The differential involvement of adrenoceptors in challenges of different intensities

We investigated a family with optic atrophy which occurred in childhood or early adulthood plus late-onset cerebellar ataxia. The magnetic resonance imaging in the proband revealed cerebellar atrophy. The proband and her brother were homoplasmic for the most common mitochondrial DNA (mtDNA) 11778 mutation associated with Leber's hereditary optic neuropathy (LHON). This study showed further evidence that central nervous system lesions can occur in cases of LHON mtDNA mutation.     

Portosystemic shunt in Budd-Chiari syndrome: long-term survival and factors affecting shunt patency in 25 patients in Western countries

BACKGROUND: In Budd-Chiari syndrome (BCS) treated by portosystemic shunt, postoperative shunt thrombosis is associated with high morbidity and mortality rates. The aim of this study was to determine factors associated with shunt thrombosis. METHODS: From 1985 to 1991, 25 patients underwent portosystemic shunt for BCS. According to the patency of the shunt during the postoperative period and follow-up, patients were divided into two groups including 17 patients with patent shunt and 8 (32%) with shunt thrombosis. RESULTS: In patients with patent shunt, actuarial survival rate at 5 years was 87% versus 38% in patients with shunt thrombosis (p < 0.05). Duration of symptoms before operation was higher in patients with shunt thrombosis than in patients with patent shunt (315 +/- 483 vs 109 +/- 168 days, p < 0.05). In patients with patent shunt, extensive fibrosis or cirrhosis was observed in 3 of 17 (18%) versus in 5 of 8 (63%) of patients with shunt thrombosis (p < 0.05). Shunt thrombosis was observed in 3 of 3 patients (100%) with the combination of myeloproliferative disorder, duration of symptoms more than 100 days, and cirrhosis versus 0 of 6 (0%) patients without this combination (p < 0.05). CONCLUSIONS: In acute form of BCS (with short history of the disease and absence of extensive fibrosis or cirrhosis), early portal decompression is mandatory, with low risk of shunt thrombosis and good long-term results. In chronic form of BCS, the risk of shunt thrombosis is high and long-term results are bad; in these patients, orthotopic liver transplantation must be considered.     

A Survey on the Numerics and Computations for the Landau-Lifshitz Equation of Micromagnetism

The Landau-Lifshitz (LL)equation of micromagnetism governs rich variety of the evolution of magnetization patterns in ferromagnetic media. This is due to the complexity of physical quantities appearing in the LL equation. This complexity causes also an interesting mathematical properties of the LL equation: nonlocal character for some quantities,nonconvex side-constraints, strongly nonlinear terms. These effects influence also the numerical approximations. In this work, recent developments on the approximation of weak solutions, together with the overview of well-known methods for strong solutions,are addressed. Author is supported by the Fund for Scientific Research - Flanders FWO (Belgium).     

Macrophage activation results in bone resorption

Monocytes or macrophages from important accessory cells in the regulation of bone metabolism and destruction. Cells of the mononuclear phagocyte lineage form the precursor cells of the osteoclasts. Soluble products produced by activated macrophages regulate progenitor cell proliferation, recruitment, differentiation, and activity of osteoblasts and osteoclasts. After osteoclasts are removed from the resorption site, macrophages process bone surfaces and create a cement line before osteoblasts enter to form new bone. Although osteolysis associated with normal bone remodeling is seen as an osteoclast driven process, it may be that in chronic inflammation macrophage activation and vascular derangements lead to low pH, local bone demineralization (acid attack), and H+ mediated stimulation of the primary afferent nociceptive nerve fibers (bone pain). Osteoclasts are not able to attach to demineralized bone or to osteoid surfaces. However, if macrophages degrade the demineralized organic bone matrix, chemotactic factors and attachment sites for osteoclasts are produced. In such a scenario, the osteoclast-osteoblast mediated activation, resorption, and formation cycle would be secondarily activated. Such events may play a role in the most common orthopaedic problem related to macrophage activation, aseptic loosening of orthopaedic joint implants, which is secondary to a chronic foreign body reaction and to micromovement.     

Negative chronotropic and inotropic effects exerted by diadenosine hexaphosphate (AP6A) via A1-adenosine receptors

1. Diadenosine hexaphosphate (AP6A) exerts vasoconstrictive effects. The purpose of this study was to investigate whether AP6A has any effect on cardiac function. 2. The effects of AP6A (0.1-100 microM) on cardiac contractility and frequency were studied in guinea-pig and human isolated cardiac preparations. Furthermore, the effects of AP6A on the amplitude of the L-type calcium current, on the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content and on the phosphorylation of regulatory phosphoproteins, i.e. phospholamban and troponin inhibitor, were investigated in guinea-pig isolated ventricular myocytes. 3. In isolated spontaneously beating right atria of the guinea-pig AP6A exerted a negative chronotropic effect and reduced the rate of contraction maximally by 35% (IC20 = 35 microM). 4. In isolated electrically driven left atria of the guinea-pig AP6A exerted a negative inotropic effect and reduced force of contraction maximally by 23% (IC20 = 70 microM). 5. In isolated electrically driven papillary muscles of the guinea-pig AP6A alone was ineffective, but attenuated isoprenaline-stimulated force of contraction maximally by 23% (IC20 = 60 microM). Furthermore, AP6A attenuated the relaxant effect of isoprenaline. 6. In human isolated electrically driven ventricular preparations AP6A alone was ineffective, but attenuated isoprenaline-stimulated force of contraction by maximally 42% (IC20 = 18 microM). Moreover, AP6A attenuated the relaxant effect of isoprenaline. 7. All these effects of AP6A were abolished by the selective A1-adenosine receptor antagonist 1,3-dipropyl-cyclopentyl-xanthine (DPCPX, 0.3 microM), whereas the M-cholinoceptor antagonist atropine (10 microM) and the P2-purinoceptor antagonist suramin (300 microM) failed to abolish the effects of AP6A. 8. AP6A 100 microM had no effect on the amplitude of the L-type calcium current, but attenuated isoprenaline-stimulated L-type calcium current. The maximum of the current-voltage relationship (I-V curve) was shifted to the left by isoprenaline and additional application of AP6A shifted the I-V curve back to the right to the control value. The phosphorylation state of phospholamban and the troponin inhibitor was unchanged by AP6A alone, but was markedly attenuated by AP6A in the presence of isoprenaline. Cyclic AMP levels remained unchanged by AP6A, even after stimulation with isoprenaline. 9. In summary, AP6A exerts negative chronotropic and inotropic effects in guinea-pig and human cardiac preparations. These effects are mediated via A1-adenosine receptors as all effects were sensitive to the selective A1-adenosine receptor antagonist DPCPX. Furthermore, the effects of AP6A on cyclic AMP levels, protein phosphorylation and the L-type calcium current are in accordance with stimulation of A1-adenosine receptors.     

