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Biomedical subjects

D Feldman

Publications and source records attributed to D Feldman.

At least 37 records · Page 2Linked to original sources
PubMed2001

The decision-making value of magnetic resonance cholangiopancreatography in patients seen in a referral center for suspected biliary and pancreatic disease.

OBJECTIVE: To assess the ability of MRCP to alter the differential diagnosis and to prevent diagnostic and/or therapeutic ERCP. The diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) for biliary and pancreatic disease is well documented. Some believe MRCP may prevent diagnostic ERCP or add useful information, however there are no reports of its impact on clinical management. METHODS: Consecutive patients referred for ERCP underwent clinic evaluation, then MRCP, and then ERCP. In Phase 1, the number of differential diagnoses and the perceived need for diagnostic ERCP were evaluated after each step by the endoscopist who performed the ERCP. In Phase 2, the process was repeated after presenting clinical information and MRCP results to different individual physicians: another endoscopist, a hepatologist, a radiologist, and a surgeon (all were blinded to ERCP results). RESULTS: Forty patients were enrolled. Clinical contexts were jaundice (19.7%), abnormal liver enzymes (42.6%), abdominal pain (11.5%), recurrent acute pancreatitis (11.5%), and suspected complications of chronic pancreatitis (14.7%). In Phase 1, adding MRCP information to diagnostic ERCP information did not change the mean number of differential diagnoses significantly and prevented no therapeutic ERCP. In Phase 2, adding MRCP to clinical information only (without ERCP) reduced the differential diagnosis significantly for the radiologist and the surgeon only and would have prevented < or =3% of diagnostic and therapeutic ERCP for all physicians. CONCLUSION: The value of MRCP information may be limited if patient selection is inappropriate and may differ in physicians depending on their speciality.

Biliary Tract Diseases↗
PubMed2001

Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486).

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.

Adrenocorticotropic Hormone↗
PubMed2001

[Optimization of aerosol therapy in otorhinolaryngology: stability and granulometry of dexamethasone-gomenol-framycetin solution].

Nebulization of solutions associating gomenol, dexamethasone and framycetin is very widespread in otorhinolaryngology (particularly for the treatment of actue laryngitis and post-traumatic laryngitis and rhinitis and for the tracheotomy care). A rigorous clinical evaluation is however lacking. The aim of this work was to evaluate use of such solutions in comparison with the recommendations issuing from the National Session in April 1997 on good practices for aerosol therapeutics. Stability and granulometry were studied in order to optimize processing. A new formulation and new technical methods of administration are proposed in relation to the results of this study and the national recommendations.

Aerosols↗
PubMed2001

Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1.

PURPOSE: We determined that insulin-like growth factor binding protein 3 (IGFBP-3) induction by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is a necessary component of 1,25-(OH)(2)D(3) mediated growth inhibition of the LNCaP human prostate cancer cell line. In addition, induction of the cyclin dependent kinase inhibitory protein p21/WAF/CIP1 by 1,25-(OH)(2)D(3) is mediated by IGFBP-3. MATERIALS AND METHODS: Induction of IGFBP-3 by 1,25-(OH)(2)D(3) was determined by enzyme-linked immunosorbent assay for IGFBP-3 protein and by Northern blot analysis for IGFBP-3 messenger (m) RNA. Growth assays for LNCaP cells were determined by measuring DNA content. The contribution of IGFBP-3 toward 1,25-(OH)(2)D(3) mediated growth inhibition was determined by adding either antisense oligonucleotides or immuno-neutralizing antibodies to culture media of growth assays. Regulation of p21/WAF/CIP1 was determined by Western blot analysis. RESULTS: Adding 1,25-(OH)(2)D(3) to LNCaP prostate cancer cells demonstrated that 1,25-(OH)(2)D(3) significantly up-regulated IGFBP-3 at the mRNA and protein levels in these cells approximately 3-fold over control levels. Also, adding IGFBP-3 protein to LNCaP cell growth medium inhibited LNCaP cell growth. Interestingly adding IGFBP-3 antisense oligonucleotides or antibodies directed toward IGFBP-3 abolished the growth inhibitory actions of 1,25-(OH)(2)D(3), indicating that this effect is IGFBP-3 dependent. Furthermore, to connect the mechanisms of IGFBP-3 and 1,25-(OH)(2)D(3) mediated growth inhibition we demonstrated that IGFBP-3 up-regulates the expression of p21/WAF1 protein to approximately 2-fold over the control level. Adding an IGFBP-3 immuno-neutralizing antibody completely prevented the 1,25-(OH)(2)D(3) induced up-regulation of p21/WAF1. CONCLUSIONS: 1,25-(OH)(2)D(3) up-regulates IGFBP-3 in the LNCaP cell line at the mRNA and protein levels. The growth inhibitory action of 1,25-(OH)(2)D(3) on LNCaP cells depends on active IGFBP-3, as evidenced by the loss of growth inhibition induced by IGFBP-3 antisense oligonucleotide and immuno-neutralization experiments. A possible connection between IGFBP-3 and 1,25-(OH)(2)D(3) lies in the cyclin dependent kinase inhibitory protein p21/WAF1 since IGFBP-3 and 1,25-(OH)(2)D(3) each up-regulate this protein and both inhibit LNCaP cell growth. Therefore, we hypothesize that the mechanism of action by which IGFBP-3 and 1,25-(OH)(2)D(3) induce growth inhibition is the induction of p21/WAF1 because IGFPB-3 immuno-neutralizing antibodies completely abrogate the 1,25-(OH)(2)D(3) mediated up-regulation of p21/WAF1 and growth inhibition.

