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Biomedical subjects

S Epstein

Publications and source records attributed to S Epstein.

At least 91 records · Page 5Linked to original sources
PubMed1995

Organ transplantation and osteoporosis.

Organ transplantation offers new life to patients who suffer from incurable disease. The problem of rejection of the transplanted organ has been overcome with the use of potent immunosuppressive drugs. These drugs, although they allow graft tolerance and graft survival, also are associated with complications such as osteoporosis. Although factors such as nutrition, gonadal status, and ambulatory status are important, the use of immunosuppressive drugs appears to be the main factor in the development of osteoporosis. The drugs that are responsible for this bone loss are glucocorticoids and the calcineurin phosphatase inhibitors, cyclosporine and tacrolimus. The incidence of bone disease depends, in part, on which organ is transplanted. Kidney transplant recipients appear to be less susceptible to the development of overt osteoporosis than do heart or liver transplant recipients. The most critical period of bone loss in organ recipients appears to be within the first 6 months, with the most dramatic reduction occurring within the first 3 months following transplantation. Trabecular (cancellous) bone of the spine appears to be most at risk, with vertebral fractures occurring most commonly. Transplant recipients should be evaluated by bone mineral densitometry and measurement of vitamin D metabolites, blood urea nitrogen, creatinine, calcium, and phosphate. Markers of bone turnover may help in assessing the rate of remodeling. Gonadal function should be ascertained by measurement of serum testosterone (males) or estradiol (females) levels. Therapy should be directed toward prevention of bone loss as well as helping to restore what already may have been lost. Administration of calcium and vitamin D and sex hormone replacement, if indicated, should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin↗
PubMed1995

Association of silent myocardial ischemia with new atherothrombotic brain infarction in older patients with extracranial internal or common carotid arterial disease with and without previous atherothrombotic brain infarction.

OBJECTIVE: To correlate silent myocardial ischemia with the incidence of new atherothrombotic brain infarction (ABI) in older patients with 40 to 100% extracranial carotid arterial disease (ECAD) with and without prior ABI. DESIGN: In a prospective study of 208 older patients with 40 to 100% ECAD diagnosed by carotid duplex ultrasonography, 24-hour ambulatory electrocardiograms were obtained to detect silent myocardial ischemia. At 42-month mean follow-up, silent myocardial ischemia was correlated with the incidence of new ABI in patients with and without prior ABI. SETTING: A large long-term health care facility where 208 older patients with 40 to 100% ECAD and technically adequate 24-hour ambulatory electrocardiograms for detecting silent myocardial ischemia were studied. PATIENTS: The 208 patients included 68 men and 140 women, mean age 81 +/- 8 years (range 60 to 100). One-hundred three (50%) of the patients had prior ABI. MEASUREMENTS AND MAIN RESULTS: Sixty-nine (33%) of the 208 patients had silent myocardial ischemia. Mean follow-up was 42 +/- 25 months (range 3 to 101 months). At follow-up, the incidence of new ABI was 64% in patients with prior ABI and 32% in patients with no prior ABI (P < .0001). At follow-up, the incidence of new ABI was 65% in patients with silent ischemia and 40% in patients with no silent ischemia (P = .0005). The multivariate Cox regression model showed that patients with prior ABI have a 2.5 times higher chance of developing new ABI than those without prior ABI after controlling other prognostic variables. Patients with silent ischemia have a 2.1 times higher probability of developing new ABI than those without silent ischemia after controlling other prognostic variables. CONCLUSIONS: Prior ABI and silent ischemia are independent risk factors for the development of new ABI in patients with 40 to 100% ECAD. This probably reflects that silent ischemia is a marker for more advanced or more significant atherosclerotic disease rather than a causal factor for ABI.

Aged↗
PubMed1995

The effect of medroxyprogesterone acetate on bone metabolism in the oophorectomized, tamoxifen-treated rat.

