Biomedical subjects
D Feldman
Publications and source records attributed to D Feldman.
MedEthEx Online: a computer-based learning program in medical ethics and communication skills.
BACKGROUND: Bioethics education often focuses on lectures and discussions to set a foundation for ethical decision making. Our goal was to bridge the gap between classroom learning and bedside competence through computer-assisted instruction. This article assesses the efficacy of MedEthEx Online, a computer-based learning program as part of a required Bioethics course. DESCRIPTION: Of 173 American medical students, 89 in Section 1 attended 8 bioethics lectures and 8 small-group discussions. Eighty-four in Section 2 had a similar course, although two group discussions were replaced with computerized learning. We compared (a) final exam scores, (b) topic-specific question scores, (c) performance with standardized patients, (d) self-assessments, and (e) course evaluations. EVALUATION: Exam scores were comparable, although computerized-learning students scored higher in specific exam areas, felt somewhat more clinically prepared, and rated the course slightly better. Standardized patient interactions differed, although they were comparable overall. CONCLUSION: MedEthEx Online is a viable option for fostering effective communication and problem resolution skills.
Vitamin D and prostate cancer.
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1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms.
We recently reported that 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits the growth of the LNCaP human prostate cancer cell line by an androgen-dependent mechanism. In the present study we examined the actions and interactions of 1,25-(OH)2D3 and the androgen 5alpha-dihydrotestosterone (DHT) on two new human prostate cancer cell lines (MDA), MDA PCa 2a and MDA PCa 2b. Scatchard analyses revealed that both cell lines express high affinity vitamin D receptors (VDRs) with a binding affinity (Kd) for [3H]1,25-(OH)2D3 of 0.1 nM. However, the MDA cell lines contain low affinity androgen receptors (ARs) with a Kd of 25 nM for [3H]DHT binding. This is 50-fold lower than the AR in LNCaP cells (Kd = 0.5 nM). Their response to DHT is greatly reduced; 2a cells do not respond to 100 nM DHT, and 2b cells show a modest response at that high concentration. 1,25-(OH)2D3 causes significant growth inhibition in both MDA cell lines, greater (for 2b cells) or lesser (for 2a cells) than that in the LNCaP cell line. Moreover, 1,25-(OH)2D3 significantly up-regulates AR messenger RNA in all three cell lines, as shown by Northern blot analysis. The growth inhibitory effect of 1,25-(OH)2D3 on LNCaP cells is blocked by the pure antiandrogen, Casodex, as we previously reported. However, Casodex (at 1 microM) did not block the antiproliferative activity of 1,25-(OH)2D3 in MDA cells. In conclusion, the growth inhibitory action of 1,25-(OH)2D3 in the MDA cell lines appears to be androgen independent, whereas the actions of 1,25-(OH)2D3 in LNCaP cells are androgen dependent. Most importantly, the MDA cell lines, derived from a bone metastasis of human prostate carcinoma, remain sensitive to 1,25-(OH)2D3, a finding relevant to the therapeutic application of vitamin D and its low calcemic analogs in the treatment of advanced prostate cancer.
Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children.
Nutritional rickets is common in Nigeria where vitamin D deficiency is rare and dietary insufficiency of calcium is common. It occurs more commonly in siblings of affected children than of unaffected children. Postulating that vitamin D receptor (VDR) polymorphisms might relate to the susceptibility of some Nigerian children to develop rickets in the setting of low calcium intake, we compared the VDR genotypes, as determined by the presence or absence of Bsm I, Apa I, Taq I, and Fok I restriction enzyme cleavage sites, between 105 children with active nutritional rickets and 94 subjects representative of the community from which the rachitic children came. In the rickets group, the ff genotype was less common than in the community group, and the FF genotype was relatively increased (f allele frequency, 17% in rachitic children and 26% in the community group, p = 0.03). Neither individual allele frequencies for the other polymorphisms nor combinations of genotypes at different sites were different between the rachitic and community groups. Although it is not clear why a presumed better-functioning VDR variant (F allele) is associated with an increased risk of developing rickets, this study raises the possibility that VDR alleles might be important in determining an individual's susceptibility to developing rickets when faced with dietary calcium deficiency.
