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Biomedical subjects

D Goldstein

Publications and source records attributed to D Goldstein.

At least 127 records · Page 7Linked to original sources
PubMed1996

Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells.

In 1321N1 astrocytoma cells, thrombin, but not carbachol, induces AP-1-mediated gene expression and DNA synthesis. To understand the divergent effects of these G protein-coupled receptor agonists on cellular responses, we examined Gq-dependent signaling events induced by thrombin receptor and muscarinic acetylcholine receptor stimulation. Thrombin and carbachol induce comparable changes in phosphoinositide and phosphatidylcholine hydrolysis, mobilization of intracellular Ca2+, diglyceride generation, and redistribution of protein kinase C; thus, activation of these Gq-signaling pathways appears to be insufficient for gene expression and mitogenesis. Thrombin increases Ras and mitogen-activated protein kinase activation to a greater extent than carbachol in 1321N1 cells. The effects of thrombin are not mediated through Gi, since ribosylation of Gi/Go proteins by pertussis toxin does not prevent thrombin-induced gene expression or thrombin-stimulated DNA synthesis. We recently reported that the pertussis toxin-insensitive G12 protein is required for thrombin-induced DNA synthesis. We demonstrate here, using transfection of receptors and G proteins in COS-7 cells, that G alpha 12 selectively couples the thrombin receptor to AP-1-mediated gene expression. This does not appear to result from increased mitogen-activated protein kinase activity but may reflect activation of a tyrosine kinase pathway. We suggest that preferential coupling of the thrombin receptor to G12 accounts for the selective ability of thrombin to stimulate Ras, mitogen-activated protein kinase, gene expression, and mitogenesis in 1321N1 cells.

Animals↗
PubMed1996

Phase I/II trial of filgrastim (r-metHuG-CSF), CEOP chemotherapy and antiretroviral therapy in HIV-related non-Hodgkin's lymphoma.

BACKGROUND: A phase I/II trial determined the maximum tolerated dose (MTD) of CEOP for AIDS-related non-Hodgkin's lymphoma (NHL) with concurrent filgrastim and antiretroviral therapy. PATIENTS AND METHODS: Fourteen AIDS-NHL patients, chemotherapy naïve and ECOG performance status < 2 received filgrastim 1.0 microgram/kg s.c. daily for 3-7 days to assess neutrophil response, followed by CEOP with filgrastim support 10 micrograms/kg s.c. daily, day 2-14, continued if the absolute neutrophil count (ANC) < 1.2 x 10(9)/l. Two CEOP dose cohorts were used: cohort 1 (5 patients) - cyclophosphamide (C) 500 mg/m2, epirubicin (E) 37.5 mg/m2, vincristine (O) 2 mg and prednisolone (P) 75 mg/m2 daily on days 1-5; cohort 2 (9 patients) - C 750 mg/m2, E 50 mg/m2, same doses of O and P. Antiretroviral therapy was maintained (zidovudine-10, ddI-3, both-1). RESULTS: In cohort 1, 4/5 patients received at least 3 courses of CEOP with one complete response after five cycles and four progressions. Four have died (3-21 months after entry) with 1 alive at 40 months. Dose limiting toxicity (DLT - grade IV febrile neutropenia in cycle 1) occurred in 1 patient. In cohort 2, 5/9 completed > or = 5 cycles with 6 complete responses, 1 partial response and 2 progressions, 6 deaths and 3 alive at > 33 months. DLT (evaluable in 8 patients) occurred in two patients. Median survival for both cohorts was 17 months. Mean relative dose intensity was > 85%. CONCLUSIONS: The dosages of CEOP in cohort 1 defined the MTD however, the cohort 2 doses with filgrastim and antiretroviral therapy gave an encouraging response, acceptable toxicities and merit further study.

Adult↗
PubMed1996

Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

Adult↗
PubMed1996

Report of the American Diabetes Association's Task Force on standardization of the insulin assay.

