Stacking-Dependent Spin Interactions in Pd/Fe Bilayers on Re(0001).

Using spin-polarized scanning tunneling microscopy and density functional theory, we have studied the magnetic properties of Pd/Fe atomic bilayers on Re(0001). Two kinds of magnetic ground states are discovered due to different types of stacking of the Pd adlayer on Fe/Re(0001). For fcc stacking of Pd on Fe/Re(0001), it is a spin spiral propagating along the close-packed (ΓK[over ¯]) direction with a period of about 0.9 nm, driven by frustrated exchange and Dzyaloshinskii-Moriya interactions. For the hcp stacking, the four-site four-spin interaction stabilizes an up-up-down-down state propagating perpendicular to the close-packed direction (along ΓM[over ¯]) with a period of about 1.0 nm. Our work shows how higher-order exchange interactions can be tuned at interfaces.

Stability of single skyrmionic bits.

The switching between topologically distinct skyrmionic and ferromagnetic states has been proposed as a bit operation for information storage. While long lifetimes of the bits are required for data storage devices, the lifetimes of skyrmions have not been addressed so far. Here we show by means of atomistic Monte Carlo simulations that the field-dependent mean lifetimes of the skyrmionic and ferromagnetic states have a high asymmetry with respect to the critical magnetic field, at which these lifetimes are identical. According to our calculations, the main reason for the enhanced stability of skyrmions is a different field dependence of skyrmionic and ferromagnetic activation energies and a lower attempt frequency of skyrmions rather than the height of energy barriers. We use this knowledge to propose a procedure for the determination of effective material parameters and the quantification of the Monte Carlo timescale from the comparison of theoretical and experimental data.

Enhanced atomic-scale spin contrast due to spin friction.

Atom manipulation with the magnetic tip of a scanning tunneling microscope is a versatile technique to construct and investigate well-defined atomic spin arrangements. Here we explore the possibility of using a magnetic adatom as a local probe to image surface spin textures. As a model system we choose a Néel state with 120° between neighboring magnetic moments. Close to the threshold of manipulation, the adatom resides in the threefold, magnetically frustrated hollow sites, and consequently no magnetic signal is detected in manipulation images. At smaller tip-adatom distances, however, the adatom is moved towards the magnetically active bridge sites and due to the exchange force of the tip the manipulation process becomes spin dependent. In this way the adatom can be used as an amplifying probe for the surface spin texture.

Conical spin-spiral state in an ultrathin film driven by higher-order spin interactions.

We report a transverse conical spin spiral as the magnetic ground state of a double-layer Mn on a W(110) surface. Using spin-polarized scanning tunneling microscopy, we find a long-range modulation along the [001] direction with a periodicity of 2.4 nm coexisting with a local row-wise antiferromagnetic contrast. First-principles calculations reveal a transverse conical spin-spiral ground state of this system which explains the observed magnetic contrast. The canting of the spins is induced by higher-order exchange interactions, while the spiraling along the [001] direction is due to frustrated Heisenberg exchange and Dzyaloshinskii-Moriya interaction.

The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease.

OBJECTIVE: Plant sterols (sitosterol, campesterol, stigmasterol and brassicasterol) are solely dietary-derivable sterols that are structurally very similar to cholesterol. In contrast to peripheral cholesterol, plant sterols can cross the blood-brain barrier and accumulate within mammalian brain. As an impaired function of the cerebrospinal fluid (CSF)-blood barrier is linked to neurodegenerative disorders, i.e. Alzheimer's disease (AD), we investigated whether this results in altered plant sterol concentrations in CSF. METHOD: Applying gas chromatography/mass spectrometry analysis, plant sterol concentrations were measured in plasma and CSF of patients with AD (n = 67) and controls (n = 29). Age, gender, plasma-to-CSF albumin ratio, CSF Aß(42) , CSF pTau, APOE4 genotype, and serum creatinine were applied as covariates in the statistical analysis for individual plant sterols in order to compare plasma and CSF plant sterol concentrations between patients with AD and controls. RESULTS: Albumin quotient was a consistent predictor in CSF for cholesterol and methyl plant sterols campesterol and brassicasterol. Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol (P < 0.001) in CSF of patients with AD. Binary logistic regression analysis revealed that brassicasterol improved the predictive value when added to pTau and Aß42 in a biomarker model. CONCLUSION: Brassicasterol might be a relevant additional biomarker in AD.