Inter-individual variability in Ca2+ signalling in platelets from healthy volunteers: effects of aspirin and relationship with expression of endomembrane Ca2+-ATPases

Increased Ca2+ signal generation may lead to hyperactivity of platelets and contribute to thrombotic complications. Using fura-2-loaded platelets from 51 healthy volunteers, high variability was detected in the Ca2+ responses evoked by the receptor agonists, thrombin and collagen, and the inhibitor of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA), thapsigargin (Tg). Oral intake of 500mg aspirin reduced the magnitude of the Ca2+ responses, and lowered the intra-individual coefficients of variance of the responses by 50%. However, the corresponding inter-individual variance coefficients were only a little influenced by aspirin intake, pointing to subject-dependent factors in Ca2+ handling that are unrelated to thromboxane formation. With each agonist, 6-9% of the subjects had platelets with relatively high Ca2+ responses (> mean + SD) both before and after aspirin intake. In 90% (9/10) of these cases the high responsiveness was confirmed in platelets obtained 6-12 months later. The Tg- but not thrombin-induced Ca2+ responses correlated inversely with the expression levels of SERCA PL/IM 430 (SERCA-3b) in platelets. After aspirin intake, the Ca2+ responses with collagen but not thrombin correlated inversely with SERCA-2b expression. These results suggest that, in the absence of potentiating effects of thromboxane, (i) the amount of PL/IM 430-recognizable SERCA may control the Ca2+ signal when SERCA-2b is specifically inhibited (with Tg), and (ii) the expression of SERCA-2b determine the collagen- but not the thrombin-evoked Ca2+ signal. Accordingly, limited Ca2+-pumping activity by low expression of one of the SERCA isoforms is likely to be one of the factors resulting in increased platelet activity towards collagen or thapsigargin but not thrombin.     

Estimation of impurity profiles of drugs and related materials: part 19: theme with variations. Identification of impurities in 3-oxosteroids

Due to the varied reactions leading to the 3-oxo group in steroids and the reactivity of its environment, a large number of impurities related to this group are formed during the reaction steps and the degradation studies. In this paper the experiences from the authors laboratory with the 3-oxo-related impurities in 19-nor-4-ene-3-oxosteroids (norgestrel, norethisterone, nandrolone, its esters and Nestorone) as well as corticosteroids (prednisolone, mazipredone, etc) are presented. The impurities include saturated 3-ones, 1-ene-3-ones, 5(10)-ene-3-ones, 3-deoxo and 3-ethinyl-3,5-diene derivatives, 6-ene, 8(14)-ene, 6,8(14)-diene, 6-hydroxy (alpha and beta), 10beta-hydroxy and 6-one derivatives in 4-ene-3-oxosteroids and 8(9)-ene, 9(11)-ene, 11alpha-hydroxy, 11-oxo and 4-ene-3-one derivatives in 11beta-hydroxy-1,4-diene-3-oxosteroids. The chromatographic, spectroscopic and hyphenated techniques used in this study include TLC, GC, HPLC with diode array UV detector, GC-MS, LC-MS and NMR methods.     

Solid state reactions in the Fe2O3-CaCO3-In2O3 system

The kinetics of solid-state reactions of powdered reactants were investigated by X-ray and by differential thermogravimetry in a magnetic field. Measurements revealed mutual diffusion of the Fe³⁺ and In³⁺ ions in the Fe₂O₃-In₂O₃ system heat treated for 3 h at 700 to 1400° C. Diffusion of indium into the Fe₂O₃ lattice caused a shift of the Curie temperature of the antiferromagnetic iron oxide towards lower temperatures. Only Caln₂O₄ was found between CaCO₃ and In₂O₃ up to 1400° C. Also, in the Fe₂O₃-CaCO₃-In₂O₃in system, the reaction started with the mutual diffusion of iron and indium and the forming of CaFe₂O₄. End-products were the magnetic -Ca₄Fe₁₄O₂₅ and CaFe₄O₇, and the non-magnetic CaFe₅O₇, depending on the In³⁺ concentration. Indium stabilized the magnetic calcium-iron oxide structures, shifting their Curie temperatures towards lower values.     

Correction to: “SPOCU”: scaled polynomial constant unit activation function

Neural Computing and Applications - Addendum on SPOCU fitting and Erratum.