High-throughput search for new permanent magnet materials.

The currently highest-performance Fe-Nd-B magnets show limited cost-effectiveness and lifetime due to their rare-earth (RE) content. The demand for novel hard magnetic phases with more widely available RE metals, reduced RE content or, even better, completely free of RE metals is therefore tremendous. The chances are that such materials still exist given the large number of as yet unexplored alloy systems. To discover such phases, an elaborate concept is necessary which can restrict and prioritize the search field while making use of efficient synthesis and analysis methods. It is shown that an efficient synthesis of new phases using heterogeneous non-equilibrium diffusion couples and reaction sintering is possible. Quantitative microstructure analysis of the domain pattern of the hard magnetic phases can be used to estimate the intrinsic magnetic parameters (saturation polarization from the domain contrast, anisotropy constant from the domain width, Curie temperature from the temperature dependence of the domain contrast). The probability of detecting TM-rich phases for a given system is high, therefore the approach enables one to scan through even higher component systems with one single sample. The visualization of newly occurring hard magnetic phases via their typical domain structure and the correlation existing between domain structure and intrinsic magnetic properties allows an evaluation of the industrial relevance of these novel phases.

Evaluation of SWI in children with sickle cell disease.

BACKGROUND AND PURPOSE: SWI is a powerful tool for imaging of the cerebral venous system. The SWI venous contrast is affected by blood flow, which may be altered in sickle cell disease. In this study, we characterized SWI venous contrast in patients with sickle cell disease and healthy control participants and examined the relationships among SWI venous contrast, and hematologic variables in the group with sickle cell disease. MATERIALS AND METHODS: A retrospective review of MR imaging and hematologic variables from 21 patients with sickle cell disease and age- and sex-matched healthy control participants was performed. A Frangi vesselness filter was used to quantify the attenuation of visible veins from the SWI. The normalized visible venous volume was calculated for quantitative analysis of venous vessel conspicuity. RESULTS: The normalized visible venous volume was significantly lower in the group with sickle cell disease vs the control group (P < .001). Normalized visible venous volume was not associated with hemoglobin, percent hemoglobin F, percent hemoglobin S, absolute reticulocyte count, or white blood cell count. A hypointense arterial signal on SWI was observed in 18 of the 21 patients with sickle cell disease and none of the 21 healthy control participants. CONCLUSIONS: This study demonstrates the variable and significantly lower normalized visible venous volume in patients with sickle cell disease compared with healthy control participants. Decreased venous contrast in sickle cell disease may reflect abnormal cerebral blood flow, volume, velocity, or oxygenation. Quantitative analysis of SWI contrast may be useful for investigation of cerebrovascular pathology in patients with sickle cell disease, and as a tool to monitor therapies. However, future studies are needed to elucidate physiologic mechanisms of decreased venous conspicuity in sickle cell disease.

MR imaging assessment of tumor perfusion and 3D segmented volume at baseline, during treatment, and at tumor progression in children with newly diagnosed diffuse intrinsic pontine glioma.

BACKGROUND AND PURPOSE: DIPG is among the most devastating brain tumors in children, necessitating the development of novel treatment strategies and advanced imaging markers such as perfusion to adequately monitor clinical trials. This study investigated tumor perfusion and 3D segmented tumor volume as predictive markers for outcome in children with newly diagnosed DIPG. METHODS: Imaging data were assessed at baseline, during, and after RT, and every other month thereafter until tumor progression for 35 patients (ages 2-16 years) with newly diagnosed DIPG enrolled in the phase I clinical study, NCT00472017. Patients were treated with conformal RT and vandetanib, a vascular endothelial growth factor receptor 2 inhibitor. RESULTS: Tumor perfusion increased and tumor volume decreased during combined RT and vandetanib therapy. These changes slowly diminished in follow-up scans until tumor progression. However, increased tumor perfusion and decreased tumor volume during combined therapy were associated with longer PFS. Apart from a longer OS for patients who showed elevated tumor perfusion after RT, there was no association for tumor volume and other perfusion variables with OS. CONCLUSIONS: Our results suggest that tumor perfusion may be a useful predictive marker for the assessment of treatment response and tumor progression in children with DIPG treated with both RT and vandetanib. The assessment of tumor perfusion yields valuable information about tumor microvascular status and its response to therapy, which may help better understand the biology of DIPGs and monitor novel treatment strategies in future clinical trials.