Tamoxifen (TAM) is used primarily in the management of breast cancer, and it also has bone-sparing effects similar to estrogen. In breast cancer patients TAM may have a potential role in the prevention and management of osteoporosis. TAM therapy is associated with uterine hyperplasia, and medroxyprogesterone acetate (MPA) added to the regimen provides protection against this. Due to the potential combined use of MPA and TAM in the clinical setting, this study was conducted to assess whether MPA acted synergistically, dampened, or enhanced the TAM effect on bone. Seventy-five female rats (60 oophorectomized; Ox), were randomized into five groups and received either TAM (0.1 mg/kg.day) and/or MPA (0.3 mg/kg.day) therapy over 28 days as follows: 1) sham; 2) Ox; 3) Ox plus TAM; 4) Ox plus MPA; and 5) Ox plus TAM plus MPA. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium, PTH, 1,25-dihydroxyvitamin D, osteocalcin, and insulin-like growth factor 1. TAM-treated rats showed a reduction in body weight serum osteocalcin, PTH, and insulin-like growth factor 1. Histomorphometric analysis of the proximal tibia showed less cancellous bone volume in Ox rats, and the effect was attenuated by TAM. MPA alone had no significant effect on cancellous bone volume. All the bone formation parameters evaluated (bone formation rate, mineral apposition rate, percent calcein-labeled surface, and number of osteoblasts) were higher in Ox rats compared with sham-operated rats and were lower in TAM-treated rats compared with Ox rats. These parameters were not changed by MPA, alone or in combination with TAM. The number of osteoclasts was higher in Ox rats compared with sham-operated rats and was reduced by TAM. MPA therapy alone or in combination with TAM did not affect number of osteoclasts. These results suggest that MPA neither dampened nor enhanced the effect of TAM on bone.

Animals↗
PubMed1994

Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years.

BACKGROUND: Because adjuvant tamoxifen citrate is given to women with early-stage breast cancer for long periods, it is important to know how it affects risk factors for osteoporotic bone fractures, particularly since rates of bone fracture increase rapidly with age in postmenopausal women. In a 2-year randomized placebo-controlled toxicity study in 140 subjects, we demonstrated that tamoxifen was associated with preservation of bone mineral density (BMD), a major risk factor for fractures, in the lumbar spine. METHODS: Five years after entry on this study we reexamined 62 of the original subjects with lumbar spine BMD and serum osteocalcin measurements. These were women available for study because they had not suffered major illnesses and had continued to receive (1) tamoxifen or (2) the no-tamoxifen regimen that they had originally been randomized to receive for the entire 5 years. RESULTS: For lumbar spine BMD at baseline, the 30 subjects in the long-term tamoxifen group and the 32 subjects in the long-term no-tamoxifen group were not significantly different (P = .26). During the first 2 years of follow-up, the 30 subjects in the long-term tamoxifen group showed the same BMD pattern as the entire 70-patient tamoxifen cohort, and similarly the 32 subjects in the long-term no-tamoxifen group showed the same pattern as the entire 70-patient cohort who received placebo. Five-year mean BMD measurements for each long-term follow-up group showed no significant changes from their respective 2-year levels. However, 5-year BMD measurements between the two groups differed (tamoxifen group, +0.8%; placebo group, -0.7%) (P = .06), and the mean regression lines for the changes in BMD over 5 years differed significantly between the two groups (P = .0005). Adjustment for differences in body mass index, reported exercise, and calcium supplementation between these two groups did not change these results. Osteocalcin levels, also comparable at baseline in the two groups, were significantly lower in tamoxifen-treated subjects at 5 years (P = .0005). CONCLUSIONS: While remodeling of bone may be lower, resorption of lumbar spine bone mineral is also lower, and tamoxifen preserves BMD in the lumbar spine over 5 years of treatment in postmenopausal women. Over longer periods, this preservation of BMD might be expected to be associated with lower fracture rates.

Bone Density↗
PubMed1994

The deleterious effects of long-term cyclosporine A, cyclosporine G, and FK506 on bone mineral metabolism in vivo.

