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Biomedical subjects

D J Goldstein

Publications and source records attributed to D J Goldstein.

At least 19 recordsLinked to original sources
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

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

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

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↗
PubMed1995

Mutational analysis of the beta-type platelet-derived growth factor receptor defines the site of interaction with the bovine papillomavirus type 1 E5 transforming protein.

The E5 polypeptide of bovine papillomavirus type 1 is a small membrane-bound protein which induces the transformation of immortalized fibroblasts, apparently via the formation of a ternary complex with the platelet-derived growth factor receptor (PDGFR) and the 16-kDa V-ATPase protein. This interaction seems to be mediated, at least in part, by their respective transmembrane domains. E5 also cooperates with transfected beta PDGFR to induce interleukin-3 (IL-3)-independent growth of a mouse myeloid precursor cell line (32D) which normally lacks expression of most known tyrosine kinase growth factor receptors. Cell proliferation induced by beta PDGFR and E5 is also highly specific, since the highly conserved alpha PDGFR and other related receptors did not physically or functionally interact with E5 in these cells. In the current study, analysis of chimeric alpha and beta PDGFRs confirmed that a short region encompassing the beta PDGFR transmembrane domain was sufficient for complex formation with E5, receptor autophosphorylation, and sustained proliferation of 32D cells in the absence of IL-3. Furthermore, a deletion mutant lacking the entire extracellular domain efficiently bound E5 and induced IL-3-independent growth. These data provide direct evidence that the interaction between E5 and the beta PDGFR involves amino acids 531 to 556 of the receptor transmembrane region and that this specific interaction is critical for activation of the PDGFR signaling complex.

Animals↗
PubMed1995

Long-term fluoxetine treatment of bulimia nervosa. Fluoxetine Bulimia Nervosa Research Group.

BACKGROUND: A large collaborative 8-week study has shown fluoxetine to be effective and safe in treating patients with bulimia nervosa. The present study evaluated fluoxetine over 16 weeks. METHOD: Fifteen US out-patient psychiatry clinics conducted a double-blind parallel study in men and women with DSM-III-R bulimia nervosa (483 patients entered, 398 randomised [3:1 ratio, fluoxetine 60 mg/day or placebo], 225 completed). Outcome measures included change in vomiting and binge-eating episodes per week. Eating Disorder Inventory, Clinical Global Impressions and Patient's Global Impression. RESULTS: Compared with placebo, fluoxetine treatment resulted in significantly greater reductions in vomiting (F[1,360] = 14.73, P < 0.0001) and binge-eating (F[1,360] = 14.39, P = 0.0002) episodes per week at endpoint and improvement in other outcome measures. Adverse event, vital sign and laboratory analyses indicated that fluoxetine was safe. CONCLUSION: Fluoxetine appeared to be safe and effective in patients with bulimia nervosa for up to 16 weeks.

Adolescent↗
PubMed1995

Startle eyeblink elicitation in attention deficit disordered children using low-intensity acoustic stimuli.

The acoustic startle eyeblink response was measured in 11 pediatric psychiatric inpatients, 7 diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and 4 diagnosed with other conditions (non-ADHD). Startle stimuli were 85 or 95 dB SPL, 50-msec. noise pulses. Startle eyeblink responses were reliably measured for all children. Startle response latency was faster for ADHD children than for clinical control subjects in all stimulus conditions. These data show that the acoustic startle eyeblink response can be reliably elicited in ADHD children at lower intensities (85-95 dB) than those used in previous published research (104 dB). This may increase the use of the startle paradigm, since less intense stimuli may be less disturbing to the children, increasing compliance and allowing longer testing sessions.

Acoustic Stimulation↗
PubMed1995

Abnormalities of esterase and glycogen in developing macrophages in non-Hodgkin's lymphoma: a quantitative cytochemical study.

Integrating microdensitometry has been used to quantitate changes in 4 cytoplasmic enzymes (NADH dehydrogenase, succinate dehydrogenase, acid phosphatase and alpha-naphthyl butyrate esterase), DNA, RNA and glycogen in developing macrophages from 17 patients with non-Hodgkin's lymphoma and 19 normal subjects. Cytochemical measurements were made at intervals over 6 days of suspension culture; over 16 000 individual cells were examined in total and the results subjected to analysis of variance. While the levels of enzymes and RNA of both groups showed increases over the period of culture, the levels of alpha-naphthyl butyrate esterase in the patients' cells were consistently lower than the corresponding values for the normal cells and glycogen levels were higher, these differences satisfying the pre-determined requirements for statistical significance. It is concluded that (a) maturational changes take place in cytochemical constituents of developing macrophages of non-Hodgkin's lymphoma (b) there are disturbances affecting the amounts of the specific enzyme alpha-naphthyl butyrate esterase and glycogen (c) these abnormalities may be part of a compromise of host defense mechanisms by the disease, although a pre-existing defect in esterase increasing the susceptibility to malignancy is another possibility, and (d) the methods used may be of value in future investigations of the cause of the disturbances and their correction.

Acid Phosphatase↗
PubMed1995

Developmental expression of the nephritogenic antigen of monoclonal antibody 5-1-6.

