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Biomedical subjects

E Young

Publications and source records attributed to E Young.

At least 19 recordsLinked to original sources
PubMed1999

A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats.

Although it is well established that long-term heparin therapy causes osteoporosis, it is unknown whether heparin-induced bone loss is reversible when heparin treatment is stopped. To address this question, we randomized rats to once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g) or saline for 28 days and then followed the rats for an additional 28 days off treatment. Based on histomorphometric analysis of the distal third of the right femur proximal to the epiphyseal growth plate, 1.0 U/g heparin caused a 30% loss in cancellous bone volume over the first 28 days. This was accompanied by a 137% increase in osteoclast surface and a 60% decrease in both osteoblast and osteoid surface. One month after cessation of heparin treatment, no recovery in these parameters was observed. Similarly, serum levels of alkaline phosphatase, a biochemical marker of bone formation, which continued to decrease over the course of heparin treatment, showed no signs of recovery in the subsequent 28 days off treatment. To explore the mechanism responsible for the prolonged effect of heparin on bone, we repeated the experiment giving 125I-labeled heparin in place of unlabeled heparin. 125I-labeled heparin was found to accumulate in bone during the course of its administration, and be retained in bone for at least 56 days after stopping heparin treatment. These findings suggest that heparin-induced osteoporosis is not rapidly reversible because heparin is sequestered in bone for an extended period.

Animals↗
PubMed1999

Vasoflux, a new anticoagulant with a novel mechanism of action.

BACKGROUND: Heparin and direct thrombin inhibitors, such as hirudin, have limitations in the treatment of acute coronary syndromes. Heparin does not inactivate fibrin-bound thrombin, whereas hirudin fails to block thrombin generation. In contrast, Vasoflux is a novel anticoagulant that inactivates fibrin-bound thrombin and attenuates factor Xa generation. METHODS AND RESULTS: Vasoflux is prepared by depolymerization of heparin, restricting molecular size to between 3000 and 8000 Da, and reducing antithrombin affinity by periodate oxidation. Vasoflux catalyzes fibrin-bound thrombin inactivation by heparin cofactor II (HCII) and inhibits factor IXa activation of factor X independently of antithrombin and HCII. Compared with other anticoagulants in a thrombogenic extracorporeal circuit, Vasoflux maintains filter patency at concentrations that produce an activated clotting time (ACT) of 220 seconds. In contrast, to maintain filter patency, heparin, low-molecular-weight heparin (LMWH), and hirudin require concentrations that produced an ACT of 720, 415, and >1500 seconds, respectively, whereas dermatan sulfate was ineffective at concentrations that produced an ACT of 360 seconds. CONCLUSIONS: Vasoflux is more effective than heparin and LMWH because it inactivates fibrin-bound thrombin and is superior to hirudin and dermatan sulfate because it also blocks factor Xa generation.

Anticoagulants↗
PubMed1999

Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI): long-term follow-up.

We describe the results of bone marrow transplantation (BMT) in four patients with mucopolysaccharidosis type VI (MPS VI, McKusick 253200)--Maroteaux-Lamy disease. The indications for transplantation were cardiomyopathy in three patients and severe obstructive sleep apnoea in one. The follow-up period ranges between 1 and 9 years, and three of the patients are at mainstream schools. In all of the patients the facial features have become less coarse and the cardiac manifestations have improved or remained stable. However, skeletal changes have persisted or even progressed, although posture and joint mobility have improved and all the patients have remained ambulatory and active. BMT appears to prolong survival and improve the quality of life in MPS VI patients, but careful selection of patients is essential.

Bone Marrow Transplantation↗
PubMed1999

Modeling the involvement of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in autoimmune and stress-related rheumatic syndromes in women.

Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes.

Animals↗
PubMed1998

Triplet pregnancy after intracytoplasmic sperm injection of cryopreserved oocytes: case report.