Administration of cyclosporine A to male and female rats accelerates bone remodeling and causes bone loss, among other side-effects. The newer immunosuppressant drugs, FK506 and CsG, have been synthesized to counteract the toxic effects of CsA, yet maintain clinical efficacy. We investigated the in vivo effects of long-term administration of these drugs on bone mineral metabolism in the rat. Five groups of Sprague-Dawley rats, 15 per group, were allocated to receive by daily gavage for a period of 28 days: (1) Cs-vehicle; (2) CsA 15 mg/kg b.w.; (3) CsG 15 mg/kg b.w.; (4) FK506 vehicle; (5) FK506 5 mg/kg b.w. Blood was sampled on days 0, 14, and 28 for measurement of ionized calcium (Ca2+), parathyroid hormone (PTH), 1,25-(OH)2-vitamin D, and bone gla protein (BGP). Tibiae were removed on day 28 after double calcein labeling for histomorphometric analysis. Immunosuppressant groups were compared with the respective vehicle groups. Neither CsA or CsG affected the levels of Ca2+ or PTH, whereas by day 28 FK506 caused a decrease in Ca2+ and a corresponding rise in PTH (P < 0.05). The 1,25-(OH)2-vitamin D and BGP levels in both the CsA and CsG groups were increased on days 14 and 28 (P < 0.05), while FK506 had no effect on these serum levels. Tibial bone histomorphometry revealed that all 3 immunosuppressants increased measures of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area, most marked with FK506. This report demonstrates that all three immunosuppressants have adverse effects on bone--most deleterious with FK506.

Animals↗
PubMed1994

Influence of age on cyclosporin A-induced alterations in bone mineral metabolism in the rat in vivo.

Cyclosporin A (CsA) administered to actively growing young rats produces a high-turnover osteopenia. We investigated and compared the effect of CsA on the bone mineral metabolism in young rats with that of older rats, which have a lower rate of bone turnover. A group of 24 young (9 weeks) and 24 older (9 months) male Sprague-Dawley rats were orally administered 15 mg/kg of CsA or placebo daily for 24 days. Rats were weighed and serum assayed serially for bone gla protein (BGP), parathyroid hormone, ionized calcium, blood urea nitrogen, creatinine, and 1,25-dihydroxyvitamin D [1,25-(OH)2D]. After sacrifice, histomorphometric analysis was performed on undecalcified proximal tibial metaphysis with double-fluorescent labeling. Serum BGP levels were significantly elevated in both young and older rats administered CsA, and 1,25-(OH)2D levels were significantly elevated in CsA-treated young rats more than in older rats. Body weight was significantly reduced in CsA-treated older rats. There were mild but significant alterations in renal function in both groups receiving CsA. In the most comprehensive examination to date of the effects of CsA on bone histomorphometry, both young (-44%) and older rats (-20%) lost significant amounts of trabecular bone compared to their respective controls. Bone loss in young rats was mainly due to a reduced number of trabecular; older rats lost mainly trabecular thickness. Microanatomic nodal studies were consistent with these results. These data demonstrate that although cancellous bone loss induced by CsA is more marked in young rats, older rats with slower bone turnover are also at risk.

Administration, Oral↗
PubMed1994

Effect of cyclosporin A on bone mineral metabolism in experimental diabetes mellitus in the rat.

Cyclosporin A (CsA) is widely used in diabetic transplant patients and early type I diabetes mellitus. Diabetes produces a low-turnover osteopenia, and CsA conversely induces high-turnover osteopenia in rats. We investigated whether CsA would exacerbate diabetic osteopenia. Four groups of 10-week-old male Sprague-Dawley rats (n = 11/group) were studied: On day -6, groups A and C received saline and groups B and D received intravenous streptozotocin (55 mg/kg) to induce diabetes. From day 0, groups A and B received CsA vehicle and C and D received CsA (15 mg/kg) by daily gavage. Rats were bled on days -6, 0, 11, and 22 for serum bone gla protein (BGP), 1,25-(OH)2D, PTH, blood ionized Ca, and blood glucose determinations. Double tetracycline labeling was performed on days 9 and 20 for bone histomorphometry. After sacrifice on day 22, histomorphometric analysis was performed. Serum BGP, 1,25-(OH)2D, and PTH levels were significantly decreased in the diabetic alone (B) and diabetic plus CsA (D) groups and significantly increased in the CsA alone (group C). CsA alone (group C) induced cancellous bone loss by stimulated bone resorption. Cancellous bone loss in the diabetic alone rats (group B) was caused primarily by inhibited bone formation. No differences were found in cancellous bone mass, formation, or resorption parameters between diabetic alone (group B) and CsA-treated diabetic rats (group D). Neither CsA alone (group C) nor diabetic alone (group B) nor their combination affected cortical bone mass. CsA alone (group C) stimulated periosteal bone formation and endocortical bone resorption and inhibited endocortical formation, and diabetic alone (group B) inhibited both periosteal and endocortical bone formation. No parameters of tibial diaphyses in CsA-treated diabetic rats (group D) were different from diabetic alone. Thus the addition of CSA to the diabetic treated rats (group D) could not stimulate remodeling and appeared not to worsen significantly some of the alterations in bone formation and resorption. Possible explanations for this may be that CsA in vivo requires adequate levels of PTH, 1,25-(OH)2D, insulin, and perhaps growth factors to stimulate remodeling. The use of CsA in type I diabetic patients or in organ transplant recipients who remain diabetic after transplantation may in the short term not aggravate existing osteopenia based on these findings.