4beta-hydroxycholesterol as a marker of CYP3A4 inhibition in vivo - effects of itraconazole in man.

OBJECTIVE: Itraconazole, a triazole antifungal agent, has been demonstrated to act as an inhibitor of the ligand induced pregnane X receptor-mediated transcriptional regulation of the CYP3A4 gene. Here, we study the potential endogenous serum marker of CYP3A4 activity, 4beta-hydroxycholesterol, during therapy with itraconazole. PATIENTS AND METHODS: 8 male patients with onychomycosis received two 1-week cycles of treatment with 400 mg itraconazole once daily in an open, prospective exploratory trial. Fasting serum samples were taken at the beginning and at the end of each cycle. The levels of cholesterol were measured using gas chromatography-flame ionization detection, while cholesterol and bile acid precursors were quantified by gas chromatography-mass spectrometry. RESULTS: Total cholesterol decreased by 10% (p < 0.0005) during the itraconazole treatment. Concentrations of the cholesterol precursor lanosterol and 24, 25-dihydrolanosterol increased 10- and 240-fold, respectively (p < 0.001 for both). Interestingly, the ratio of serum lathosterol to cholesterol, an indicator of endogenous cholesterol synthesis downstream from lanosterol, remained unchanged. Absolute and cholesterol-corrected concentrations of 4beta-hydroxycholesterol, formed by CYP3A4-mediated oxidation, decreased significantly during both cycles, on average by 29.1% (p = 0.0006) and 20.8% (p = 0.0062), respectively. The brain-specific cholesterol metabolite 24S-hydroxycholesterol as well as its ratio to cholesterol increased by 19.7% (p = 0.0422) and 34.9% (p = 0.0013), respectively, while the concentrations of the other bile acid precursors, 7alpha-hydroxycholesterol and 27-hydroxycholesterol, remained unchanged. CONCLUSIONS: In conclusion, 4beta-hydroxycholesterol appears to be a sensitive endogenous surrogate marker in human serum for inhibition of CYP3A4 by itraconazole.

Atomic-scale spin spiral with a unique rotational sense: Mn monolayer on W(001).

Using spin-polarized scanning tunneling microscopy we show that the magnetic order of 1 monolayer Mn on W(001) is a spin spiral propagating along 110 crystallographic directions. The spiral arises on the atomic scale with a period of about 2.2 nm, equivalent to only 10 atomic rows. Ab initio calculations identify the spin spiral as a left-handed cycloid stabilized by the Dzyaloshinskii-Moriya interaction, imposed by spin-orbit coupling, in the presence of softened ferromagnetic exchange coupling. Monte Carlo simulations explain the formation of a nanoscale labyrinth pattern, originating from the coexistence of the two possible rotational domains, that is intrinsic to the system.

Long-term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2-year, open-label extension study.