Calcitriol↗
PubMed2000

Conceptually new 20-epi-22-oxa sulfone analogues of the hormone 1alpha,25-dihydroxyvitamin D(3): synthesis and biological evaluation.

New C,D-ring side-chain-modified sulfone 4a, with natural 1alpha, 3beta-hydroxyl groups but lacking the 25-hydroxyl group characteristic of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1), has been prepared and characterized. Novel synthetic features include: (1) chemoselective oxidation of only a primary silyl ether in a primary-secondary bis-silyl ether intermediate and (2) smooth reductive etherification without interference by a neighboring sulfonyl group. Sulfone 4a, but not its 1beta, 3alpha-diastereomer 4b, is powerfully antiproliferative and transcriptionally active in vitro but desirably noncalcemic in vivo. Although sulfone 4a, designed to resemble Leo Pharmaceutical Co.'s KH-1060 (3), is recognized by catabolic enzymes, the selective biological profile of sulfone 4a is likely not due to its metabolites that are formed in only minor amounts.

Animals↗
PubMed2000

Fluorescent in situ hybridization study of c-myc oncogene copy number in prostate cancer.

We previously conducted a study of 88 cases of prostate cancer in an attempt to identify potential prognostic biomarkers that can distinguish aggressive cases that must be treated immediately. Prostate cancer is a serious disease affecting men worldwide and compromises the quality of life of its patients. Biomarkers studied included chromosome 7 trisomy, chromosome 8 trisomy, and HER-2/neu oncogene amplification. These biomarkers were initially studied because trisomy 8 and oncogene amplification of the HER-2/neu gene have been reported in many other cancers, including those studied in this laboratory. In view of the fact that HER-2/neu amplification was not found to play a prominent role in the group of prostate cancer specimens that we studied, an exploration of other biomarkers was felt to be warranted. Thus, we began a pilot study of c-myc oncogene copy number in prostate cancer using the same protocol for fluorescent in situ hybridization and a direct-labeled SpectrumOrange LSI c-myc probe (Vysis, Inc., Downers Grove, IL) on formalin-fixed, paraffin-embedded tissue. From a total of 36 cases of prostate cancers successfully analyzed, we found 11 (31%) tumors exhibiting 3 or more positive signals for c-myc in 15% or more of the cells. Of these, only 7 tumors (19% of the total cases studied) had >/=3 signals in 20% or more of the cells. No case had >/=3 signals in 25% or more of the cells. Compared to other molecular probes tested, the c-myc signals were more faint and the quality of the preparation was less optimal than other tumor specimens that we previously studied. Based on the information available thus far, we conclude that an increased copy number in c-myc oncogene copy number was not a prominent finding in our cohort of prostate cancer patients.

Adenocarcinoma↗
PubMed2000

1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration.

1,25-Dihydroxyvitamin-D3 [1,25(OH)2D3], the active hormonal metabolite of vitamin D, acts through a specific nuclear receptor to inhibit proliferation and promote differentiation of several tumor cell types including the LNCaP, DU145 and PC-3 prostate cancer cell lines as well as primary prostate tumor lines. 1,25(OH)2D3 can also decrease invasion of breast and prostate cancer cell lines in vitro. We confirm this latter finding in the DU145 and PC-3 prostate cancer cell lines, and further show that 1,25(OH)2D3 inhibits overall invasion, cell adhesion and migration to the basement membrane matrix protein laminin. These changes appear to be due in part to a 1,25(OH)2D3-induced decrease in expression of alpha6 and beta4 integrins, both of which are receptors for laminin and associated with increased migration and invasion of prostate cancer cells in vitro. Blocking function of these particular integrins with antibodies inhibits both adhesion and migration of the cells. Collectively, these data demonstrate that 1,25(OH)2D3, in addition to decreasing proliferation of tumor cells, can also inhibit prostate cancer cell invasion through modulation of select cell surface adhesion molecules.

Calcitriol↗
PubMed2000

Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor.