Subcutaneous hydration by hypodermoclysis. A practical and low cost treatment for elderly patients.
As the world's population ages, chronic and degenerative diseases are rising. This scenario demands the development of new treatment techniques with lower costs, which are as efficient as the existing ones. Hypodermoclysis is the infusion of fluids into the subcutaneous tissue with a butterfly needle. This technique may be used for isotonic fluid replacement and to administer cytosine arabinoside, clodronate, antibiotics and narcotic analgesics. This review evaluates the evidence supporting the use of hypodermoclysis to treat elderly patients with dehydration and patients with terminal cancer, and discusses its indications, adverse effects and perspectives. A MEDLINE search of the last 30 years was done to recover all available literature. Hypodermoclysis therapy is a safe and effective method to provide fluids and narcotic analgesic therapy in elderly patients that are mild and moderate dehydrated and in patients with cancer. It seems a good option to provide antibiotics, but there is a need for more studies to evaluate this indication.
1alpha,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells.
1alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D, is a potent inhibitor of breast cancer cell growth. Because the estrogen receptor (ER) plays a key role in breast cancer progression, we have studied the effects of 1,25(OH)2D3 on the regulation of ER in the estrogen-responsive MCF-7 human breast cancer cell line, which is known to predominantly express ERalpha. 1,25(OH)2D3 causes significant inhibition of MCF-7 cell growth, and it also decreases the growth-stimulatory effect of 17beta-estradiol (E2). Treatment of MCF-7 cells with 1,25(OH)2D3 reduces ER levels in a dose-dependent manner, as shown by ligand binding assays and Western blot analysis. The 1,25(OH)2D3 analogues EB-1089, KH-1060, Ro 27-0574, and Ro 23-7553 are more potent than 1,25(OH)2D3 in both their antiproliferative actions as well as ER down-regulation. There is a striking correlation (R2 = 0.98) between the growth-inhibitory actions of 1,25(OH)2D3 or analogues and their ability to down-regulate ER levels. Treatment with 1,25(OH)2D3 shows that the reduction in ER is accompanied by a significant decrease in the steady-state levels of ER mRNA. The decrease in ER mRNA is not abolished by the protein synthesis inhibitor cycloheximide. Inhibition of mRNA synthesis with actinomycin D reveals no significant differences between ER mRNA half-life in control and 1,25(OH)2D3-treated cells. Nuclear run-on experiments demonstrate significant decreases in ER gene transcription at the end of 17 h of treatment with 1,25(OH)2D3. These findings indicate that 1,25(OH)2D3 exerts a direct negative effect on ER gene transcription. Coincident with the decrease in ER levels there is an attenuation of E2-mediated bioresponses after 1,25(OH)2D3 treatment. Induction of progesterone receptor by E2 is suppressed by 1,25(OH)2D3, and the E2-mediated increase in breast cancer susceptibility gene (BRCA1) protein is reduced by 1,25(OH)2D3 treatment. Overall, these results suggest that the antiproliferative effects of 1,25(OH)2D3 and its analogues on MCF-7 cells could partially be mediated through their action to down-regulate ER levels and thereby attenuate estrogenic bioresponses, including breast cancer cell growth.
PPARgamma agonists enhance human vascular endothelial adhesiveness by increasing ICAM-1 expression.
Early atherosclerotic lesions are characterized by increased monocyte adhesion to the overlying endothelium. Oxidized LDL (oxLDL) stimulates the adhesion of human monocytes to endothelial cells, in part, by increasing expression of ICAM-1. However, the cellular role of oxLDL in endothelial adhesiveness is not well understood. The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is expressed in vascular endothelial cells. Whether it can be activated by a synthetic ligand, troglitazone, as well as by natural ligands, oxLDL and its lipid components (i.e., 9- and 13-HODE), has not yet been explored. This study was undertaken to determine whether PPARgamma is expressed in ECV304 human vascular endothelial cells and if so to define the biological effects of its activation by these agonists. Our results demonstrate that PPARgamma mRNA is expressed in ECV304 cells, and transfected cells with a PPARE luciferase construct respond to these agonists. In addition, ligand-dependent PPARgamma activation increased ICAM-1 protein expression and enhanced adherence of monocytes to ECV304 cells by two- to threefold. These findings suggest that the PPARgamma signaling pathway might contribute to the atherogenicity of oxLDL in vascular endothelial cells.
Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an increased biosynthesis in the pravastatin-treated rat.
An increase of biliary lipid secretion is known to occur in the rat under sustained administration of statin-type 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors. The present study has addressed critical mechanisms of hepatic lipid synthesis and phosphatidylcholine (PC) biliary transport in the rat fed with a 0.075% pravastatin diet for 3 weeks. After treatment, biliary secretion of PC and cholesterol increased to 233% and 249% of controls, while that of bile salts was unchanged. Activity of cytidylyltransferase (CT), a major regulatory enzyme in the CDP-choline pathway of PC synthesis, was raised in both microsomal and cytosolic fractions (226% and 150% of controls), and there was an increase to 187% in the mass of active enzyme as determined by Western blot of microsomal protein using an antibody specific to CT. Cytosolic activity of choline kinase, another enzyme of the CDP-choline pathway, also increased to 175% of controls. In addition, there was an over eightfold increase in the HMG CoA reductase activity and mRNA. Thus, an increased PC and cholesterol synthetic supply to hepatocytes appeared as a basic mechanism for the biliary hypersecretion of these lipids. Notwithstanding the increased synthesis, hepatic PC content was unchanged, suggesting an enhanced transfer of this lipid into bile. Indeed, there was a sevenfold increase of multidrug resistance gene 2 (mdr2) gene mRNA coding for a main PC canalicular translocase. Thus, hypersecretion of biliary PC in the model studied can be explained by an up-regulation of mdr2 gene transcription and its P-glycoprotein product mediating the biliary transfer of PC supplied by an increased biosynthesis.
Fluorescence in situ hybridization study of HER-2/neu oncogene amplification in prostate cancer.
Prostate cancer is a serious disease affecting men worldwide and treatment compromises the quality of life of prostate cancer patients. We conducted a study of 88 cases of prostate cancer in an attempt to identify prognostic biomarkers that can distinguish aggressive cases that must be treated immediately. HER-2/neu oncogene amplification was initially studied because amplification of this gene has been reported in many other cancers, including those studied in this laboratory. Fluorescence in situ hybridization (FISH) using a HER-2/neu gene probe with a chromosome 17 centromere control probe was performed on formalin-fixed, paraffin-embedded tissues. Of a total of 86 cases successfully analyzed, only 8 (9.3%) were found to be amplified. This frequency was lower than the frequency of amplification found in other cancers studied. Furthermore, no case was found where the level of amplification can be considered high. Only one case was found to have moderate amplification. The rest of the positive cases can all be classified as low amplification. Thus, while we have demonstrated that FISH is a sensitive technique for detecting oncogene amplification, the frequency and level of HER-2/neu amplification detected in prostate cancer seem to be lower than those in most cancers that we studied. In view of the fact that HER-2/neu amplification does not seem to play as significant a role, exploration of other biomarkers in prostate cancer is warranted.
Assessment of chromosome 8 copy number in cervical cancer by fluorescent in situ hybridization.
Cervical carcinoma is a malignancy which typically occurs at the transformation zone between squamous and glandular epithelium. The vast majority falls into two histologic types, squamous cell and adenocarcinoma. In an effort to identify a subset of cervical cancer characterized by chromosome 8 trisomy, a biomarker extensively explored by this laboratory, we conducted a study of formalin-fixed, paraffin-embedded materials of cervical cancer. A total of 24 cases of cervical cancer were identified from the archives of the Rhode Island Hospital. Fluorescent in situ hybridization (FISH) using a chromosome 8 centromere enumeration probe was conducted to assess the chromosome 8 copy number in these specimens. Hybridization signals were scored among tumor cells in a blinded fashion. Tumors with >/=15% of cells with three signals were scored as trisomic. Of 24 cases studied, 23 were informative. Of the 23 informative cases, 12 (52.2%) were found to be trisomic. Eleven cases (47.8%) were disomic. The frequency of trisomy in a control chromosome 17 probe was 13.0% (3/23). Selected clinicopathologic characteristics of the tumors were also reviewed. The frequency of trisomy 8 among cases of invasive squamous cell carcinoma was 44.4% (8 of 18 tumors) and that of invasive adenocarcinoma was 80% (4 of 5 tumors). The sole tumor which was both trisomic 8 and amplified for the HER-2/neu oncogene was found to be an invasive adenocarcinoma. While the sample size in this pilot study is not large, the data obtained thus far clearly demonstrate that FISH is an appropriate technique for detecting chromosomal trisomies and that a subset of cervical cancer exists that is characterized by chromosome 8 trisomy. Further exploration of this biomarker is warranted.
