Density of states in graphene with vacancies: midgap power law and frozen multifractality.

The density of states ϱ(E) of graphene is investigated numerically and within the self-consistent T-matrix approximation in the presence of vacancies within the tight binding model. The focus is on compensated disorder, where the concentration of vacancies n(A) and n(B) in both sublattices is the same. Formally, this model belongs to the chiral symmetry class BDI. The onlinear sigma model predicts for BDI a Gade-type singularity ϱ(E)∼|E|(-1)exp[-|log(E)|(-1/x)]. Our numerical data are comparable to this result in a preasymptotic regime that gives way, however, at even lower energies to ϱ(E)∼E(-1)|log(E)|(-x̃), 1≤x̃<2. We take this finding as evidence that, similar to the case of dirty d-wave superconductors, generic bipartite random hopping models may also exhibit unconventional (strong-coupling) fixed points for certain kinds of randomly placed scatterers if these are strong enough. Our research suggests that graphene with (effective) vacancy disorder is a physical representative of such systems.

[Drug interactions]. / Arzneimittelinteraktionen.

Drug-drug interactions can be used to enhance effectiveness but they are also a significant cause of adverse drug reactions. Alterations in liberation, absorption, distribution, metabolism, and excretion may all affect the pharmacokinetics of a drug. Cytochrome P450 enzymes and drug transporters like ABC-transporters determine the clearance of many drugs leading to alterations in therapeutic effect. In contrast pharmacodynamic drug interactions will alter drug effects in the absence of concentration changes of the co-administered drug. Alterations of a drug effect may require changes in dose to maintain the therapeutic effect.

Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity.

We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed-sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration-time curve (AUC)(0-8 h) of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 h) of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.

Calcium balance during calcitriol and paricalcitol administration in healthy humans.

OBJECTIVE: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. METHODS: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 microg/day) and calcitriol (0.5 microg/day). RESULTS: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03+/-0.69 pmol/l), whereas paricalcitol had no effect. CONCLUSION: Using a dosing ratio of 1:3 for calcitriol:paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.

[Safety of blood transfusion at the international level. The role of WHO]. / La sécurité transfusionnelle à l'échelle internationale: le rôle de l'OMS.

Blood safety is an international public health challenge, particularly since the emergence of HIV AIDS. Recognizing the gross disparities between countries in the adequacy of national blood supplies and the risks arising from poorly organized services, particularly in developing countries, the World Health Organization has developed a global strategy for blood safety and availability. Dr N. Dhingra, coordinator, blood transfusion safety, WHO Headquarters, and Dr V. Hafner, focal point for blood safety in the WHO regional office for Europe, present the main features of this strategy: well-organized, nationally coordinated blood transfusion services with quality systems in all areas; the collection of blood only from voluntary non-remunerated blood donors from low-risk populations; the quality-assured testing of all donated blood; the safe and appropriate use of blood and blood products; and global collaboration for blood safety. WHO's programs, some difficulties encountered and outcomes are also described in this article.

Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis.

Giant cell arteritis (GCA) is a systemic vasculitis preferentially affecting large and medium-sized arteries. Inflammatory infiltrates in the arterial wall induce luminal occlusion with subsequent ischemia and degradation of the elastic membranes, allowing aneurysm formation. To identify pathways relevant to the disease process, differential display-PCR was used. The enzyme aldose reductase (AR), which is implicated in the regulation of tissue osmolarity, was found to be upregulated in the arteritic lesions. Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells. The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation. In vitro exposure of mononuclear cells to HNE was sufficient to induce AR production. The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat. Inhibition of AR increased HNE adducts twofold and the number of apoptotic cells in the arterial wall threefold. These data demonstrate that AR has a tissue-protective function by preventing damage from lipid peroxidation. We propose that AR is an oxidative defense mechanism able to neutralize the toxic effects of lipid peroxidation and has a role in limiting the arterial wall injury mediated by reactive oxygen species.

Giant cell arteritis--a molecular approach to the multiple facets of the syndrome.

Molecular studies of giant cell arteritis indicate that T cells are recruited to the wall of medium-sized and large arteries, are activated locally, produce IL-2 and IFN-gamma, and regulate the activity of tissue-infiltrating macrophages. Downstream effects of T cell activation include the production of proinflammatory cytokines, metalloproteinases, and growth factors. Growth factors are instrumental in the process of intimal hyperplasia, leading to luminal occlusion and tissue ischemia. The amounts of IL-2, IFN-gamma, and the growth factor PDGF in the vascular lesions varies among patients and are correlated with differences in patterns of clinical manifestations. Giant cell arteritis complicated by cranial ischemia, such as anterior optic neuropathy or stroke, is characterized by high levels of IFN-gamma and PDGF. If the IFN-gamma-PDGF loop is less developed, fever and wasting can dominate the disease. Dominant production of IL-2 is associated with polymyalgia rheumatica. The finding of different inflammatory pathways translating into different clinical phenotypes may reflect differences in the contribution of the arterial wall. Alternative hypotheses include a role of multiple disease-inducing antigens with different tissue distributions or tropisms.

[Temporary changes and permanent changes in the erythrocyte blood-group antigens in malignant hemopathies]. / Modifications temporaires et modifications persistantes des antigènes érythrocytaires de groupe sanguin au cours des hémopathies malignes.

Samples of peripheral blood were taken from 11 patients (blood group A, B and O), suffering from acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), before and after chemotherapy, compared to normal control samples. The RBC's typing was done by standard agglutination technique (with conventional human and murine anti-sera) and flow cytometry. While using different reagent dilutions, a lower expression of the A or B antigen was noticed in all patients, even if direct typing of the RBC's revealed an apparently normal pattern. The most important depletion of antigenic expression was found to correspond to the highest concentration of myeloblasts in the bone marrow, with hypoplastic erythrocytic series. The modified H reactivity, detected at admission, was still present after complete remission, as an expression of the residual disease. Studies of the H expression could eventually become a parameter of evaluating the moment of relapse of the myeloproliferative disease.