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Biomedical subjects

D J Goldstein

Publications and source records attributed to D J Goldstein.

At least 73 records · Page 4Linked to original sources
PubMed1996

Development of an intraluminal device for the treatment of aortic regurgitation: prototype and in vitro testing system.

OBJECTIVES: Development of an intraluminal device to reduce aortic regurgitation could provide a strategy intermediate between medical treatment and aortic valve replacement. An initial prototype and a testing system have been designed. METHODS: Aortic valves obtained from heart transplant recipients were explanted and assessed in a mock circulatory loop with resistive and capacitive elements, including pressure-flow characteristics, similar to those of a normal arterial system. Normal heart function was simulated by a pulsatile ventricular-assist device. Pressure on each side of the valve and flow through the valve were recorded, allowing the calculation of regurgitant fractions and transvalvular gradients. Six solid geometrically differing obturators were tested. RESULTS: All six designs resulted in significant reduction in aortic regurgitation (p < 0.0001), ranging from 15% to 38% improvement compared with control values. Small increases in transvalvular gradients (from 0 to 7 mm Hg) were also noted. DISCUSSION: Initial results suggest that an intraluminally placed obturator can reduce aortic regurgitation without creating clinically significant transvalvular gradients. These initial in vitro experiments demonstrate the feasibility of an intraluminal device for the treatment of aortic valve disease, and further investigation is warranted.

Aortic Valve↗
PubMed1996

Effects of omega-3 fatty acids on complement-mediated glomerular epithelial cell injury.

To define the mechanisms by which fish oil protects rats with passive Heymann nephritis (PHN) from proteinuria in vivo, we investigated whether omega-3 fatty acid substitution of glomerular epithelial cells (GEC) in culture alters their susceptibility or response to complement-mediated sublethal injury. The results show that GECs can be cultured under conditions that effectively incorporate omega-3 or omega-6 fatty acids into membrane phospholipids without causing toxicity. Under these conditions, sublethal injury with anti-Fx1A and C5b-9 stimulated a 6.6-fold increase in TxA2 production by GECs substituted with arachidonic acid (AA, omega-6) but no increase was detected in eicosapentaenoic acid (EPA, omega-3) substituted cells. Sublethal cell membrane injury was of equal severity in both groups as measured by the release of preloaded biscarboxyethyl carboxyfluorescein and by the transepithelial flux of albumin. In addition, omega-3 and omega-6 fatty acid substituted cells showed similar increases in diacylglycerol mass in response to sublethal injury by C5b-9, suggesting that omega-3 incorporation did not limit phospholipid (PL) hydrolysis by PLC. From this we can conclude that the protective effect of fish oil in PHN does not appear to result from the preservation of GEC integrity but is likely related to changes in the production of lipid mediators.

Animals↗
PubMed1996

Outcome at 4 to 5 years of age in children recovered from neonatal chronic lung disease.

Outcomes were compared for 31 very-low-birthweight children recovered from chronic lung disease and 31 very-low-birthweight controls. All children had been free of major abnormalities on neonatal cranial ultrasonography. At 4 to 5 years of age, children were examined by a pediatrician and tested by a psychologist who administered the Wechsler Preschool and Primary Scale of Intelligence-Revised. Despite similar medical outcomes, the children who had had neonatal chronic lung disease had lower Full-scale IQs (median 83 vs 87) and Performance IQs (79 vs 90). Median Verbal IQ was similar in the two groups (85 vs 87). A higher proportion of children who had had chronic lung disease had Full-scale IQ < 70 (8/31 [26%] vs 1/31 [3%]) and Performance IQ < 70 (8/31 [26%] vs 0/31). These effects persisted after adjustment for confounding factors.

Child, Preschool↗
PubMed1996

Duration of left ventricular assist device support affects transplant survival.