Assessment of chromosomal trisomies in prostate cancer using fluorescent in situ hybridization.
In a previous study, we observed a low frequency of HER-2/neu oncogene amplification in prostate cancer using fluorescent in situ hybridization (FISH). In our continued effort to identify prognostic biomarkers in prostate cancer, we analyzed 74 cases of prostate cancer to assess the presence of chromosomal trisomies in this cohort of patients. Previous results from this laboratory have implicated a role of chromosomal trisomies in various cancers. FISH using a chromosome 7 and a chromosome 8 centromere probe was utilized to study abnormal chromosome copy numbers together with data from a chromosome 17 control. The frequency of trisomy 7 was found to be 58.1% (43 of 74 informative cases), while the frequency of trisomy 8 was found to be 9.5% (7 of 74 informative cases). The frequency of cells showing chromosome 17 trisomy was 18.5% (15 of 81 cases successfully studied). While chromosome 8 trisomy did not seem to play as significant a role here as in other cancers that we studied, the results of chromosome 7 trisomy are consistent with those reported in the literature. Further exploration of selected trisomies as biomarkers in prostate cancer using a larger study sample size is warranted to establish their clinical utilities.
Correlates of a perceived need for mental health assistance and differences between those who do and do not seek help.
BACKGROUND: This study examined prevalence of perceived need for mental health assistance, characteristics of people with a perceived need, and how persons with a need who sought help were different from those who did not. METHODS: A national random phone survey (n = 1,394) was conducted in Israel, which included questions about (1) perceived need for mental health assistance and (2) help seeking. RESULTS: Prevalence of life-time and recent perceived need for males was 21% and 10.7%, and for females 31% and 15.1%. Of those with a perceived need, 31.4% of males and 41.6% of females had gone for help. Based on logistic regression models, the variables associated with need were being female, divorced, having a chronic physical disease, and low income (for males only), while predictors of help seeking were living in a big city and not being a recent immigrant. The major sources of help in descending order were: mental health professionals (46%), family physician (25%), family or friends (19%), and other (10%). CONCLUSIONS: A majority of people who feel that they need help for mental health problems do not get help.
Effects of platelet glycoprotein IIb/IIIa inhibition with abciximab on thrombin generation and activity during percutaneous coronary intervention.
BACKGROUND: Antagonists of the platelet glycoprotein IIb/IIIa decrease acute ischemic complications after percutaneous coronary interventions (PCI). Abciximab (c7E3 Fab, ReoPro) has been reported to decrease thrombin generation in vitro. We investigated in vivo the effect of abciximab therapy on thrombin generation, thrombin activity, and the activated clotting time (ACT) during PCI. METHODS: We studied 32 consecutive patients who underwent PCI for unstable coronary syndromes. Group I (n = 11) was treated with heparin plus aspirin, and group II (n = 21) was treated with heparin plus aspirin plus standard-dose abciximab, administered 5 minutes after the initial heparin bolus. Patients received a standardized heparin bolus at time 0, and arterial blood specimens for prothrombin fragment F1.2, fibrinopeptide A (FPA), and ACT were obtained from the guiding catheter at 5 minutes, 10 minutes (ACT only), 20 minutes, and at the end of the PCI. Standard-dose abciximab was administered in group II only. Each patient served as his or her own control, and the changes against the baseline were compared between the 2 groups. RESULTS: There were no significant differences between the 2 groups regarding baseline characteristics, hematocrit, and platelet count. Group I patients had higher ACT and lower F1.2 and FPA compared with group II at baseline. Subsequent measurements demonstrated a gradual decrease in FPA and F1.2 in group II; the end of procedure versus baseline changes that occurred in F1.2 were significantly different compared with group I (decrease of 0.59 +/- 0.22 nmol/L in group II vs increase of 0.22 +/- 0.3 nmol/L in group I, P =.04), and a trend in the same direction was evident for FPA changes (decrease of 1.46 +/- 1.16 ng/mL in group II vs increase of 2.25 +/- 1.58 ng/mL in group I, P =.07). The ACT response to abciximab was variable, but a 6.3% increase (+20 sec) in ACT was documented 5 minutes after abciximab bolus in group II compared with the 3.4% decrease (-10 sec) observed in group I at the same time point (P =.1). CONCLUSION: Addition of abciximab to heparin plus aspirin during PCI was associated with a significant decrease in thrombin generation and a borderline decrease in thrombin activity.