Recent large-scale epidemiological studies demonstrate that blood concentrations of immunoreactive insulin predict the development of NIDDM and IDDM and are associated with the risk of several degenerative diseases, such as coronary and peripheral vessel atherosclerosis, hypertension, and dyslipidemia. The reliability of these measurements is dependent on a biological assay that has not been well standardized between laboratories. Recognizing this, the American Diabetes Association organized a task force to assess comparability of blood insulin measurements between laboratories and to suggest techniques to improve comparability. The task force found that identical serum and plasma samples measured in different laboratories produced widely disparate values that were unacceptable for population comparisons. Use of a single reference standard did little to improve comparability. Assay characteristics such as linearity, recovery, accuracy, and cross-reactivity to proinsulin and its primary conversion intermediates varied among the laboratories, and they did not readily explain differences in the measurements made from assay to assay. Use of the same assay kit in different laboratories did not always ensure comparable measurements. Linear regression of assay results from one laboratory to an arbitrarily chosen reference assay greatly improved comparability and demonstrated the potential value in comparing each assay to a reference method. The task force report defines acceptable assay characteristics and proposes a three-step process of insulin assay proficiency and comparability. A central reference assay and ongoing sample exchange will be needed to allow reliable comparisons of insulin measurements made in different laboratories. Rigorous quality control and continuous quality improvement are needed to maintain reliability of the insulin measurement.

Diabetes Mellitus↗
PubMed1996

[Stratification of the thromboembolic risk in patients with non-rheumatic atrial fibrillation: assessment of left atrial dysfunction].

BACKGROUND: Patients with non rheumatic atrial fibrillation (NRAF) have an increased risk for thromboembolic complications. Recent evidence suggests that left atrial appendage function (contraction, filling dynamics) may provide clues to the thrombogenic potential of this structure. The aim of this study was to identify left atrial spontaneous echocontrast and thrombus between patients with NRAF and their relationship with left atrial appendage function. METHODS: Transthoracic (TTE) and biplane or multiplane transesophageal echocardiography (TEE) were performed in 143 patients with chronic NRAF enrolled in the Trieste Area Study on non rheumatic Atrial Fibrillation (TASAF), an ongoing prospective community study with a follow-up period of 2 years. The maximal and minimal areas of the left atrial appendage were measured during three cardiac cycles and the peak emptying and filling velocities profile were obtained by pulsed wave Doppler at the orifice of the left atrial appendage. The left atrium and appendage were inspected for thrombus and spontaneous echocontrast. RESULTS: Left atrial appendage thrombus was present in 37 patients (26%) and spontaneous echocontrast in 60 patients (42%), 45% of patients with spontaneous echocontrast had thrombus. Univariate analysis identified positive correlation of thrombus with duration of atrial fibrillation (p = 0.05), hypertension (p = 0.01), left atrial area (p = 0.005), mitral annular calcification (p = 0.01), left ventricular dysfunction (p = 0.03) and a non significant correlation with the mitral valve prolapse (p = 0.08) in the TTE. The presence of mitral regurgitation did not demonstrate a protective effect (p = 0.73) against thrombosis. The variables of left atrial appendage function identifying a subgroup of patients with increased risk of thrombus formation were: shortening fraction of the area in the horizontal and vertical sections (p = 0.0001 and p = 0.002 respectively), the peak filling and emptying velocity in horizontal (p = 0.0001 equal for both) and vertical sections (p = 0.0001 equal for both). In summary these patients have a larger left atrial maximal area (p = 0.004) and a lower flow velocity profile (p < 0.00001) and more intense spontaneous echocontrast (p < 0.00001) than the others. Spontaneous echocontrast was correlated with left ventricular dysfunction (p = 0.008), left atrial area (p = 0.02) and there was a non-significant correlation with mitral annular calcification (p = 0.09) and lower left ventricular shortening fraction (p = 0.06). Transesophageal echocardiography variables have identified the subgroup of patients with an increased risk of echocontrast formation. This was positively associated with a low flow velocity profile (p = 0.0001), a left atrial appendage low shortening fraction in horizontal section (p = 0.001) and in vertical section (p = 0.05) and a low peak filling velocity in horizontal section (p = 0.003) and in vertical section (p = 0.004) and a low peak emptying velocity in horizontal section (p = 0.003) and in vertical section (p = 0.001). Prophylactic therapy with anticoagulant or antiplatelet agents has little benefits in our experience. CONCLUSIONS: Spontaneous echocontrast and low flow profile velocity (low peak emptying and filling velocity) and increased area of left atrial appendage were strongly associated with left atrial and/or appendage thrombus in patients with NRAF. The assessment of left atrial appendage function by TEE is an important component of the comprehensive evaluation of potentially increased risk of thrombus formation.

