly responsive to adjuvant therapy.

Adolescent↗

PubMed1996

Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels.

BACKGROUND: The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium. METHODS AND RESULTS: Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n = 14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n = 21) and ischemic cardiomyopathy (n = 11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n = 12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by approximately 50% to 70% (P < .01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-microns sarcomere length, the EC50 value was 5.56 +/- 0.06, and at 2.3 microns it was 5.70 +/- 0.05 (P < .01; n = 7). CONCLUSIONS: The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.

Analysis of Variance↗

PubMed1996

Tumor necrosis factor alpha interferes with the cell cycle of normal and papillomavirus-immortalized human keratinocytes.

We have shown that normal and human papillomavirus (HPV) type 16 immortalized human foreskin keratinocytes are growth inhibited by tumor necrosis factor alpha (TNF-alpha), whereas HPV-18- and SV40-immortalized keratinocytes are resistant to this cytokine (1). In this report, we investigated the expression of mitotic regulatory proteins, such as cyclin A, cyclin B, and p34cdc2. After exposure to TNF-alpha, normal and HPV-16-immortalized cells exhibited a dramatic decrease in the expression of these proteins. In contrast, no alteration in the levels of these proteins was observed after treatment of the resistant cell lines, as well as two HPV-positive cervical carcinoma cell lines. Expression of cyclin E does not seem to be modulated by TNF-alpha in any of the cells tested. On the other hand, cyclin D1, expression is slightly increased in normal keratinocytes and in the HPV-16-immortalized cells, whereas no alteration was observed in the HPV-18-transfected cells. The phosphorylation state of pRb correlated with cell growth; sensitive cells, which accumulate in G0-G1, after exposure to TNF-alpha, exhibited an accumulation of hypophosphorylated pRb, whereas no effect on pRb phosphorylation was observed for HPV-18-immortalized cells. These results clearly correlate with TNF-alpha-induced growth arrest in G0-G1.

CDC2 Protein Kinase↗

PubMed1996

Wearable long-term mechanical support for patients with end-stage heart disease: a tenable goal.

Increasing in frequency, and claiming more than 250,000 lives per year, heart failure represents a major public health problem. In spite of newer medical therapies, a significant proportion of patients progress to irreversible end-stage heart disease, for which cardiac transplantation remains the only long term hope. The inability to meet the demand for donor organs has led to the development of left ventricular assist devices as a temporizing measure while awaiting a transplantation. The "bridging to transplantation" experience has firmly established the efficacy of these devices as short-term and medium-term mechanical assistance and has provided valuable lessons applicable to long-term support. Mechanical cardiac assistance technology has dramatically improved and can provide reliable univentricular support with minimal thromboembolic and infectious complications. Although major obstacles remain, the potential benefits are great enough and the morbidity and mortality of end-stage heart disease high enough to warrant the evaluation of wearable left ventricular assist devices for long-term mechanical assistance.

Cardiac Output, Low↗

PubMed1996

Safety of repeat aprotinin administration for LVAD recipients undergoing cardiac transplantation.

BACKGROUND: Anecdotal reports of allergic and anaphylactic reactions after aprotinin therapy have raised concern that its repeat use may be associated with substantial morbidity. METHODS: To address this concern, we reviewed our experience with all patients who underwent implantation of a left ventricular assist device and subsequent cardiac transplantation with perioperative use of aprotinin. RESULTS: Twenty-three patients received full-dose aprotinin during left ventricular assist device implantation and subsequent cardiac transplantation. All patients tolerated primary exposure to aprotinin without complication. One episode of anaphylaxis after secondary exposure was treated with rapid institution of cardiopulmonary bypass. Although renal dysfunction was observed shortly after cardiac transplantation in 30.4% of patients, the effect was transient and occurred in the presence of cyclosporine. The one perioperative death after secondary exposure was unrelated to bleeding complications. No clinically evident thromboembolic events were documented. CONCLUSIONS: Primary and secondary exposure to aprotinin during operation with cardiopulmonary bypass is associated with limited intraoperative blood use, a low incidence of transient renal dysfunction and anaphylaxis, a rare need of reoperation for bleeding, and no clinical thromboembolic events.

Adult↗

PubMed1996

Outpatient left ventricular assist device support: a destination rather than a bridge.

BACKGROUND: To evaluate the feasibility and efficacy of outpatient left ventricular assist devices as a bridge to transplantation, we reviewed the initial clinical experience with this modality at our institution. METHODS: During January 1993 to November 1995, 12 male and 2 female patients with an average age of 47 +/- 17 years were supported for an average of 117 +/- 24 days with the Thermo Cardiosystems VE wearable left ventricular assist device. Seven patients were discharged home an average of 35 +/- 4 days after implantation. RESULTS: No device failures occurred, although 29 controller malfunctions were identified during 1,640 total support days. All patients were able to safely maintain their devices. Outflow graft bleeding and driveline infection were responsible for two readmissions. No long-term anticoagulation treatment was used; one small thromboembolic episode occurred, but without significant long-term sequelae. CONCLUSIONS: None of the 7 patients released from the hospital died, and all were able to successfully maintain their devices at home. Hospital discharge of patients supported with left ventricular assist devices has allowed long-term evaluation of this technology, and the findings should prompt study of their use as a long-term alternative treatment to medical management for congestive heart failure.

Adolescent↗