The androgen receptor (AR) is involved in the development, growth and progression of prostate cancer (CaP). CaP often progresses from an androgen-dependent to an androgen-independent tumor, making androgen ablation therapy ineffective. However, the mechanisms for the development of androgen-independent CaP are unclear. More than 80% of clinically androgen-independent prostate tumors show high levels of AR expression. In some CaPs, AR levels are increased because of gene amplification and/or overexpression, whereas in others, the AR is mutated. Nonetheless, the involvement of the AR in the transition of CaP to androgen-independent growth and the subsequent failure of endocrine therapy are not fully understood. Here we show that in CaP cells from a patient who failed androgen ablation therapy, a doubly mutated AR functioned as a high-affinity cortisol/cortisone receptor (ARccr). Cortisol, the main circulating glucocorticoid, and its metabolite, cortisone, both equally stimulate the growth of these CaP cells and increase the secretion of prostate-specific antigen in the absence of androgens. The physiological concentrations of free cortisol and total cortisone in men greatly exceed the binding affinity of the ARccr and would activate the receptor, promoting CaP cell proliferation. Our data demonstrate a previously unknown mechanism for the androgen-independent growth of advanced CaP. Understanding this mechanism and recognizing the presence of glucocorticoid-responsive AR mutants are important for the development of new forms of therapy for the treatment of this subset of CaP.

Aldosterone↗
PubMed2000

Evaluation of myocardial viability in asymptomatic patients early after infarction with perfusion/metabolism single-photon-emission computed tomographic imaging and dobutamine echocardiography.

OBJECTIVE: To study the impact of detection of viability of myocardium in asymptomatic patients early (3-10 days) after Q-wave myocardial infarction on segmental recovery of left ventricular function after elective revascularization. METHODS: Patients were studied with low-dose dobutamine echocardiography (LDDE) and single photon-emission computed tomography with 99mTc sestamibi and [18F]-fluorodeoxyglucose (FDG) imaging. Viability of myocardium was defined as detection of improvement in segmental thickening of left ventricle by LDDE (versus baseline echocardiographic data), uptake of 99mTc sestamibi > 50% of maximum counts, uptake of [18F]-FDG > 50% of maximum normal, combined uptake of 99mTc sestamibi or [18F]-FDG > 50% of normal maximum, uptake of [18F]-FDG > 50% or mismatched pattern (uptake of [18F]-FDG greater than that of 99mTc sestamibi). Functional recovery was defined as improvement of segmental thickening of left ventricle detected at follow-up 8 weeks after infarction (versus baseline resting echocardiographic data). Interpretation of the tests was blinded with respect to the angiographic data and the results of the alternative method. RESULTS: In total 18 patients with 133 left-ventricle segments with abnormal contractile function at baseline were analysed; 29% were hypocontractile and 71% were noncontractile. Examination with LDDE showed that 18% of the segments had normal contractility and 26% were hypocontractile; the respective percentages were 29 and 28% according to follow-up resting echocardiography. Radionuclide tests for viability of myocardium gave positive results in 57% (uptake of [18F]-FDG > 50%) and 62% (uptake of 99mTc sestamibi > 50%) of cases. With respect to segmental analysis, there was a 25-27% positive concordance, a 24-27% negative concordance, and a 48-50% discordance between the LDDE and the radionuclide definitions of viability of myocardium. Additionally, there was no significant difference among sensitivities and specificities for the definitions of viability. The sensitivity was 69% for the uptake of 99mTc sestamibi > 50% criterion, and the highest specificity was 66% for the LDDE. Incorporation of imaging with [18F]-FDG into the analysis yielded a marginally higher sensitivity of 71% for the criterion of uptake of [18F]-FDG or 99mTc sestamibi > 50%, versus imaging with the 99mTc sestamibi alone. CONCLUSION: LDDE was more specific and radionuclide imaging more sensitive for detection of viability of myocardium in asymptomatic patients early after infarction. Possibly defective myocardial metabolization of glucose in the period early after infarction and the specific LDDE protocol applied account for the limited benefit of these studies in terms of facilitating prediction of segmental functional recovery after revascularization in this clinical setting.

Cardiotonic Agents↗
PubMed2000

The pervasiveness of the illness suffered by workers seeking compensation for disabling arm pain.

Disability from work-related arm pain has become prevalent in several countries in recent years. Many of these individuals present with chronic musculoskeletal symptoms that, for lack of a more specific diagnosis, are often labeled as a repetitive strain injury or cumulative trauma disorder. Indemnity for such conditions can be contentious; many of these sufferers are involved in litigation in their quest for financial compensation for temporary or permanent disability. This article describes our experience with 103 patients referred to a Health Reference Center for Workers for the management of repetitive strain injury. Their illness is far more global than the work-related arm pain that such labeling implies. From the total group, 73 fulfilled the American College of Rheumatology Criteria for the Classification of Fibromyalgia Syndrome. This means that they were suffering pain above and below the diaphragm, far from the arm pain for which they were referred. These 73 patients were clinically and psychologically indistinguishable from 165 patients followed in our clinic at the Federal University of São Paulo, Rheumatology Division, who also fulfilled these criteria but did not consider their illness work-related. This observation calls for longitudinal investigations that might offer insights as to whether the more global aspects of the illness are antecedent, coincident, or confounding aspects of the illness experience labeled repetitive strain injury or cumulative trauma disorder.

Adult↗
PubMed2000

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.

Bioethics↗
PubMed2000

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.

Androgen Antagonists↗
PubMed2000

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.

Adult↗
PubMed2000

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.

Aged↗
PubMed2000

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.

Breast Neoplasms↗