OBJECTIVE: To report a triplet pregnancy that occurred after intracytoplasmic injection of sperm into cryopreserved oocytes. DESIGN: Case report. SETTING: Instituto de Ginecología y Fertilidad (IFER), Buenos Aires, Argentina. PATIENT: A 36-year-old infertile patient with premature ovarian failure and a previous term pregnancy with fresh donated oocytes. INTERVENTION(S): We administered leuprolide acetate for pituitary down-regulation followed by E2 valerianate in incremental doses until an endometrial lining of >8 mm was observed by ultrasound. Thawing of frozen donated oocytes, intracytoplasmic sperm injection (ICSI), and translaparoscopic fallopian tube ET also were performed. Natural micronized progesterone was administered intravaginally (600 mg/d) before ET. MAIN OUTCOME MEASURE(S): Ultrasound at the 8th week of gestation revealed a triplet pregnancy with active fetal heartbeats. RESULT(S): A triple intrauterine gestation was achieved with the use of microinjection into cryopreserved oocytes. CONCLUSION(S): This case illustrates the feasibility of oocyte cryopreservation for clinical use in the era of ICSI.

Adult↗
PubMed1998

Sialyl-Tn antigen as a marker of colon cancer risk in ulcerative colitis: relation to dysplasia and DNA aneuploidy.

BACKGROUND & AIMS: Expression of the mucin-associated carbohydrate antigen sialyl-Tn (STn) and DNA aneuploidy has each been shown to correlate with malignant transformation in patients with sporadic colon cancer and in those with ulcerative colitis (UC). This study aimed to determine how STn expression topographically and temporally relates to aneuploidy and neoplasia in patients with long-standing UC. METHODS: Twenty-six patients enrolled in a cancer surveillance program were studied, and 1691 mucosal specimens from repeated colonoscopies and colectomies were assessed in a standardized, prospective fashion for the presence of dysplasia, aneuploidy, and STn antigen. RESULTS: STn was expressed in 47% of specimens from 6 patients who underwent colectomy for dysplasia and 7% of specimens from 6 well-matched patients who underwent surgery for medical intractability. Seven other patients who never developed dysplasia or aneuploidy expressed STn in 6% of biopsy specimens. STn expression was independent of aneuploidy in colons both with and without dysplasia. Of 5 patients with aneuploidy but without dysplasia, 4 expressed STn earlier than aneuploidy. CONCLUSIONS: In UC, STn antigen and DNA aneuploidy are independent markers of neoplastic transformation. Determination of STn expression may complement dysplasia and aneuploidy for identification of risk for colonic neoplasia in UC.

Adolescent↗
PubMed1998

Psychoneuroendocrinology of depression. Hypothalamic-pituitary-gonadal axis.

Women are more susceptible than men to depression, particularly during periods of rapid fluctuation of gonadal hormones, such as premenstrually, postpartum, and during the climacteric. This review summarizes the evidence for the association of depression with abnormalities in reproductive hormones. Although there are similarities in stress hormones changes between depressed women and women with stress-related amenorrhea, no abnormalities in LH activity have been documented in depression. Similarly no abnormalities in LH, estradiol, or progesterone have been documented in premenstrual syndrome (PMS), although complete elimination of monthly cycling with leuprolide improves mood. Some studies have suggested beneficial effects of estrogen on mood in postmenopausal women but as yet there have been no adequately controlled studies of estrogen treatment of either premenopausal or postmenopausal women.

Adrenal Cortex Hormones↗
PubMed1998

A complex control system for transcriptional activation from the sid promoter of bacteriophage P4.

The sid gene promoter (Psid), which controls expression of the late genes from satellite phage P4, is activated by a unique class of small DNA-binding proteins. The activators from both satellite and helper phages stimulate transcription from Psid. These activators bind to sites centered at position -55 in all the helper and satellite phage late promoters. P4 Psid is unique in that it has an additional activator binding site centered at position -18 (site II). We have constructed a mutant of site II that no longer binds activators. Transcription under the control of satellite phage activators is increased by the site II mutation. In contrast, helper phage activators do not show this increase in transcription from Psid mutated at site II. Competition gel shift analysis reveals that the P4 satellite phage activator, Delta, binds eightfold better to site II than to site I. The products of the sid transcription unit are needed only when a helper phage is present; thus, the satellite phage activators repress transcription until the helper is present to supply a nonrepressing activator.

Base Sequence↗
PubMed1998

Prenatal diagnosis of the carbohydrate-deficient glycoprotein syndrome type 1A (CDG1A) by a combination of enzymology and genetic linkage analysis after amniocentesis or chorionic villus sampling.

