A randomized placebo-controlled trial of short-term graded transdermal estradiol in healthy gonadotropin-releasing hormone agonist-suppressed pre- and postmenopausal women: effects on serum markers of bone turnover, insulin-like growth factor-I, and osteoclastogenic mediators

The acute effects of estradiol on procollagen type 1 formation in pre- and postmenopausal women are controversial. Twenty-three premenopausal women and 13 postmenopausal women received two consecutive im injections of 3.75 mg leuprolide acetate 3 wk apart to block endogenous ovarian steroidogenesis. Transdermal estradiol therapy commenced on the night of the second leuprolide injection in all subjects, except five pre- and two postmenopausal women who were randomized to receive placebo patches. Estradiol therapy was applied incrementally, with each dose of 0.05, 0.10, 0.15, and 0.20 mg/d administered for 4 consecutive days, to mimic the estradiol changes typifying the follicular phase of the menstrual cycle. Blood aminoterminal propeptide of type I procollagen (PINP), intact osteocalcin (OC), carboxyterminal telopeptide of type I collagen (CTx), IGF-I, and estradiol were measured before and at the end of each estradiol increment. Potential mediators such as osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) were also measured. Despite comparable increases in serum estradiol, PINP increased more in postmenopausal compared with premenopausal women (between-group P = 0.03) and occurred at a time when CTx and OC did not change. CTx and IGF-I changed minimally and inconsistently, whereas OC, RANKL, and osteoprotegerin were stable. Repeated measures linear regression disclosed a significant negative association between increases in estradiol and PINP in premenopausal women (P = 0.0006) only. This suggests that lower dose estradiol should greatly increase PINP. Analogous regressions also showed significant negative relationships between changes in estradiol and RANKL in both pre- (P = 0.04) and postmenopausal (P = 0.002) women. Changes in serum markers of bone formation (PINP or OC) did not correlate with those of IGF-I. We conclude that lower dose estradiol rapidly increases osteoblastic collagen synthesis in women at a time when collagen degradation is stable and that this response differs between pre- and postmenopausal women. The effect of estradiol on bone formation does not appear to be mediated by IGF-I. In contrast, RANKL is likely to mediate the effect of estradiol on osteoclastogenesis.     

Impairment by Heparin of Primary Haemostasis and Platelet [14C]5-Hydroxytryptamine Release

Heparin was administered to 34 normal subjects by intravenous injection (100 u/kg) and the template bleeding time was significantly increased both 10 min and 120 min following injection. Before heparin the bleeding time was 5.3±1.0 min (mean±1 SD); 10 min after injection it was 9.8±5.6 min ( P <0.001); and 120 min after injection it was 7.2±3.9 min ( P <0.001). Increases in the bleeding time were unrelated to changes in platelet count, and independent of heparin's effect on plasma coagulation. In blood drawn 10 min and 120 min following heparin injection, there was significantly less [¹⁴C]5-HT released from platelet-rich plasma (PRP) in response to collagen, 0.41 mM epinephrine and 8 μM ADP, although in vitro addition of heparin (0.1 u/ml, 0.5 u/ml and 2.5 u/ml) to baseline PRP of three subjects did not depress [¹⁴C]5-HT release. Our experiments suggest that intravenous administration of a therapeutic dose of heparin can cause a significant reversible impairment of platelet haemostatic properties, possibly by an indirect mechanism.     

Avoided valence transition in a plutonium superconductor

The d and f electrons in correlated metals are often neither fully localized around their host nuclei nor fully itinerant. This localized/itinerant duality underlies the correlated electronic states of the high-T_c cuprate superconductors and the heavy-fermion intermetallics and is nowhere more apparent than in the 5f valence electrons of plutonium. Here, we report the full set of symmetry-resolved elastic moduli of PuCoGa₅—the highest T_c superconductor of the heavy fermions (T_c = 18.5 K)—and find that the bulk modulus softens anomalously over a wide range in temperature above T_c. The elastic symmetry channel in which this softening occurs is characteristic of a valence instability—therefore, we identify the elastic softening with fluctuations of the plutonium 5f mixed-valence state. These valence fluctuations disappear when the superconducting gap opens at T_c, suggesting that electrons near the Fermi surface play an essential role in the mixed-valence physics of this system and that PuCoGa₅ avoids a valence transition by entering the superconducting state. The lack of magnetism in PuCoGa₅ has made it difficult to reconcile with most other heavy-fermion superconductors, where superconductivity is generally believed to be mediated by magnetic fluctuations. Our observations suggest that valence fluctuations play a critical role in the unusually high T_c of PuCoGa₅.PuCoGa₅ enters the superconducting state below T_c = 18.5 K (1)—an order of magnitude higher than all Ce- or U-based superconductors. This contrast raises the question of whether PuCoGa₅ simply benefits from a higher superconducting-pairing energy scale than its U- and Ce-based relatives or instead, whether PuCoGa₅ is host to a completely different pairing mechanism. In many lanthanide and actinide compounds, the f electrons are nearly degenerate with the conduction band. In addition, the outer f-shell states are close in energy and may support two (or more) nearly degenerate valence configurations (2). In some cases, this valence degeneracy becomes unstable, leading to valence fluctuations and ultimately, a transition to a different valence state as a function of temperature, pressure, and/or doping (3). X-ray and photoemission spectroscopy (4, 5), neutron form factor measurements (6), and theoretical calculations (7) all indicate that PuCoGa₅ is in an intermediate valence state, with the 5f⁶ (Pu²⁺), 5f⁵ (Pu³⁺), and 5f⁴ (Pu⁴⁺) orbitals all residing near the chemical potential and all partially occupied. PuCoGa₅ exhibits no localized magnetic moments (6), and like other plutonium systems, its 5f electrons cannot be treated as fully localized or fully itinerant (4). [Strong Curie–Weiss-like magnetic susceptibility was initially reported for PuCoGa⁵, consistent with a local moment. However, additional susceptibility measurements (including polarized neutron scattering) have not reproduced this result (6).]In contrast, the analogous CeMIn₅ (M = Co, Rh, and Ir) series of superconductors has localized Ce 4f magnetic moments, with a tendency toward antiferromagnetic order (8). These systems reside close to an antiferromagnetic quantum critical point (9), where antiferromagnetic fluctuations are believed to mediate unconventional superconductivity. Because there is no evidence for PuCoGa₅ being in proximity to a magnetically ordered state (10), it is unlikely that magnetic fluctuations are the primary driver of its anomalously high T_c of 18.5 K (11). Valence fluctuations—where the total number of f electrons per ion fluctuates with the conduction band or the configuration of a fixed number of f electrons fluctuates between two or more nearly degenerate f states (sometimes known as orbital fluctuations)—have been proposed as a possible alternative mechanism for superconductivity in several heavy-fermion systems (12–15). Here, we report that PuCoGa₅’s elastic moduli soften over a large temperature range above T_c. Analysis of the observed temperature dependence of the softening, the symmetry channel in which it occurs, and its interplay with the superconducting transition suggests that valence fluctuations are critical for superconductivity in this system.     