BACKGROUND: Left ventricular assist devices have become an important tool in the successful treatment of heart failure as bridges to transplantation. The optimal duration of device support before heart transplantation is debated. We report the effect of left ventricular device support duration on survival after heart transplantation. METHODS: All patients bridged to heart transplantation with the ThermoCardiosystems Heartmate 1,000 IP left ventricular assist device between January 1, 1986, and October 15, 1994, were included in our study. Parameters studied included duration of support, measures of end-organ function, and complications while supported with the device. Patients supported < 30 days were compared with patients supported > 30 days before undergoing transplantation. RESULTS: Patients supported for < 30 days had a threefold increased perioperative mortality compared with patients supported > 30 days (p = 0.031). Laboratory values of end-organ function were similar before left ventricular device insertion in both groups, although at the time of transplantation patients supported < 30 days had a significantly elevated bilirubin level compared with patients supported > 30 days (p < 0.001). Patients supported > 30 days had significantly more infections than the < 30 days group (p = 0.0345). CONCLUSIONS: Patients supported for > 30 days with left ventricular assist devices have improved post-transplant perioperative survival because of normalization of end-organ function and improved physiologic status secondary to aggressive physical rehabilitation. Patients should be supported for > 30 days in combination with physical rehabilitation, to improve early survival after heart transplantation.

Adult↗
PubMed1996

The transient pore formed by homologous terminal complement complexes functions as a bidirectional route for the transport of autocrine and paracrine signals across human cell membranes.

BACKGROUND: We have previously shown that the membrane attack complex (MAC) of complement stimulates cell proliferation and that insertion of homologous MAC into the membranes of endothelial cells results in the release of potent mitogens, including basic fibroblast growth factor (bFGF). The mechanism of secretion of bFGF and other polypeptides devoid of signal peptides, such as interleukin 1 (IL-1) is still an open problem in cell biology. We have hypothesized that the homologous MAC pore itself could constitute a transient route for the diffusion of biologically active macromolecules in and out of the target cells. MATERIALS AND METHODS: Human red blood cell ghosts and artificial lipid vesicles were loaded with labeled growth factors, cytokines and IgG, and exposed to homologous MAC. The release of the 125I-macromolecules was followed as a function of time. The incorporation of labeled polypeptides and fluorescent dextran (MW: 10,000) was measured in MAC-impacted human red blood cells and human umbilical endothelial cells (HUVEC), respectively. RESULTS: Homologous MAC insertion into HUVEC resulted in the massive uptake of 10-kD dextran and induced the release of bFGF, in the absence of any measurable lysis. Red blood cell ghosts preloaded with bFGF, IL-1 beta, and the alpha-chain of interferon-gamma (IFN-gamma) released the polypeptides upon MAC insertion, but they did not release preloaded IgG. MAC-impacted ghosts took up radioactive IFN-gamma from the extracellular medium. Vesicles loaded with IL-I released the polypeptide when exposed to MAC. CONCLUSIONS: The homologous MAC pore in its nonlytic form allows for the export of cytosolic proteins devoid of signal peptides that are not secreted through the classical endoplasmic reticulum/Golgi exocytotic pathways. Our results suggest that the release, and perhaps the uptake, of biologically active macromolecules through the homologous MAC pore is a novel biological function of the complement system in mammals.

Biological Transport↗
PubMed1995

Screening scale predicts patients successfully receiving long-term implantable left ventricular assist devices.

BACKGROUND: Although use of long-term implantable left ventricular assist devices (LVAD) is becoming more popular, further reduction of the mortality rate accompanying device insertion through improved patient selection would make this alternative even more appealing. We sought to develop a scoring system that was based on criteria obtainable at the time of evaluation and predictive of successful early outcome and simple to apply. METHODS AND RESULTS: Patients (n = 56) undergoing LVAD insertion between 1990 and 1994 were screened for easily obtainable preoperative risk factors. To test the association between survival and each risk factor, a chi 2 analysis was performed, and relative risks were estimated. Oliguria, ventilator dependence, elevated central venous pressure, elevated prothrombin time, and reoperation stats had low probability values and high estimated relative risks. On the basis of these relations, a risk factor-selection scale (RFSS) (range, 0 to 10) was developed by computing appropriate weights for each risk factor. The distribution of patients for each scale score reveal that with RFSS > or = 5, most device recipients will die (P < .001). The average RFSS (+/- SD) of survivors (n = 42) was 2.45 +/- 1.73 compared with 5.43 +/- 2.85 in nonsurvivors (n = 14) (P < .0001). Univariate logistical regression was also significant (score statistic, 16.2; df = 1; P = .001). CONCLUSIONS: The RFSS is simple, easy to apply, and statistically valid. Physicians could use the scale as a starting point in discussing the suitability for LVAD implantation in a specific patient and as a basis for comparing patient outcomes.