Attenuation of cerebral venous contrast in susceptibility-weighted imaging of spontaneously breathing pediatric patients sedated with propofol.

BACKGROUND AND PURPOSE: SWI is known for its detailed visualization of the cerebral venous system and seems to be a promising tool for early detection of cerebrovascular pathologies in children, who are frequently sedated for MR imaging. Because sedation influences cerebral hemodynamics, we hypothesized that it would affect cerebral venous contrast in SWI. MATERIALS AND METHODS: SWI (125 examinations) of 26 patients (age, 2-16 years) was reviewed in this study. Images were acquired of patients sedated with propofol. Reviewers classified the images by weak or strong venous contrast. Physiologic data, such as etCO(2), BP, age, and CBF by arterial spin-labeling, were monitored and collected during MR imaging. A generalized estimating equation approach was used to model associations of these parameters with venous contrast. RESULTS: EtCO(2) and CBF were found to correlate with venous contrast, suggesting that patients with high etCO(2) and CBF have weak contrast and patients with low etCO(2) and CBF have strong contrast. BP was also found to correlate with the venous contrast of SWI, suggesting that patients with high BP have strong venous contrast. No significant correlations were found for any other physiologic parameters. CONCLUSIONS: We found that the venous contrast in SWI is affected by propofol sedation in spontaneously breathing patients. We also found that low etCO(2), low CBF, and high BP are associated with strong venous contrast. Reviewing SWI data in light of physiologic measures may therefore help prevent potential misinterpretations of weak venous contrast in SWI examinations under propofol sedation.

Validation of MR thermometry technology: a small animal model for hyperthermic treatment of tumours.

BACKGROUND: Local hyperthermia has been shown to be an effective adjuvant therapy for cancer. However, progress in this treatment modality requires the non-invasive assessment of temperature distribution in the entire tumour to enable administration of an efficient thermal dose to all tumour areas. Magnetic resonance (MR) imaging offers a promising tool to quantify, non-invasively and three-dimensionally, temperature distribution within tumours. An animal model taking into account the complex interrelationship between pathophysiological changes within a tumour during hyperthermia and temperature-sensitive MR parameters is warranted for the development and validation of new MR thermometry technology. METHODS: An experimental set-up was implemented to allow simultaneous measurements of temperature, tumour blood flow and temperature-sensitive MR parameters under standardised conditions in vivo. Local hyperthermia was induced at 44 degrees C for 20 min under inhalation anaesthesia on seven Syrian Golden hamsters bearing an amelanotic melanoma. Fibreoptic probes were used for reference temperature measurements. Laser Doppler flowmetry served for on-line tumour blood flow determination, and MR thermometry was performed using longitudinal T1 relaxation time measurements. RESULTS: The experimental design enables multifunctional MR thermometry. T1 relaxation times of tumours were 1.44 s (1.36, 1.46) and 1.53 s (1. 48, 1.75) at 37 degrees C and during hyperthermia at 44 degrees C, respectively (median, 25% and 75% quartiles, respectively; P<0.05). At the end of 20 min of hyperthermic treatment at 44 degrees C, relative tumour blood flow was reduced to 40.5% (20.7, 43.3) compared to values before treatment (median, 25% and 75% quartiles, respectively; P<0.05). Imaging of T1 relaxation times revealed a heterogeneous distribution in temperature during hyperthermic treatment. CONCLUSION: This novel in vivo model allows standardised investigations for the development and validation of MR thermography methods.