OBJECTIVE: To assess the long-term efficacy and safety profile of ezetimibe 10 mg/day in patients with homozygous sitosterolemia. METHODS: This was an extension of a multi-centre, randomised, double-blind, placebo-controlled base study in which patients with homozygous sitosterolemia and plasma sitosterol concentrations > 5 mg/dl were randomised 4 : 1 to ezetimibe 10 mg/day (n = 30) or placebo (n = 7) for 8 weeks. Patients who successfully completed the base study with > 80% compliance to study medication were eligible to enter two, successive, 1-year extension studies in which ezetimibe 10 mg/day was administered in an open-label manner. Patients remained on their current treatment regimen (e.g. bile salt-binding resins, statins and low-sterol diet) during the base and extension studies. Patients had to be off ezetimibe therapy for > or = 4 weeks prior to entering the first extension. Efficacy and safety/tolerability parameters were evaluated every 12 and 26 weeks in the first and second years respectively. The primary efficacy end-point was mean percentage change in plasma sitosterol from baseline to study end for the cohort of patients (n = 21) who successfully completed the second extension study. RESULTS: Treatment with ezetimibe 10 mg/day led to significant mean percentage reductions from baseline in plasma concentrations of sitosterol (-43.9%; p < 0.001), campesterol (-50.8%; p < 0.001), low-density lipoprotein (LDL) sterols (-13.1%; p < 0.050), total sterols (-10.3%; p < 0.050) and apolipoprotein (apo) B (-10.1%; p < 0.050). No significant changes from baseline were observed for lathosterol, high-density lipoprotein sterol, triglycerides or apo A-1. Maximal reductions in sitosterol and campesterol occurred within the first 52 weeks of treatment and were sustained for the duration of the study. For LDL sterol, total sterols and apo B, maximal reductions were achieved early (by weeks 4 or 16) and waned slightly through the remainder of the study. Overall ezetimibe 10 mg was well tolerated. CONCLUSION: In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.

Efficacy and safety of ezetimibe 40 mg vs. ezetimibe 10 mg in the treatment of patients with homozygous sitosterolaemia.

OBJECTIVE: To assess the effect of ezetimibe (EZE) 40 mg/day on non-cholesterol sterol plasma concentrations in patients with homozygous sitosterolaemia (HoS). METHODS: This was a multi-centre, randomised, double-blind, placebo-controlled parallel group study. Twenty-seven patients (> or = 18 years) with HoS and plasma sitosterol levels > 5 mg/dl who had been taking EZE 10 mg/day for > or = 6 months prior to enrolment received open-label EZE 10 mg/day for the duration of the study and were randomised 1 : 1 to blinded EZE 30 mg/day (4 x EZE 10 mg tablets; n = 13) or placebo (1 x EZE 10 mg tablet and 3 x matching placebo tablets; n = 14) for 26 weeks. Patients were permitted to remain on other ongoing treatments (e.g. bile salt-binding resin, statin and/or low sterol diet). End-points included median per cent between-group changes from baseline in plasma sitosterol, campesterol, lathosterol, low-density lipoprotein (LDL) sterols, LDL cholesterol (LDL-C) measured by gas-liquid chromatography, and Achilles tendon thickness size measured radiographically. RESULTS: Ezetimibe 40 mg/day resulted in median per cent changes from baseline in plasma sitosterol levels of 3.3% vs. -10% in the EZE 10 mg/day group, in plasma campesterol of -0.5% vs. -9.7% in the EZE 10 mg/day group, and in plasma lathosterol of 0.8% vs. 1.1% in the EZE 10 mg/day group (p = ns for all between-group differences). Median per cent changes in the EZE 40 mg/day and EZE 10 mg/day groups, respectively, were 1.3% and 0% for LDL sterols and 2.5% and 4.4% for LDL-C (p = ns for both between-group differences). At study end-point, Achilles tendon thickness remained unchanged in the EZE 40 mg/day group and increased slightly in the EZE 10 mg/day group (2.2%), yielding a non-significant between-group difference of -2.2%. EZE 40 mg/day was generally well tolerated. CONCLUSIONS: In patients with HoS, treatment with EZE 40 mg/day for 26 weeks was no more effective at reducing plasma plant sterol concentrations vs. EZE 10 mg/day. EZE 40 mg/day had a safety and tolerability profile similar to EZE 10 mg/day.

Degradation of 24S-hydroxycholesterol in men is not regulated by CYP7A1.