Aged↗
PubMed1995

Bacillus Calmette-Guerin (BCG) enhances monocyte- and lymphocyte-mediated bladder tumour cell killing.

A cytotoxicity assay was used to study the action of bacillus Calmette-Guerin (BCG) and cytokines on four human bladder cancer cell lines. Monocytes and lymphocytes from peripheral blood were incubated with or without BCG or cytokines for 24 h, after which [3H]thymidine-labelled target cells were added and the 72 h percentage specific release determined. BCG had a direct cytotoxic effect against tumour cells and significantly enhanced monocyte/macrophage and enhanced lymphocyte cytotoxicity against one cell line (UCRU-BL-17). Supernatants (SNs) from BCG-activated monocytes/macrophages and lymphocytes increased the percentage specific release of [3H]thymidine from UCRU-BL-17 cells. Interferon alpha (IFN-alpha) and interleukin 2 (IL-2) were cytotoxic towards UCRU-BL-17. No synergy occurred between BCG and cytokines at the concentrations tested. The results suggest that BCG is superior to IFN-alpha, interferon gamma (IFN-gamma) and IL-2 in enhancing cell-mediated cytotoxicity.

Carcinoma, Transitional Cell↗
PubMed1995

Metastatic carcinoma infiltrating lung mimicking BOOP.

A 38 year old female with treated carcinoma of the breast presented with a clinical and radiological diagnosis of bronchiolitis obliterans organising pneumonia. Based on these findings a biopsy was not performed and she was treated with steroids. Following lack of response to steroid therapy a lung biopsy was performed showing peribronchiolar, lymphatic, venular and arteriolar metastatic carcinoma. Her symptoms responded to chemotherapy. Interstitial and intracellular spread of carcinoma should be considered in the differential diagnosis of the radiological appearance of BOOP, and therefore a histological diagnosis should be obtained to determine appropriate management.

Adult↗
PubMed1995

Effect of 17-beta-estradiol on the healing of tibial bone after marrow ablation.

The present study has been undertaken to demonstrate the effect of 17 beta-estradiol on the healing of tibial bones after marrow ablation. Ninety-six 4-month-old female rats were divided into three experimental groups: group 1 was subjected to ablation in both tibiae and to injection of vehicle; group 2 to ablation in both tibiae and estradiol administration, and group 3 to estradiol administration without ablation. Before the rats were killed, all on the same day, 8 animals of each group underwent treatment for 3, 6, 14 and 21 days, respectively: every second day, 0.1 ml arachis oil was injected intramuscularly into group 1 and 17 beta-estradiol into groups 2 and 3. An additional 8 untreated animals were used as controls. Tibial bones were studied chemically and morphologically. While the control and ablated animals gained weight, there was a significant decrease in the gain in body weight of estradiol-treated rats. Bone and ash weight were increased in all experimental groups. The ratios (%) of tibial ash weight and of tibial Ca and Mg contents to body weight significantly increased in all experimental groups, compared to the controls; whereas P increased only at 6 and 14 days. As shown by computerized histomorphometry, the height of the proximal tibial growth plate was increased following ablation, but not with estradiol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Moving beyond generic integration models.

Rigid adherence to generic models of integration often fails because healthcare executives and physicians have not laid a proper foundation for integration. A series of building blocks must be in place before an integrated delivery system can be properly implemented. These building blocks are essential for management of integrated systems so physicians, executives, and managers can respond effectively to the needs of purchasers and patients.