Non-invasive temperature mapping using MRI: comparison of two methods based on chemical shift and T1-relaxation.

PURPOSE: To implement and evaluate the accuracy of non-invasive temperature mapping using MRI methods based on the chemical shift (CS) and T1 relaxation in media of various heterogeneity during focal (laser) and external thermal energy deposition. MATERIALS AND METHODS: All measurements were performed on a 1.5 T superconducting clinical scanner using the temperature dependence of the water proton chemical shift and the T1 relaxation time. Homogeneous gel and heterogeneous muscle phantoms were heated focally with a fiberoptic laser probe and externally of varying degree ex vivo by water circulating in a temperature range of 20-50 degrees C. Magnetic resonance imaging data were compared to simultaneously recorded fiberoptic temperature readings. RESULTS: Both methods provided accurate results in homogeneous media (turkey) with better accuracy for the chemical shift method (CS:+/-1.5 degrees C, T1:+/-2.0 degrees C). In gel, the accuracy with the CS method was +/-0.6 degrees C. The accuracy decreased in heterogeneous media containing fat (T1:+/-3.5 degrees C, CS: +5 degrees C). In focal heating of turkey muscle, the accuracy was within 1.5 degrees C with the T1 method. CONCLUSION: Temperature monitoring with the chemical shift provides better results in homogeneous media containing no fat. In fat tissue, the temperature calculation proved to be difficult.

Amphotericin B resistant isolates of Cryptococcus neoformans without alteration in sterol biosynthesis.

Amphotericin B resistant mutants of Cryptococcus neoformans were isolated accumulating mainly ergosterol. Cross-resistance to azole antifungals was not observed. Together with previous data this indicates that at least three categories of amphotericin B resistance can arise: sterol mutants, amphotericin B and azole cross-resistant mutants and amphotericin B resistant mutants with no azole cross-resistance.

Altered P450 activity associated with direct selection for fungal azole resistance.

Azole antifungals inhibit CYP51A1-mediated sterol 14 alpha-demethylation and the mechanism(s) of resistance to such compounds in Ustilago maydis were examined. The inhibition of growth was correlated with the accumulation of the substrate, 24-methylene-24,25-dihydrolanosterol (eburicol), and depletion of ergosterol. Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CYP51A1 activity which was resistant to inhibition. The results demonstrate that alterations at the level of inhibitor binding to the target site can produce azole resistance. Similar changes may account for fungal azole resistance phenomena in agriculture, and also in medicine where resistance has become a problem in immunocompromised patients suffering from AIDS.

Cross-resistance to polyene and azole drugs in Cryptococcus neoformans.

Fluconazole was observed to inhibit sterol 14 alpha-demethylase in the human pathogen Cryptococcus neoformans, and accumulation of a ketosteroid product was associated with growth arrest. A novel mechanism(s) of azole and amphotericin B cross-resistance was identified, unrelated to changes in sterol biosynthesis, as previously identified in Saccharomyces cerevisiae. Reduced cellular content of drug could account for the resistance phenotype, indicating the possible involvement of a mechanism similar to multidrug resistance observed in higher eukaryotes.

Polymeric delivery of the active isomer of misoprostol reduces systemic availability and uterotonic activity.