Animals↗
PubMed1994

Isotopic analyses of nitrogenous compounds from the Murchison meteorite: ammonia, amines, amino acids, and polar hydrocarbons.

The combined volatile bases (ammonia, aliphatic amines, and possibly other bases), ammonia, amino acids, and polar hydrocarbons were prepared from the Murchison meteorite for isotopic analyses. The volatile bases were obtained by cryogenic transfer after acid-hydrolysis of a hot-water extract and analyzed by combined gas chromatography-mass spectrometry of pentafluoropropionyl derivatives. The aliphatic amines present in this preparation comprise a mixture that includes both primary and secondary isomers through C5 at a total concentration of > or = 100 nmoles g-1. As commonly observed for meteoritic organic compounds, almost all isomers through C5 are present, and the concentrations within homologous series decrease with increasing chain length. Ammonia was chromatographically separated from the other volatile bases and found at a concentration of 1.1-1.3 micromoles g-1 meteorite. The ammonia analyzed includes contributions from ammonium salts and the hydrolysis of extractable organic compounds, e.g., carboxamides. Stable isotope analyses showed the volatile bases to be substantially enriched in the heavier isotopes, relative to comparable terrestrial compounds delta D < or = +1221%; delta 13C = +22%; delta 15N = +93%). Ammonia, per se, was found to have a somewhat lower delta 15N value (+69%) than the total volatile bases; consequently, a higher delta 15N (>93%) can be inferred for the other bases, which include the amines. Solvent-extractable polar hydrocarbons obtained separately were found to be enriched in 15N (delta 15N = +104%). Total amino acids, prepared from a hydrolyzed hot-water extract by cation exchange chromatography, gave a delta 15N of +94%, a value in good agreement with that obtained previously. Nitrogen isotopic data are also given for amino acid fractions separated chromatographically. The delta 15N values of the Murchison soluble organic compounds analyzed to date fall within a rather narrow range (delta 15N = +94 +/- 8%), an observation consistent with their formation, or formation of their precursors, by interstellar chemistry.

Amines↗
PubMed1994

Utilization of cyclosporine H to elucidate the possible mechanisms of cyclosporine A-induced osteopenia in the rat.

The immunosuppressive agent cyclosporine A (CsA) produces in vivo in the rat marked osteopenia and elevation of serum bone gla protein (BGP) that reflects the high bone turnover and increased circulating levels of 1,25-dihydroxyvitamin D [1,25(OH)2D]. Cyclosporine H (CsH), a D-N-MeVal11 analog of CsA, is not immunosuppressive, and in contrast to CsA, it neither binds to cyclophilin nor alters cytokine activity. This distinction between CsH and CsA provides a means of elucidating whether CsA exerts an effect on bone and 1,25(OH)2D via immune-mediated mechanisms. We therefore studied three groups of male Sprague-Dawley rats (300 to 350 g body weight [BW]) randomly divided to receive either cyclosporine vehicle, CsA, or CsH 15 mg/kg BW by daily gavage for 28 days. Blood samples were assayed for ionized calcium (Ca2+), serum BGP, serum parathyroid hormone (PTH), and 1,25(OH)2D by specific radioimmunoassay on days 0, 14, and 28. Histomorphometric evaluations were performed on the right tibia after tetracycline and calcein labeling and killing of the rats at the end of 28 days of treatment. In CsA-treated rats, serum BGP levels were significantly increased (155.2 +/- 30.7 ng/mL v 107.3 +/- 16.8 and 111.5 +/- 13.1 at day 28, P < .05) compared with control and CsH groups, respectively. Similarly, 1,25(OH)2D was significantly increased in CsA-treated rats versus control and CsH group (134.9 +/- 35.3 pg/mL v 70.2 +/- 16.6 and 69.8 +/- 20.6 [P < .05], respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Integration of the cognitive and the psychodynamic unconscious.