OBJECTIVE: The conversion of cholesterol into bile acids occurs via a long cascade of enzymatically regulated oxidative processes. Our aim was to examine if an up-regulation of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) in humans by cholestyramine, a bile acid-binding resin, has an effect on the degradation of brain-specific 24S-hydroxycholesterol. PATIENTS AND METHODS: Six normocholesterolemic male volunteers received 4 g cholestyramine b.i.d. for 2 weeks in an open, prospective exploratory trial. Serum concentrations of lipoproteins and triglycerides were measured by routine enzymatic assays. Sterols and oxysterols were measured by gas chromatography/mass spectrometry. RESULTS: Total and LDL-cholesterol decreased on the average by 9.3% (p = 0.002) and 19.8% (p = 0.001) after 2 weeks of treatment, respectively. Absolute serum concentrations of 7alpha-hydroxycholesterol, a marker for bile acid production, increased 4-fold after 2 weeks, while 24S- and 27-hydroxycholesterol remained unchanged. Treatment with cholestyramine elevated serum levels of lathosterol, an indicator for the endogenous synthesis of cholesterol, by 146% (p = 0.009). CONCLUSION: In addition to lowering serum concentrations of total cholesterol and LDL-cholesterol, cholestyramine at a dose rate of 4 g b.i.d. causes a significant increase in the CYP7A1 catalyzed 7alpha-hydroxylation of cholesterol and an up-regulation of endogenous cholesterol synthesis, as proven indirectly by an increase in serum lathosterol levels. Total serum levels of 24S- and 27-hydroxycholesterol remained unchanged indicating that an up-regulation in CYP7A1 activity is not responsible for the subsequent oxidative degradation of these hydroxylated sterols.

Effects of high-dose itraconazole treatment on lipoproteins in men.

OBJECTIVE: Epidemiological studies have convincingly demonstrated a positive association between LDL-cholesterol (LDL-C) and coronary artery disease but, in the case of HDL-C, there is an inverse association. Administration of high doses of the antifungal agent ketoconazole (800 mg/d) reduces serum concentrations of total cholesterol and LDL-C and there is a tendency for an increase in HDL-C. Our goal was to examine whether high-dose itraconazole raises HDL-C in subjects with normal levels of cholesterol. PATIENTS AND METHODS: 8 male patients with onychomycosis received 2 one-week cycles of treatment with itraconazole at a dose of 400 mg once daily in an open, prospective exploratory trial. Serum levels of itraconazole and its active metabolite hydroxyitraconazole were determined using high-performance liquid chromatography at the end of each treatment cycle. Fasting levels of serum lipoproteins and triglycerides were measured twice using routine enzymatic assays at the beginning and end of each cycle. The effects of itraconazole and hydroxyitraconazole on HDL-C metabolism were assessed in vitro using a human Caco-2 cell line and analyzing apoA-I levels with an enzyme-linked immunosorbent assay. RESULTS: During itraconazole treatment total cholesterol and LDL-C decreased on average by 12% (p < 0.001) and 17% (p < 0.001), respectively, whereas HDL-C increased by 21% (p < 0.001). The ratio LDL: HDL-C, an index of atherogenic risk, decreased by 30% (p < 0.001). Incubation of Caco-2 cells in the presence of itraconazole and hydroxyitraconazole for 3 hours resulted in a significant increase in apoA-I concentration in the medium (913 and 412%, respectively) compared with control. CONCLUSION: In addition to its inhibitory effect on cholesterol synthesis, high-dose itraconazole (400 mg/d) causes a significant decrease in serum LDL-C and, in contrast to ketoconazole, a significant increase in HDL-C. In vitro studies with Caco-2 cells indicate that the latter observation might be caused by an increase in apoA-I levels.

Chiral magnetic order at surfaces driven by inversion asymmetry.

