An expression relating breaking stress and density of trabecular bone

Bone mineral density (BMD) is the principal diagnostic tool used in clinical settings to diagnose and monitor osteoporosis. Experimental studies on ex vivo bone samples from multiple skeletal locations have been used to propose that their breaking stress bears a power-law relationship to volumetric BMD, with a location-dependent index. We argue that a power-law cannot represent effects of trabecular removal, which is one of the leading causes of reduction in bone strength. A new expression, proposed on the basis of theoretical and numerical analysis of a mathematical model, is tested using previously published data on bone samples from iliac crest and vertebral body. It represents the experimental biomechanical data at least as well as the power-law, and provides means for extrapolating results from small biopsy samples to an entire bone. In addition, changes caused by trabecular thinning and anisotropy can be modeled by the expression.     

Novel multi-target compounds in the quest for new chemotherapies against Alzheimer’s disease: An experimental and theoretical study

The lack of any effective therapy along with the aging world population anticipates a growth of the worldwide incidence of Alzheimer’s disease (AD) to more than 100 million cases by 2050. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. In the amyloidogenic process, a β-secretase, known as BACE 1, plays a fundamental role in the production of Aβ fragments, and therefore, inhibition of such enzymes represents a major strategy for the rational design of anti-AD drugs. In this work, a series of four multi-target compounds (1–4), inspired by previously described ionophoric polyphenols, have been synthesized and studied. These compounds have been designed to target important aspects of AD, including BACE 1 enzymatic activity, Aβ aggregation, toxic concentrations of Cu²⁺ metal ions and/or ROS production. Two other compounds (5 and 6), previously reported by some of us as antimalarial agents, have also been studied because of their potential as multi-target species against AD. Interestingly, compounds 3 and 5 showed moderate to good ability to inhibit BACE 1 enzymatic activity in a FRET assay, with IC₅₀′s in the low micromolar range (4.4?±?0.3 and 1.7?±?0.3?μM, respectively), comparable to other multi-target species, and showing that the observed activity was in part due to a competitive binding of the compounds at the active site of the enzyme. Theoretical docking calculations overall agreed with FRET assay results, displaying the strongest binding affinities for 3 and 5 at the active site of the enzyme. In addition, all compounds selectively interacted with Cu²⁺ metal ions forming 2:1 complexes, inhibited the production of Aβ-Cu²⁺ catalyzed hydroxyl radicals up to a ～100% extent, and scavenged AAPH-induced peroxyl radical species comparably to resveratrol, a compound used as reference in this work. Our results also show good anti-amyloidogenic ability: compounds 1–6 inhibited both the Cu²⁺-induced and self-induced Aβ(1–40) fibril aggregation to an extent that ranged from 31% to 77%, while they disaggregated pre-formed Aβ(1–40) mature fibrils up to a 37% and a 69% extent in absence and presence of Cu²⁺, respectively. Cytotoxicity was additionally studied in Tetrahymena thermophila and HEK293 cells, and compared to that of resveratrol, showing that compounds 1–6 display lower toxicity than that of resveratrol, a well-known non-toxic polyphenol.     

Polychaete diversity in the Scotia Arc benthic realm: Are polychaetes tracers for faunal exchange?

The Scotia Arc is the only shallow-water and island bridge linking nowadays Patagonia and the Antarctic. The Antarctic Circumpolar Current as an oceanographic peculiarity makes this region an interesting biogeographic transition zone, because this frontal system traditionally is said to isolate the Antarctic fauna from that of the adjacent northern ecosystems. Based on benthos samples from three expeditions onboard R/V Polarstern, we studied distribution patterns of 200 polychaete species and 34 major benthic taxa in order to evaluate the role of polychaetes in the benthic realm of this part of the Southern Ocean. ANOSIM test distinguished three station groups: the central eastern Scotia Sea, the continental shelf off South America and stations at the tip of the Antarctic Peninsula. These station groups differed in organism densities and diversities with stations at the tip of the Antarctic Peninsula hosting the most diverse and dense community. The polychaete diversity patterns in the three assemblages evidenced closer connectivity between the tip of the Antarctic Peninsula and the central eastern Scotia Sea than between the continental shelf off South America with either the stations off the tip of the Peninsula or the central eastern Scotia Sea. This is probably supported by the Polar Front, which divides the island chain into two branches. Species distribution and community patterns of polychaetes appear to be associated with oceanographic and sediment conditions in this region. Most of the shared species showed the capability to tolerate differences in hydrostatic pressure. We suggest that the islands of the Scotia Sea may constitute a bridge for exchange of benthic species, particularly for polychaetes with eurybathic distribution and high dispersal capabilities.     