Continuity of Patient Care↗
PubMed1995

[SFAAT: the study of nonrheumatic chronic atrial fibrillation in the Trieste area. Results of an enrollment study].

BACKGROUND: Chronic atrial fibrillation unassociated with rheumatic valvular heart disease (NRAF) considerably increases the risk of thromboembolism. Recent studies have provided new evidence concerning the risk-benefit ratio of anticoagulant therapies in patients with AF. OBJECTIVE: To evaluate the incidence of primary end points (ischemic stroke, systemic embolism, bleeding complications to oral anticoagulant or antiplatelet therapy) and secondary end points (death, TIA) in patients with NRAF. METHODS AND RESULTS: Between November 1992 and June 1993, 694 patients with chronic NRAF were enrolled in the Trieste Area Study on Nonrheumatic Atrial Fibrillation (TASAF), an ongoing prospective community study with a follow-up period of 2 years. The preliminary results of the enrolled study population show: an elevated mean age (71 +/- 9 years), the prevalence of males (383/694), high prevalence of overt or previous heart failure (23%), of mitral regurgitation confirmed at echocardiography (30%) and of previous myocardial infarction (11%). Many of the enrolled patients had a history of hypertension (58%). With regard to the etiology of the underlying heart disease, the following should be emphasized: a high incidence of cardiac hypertrophy (with or without history of hypertension) (28%) and of degenerative cardiopathy (20%); unclassifiable cardiopathy (14%); and lone AF (13%). Echocardiographic findings: left ventricular dysfunction (17%); mitral annular calcification (27%); and good mean left ventricular function (EF 0.50 +/- 0.15). Retrospectively there were 96 clinically documented embolic events in 78 subjects while in 34 patients there were 38 episodes suspected for embolism or TIA. Nine patients suffered 1 recurrence of embolism; three patients suffered 2 recurrences; one patient had 3 recurrences; and 4 patients had one suspected recurrence of TIA. In 35 cases the embolic events clustered around the time of the onset of the arrhythmia. In the other 99 subjects the embolic complication appeared after the onset of AF: range 1-266 months. The group of patients with true embolic events in comparison with patients without embolism or with suspected embolism or TIA had same variables predictive of thromboembolic complications: arrhythmia duration (p = 0.09) and previous myocardial infarction (p = 0.03); in contrast mitral annular calcification (p = 0.06), history of hypertension (p = 0.09) and cardiac hypertrophy (with or without hypertension) (p = 0.07) demonstrated only a slight trend of statistical significance. Comparing the clinical characteristics and echocardiographic findings of patients without embolism with those of patients with tru embolism, or suspected embolism, or TIA the variables predictive of thromboembolic events were: arrhythmia duration (p = 0.007), history of hypertension (p = 0.01), cardiac hypertrophy (with or without hypertension (p = 0.02) and mitral annular calcification (p = 0.01), at the same time, age showed only a trend of statistical significance (p = 0.06). Among the 616 patients without a history of embolism only 3% were treated with oral anticoagulant agents and 28% with antiplatelet therapy, while among the 78 subjects with documented embolism only 28% were receiving anticoagulant therapy and 58% were receiving antiplatelet agents. CONCLUSIONS: NRAF is an important risk factor for thromboembolism. Some clinical characteristics and echocardiographic findings increase the risk. Physicians still hesitate to use oral anticoagulants and antiplatelet agents in their patients for the prevention of embolic complications.

Aged↗
PubMed1994

The E5 protein of HPV-6, but not HPV-16, associates efficiently with cellular growth factor receptors.

