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.

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.

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.

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.

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.

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.

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.

Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia.

BACKGROUND: Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. METHODS AND RESULTS: In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% (P<0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P<0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P<0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported. CONCLUSIONS: Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.

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.

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.

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.

Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women.

We investigated the effect of physiologic variations in sex hormone levels during the menstrual cycle on biomarkers of bone turnover. Blood and 24-h and fasting urine samples were obtained in nine women (age, 25.1+/-3.0 yr) with regular menstrual cycles during the early follicular period (t1), 3 days before ovulation (t2), 3 days after ovulation (t3), at the midluteal period (t4) and again during the early follicular period of the next cycle (t5). All subjects had a calcium intake covering current dietary recommendations (above 1,000 mg/day, standardized food record). Serum calcium, phosphorus, calcitriol, 24-h and 2-h fasting urinary calcium, and phosphorus excretion remained constant during the menstrual cycle. Serum 25-hydroxyvitamin D3 levels decreased slightly from the beginning until the end of the study (P<0.05), indicating low cutaneous vitamin D synthesis during wintertime. The serum levels of sex hormones showed typical monthly variations, with the lowest estradiol (E2) levels at t1 and t5. Fasting 2-h pyridinoline (Pyd) concentrations (a marker of bone resorption) fell from t1 to t3 and rose again at t5 (P<0.01). Similar variations were observed for the resorption marker deoxypyridinoline (Dpd; P<0.05). The amplitude of the two biomarkers was 32% and 33%, respectively. The serum levels of the carboxyterminal propeptide of type I collagen (a marker of bone formation) showed an inverse cyclic pattern, as compared with the pyridinium cross-links. Low concentrations were observed at t1; a rise occurred until t3 and was followed by a decrease until t5 (P<0.05). A similar cyclic pattern was observed for serum PTH levels, with the highest concentrations at t3 (P<0.05). Dpd and Pyd values were significantly correlated with serum E2 levels (r = 0.52; P<0.0001 and r = 0.50; P<0.001, respectively). Neither progesterone nor LH nor FSH was correlated with Pyd or Dpd levels. The data suggest that normal menstrual cycling in young women is associated with monthly fluctuations in bone turnover. This physiological effect of the menstrual cycle is most probably related to variations in serum E2 concentrations.

Serum cholesterol, precursors and metabolites and cognitive performance in an aging population.

The present study investigated if a causal relation exists between serum concentrations of precursors and metabolites of cholesterol and cognitive performance in a healthy aging population. Cognitive function addressing four domains of 144 individuals (30-80 years) was tested at baseline and after 6 years of follow-up. Serum concentrations of different sterols related to cholesterol were measured. Serum levels of lathosterol and lanosterol correlated negatively with cognitive performance on the Word Learning tests for verbal learning and memory. This was observed at baseline and follow-up and was independent of age, sex and educational level. Furthermore, the levels of lathosterol and lanosterol at baseline correlated with performance on the Stroop test and Word Learning tests over the 6-year follow-up period. Serum levels of 27-hydroxycholesterol and 24S-hydroxycholesterol showed inconsistent correlations, while cholesterol, desmosterol, sitosterol and campesterol were not related to cognitive performance.Thus, relative high serum ratios of the cholesterol precursors lanosterol and lathosterol, indicative for a high rate of endogenous cholesterol synthesis, are associated with relatively low memory performance in this aging population.

Combination of serum markers related to several mechanisms in Alzheimer's disease.

Alzheimer's disease (AD) probably involves several pathobiochemical mechanisms and this may be reflected by changes in different serum components. The present study investigated whether the combined analysis of serum molecules related to different mechanisms improves the discrimination of AD patients from healthy controls. Serum of patients with AD was analyzed for a broad spectrum of marker molecules, including 11 inflammatory proteins, 12 sterol intermediates and phytosterols, 2 brain-specific proteins and 4 constituents involved in homocysteine homeostasis. The serum molecule concentrations were combined in a logistic regression model, using a forward stepwise inclusion mode. The results showed that the combination of interleukin-6 (IL-6) receptor, protein alpha1 fraction, cysteine and cholesterol concentrations improved the discrimination between AD patients and healthy controls compared to the single markers. In conclusion, the results of this study have shown that the complex pathology in AD is reflected in a pattern of altered serum concentrations of several marker molecules related to several pathobiochemical mechanisms.

Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans.

A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082, N-(2,4-difluorophenyl)-N-(4-neopentylbenzyl)-N-(n-heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single-blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study.

Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide.

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.