Adolescent↗
PubMed1995

Creation of a controlled venoarterial shunt. A surgical intervention for right-side circulatory failure.

BACKGROUND: Right-side circulatory failure (RSCF), a common complication of heart transplant and left ventricular assist device recipients, results in decreased cardiac output because of diminished flow across the pulmonary circuit. We hypothesized that creation of a controlled venoarterial shunt would result in decompression of the right ventricle and improved systemic cardiac output at tolerable oxygen saturations. METHODS AND RESULTS: A venoarterial shunt was created in a large-animal model (calf, n = 6). RSCF was induced by banding the pulmonary artery. Hemodynamic measures and blood gas determinations were obtained during nonshunted and shunted states. Pulmonary artery banding increased mean right ventricular systolic pressure from 44.9 +/- 2.1 mm Hg (mean +/- SEM) to 85.9 +/- 6.9 mm Hg (P < .05, paired t test) and decreased mean aortic flow from 7.8 +/- 1.0 to 4.2 +/- 1.1 L/min (P < .05). Flow through a venoarterial shunt at approximately 40% of cardiac output resulted in a decrease in right ventricular end-systolic pressure from 85.9 +/- 6.9 to 72.1 +/- 5.6 mm Hg (P < .01, ANOVA), a decrease in mean pulmonary artery pressure from 42.9 +/- 5.0 to 37.2 +/- 3.8 mm Hg (P < .01), and an increase in aortic flow from 4.2 +/- .05 to 5.1 L/min (P < .01). Left ventricular stroke work decreased from 2.22 +/- 0.28 to 1.55 +/- 0.88 (P < .05). Carotid artery oxygen saturation did not change significantly (99.9 +/- .02 to 97.6 +/- 1.7) during shunting. CONCLUSIONS: A controlled venoarterial shunt improved hemodynamics and cardiac output in a large animal model with RSCF. This strategy may be useful in the management of transplant and left ventricular assist device recipients with perioperative RSCF.

Animals↗
PubMed1995

Vacuolar H(+)-ATPase mutants transform cells and define a binding site for the papillomavirus E5 oncoprotein.

The 16K subunit of the vacuolar H(+)-ATPase binds specifically to the bovine (BPV) and human (HPV) papillomavirus E5 oncoproteins, and it has been suggested that this interaction may contribute to cell transformation (Goldstein, D. J., and Schlegel, R. (1990) EMBO J. 9, 137-146; Goldstein, D. J., Finbow, M. E., Andresson, T., McLean, P., Smith, K., Bubb, V. J., and Schlegel, R. (1991) Nature 352, 347-349; Conrad, M., Bubb, V. J., and Schlegel, R. (1993) J. Virol. 67, 6170-6178; Goldstein, D. J., Toyama, R., Schlegel, R., and Dhar, R. (1992) Virology 190, 889-893). We generated mutations within the 16K protein to define binding domains for BPV-1 E5 as well as to characterize the role of 16K in cell transformation. 16K consists predominantly of 4 transmembrane (TM) domains. We showed that mutations within the TM4 domain severely inhibited E5 binding. More specifically, conversion of glutamic acid 143 to arginine within TM4 severely reduced 16K/E5 binding, suggesting that charged interactions facilitated efficient binding. This hypothesis was confirmed by demonstrating that binding to the defective 16K arginine mutant could be restored by complementary charge mutations in E5; conversion of E5 glutamine 17 to glutamic acid or aspartic acid enhanced interactions with the 16K arginine mutant. Surprisingly, mutants in TM4 not only bound poorly to wild-type E5 but were converted into an oncoprotein and induced anchorage-independent growth of NIH 3T3 cells. These data define glutamic acid 143 in the 16K TM4 domain and glutamine 17 within E5 as important contributors to E5/16K binding and suggest a role for the 16K protein in the regulation of cell proliferation.

3T3 Cells↗
PubMed1995

Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success.

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.

Double-Blind Method↗
PubMed1995

Use of aprotinin in LVAD recipients reduces blood loss, blood use, and perioperative mortality.