Rehabilitation of ectodermal dysplasia patients presenting with hypodontia: outcomes of implant rehabilitation part 1

Purpose

This study has evaluated the pre and post perceptions of patients with ectodermal dysplasia (ED) who have been referred to Westmead Centre for Oral Health for treatment with dental implants.

Analysis of human hemopoietic progenitor cells for the expression of glycoprotein IIIa

Human hemopoietic progenitor cells were examined for the expression of glycoprotein IIIa (GPIIIa). This protein, which forms the beta-subunit of the GPIIb/IIIa receptor for cytoadhesive proteins as well as the beta-subunit of the vitronectin receptor, represents the most sensitive cell surface marker so far identified for the megakaryocytic lineage. Bone marrow cells were fractionated by a discontinuous Percoll gradient to separate cells that form megakaryocytic colonies in culture (1.05 greater than rho less than 1.077 g/ml). Density centrifugation was followed by indirect immunopanning to select for an enriched population of progenitor cells depleted of most of the mature cells of the myeloid, lymphoid, and erythroid lineages. This cell suspension was labeled with antibodies directed against determinants of GPIIIa and analyzed using a fluorescence-activated cell sorter (FACS). Fractions of cells were sorted and analyzed for the ability to form hemopoietic colonies in culture. Our study demonstrated that megakaryocytic progenitor cells (CFU-M) as well as granulocyte-macrophage colony-forming units (CFU-C), erythroid colony-forming units (BFU-E), and mixed lineage colony-forming units (CFU-GEMM) express HLA-DR antigens but lack GPIIIa. Therefore GPIIIa represents a marker that is not present on hemopoietic progenitor cells, but is expressed on the progenies of CFU-M. In view of the importance of GPIIIa as a component of receptors for cytoadhesive proteins, this finding may help to elucidate the adhesive interactions between early hemopoietic cells and bone marrow interstitium.     

Platelets as target cells in rheumatoid arthritis and systemic lupus erythematosus: A platelet specific immunoglobulin inducing the release reaction

Summary Sera from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were assessed for in vitro platelet activation as measured by serotonin release; 24% (30) of 124 tested RA sera and 51% (35) of 69 SLE sera induced a significant 3H serotonin release. Investigation of 17 synovial fluid samples from RA patients revealed significant release in 82%. Concomitant testing for lymphocytotoxic antibodies and immune complexes did not show any correlation to platelet activation. Upon gel filtration the release-inducing activity of positive sera was localized in the region of 160 000 Daltons. Further characterization by ion exchange chromatography, immune electrophoresis, chromatographic and SDS PAGE molecular weight determinations, as well as analytical ultracentrifugation all confirmed the IgG nature of the release-inducing protein. Negative blocking experiments performed by preincubation of platelets with Fc-IgG fragments prior to challenge with a release-inducing serum excluded the participation of Fc receptors in the reaction. It was concluded that the release was caused by a platelet reactive IgG antibody. This antibody may also cause release of platelet mediators in vivo and may thus contribute to the pathogenesis of the generalized vasculopathy in both diseases.     

Progress on the design and development of the continuous-flow total artificial heart

Cleveland Clinic's continuous‐flow total artificial heart has one motor and one rotating assembly supported by a hydrodynamic bearing. The right hydraulic output is self regulated by passive axial movement of the rotating assembly to balance itself with the left output. The purpose of this article is to present progress in four areas of development: the automatic speed control system, self‐regulation to balance right/left inlet pressures and flows, hemolysis testing using calf blood, and coupled electromagnetics (EMAG) and computational fluid dynamics (CFD) analysis. The relationships between functions of motor power and speed, systemic flow, and systemic vascular resistance (SVR) were used for the sensorless speed control algorithm and demonstrated close correlations. Based on those empirical relationships, systemic flow and SVR were calculated in the system module and showed good correlation with measured pump flow and SVR. The automatic system adjusted the pump's speed to obtain the target flow in response to the calculated SVR. Atrial pressure difference (left minus right atrial pressure) was maintained within ±10 mm Hg for a wide range of SVR/pulmonary vascular resistance ratios, demonstrating a wide margin of self‐regulation under fixed‐speed mode and 25% sinusoidally modulated speed mode. Hemolysis test results indicated acceptable values (normalized index of hemolysis <0.01 mg/dL). The coupled EMAG/CFD model was validated for use in further device development.