Two pregnancies at risk for the carbohydrate-deficient glycoprotein syndrome Type 1A (CDG1A, phosphomannomutase deficient) were monitored by enzyme and genetic linkage analyses. The index case in both families had a proven deficiency of phosphomannomutase (PMM). An unaffected fetus was predicted in family 1 following amniocentesis. Normal PMM activity was found in cultured amniotic fluid cells and there was no elevation of lysosomal enzymes in the amniotic fluid. Genetic linkage analysis using microsatellite markers closely linked to the CDG1A gene confirmed this prediction. A healthy child was born. In the second family direct assay of chorionic villi showed a profound deficiency of PMM and genetic linkage analysis showed the fetus to have the same haplotype as the proband. The pregnancy was terminated and a deficiency of PMM was confirmed in cultured fibroblasts from the fetus. Reliable prenatal diagnosis of CDG Type 1A (PMM-deficient) can be achieved by a combination of biochemical and molecular genetic tests.

Amniocentesis↗
PubMed1998

The effects of standard and low molecular weight heparin on bone nodule formation in vitro.

Previously, we demonstrated in a rat model of heparin-induced osteoporosis that low molecular weight heparin (LMWH) produces less bone loss than unfractionated heparin, and that only heparin increases osteoclast number and activity. In contrast, both heparin and LMWH were found to decrease osteoblast function to a similar extent, possibly because at the doses tested both agents produced maximal inhibition. To examine the relative effects of heparin and LMWH on osteoblast function more closely we used an in vitro bone nodule assay, together with measurements of alkaline phosphatase (ALP) activity. Both agents inhibited bone nodule formation and ALP activity in a concentration-dependent manner, but 6 to 8-fold higher concentrations of LMWH were required to achieve equivalent effects. The effect of heparin on osteoblast function was both chain-length and negative charge-dependent because the ability of defined heparin fragments to inhibit nodule formation correlated with their molecular weight (r = 0.98), and N-desulfated heparin was less inhibitory than heparin. In contrast, the effect of heparin on osteoblast function was pentasaccharide-independent because heparin with low affinity for antithrombin had similar activity to heparin with high antithrombin activity. These findings help to explain mounting clinical evidence that the risk of osteoporosis is lower with LMWH than with heparin.

Animals↗
PubMed1997

A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats.

Long-term heparin treatment causes osteoporosis through, an as yet, undefined mechanism. To investigate this phenomenon and to determine the relative benefits of low-molecular-weight heparin (LMWH) use, we treated rats with once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g), the LMWH, Tinzaparin (1.0 U/g or 0.5 U/g), or placebo (saline) for a period of 32 days. The effects on bone were then compared both histomorphometrically and biochemically by measuring urinary type I collagen cross-linked pyridinoline (PYD) and serum alkaline phosphatase, markers of bone resorption and formation, respectively. Histomorphometric analysis of the distal third of the right femur, in the region proximal to the epiphyseal growth plate, demonstrated that both heparin and LMWH decrease cancellous bone volume in a dose-dependent fashion, but that heparin causes significantly more cancellous bone loss than does LMWH. Although both heparin and LMWH decrease osteoblast and osteoid surface to a similar extent, only heparin increases osteoclast surface. In support of these histomorphometric findings, biochemical markers of bone turnover demonstrated that both heparin and LMWH treatment produce a dose-dependent decrease in serum alkaline phosphatase, consistent with reduced bone formation, whereas only heparin causes a transient increase in urinary PYD, consistent with an increase in bone resorption. Based on these observations, we conclude that heparin decreases cancellous bone volume both by decreasing the rate of bone formation and increasing the rate of bone resorption. In contrast, LMWH, causes less osteopenia than heparin because it only decreases the rate of bone formation.

Alkaline Phosphatase↗
PubMed1997

Effect of nonspecific binding to plasma proteins on the antithrombin activities of unfractionated heparin, low-molecular-weight heparin, and dermatan sulfate.

BACKGROUND: Nonspecific binding to plasma proteins decreases the anti-factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins. METHODS AND RESULTS: There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are < 6000 D, and only heparin fractions > 6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer. CONCLUSIONS: Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.

Anticoagulants↗
PubMed1997

The variable anticoagulant response to unfractionated heparin in vivo reflects binding to plasma proteins rather than clearance.