Chirality is a fascinating phenomenon that can manifest itself in subtle ways, for example in biochemistry (in the observed single-handedness of biomolecules) and in particle physics (in the charge-parity violation of electroweak interactions). In condensed matter, magnetic materials can also display single-handed, or homochiral, spin structures. This may be caused by the Dzyaloshinskii-Moriya interaction, which arises from spin-orbit scattering of electrons in an inversion-asymmetric crystal field. This effect is typically irrelevant in bulk metals as their crystals are inversion symmetric. However, low-dimensional systems lack structural inversion symmetry, so that homochiral spin structures may occur. Here we report the observation of magnetic order of a specific chirality in a single atomic layer of manganese on a tungsten (110) substrate. Spin-polarized scanning tunnelling microscopy reveals that adjacent spins are not perfectly antiferromagnetic but slightly canted, resulting in a spin spiral structure with a period of about 12 nm. We show by quantitative theory that this chiral order is caused by the Dzyaloshinskii-Moriya interaction and leads to a left-rotating spin cycloid. Our findings confirm the significance of this interaction for magnets in reduced dimensions. Chirality in nanoscale magnets may play a crucial role in spintronic devices, where the spin rather than the charge of an electron is used for data transmission and manipulation. For instance, a spin-polarized current flowing through chiral magnetic structures will exert a spin-torque on the magnetic structure, causing a variety of excitations or manipulations of the magnetization and giving rise to microwave emission, magnetization switching, or magnetic motors.

Atomic spin structure of antiferromagnetic domain walls.

The search for uncompensated magnetic moments on antiferromagnetic surfaces is of great technological importance as they are responsible for the exchange-bias effect that is widely used in state-of-the-art magnetic storage devices. We have studied the atomic spin structure of phase domain walls in the antiferromagnetic Fe monolayer on W(001) by means of spin-polarized scanning tunnelling microscopy and Monte Carlo simulations. The domain wall width only amounts to 6-8 atomic rows. Although walls oriented along <100> directions are found to be fully compensated, detailed analysis of <110>-oriented walls reveals an uncompensated perpendicular magnetic moment. Our result represents a major advance in the field of antiferromagnetism, and may lead to a better understanding of the magnetic interaction between ferromagnetic and antiferromagnetic materials.

Observation of a complex nanoscale magnetic structure in a hexagonal Fe monolayer.

We have observed a novel magnetic structure in the pseudomorphic Fe monolayer on Ir(111). Using spin-polarized scanning tunneling microscopy we find a nanometer-sized two-dimensional magnetic unit cell. A collinear magnetic structure is proposed consisting of 15 Fe atoms per unit cell with 7 magnetic moments pointing in one and 8 moments in the opposite direction. First-principles calculations verify that such an unusual magnetic state is indeed lower in energy than all solutions of the classical Heisenberg model. We demonstrate that the complex magnetic structure is induced by the strong Fe-Ir hybridization.

Polymorphism in neuropeptide Y influences CSF cholesterol levels but is no major risk factor of Alzheimer's disease.

Neuropeptide Y (NPY) is a neurotransmitter expressed in the central nervous system and involved in learning and memory. The NPY L7P polymorphism has been associated with altered cholesterol levels in obese patients. Since altered cholesterol metabolism is also involved in Alzheimer's disease (AD), the effects of two NPY polymorphisms (L7P and IVS1-100 T/G) on CSF and plasma cholesterol and 24S-hydroxycholesterol were investigated in AD patients and non-demented controls. Furtheremore, the effect of both NPY polymorphisms on the risk of AD was studied. The NPY IVS1-100 T/G polymorphism influenced CSF levels of cholesterol, whereas CSF and plasma levels of 24S-hydroxycholesterol and plasma cholesterol were not altered by genotype. NPY L7P polymorphism did not influence CSF or plasma cholesterol or 24S-hydroxycholesterol. Both NPY polymorphisms did not influence the risk of AD. Our data support the observation, that NPY polymorphisms might influence cholesterol metabolism, but might not act as major risk factor in AD.

Effects of colesevelam HC1 on sterol and bile acid excretion in patients with type IIa hypercholesterolemia.