Functionally abnormal stromal cells and megakaryocyte size, ploidy, and ultrastructure in Sl/Sld mice

The first goal of the present studies was to determine if Sl/Sld megakaryocytes have features in common with the macrocytic megakaryocytes that genetically normal mice produce in response to acute platelet depletion. The second was to test the hypothesis that megakaryocyte abnormalities in Sl/Sld mice are due to genetically determined hemopoietic stromal cell abnormalities. Sizes and ploidies of mature Sl/Sld megakaryocytes were measured. Macrocytosis and a shift to higher ploidy values were found compared with normal. Within ploidy groups 16N-64N, Sl/Sld megakaryocytes were larger than normal megakaryocytes of the same ploidy. Transmission electron microscopy revealed that Sl/Sld megakaryocyte nuclei contain more and larger nucleoli, and the chromatin was more dispersed than in normal megakaryocyte nuclei of comparable maturity. Asynchronous megakaryocyte cytoplasmic maturation was found. Sl/Sld macrophages were also ultrastructurally abnormal. Megakaryocytic macrocytosis was reproduced in long-term bone marrow cultures in which the adherent layer was formed by Sl/Sld cells. It was the same if cultures were recharged with Sl/Sld or +/+ hemopoietic cells. Previously reported ambiguities in mixed cell cultures were avoided by recharging the adherent layers with only a million cells. These results were correlated with previously published observations. Sl/Sld megakaryocytes have features in common with megakaryocytes from acutely thrombocytopenic animals. One feature, macrocytosis, appears to be due to abnormal Sl/Sld stromal cells that are reproduced as adherent layer cells in long-term cultures. The responsible stromal cells in Sl/Sld mice may be counterparts of megakaryocytopoietic regulatory cells in the marrow stroma of normal animals.     

Regulation of murine megakaryocyte size and ploidy by non-platelet-dependent mechanisms in radiation-induced megakaryocytopenia

Megakaryocytic macrocytosis was evaluated in mice after irradiation with 6.5 Gy 60Co gamma rays. During the second and third months after sublethal irradiation, one or more of the following abnormalities of thrombocytopoiesis was present: thrombocytopenia, megakaryocytopenia, macromegakaryocytosis, a shift to higher ploidies, and enlargement of cells within ploidy groups. After transfusion-induced thrombocytosis, reductions in megakaryocyte size were delayed or absent relative to non-irradiated mice, and there was more of a tendency to shift to lower values for megakaryocyte ploidy. Mice with radiation-induced megakaryocytopenia failed to show rebound thrombocytosis during recovery from immunothrombocytopenia, in spite of further increases in megakaryocyte size and ploidy. The findings support the hypotheses that numbers of megakaryocytes may influence the regulation of megakaryocytopoiesis even when there is an excess of platelets and that ploidy distribution is not the sole determinant of the average size of a population of megakaryocytes. After irradiation, persistent megakaryocytopenia may not severely affect platelet production under steady-state conditions, but the ability of the marrow to respond to homeostatic regulation is compromised.     

Correlation between bioassay and radioimmunoassay for erythropoietin in human serum and urine concentrates

Both immunoreactive erythropoietin (Ep) and biologically active Ep were measured in 23 samples of human serum and 21 concentrates of human urine. Immunoreactive Ep was measured by radioimmunoassay (RIA). Biological activity was determined in the plethoric mouse bioassay in which 59Fe incorporation was converted to units of Ep from standard reference curves. Low values for Ep were determined from standard curves plotted as probits to improve sensitivity for levels of Ep as low as 30 mU/ml. Ep levels in 35 samples ranged between 30 and 1000 mU/ml by both assays; in 9 samples Ep was 15.2-37.5 mU/ml by RIA but was not detectable by bioassay. Analysis of the data for the 35 samples in which Ep could be measured by both assays showed a strong correlation between the values obtained by the two assays. These results indicate that the RIA used in these experiments detects biologically active Ep in human serum and urine when it is present in amounts only moderately higher than normal. The ultrafiltration method used for preparation of urine samples was effective in concentrating Ep in some urines, but the results were too erratic and nonquantitative to permit its use as a method for quantifying human urinary Ep excretion.     

Regulation of megakaryocytes in W/Wv mice

W/Wv mice were injected with antiplatelet serum to produce thrombocytopenia or with platelet transfusions to induce thrombocytosis. The responses of their platelets and megakaryocytes were followed to determine if proliferative abnormalities of the megakaryocytic system would be detected. W/Wv mice responded normally to the stimulation from thrombocytopenia with rebound thrombocytosis, macromegakaryocytosis, and macrothrombocytosis. The megakaryocytes of these mice became smaller than normal in response to post-thrombocytopenic rebound thrombocytosis but not to transfusion-induced thrombocytosis. Thus, endogenous thrombocytosis appeared to be a more potent suppressor of megakaryocyte growth than exogenous. These results failed to reveal an effective abnormality of the thrombocytopoietic regulatory system of W/Wv mice in spite of their intrinsically reduced numbers of megakaryocytes and the well known defect of stem cell proliferation. Thrombocytopoietic regulation appeared, therefore, to occur mainly at the committed, rather then pluripotential, stem cell level, and normal responses of the platelet system were observed in spite of severe abnormalities at the pluripotential stem cell level.