The biogenesis of p51, the target of nephritogenic monoclonal antibody 5-1-6, was studied in the developing glomerulus by immunolocalization and metabolic labeling. The localization of p51 was compared with that of ZO-1, a component of the cytoplasmic face of the epithelial slit diaphragm, and with that of podocalyxin, and apical marker of the podocyte. p51 first became faintly, but clearly, detectable on the basal and lateral sides of the developing podocytes at the S-shaped body stage. Staining intensity increased with further maturation and was restricted to the visceral epithelial cells. On immunoelectron microscopy, the antigen was seen along the basal and lateral surfaces below occluding junction at the early capillary loop stage and later, with the interdigitation of foot processes, became concentrated in the slit pores. At no stage was p51 seen on the apical surface. p51 and ZO-1 were closely localized in the mature glomerulus but arrived at their final positions from opposite directions. p51 was on basal and podocalyxin was on apical sides of the glomerular epithelium from the S-shaped body stage onwards. Metabolic labeling studies showed that p51 is actively synthesized during initial glomerular development and that the rate of synthesis declines substantially with maturation. We conclude that p51 is primarily synthesized during the initial glomerular development, becomes concentrated in the slit pores of mature podocytes, and serves as a basal differentiation marker for podocytes.

Aging↗
PubMed1994

Long-term weight loss: the effect of pharmacologic agents.

We reviewed 20 English-language weight-reduction studies, reported between 1967 and March 1993, of the effect of > or = 6 mo of pharmacologic therapy on weight loss and its maintenance to determine the clinical benefits of extended treatment, propose treatment guidelines, and identify future research needs. Pharmacologic agents included phentermine, mazindol, fenfluramine, dexfenfluramine, and fluoxetine. Study designs varied with respect to blinding, use of a single agent vs a combination, dosing, length of therapy, patient selection, adjunctive therapy, and visit frequency. At endpoint, weight loss varied from study to study but a plateauing of weight loss or weight regain was observed after approximately 6 mo. The benefits of extended treatment appear to outweigh the risks for those patients who are unable to lose sufficient weight without pharmacologic therapy but who maintain adequate weight loss with long-term pharmacologic therapy. Future studies should define and evaluate pharmacologically responsive and unresponsive subgroups.

Appetite Depressants↗
PubMed1994

Evaluating success of weight loss programs, with an application to fluoxetine weight reduction clinical trial data.

We modified criteria for judging successful obesity treatment proposed by Atkinson to provide objective criteria for successful benefit from weight reduction programs with respect to data from a clinical trial. The criteria include assessments of changes in both weight-related factors (e.g. excess weight, excess body fat) and obesity-related risk factors (e.g. hypertension, hyperglycemia, hyperlipemia). To demonstrate the use of this methodology, we applied the criteria in an analysis of eight randomized, double-blind controlled trials comparing fluoxetine (n = 522) with placebo (n = 504) for weight loss. The results suggest these criteria can be useful for evaluating a treatment program or for comparing treatments from clinical trials.

Adolescent↗
PubMed1993

Increase in RNA and glycogen but not in DNA in developing human macrophages proven by integrating microdensitometry.

In order to quantitate DNA, RNA and glycogen contents of developing macrophages, blood monocytes were obtained from 19 healthy human subjects and examined after 0, 2, 4 and 6 days of suspension culture. Cytochemical staining was carried out by standard methods using Feulgen, cuprolinic blue and PAS. All specimens from all subjects were stained at the same time. Examination was carried out in an integrating microdensitometer, the staining intensities of individual cells being measured at appropriate wavelengths. Over the 6 days of culture, highly significant increases took place in RNA and glycogen, but no significant change was found in DNA content. These findings are taken to indicate that increased protein synthesis and the building up of fuel reserves are features of macrophage development but that S phase DNA replication does not occur.

Adult↗
PubMed1992

The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions.

The E5 oncoprotein of bovine papillomavirus type 1 is a 44 amino acid, highly hydrophobic protein that induces the stable transformation of immortalized murine fibroblasts, presumably through its activation of growth factor receptors. Previous studies have shown that the E5 protein complexes with the 16 kDa (16k) pore-forming protein of vacuolar H(+)-ATPases. This integral membrane protein is essential for the acidification and function of subcellular compartments that process growth factor receptors. Using an SV40 expression system in COS cells, we analyzed whether the E5-16k complexes bind additional cellular proteins, including growth factor receptors. These studies demonstrate that E5 binds to both the 16k protein and the PDGF receptor and that this tri-component complex can be isolated with antibodies specific for each protein. Importantly, the 16k protein bound to the PDGF receptor in the absence of E5, suggesting that E5 binds to the PDGF receptor via its interaction with the 16k protein. An E5 mutant lacking the hydrophilic carboxyl-terminal 14 amino acids retained binding to both 16k and the PDGF receptor, indicating that E5 binds to these proteins through its hydrophobic, membrane-associating domain. These studies reveal that hydrophobic, intramembrane interactions govern the association of E5, 16k and the PDGF receptor, suggesting a ligand-independent mechanism for receptor activation and a potential link between receptor signal transduction pathways and membrane pore activity.

Adenosine Triphosphatases↗