Vitamin D, parathyroid hormone, and calcium: a complex regulatory network.
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Two mutations identified in the androgen receptor of the new human prostate cancer cell line MDA PCa 2a.
PURPOSE: We have characterized the androgen receptor (AR) in a new human prostate cancer cell line, MDA PCa 2a, that has recently been established from a bone metastasis of a patient whose cancer exhibited androgen-independent growth. MATERIALS AND METHODS: Androgen responsiveness of these cells was assessed by measuring the effect of DHT and R1881 on cell growth and PSA secretion. Scatchard analysis was used to characterize the affinity and abundance of AR protein. Using a PCR based strategy, genomic DNA of the entire coding region of AR gene was sequenced to identify possible mutations. RESULTS: These cells express abundant AR (Nmax = 685 +/- 149 fmol./mg. protein), but the AR binding affinity (Kd) for DHT is only 25 nM, approximately 50-fold lower affinity than the mutated AR in LNCaP prostate cancer cells (Kd = 0.5 nM) or the wildtype AR in MCF-7 breast cancer cells (Kd = 0.4 nM). Two mutations, L701H and T877A, were identified in the ligand binding domain of the AR gene. Compared with LNCaP cells, the new cell line is significantly less responsive to DHT and R1881 as well as to other androgens such as testosterone, androstenedione, and DHEA. Similar to LNCaP cells, the ligand specificity of the AR in MDA PCa 2a cells appears to be relaxed and non-androgens such as progesterone and estradiol act as agonists although with less potency than in LNCaP cells. Interestingly, in the absence of androgens, the new cell line expresses 15-fold higher baseline levels of PSA than LNCaP. CONCLUSIONS: Two mutations were identified in the AR gene of the MDA PCa 2a cell line that are likely responsible for the decreased androgen sensitivity and altered ligand specificity observed in these cells. Thus, this new cell line with partial androgen responsiveness and PSA expression can serve as a functionally relevant model system of bone metastatic prostate cancer, and can be used to investigate the role of AR mutations in prostate cancer and its progression to androgen independence.
HER-2/neu oncogene amplification in cervical cancer studied by fluorescent in situ hybridization.
Oncogene amplification, such as HER-2/neu (C-erbB-2), is a manifestation of genetic instability often associated with the genesis and progression of cancer, including cervical cancer. Oncogene overexpression is traditionally studied using immunohistochemistry. We previously reported studies of oncogene amplification in breast cancer using fluorescent in situ hybridization (FISH), where the data support the hypothesis that HER-2/neu is a prognostic marker of poor outcome. To explore further the possible significance of HER-2/neu oncogene amplification in cervical cancer, we conducted a pilot study of 24 cervical cancer cases. The HER-2/neu FISH probe (Vysis, Inc., Downers Grove, IL) was used to measure gene amplification, with a chromosome 17 centromeric probe as an internal control. Out of 24 cases studied, 23 were informative. Of the 23 informative cases, 2 (8.7%) were found to be amplified. The rest (21 out of 23 or 91.3%) were nonamplified. Both amplified cases were invasive adenocarcinoma. Although the sample size of this pilot study may be somewhat small, the data obtained so far clearly demonstrated that detection of oncogene amplification in cervical cancer is not only feasible but is very sensitive, and suggest that further exploration using a larger sample size may be warranted.