Cognitive-experiential self-theory integrates the cognitive and the psychodynamic unconscious by assuming the existence of two parallel, interacting modes of information processing: a rational system and an emotionally driven experiential system. Support for the theory is provided by the convergence of a wide variety of theoretical positions on two similar processing modes; by real-life phenomena--such as conflicts between the heart and the head; the appeal of concrete, imagistic, and narrative representations; superstitious thinking; and the ubiquity of religion throughout recorded history--and by laboratory research, including the prediction of new phenomena in heuristic reasoning.

Cognition↗
PubMed1994

Conflict between intuitive and rational processing: when people behave against their better judgment.

When offered an opportunity to win $1 on every "win" trial in which they drew a red jelly bean, subjects frequently elected to draw from a bowl that contained a greater absolute number, but a smaller proportion, of red beans (e.g., 7 in 100) than from a bowl with fewer red beans but better odds (e.g., 1 in 10). Subjects reported that although they knew the probabilities were against them, they felt they had a better chance when there were more red beans. Similar, but less extreme results were obtained on "lose" trials, where drawing a red bean meant losing $1. These results were predicted from the concretive and experiential principles of cognitive-experiential self-theory. Nonoptimal choices in the laboratory were significantly correlated with heuristic responses to relevant vignettes and with self-reported gambling in real life.

Adult↗
PubMed1994

Signal-averaged electrocardiography in elderly subjects with and without heart disease.

Prevalence of abnormal signal-averaged electrocardiography in normal populations appears to be low, but has not been studied previously in an asymptomatic elderly population. To study the prevalence of abnormal ventricular late potentials in an elderly population, a group of 51 subjects with no evidence of cardiac disease and ranging in age from 62 to 102 years underwent signal-averaged electrocardiography. Results were compared to a group of 179 patients similar in age but with complex ventricular arrhythmias, and to a group of 25 asymptomatic volunteers under the age of 50. The prevalence of an abnormal signal-averaged ECG was 14% in the normal elderly subjects, and 31% in the patients (P = 0.01), and 4% in the young subjects (P = NS). We conclude that the prevalence of abnormal ventricular late potentials in elderly patients without heart disease is similar to levels reported in other populations of normal controls, but elderly patients with cardiac disease have a significantly higher prevalence of abnormal signal-averaged ECG studies than the normals.

Action Potentials↗
PubMed1994

Interferon-gamma causes loss of bone volume in vivo and fails to ameliorate cyclosporin A-induced osteopenia.

Interferon-gamma (IFN gamma) in vitro inhibits both bone resorption and bone formation, resulting in a net decrease in bone turnover. In vivo administration of cyclosporin A (CsA) produces accelerated bone remodeling with resultant bone loss. The aim of this study was to investigate whether administration of IFN gamma to rats would favorably modify the high turnover osteopenia caused by CsA. Thirty-six male Sprague-Dawley rats were randomized into 4 equal groups to receive either CsA (15 mg/kg.day) or vehicle by gavage and IFN gamma (10(6) IU/kg.day) or vehicle by ip injection for 8 days. Group 1 received CsA vehicle plus IFN gamma vehicle; group 2 received CsA plus IFN gamma vehicle; group 3 received CsA vehicle plus IFN-gamma; group 4 received CsA plus IFN gamma. Blood was sampled on days 0, 4, and 8 for measurement of ionized calcium (Ca2+), PTH, 1,25-dihydroxyvitamin D, and bone gla protein. Tibiae were removed on day 8 after double tetracycline labeling for histomorphometric analysis. Ca2+ and PTH levels were similar in all groups during the study period. Rats receiving CsA (groups 2 and 4) had elevated levels of 1,25-dihydroxyvitamin D and bone gla protein, whereas rats receiving IFN gamma alone (group 3) had no change in levels of these parameters. Bone histomorphometry revealed that treatment with CsA and/or IFN gamma (groups 2-4) caused an increase in bone resorption surface and a decrease in some parameters of bone formation, resulting in a net loss of bone volume. Thus, IFN gamma failed to influence the osteopenia caused by CsA and on its own had adverse effects on bone in vivo. These results demonstrate that immune-mediating agents have opposing actions in vitro as compared to in vivo.

Animals↗