Colesevelam HC1 is a potent bile acid-binding polymer. This study's aim was to determine effects of colesevelam HCl on sterol and bile acid excretion in patients with type IIa hypercholesterolemia. Twenty-four patients (low-density lipoprotein cholesterol, 130 to 220 mg/dL) enrolled in an open-label, parallel-design study, entered an American Heart Association/National Cholesterol Education Program diet for 6 weeks and were randomized to colesevelam HCl, 2.3 or 3.8 g/day for 4 weeks. In an apparent dose-related manner, respective mean serum concentrations HCl of low-density lipoprotein cholesterol decreased by 10% (P < 0.01) and 13% (P = 0.05), mean total cholesterol levels decreased by 4.9% (P = 0.05) and 6.1% (P = 0.09), and total fecal bile acid excretion showed median changes of +324% (P < 0.05) and +316% (P < 0.05). Colesevelam HCl did not affect fecal neutral sterol or fecal fatty acid excretion; however, 24-hr urinary mevalonic acid levels significantly increased in both treatment groups (P < 0.05). The cholesterol-lowering action of colesevelam HCl appears to be mediated through increased bile acid excretion.

Ratio of lathosterol to campesterol in serum predicts the cholesterol-lowering effect of sitostanol-supplemented margarine.

OBJECTIVE: Plant sterol/stanol margarines are recommended as a lipid-lowering dietary supplement in the treatment of hypercholesterolemia. Parameters predicting the individual cholesterol-lowering effect have not been elucidated so far. Therefore, we investigated the responsiveness to sitostanol-supplemented margarine in a specially selected population. METHODS AND RESULTS: From a total number of 137 male subjects with hypercholesterolemia, eight subjects with the lowest and eight subjects with the highest ratios of lathosterol to campesterol in serum were included in the study. They received 1 g sitostanol-supplemented margarine b.i.d. for four weeks. Serum lipoproteins, the cholesterol precursor lathosterol, the plant sterols campesterol and sitosterol were measured. Subjects with a low ratio of lathosterol to campesterol had a significant decrease of serum total cholesterol (-14.2%; p < 0.01) and LDL cholesterol (-13.8%; p < 0.01; responder). In subjects with a high ratio there was no significant change in total cholesterol and LDL cholesterol (2.2 and 4.3%; non-responder). CONCLUSION: The ratio of serum lathosterol to campesterol predicts the reduction of total cholesterol and LDL cholesterol during administration of sitostanol-supplemented margarine in patients with mild hypercholesterolemia.

Imaging the switching behavior of superparamagnetic nanoislands by spin-polarized scanning tunneling microscopy.

In the past, spin-polarized scanning tunneling microscopy (SP-STM) was mainly applied to static domain configurations that do not vary in time. Here, we show that SP-STM may also be used to image the thermal switching behavior of superparamagnetic nanoislands. Special experimental care has to be taken in order to allow the unambiguous interpretation of the obtained data. Most important, the imaging of superparamagnetic particles requires the use of antiferromagnetic probe tips as the stray field of ferromagnetic tips may modify the sample's intrinsic switching behavior. Our results show that Fe monolayer islands on Mo(110) switch thermally when their area is smaller than 40 nm2. Dipolar coupling between adjacent islands is observed at small inter-particle distance. A pronounced shape dependence is found that confirms existing but yet unverified analytical predictions. The first experiments performed on Fe double-layer islands on W(001) also show thermal switching events, but no clear-cut size dependence is found.

Spin-polarized scanning tunneling microscopy: insight into magnetism from nanostructures to atomic scale spin structures.

The system of Fe on W(001) is investigated using spin-integrated as well as spin-resolved scanning tunneling microscopy (STM). This study ranges from three-dimensional Fe islands down to the Fe monolayer and different growth modes are observed related to the preparation temperature. With scanning tunneling spectroscopy (STS), a layer-dependent electronic structure is observed that can easily be used to assign the local coverage to the investigated sample areas. Spin-resolved measurements of the ferromagnetic layers in the pseudomorphic regime immediately reveal the fourfold magnetic in-plane anisotropy. A direct comparison of the observed arrangement of the domains of the exposed layers shows a rotation of the easy axis from the fourth to the third monolayer and a collinear magnetic alignment of third and second monolayer. This is confirmed by the quantitative analysis of the layer-resolved intensities of differential tunneling conductance. The first monolayer does not show a magnetic component parallel to the surface but has a perpendicular anisotropy. For this layer, measurements with an applied magnetic field prove a c(2x2) antiferromagnetic structure, i.e., a checkerboard arrangement of spins.