Aprotinin, a bovine protease inhibitor, has been used extensively in patients undergoing cardiac surgical procedures in an effort to minimize blood loss and prevent the complications associated with blood replacement. We sought to evaluate the effect of aprotinin on postoperative blood loss, renal function, and the incidence of right ventricular failure in patients undergoing placement of a TCI Heartmate left ventricular assist device as a bridge to cardiac transplantation. Retrospective data analysis in 142 patients (42 receiving aprotinin and 100 untreated) demonstrated that the use of aprotinin was associated with a significant decrease in postoperative blood loss (p = 0.019) and in the intraoperative packed red blood cell transfusion (p = 0.019) and total blood product (p = 0.016) requirements. A transient, yet significant, increase in the postoperative creatinine level in the aprotinin group (p = 0.0006), but not in blood urea nitrogen level (p = 0.22), was noted. Interestingly, we noted an association between blood loss and the subsequent development of right ventricular failure; patients who required a right ventricular assist device bled significantly more than did those who did not suffer right ventricular failure (p = 0.02). Additionally, aprotinin recipients benefited by a reduction of nearly one half in the incidence of the need for a right ventricular assist device. The incidence of perioperative mortality was reduced in those receiving aprotinin compared with that in untreated patients, (p = 0.05). We conclude that aprotinin is safe and effective in decreasing postoperative blood loss and intraoperative blood product requirements, and in reducing perioperative mortality in patients undergoing left ventricular assist device placement as a bridge to cardiac transplantation.

Adult↗
PubMed1995

Radical excisional therapy and total cardiac transplantation for recurrent atrial myxoma.

We describe the management of a recurrent atrial myxoma extending to the pulmonary veins and superior vena cava. Deep hypothermia and circulatory arrest with left atrial and caval excision was required to achieve complete resection of the tumor. The patient is alive and well without evidence of tumor recurrence 18 months after transplantation. Radical en bloc cardiac resection is feasible in selected cases of cardiac tumors.

Echocardiography, Transesophageal↗
PubMed1995

Right-to-left veno-arterial shunting for right-sided circulatory failure.

BACKGROUND: Right-sided circulatory failure, a complication of heart transplantation and left ventricular assist device use, results in decreased cardiac output due to diminished flow across the pulmonary circuit. We hypothesized that creation of a controlled right-to-left shunt would result in decompression of the right ventricle and improved systemic cardiac output at tolerable oxygen saturations. We also hypothesized that a peripheral veno-arterial shunt is physiologically superior to a central shunt. METHODS: Right atrial-femoral artery and right atrial-left atrial shunts were created in a large animal model (calf). Right-sided circulatory failure was induced by banding the pulmonary artery. Hemodynamic measures and blood gas determinations were obtained during nonshunted and shunted states. RESULTS: Peripheral and central shunts resulted in decreased right-sided pressures and increased cardiac output. Arterial oxygen saturation remained greater than 90% during shunting. The peripheral shunt had the added advantage of decreasing left ventricular end-diastolic pressure and left ventricular stroke work. CONCLUSIONS: A controlled right-to-left shunt improved hemodynamics and cardiac output in a large animal model with right-sided circulatory failure. This strategy may be useful in the management of transplant and left ventricular assist device recipients with perioperative right-sided circulatory failure. Our studies also indicate that creation of a peripheral shunt has both physiologic and technical advantages over a central shunt.

Animals↗
PubMed1995

De novo solid malignancies after cardiac transplantation.

BACKGROUND: As long-term survival after cardiac transplantation improves, neoplastic complications are increasingly being discovered. Although lymphoproliferative disorders predominate, the incidence and clinical spectrum of solid tumors in a uniform population of heart transplant recipients remains uncertain. METHODS: We reviewed our experience with 712 patients who underwent cardiac transplantation. Clinical charts were reviewed and telephone interviews were conducted, when possible. RESULTS: De novo solid malignancies were identified in 3.3% of patients at risk (21 of 633 patients). Twenty patients were male; mean age was 51.5 +/- 8.6 years. Most patients reported a significant smoking history. Pulmonary, urologic, and Kaposi's sarcoma were the most common malignancies identified. Mean interval from transplantation to diagnosis was 35 months. Six patients were diagnosed within 6 months of transplantation. One-year and 5-year survival after transplantation were 90% and 49%, respectively. One-year and 3-year survival after cancer diagnosis were 60% and 52%, respectively. CONCLUSIONS: De novo solid malignancy after transplantation occurred with about half the frequency of lymphoproliferative disorders. A striking male predominance was noted. The interval from transplantation to the appearance of cancer is variable, and no clustering was identified. A significant smoking history warrants aggressive search for occult malignancy during pretransplantation evaluation of potential heart recipients.