The anticoagulant response to fixed doses of unfractionated heparin is variable in patients with acute illness, and some patients with venous thromboembolism require high doses of heparin to achieve a therapeutic anticoagulant response. To investigate the mechanism responsible for the variable anticoagulant response to heparin in acute illness, heparin clearance and nonspecific protein binding were compared in control and endotoxin-treated rabbits. The plasma half-life (t 1/2) of radiolabeled heparin increased in a dose-dependent fashion. At all doses of heparin studied, the t 1/2 of radiolabeled heparin was unaffected by experimental endotoxemia when compared with control animals. In contrast, the amount of heparin recovered was lower in the plasma of endotoxemic animals because of increased binding to plasma proteins. A chemically modified heparin with low affinity for antithrombin III was added ex vivo or in vivo to displace heparin bound nonspecifically to plasma proteins. The proportion of heparin bound to plasma proteins was significantly greater in the plasma of endotoxemic animals than in controls. These findings indicate that acute inflammation alters heparin recovery but does not affect heparin clearance. The variability of the anticoagulant response to heparin seen in patients with thromboembolism may, in part, be due to this effect of the underlying disease process.

Animals↗
PubMed1997

Plasma chitotriosidase activity in Gaucher disease patients who have been treated either by bone marrow transplantation or by enzyme replacement therapy with alglucerase.

A marked elevation in plasma chitotriosidase (chitinase) activity has recently been observed in patients with Gaucher disease (Hollak et al 1994). It has been suggested that this phenomenon may serve as a useful marker for the efficacy of treatment with enzyme replacement therapy. We report our findings on the comparison of plasma chitotriosidase levels in 8 patients treated with the modified human placental enzyme alglucerase and 8 patients treated by allogeneic bone marrow transplantation (BMT). Two years after transplantation the activity in the BMT patients had fallen by over 93% and has continued to fall. Now, 5-12 years post-BMT, 6 patients have normal levels of plasma chitotriosidase and 2 patients have activities slightly above the reference range. Patients have been treated with alglucerase for a considerably shorter time than the BMT patients. The chitotriosidase activities have fallen and are continuing to fall in 7 patients but at a slower rate than in the BMT group. In one patient there has been no appreciable change in activity over the last 6 months, which would suggest that she may be on too low a dosage.

Adolescent↗
PubMed1997

Compositae sensitivity and chronic hand dermatitis in a seven-year-old boy.

Compositae dermatitis is rare in childhood, with few cases documented in the literature. We report a 7-year-old boy who presented with a dermatitis mainly affecting his dominant hand. Patch testing revealed contact sensitivity to sesquiterpene lactone (SL) mix, and subsequent testing with Compositae oleoresins showed sensitivity to daisy, dandelion and chrysanthemum. The dermatitis improved on avoidance of handling plants. We have not documented any other cases of Compositae sensitivity in 187 other children, aged under 16 years, who have undergone patch testing with SL mix between 1992 and 1996 in our department. This case illustrates that Compositae sensitivity may present with a localized dermatitis and that, although uncommon, sensitization may occur in early childhood.

Allergens↗
PubMed1997

Transient leukaemia cutis in chronic lymphocytic leukaemia.

Leukaemia cutis arises due to cutaneous infiltration of neoplastic leukocytes or their precursors. Recent evidence suggests that this sign does not necessarily herald a poor prognosis. We describe a 72-year-old woman with B-cell chronic lymphatic leukaemia (CLL) who developed a papular eruption on her breast at the site of a recent herpetic eruption. Histology and immunostaining showed a dense dermal B-cell infiltrate in keeping with leukaemia cutis. The papules cleared in 6 months without treatment, leaving atrophic scars. The histological features and possible aetiological mechanisms of post-herpetic papular eruptions in CLL are reviewed.

Aged↗
PubMed1997

Transient leukaemia cutis in chronic lymphocytic leukaemia.

Leukaemia cutis arises from cutaneous infiltration by neoplastic leukocytes or their precursors. Recent evidence suggests that this sign does not necessarily herald a poor prognosis. We describe a 72-year-old woman with B-cell chronic lymphatic leukaemia who developed a papular eruption of her breast at the site of a recent herpetic eruption. Histology and immunostaining showed a dense dermal B-cell infiltrate in keeping with leukaemia cutis. The papules cleared in 6 months without treatment, leaving atrophic scars. The histological features and possible aetiological mechanisms of post-herpetic papular eruptions in chronic lymphatic leukaemia are reviewed.

Aged↗