The transforming activity of the prototype E5 protein of bovine papillomavirus type 1 (BPV-1) is associated with its binding to, and activation of, both the platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors. The E5 proteins of human papillomavirus types 6 and 16 (HPV-6, HPV-16) also transform rodent cells in the presence of the EGF receptor. In this study we examined whether epitope-tagged HPV E5 proteins could associate with three different tyrosine kinase-containing growth factor receptors: the EGF receptor, the erbB2 receptor, and the PDGF receptor. The HPV-6 E5 protein was found to associate efficiently with all three of these growth factor receptors, while the HPV-16 E5 protein did not. These findings suggest either that the in vitro transforming activities of HPV-6 and HPV-16 E5 proteins involve a similar mechanism unrelated to receptor binding (e.g., binding to the 16-kDa membrane pore protein) or that they proceed along distinct pathways, with receptor binding being important for HPV-6. Regardless of the ultimate mechanisms, the differences between the HPV-6 and HPV-16 E5 proteins in binding to growth factor receptors may potentially contribute to the distinctive morphologies of their respective neoplastic lesions.

ErbB Receptors↗
PubMed1994

Expression of multiple isoforms of protein kinase C in normal human colon mucosa and colon tumors and decreased levels of protein kinase C beta and eta mRNAs in the tumors.

Previous studies have suggested that protein kinase C (PKC) may play an important role in colon carcinogenesis and that human colon tumors have less total PKC enzyme activity than normal tissue. Because PKC is a multigene family that encodes for at least 11 distinct isoforms, in the study reported here we analyzed the expression of six of these isoforms at the mRNA level by northern blot hybridization in 22 pairs of primary colon tumors (of various stages), and adjacent normal mucosa samples. We found that the normal mucosa samples expressed the mRNAs of the following isoforms of PKC, in decreasing order of abundance: PKC delta > PKC eta > PKC alpha > PKC beta > PKC epsilon. There was no consistent difference in the levels of PKC alpha, PKC delta, and PKC epsilon mRNAs between the normal mucosa and the tumor samples. PKC gamma was expressed at a very low level in two of the colon tumors but could not be detected in the remaining tumors or any of the normal mucosa samples. The levels of both PKC beta and PKC eta mRNAs were significantly lower in the tumor samples than in the normal mucosa samples, and this was true of adenomas as well as Dukes' stage A, B, and C adenocarcinomas. Furthermore, the decrease in PKC eta mRNA appeared to be greater in the more poorly differentiated carcinomas. This finding is of interest because PKC eta is normally expressed in the more differentiated cells of epithelial tissues. The decreased levels of both PKC beta and PKC eta mRNAs occurred early in the multistage process of colon carcinogenesis, as it was also seen in adenomas. The functional significance of these changes remains to be determined.

Adenoma↗
PubMed1994

Effects of two formats of informed consent on knowledge amongst persons with advanced HIV disease in a clinical trial of didanosine.

To determine subjects' perception of the purpose of informed consent, 113 subjects were recruited from a dose-controlled clinical trial of didanosine (ddI). Subjects were surveyed regarding how they made decisions regarding their medical care in general, about how they obtained information about this trial in particular, and several aspects of the informed consent procedure. Subjects were then randomly allocated to receive information about the trial by either a written only format or a written and verbal format 1 week before commencement of the trial. An eight-item instrument assessed knowledge of ddI prior to and subsequent to receiving information. Most subjects obtained information about HIV-related issues from their specialist (70%) or general (51%) medical practitioner. A large proportion of subjects (88%) reported that they believed their specialist medical practitioner always acted in their best interest. The majority of subjects (79%) believed that subjects should be allowed the choice between participating in the clinical trial and receiving the drug outside the trial mechanism. Of the subjects, 96% believed that informed consent was necessary in clinical trials; however, their opinions of the purpose of informed consent varied widely. Although they signed the informed consent, 44% of the subjects stated that they did not understand 'all' of the information that was provided. We found that the provision of information by written mode alone, or written and verbal modes were both associated with significant increases in knowledge levels and that there was a significant interaction in the degree of change between the two methods, with the written plus verbal method showing the most improvement over time. There was an interaction between degree of improvement in knowledge of didanosine in subjects who received written information versus those who received written and verbal knowledge and time (pre- versus post-consent) and a significant main effect for time. All subjects were relatively well-informed about the drug and stated that specialist and general medical practitioners were their major source of knowledge for all aspects of their HIV health care.

Adult↗