Adolescent↗
PubMed1995

Safety and efficacy of aprotinin under conditions of deep hypothermia and circulatory arrest.

Aprotinin has been successfully used to reduce blood loss and blood product requirements in patients undergoing primary and reoperative cardiac operations. Its safety and efficacy during profound hypothermia and circulatory arrest have been questioned, however. A retrospective review compared 24 patients who received aprotinin during complex aortic procedures under profound hypothermia and circulatory arrest with 24 age-matched patients undergoing similar procedures without aprotinin. Activated clotting time was maintained at longer than 500 seconds (kaolin activating agent) or longer than 750 seconds (celite). We observed no statistically significant difference in the incidence of neurologic events (p not significant) or myocardial infarctions (p not significant), and there was a trend toward reduced in-hospital mortality rate in aprotinin-treated patients. A higher incidence of postoperative renal dysfunction was encountered in aprotinin-treated patients. Aprotinin recipients had a significant reduction in requirements for postoperative homologous erythrocytes (p = 0.01). We conclude that aprotinin may be safely and effectively used in patients undergoing deep hypothermia and circulatory arrest.

Aortic Dissection↗
PubMed1995

Noncardiac surgery in long-term implantable left ventricular assist-device recipients.

OBJECTIVE: The authors describe their experience with left ventricular assist-device (LVAD) recipients undergoing noncardiac surgery and delineate surgical, anesthetic, and logistic factors important in the successful intraoperative management of these patients. SUMMARY BACKGROUND DATA: Left ventricular assist-devices have become part of the armamentarium in the treatment of end-stage heart failure. As the numbers of patients chronically supported with long-term implantable devices grows, general surgical problems that are commonly seen in other hospitalized patients are becoming manifest. Of particular interest is the intraoperative management of patients undergoing elective noncardiac surgical procedures. METHODS: The anesthesia records and clinical charts were reviewed for eight ventricular assist-device recipients undergoing general surgical procedures between August 1, 1990 and August 31, 1994. RESULTS: A total of 12 procedures were performed in 6 men and 2 women averaging 52.7 years of age. Mean time elapsed from device implantation to operation was 68 +/- 35 days. Conventional inhalational and intravenous anesthetic techniques were well tolerated in these patients undergoing diverse surgical procedures. No perioperative mortality was observed. Five of eight patients went on to successful cardiac transplantation. CONCLUSIONS: Hemodynamic recovery after LVAD insertion has defined a new group of patients who develop noncardiac surgical problems often seen in other critically ill patients. Recognition of the unique potential problems that the LVAD recipient may encounter in the perioperative period--in particular patient positioning, device limitations, and fluid and inotropic management--will ensure an optimal surgical outcome for LVAD recipients undergoing noncardiac surgery.

Adult↗
PubMed1995

Effects of third trimester fluoxetine exposure on the newborn.

Prospectively identified fluoxetine-exposed pregnancies were evaluated to determine whether fluoxetine, a serotonin reuptake inhibitor commonly used for the treatment of depression and obsessive-compulsive disorder, might be associated with neonatal complications after maternal fluoxetine exposure during the third trimester through delivery. The outcomes of all prospectively identified, spontaneously reported pregnancies with confirmed fluoxetine exposure during the third trimester through delivery were evaluated. Postnatal complications unrelated to malformations were reported in 15 of the 112 identified pregnancies (115 infants), but there was neither a consistent or recurring pattern nor a dose relationship. On the basis of this survey and comparison with reported rates from the National Hospital Discharge Survey, it is unlikely that maternal fluoxetine use during the third trimester results in significant postnatal complications.

Abnormalities, Drug-Induced↗
PubMed1995

Preperitoneal placement of ventricular assist devices: an illustrated stepwise approach.

Improvement in left ventricular assist device (LVAD) implantation techniques may favorably impact on the significant perioperative morbidity and mortality that follows placement of these devices. Based on the difficulties faced and complications encountered during our 45 case experience, we developed a quick-reference illustrated guide which outlines in detail the steps and considerations critical for successful LVAD implantation.

Anastomosis, Surgical↗