SC-30249 is the active isomer of misoprostol responsible for its mucosal protective effects against nonsteroidal anti-inflammatory drugs (NSAIDS). Linkage of SC-30249 to a polybutadiene polymer results in a delivery system (SC-55307) that releases the active component only under the acidic conditions of the stomach. This approach could be used to minimize side effects and systemic availability of synthetic prostaglandins. These studies were done to determine whether uterotonic activity could be recorded after treatment with SC-55307. Female beagles were implanted with uterine strain gauge force transducers, allowed 10 days for recovery and treated with estrogen to sensitize the uterus to the actions of prostaglandins. Base-line responses were determined with SC-30249, i.v., and then a randomized series of four treatments were given: SC-30249, IG, 10 micrograms/kg; SC-55307, IG, equivalent to 30 and 100 micrograms/kg of SC-30249; and a blank polymer control. HCI was given IG to provide an acid environment in the stomach, uterine responses were obtained for up to 4 h and plasma concentrations of SC-30249 free acid was determined. No uterotonic effect was seen after a low dose of SC-55307, whereas the high dose caused a brief but statistically significant increase equal to 8.8% and 17.8% of the responses to SC-30249, i.v. and IG, respectively. Peak plasma levels of SC-30249 free acid were 176.4 +/- 17.4 and 59.5 +/- 10.6 pg/ml after SC-30249, i.v. and IG, respectively, but were only 3.9 +/- 1.7 and 15.5 +/- 6.6 pg/ml after low and high doses of SC-55307, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism.

SC-49518 (N-[exo-(hexahydro-1H-pyrrolizine-1-yl)methyl]-2-methoxy-4- amino-5-chlorobenzamide HCl), a new benzamide gastrointestinal prokinetic compound, was investigated to determine its ability to stimulate gastrointestinal motility in vivo and whether these actions could be mediated by agonist activity at the putative 5-hydroxytryptamine (5-HT)4 receptor. In conscious fasted dogs with strain gauge transducers and myoelectrodes, SC-49518 disrupted gastric and small intestinal migrating motility complex cycling for more than 3.5 hr. It stimulated gastric antral contractile and intestinal myoelectric spike burst activities during the normally quiescent Phase I of the migrating motility complex at doses as low as 0.01 and 0.03 mg/kg i.v., respectively. In a canine model of gastroparesis, SC-49518 reversed completely alpha-2 adrenergically delayed gastric emptying of a solid meal with an ED50 value of 0.1 mg/kg intragastrically and partially reversed delayed emptying of a liquid meal. SC-49518, like 5-HT, cisapride and renzapride, acted as an agonist (EC50 = 6.6 +/- 1.1 x 10(-8) M) at the putative 5-HT4 receptor in rat esophageal tunica muscularis mucosae by relaxing carbachol-induced contractions. SC-49518 was a partial agonist at 5-HT4 receptors, but also blocked high affinity (5-HT4-mediated) responses to 5-HT (10(-9) M to 3 x 10(-7) M) in guinea pig ileum with a pA2 value of 8.39.(ABSTRACT TRUNCATED AT 250 WORDS)

Measuring quality of care in physicians' offices.

Quality ultimately is not solely the province of the physician. The chain of responsibility to prevent and treat disease is complex. It involves not only physicians and patients but also the payors of health care who are demanding more involvement in health care decision making. Payors want understandable information upon which to base their decisions. They are acquiring the means and the resolve to direct their patients to those who will effectively report such information and away from those who will not. Accordingly, physicians should be able to explain their quality assurance methods and be willing to demonstrate and document quality of care in their offices.

Alpha 2-adrenergic model of gastroparesis: validation with renzapride, a stimulator of motility.

Motility-stimulating drugs can increase gastric antral and intestinal contractions but do not usually enhance emptying unless gastroparesis is present. An alpha 2-adrenergic agonist (SC-39585A) was used to inhibit antroduodenal motility and simulate gastroparesis in dogs. SC-39585A caused dose-related inhibition of emptying of solid and liquid meals as well as the antral and duodenal motility responses to the solid meal. The motility-enhancing agent renzapride (100 micrograms/kg iv) did not enhance emptying of the solid meal under nondelayed conditions. However, at the same dose it partially reversed the delay in solid emptying but only when antroduodenal motility was incompletely (30 micrograms/kg sc) and not totally (100 micrograms/kg sc) inhibited by SC-39585A. This was done in part by antagonizing antral but not duodenal inhibition of motility. Renzapride was also effective orally in reversing the delay in solid emptying. Similarly, renzapride reversed the delay in liquid emptying caused by SC-39585A (30 micrograms/kg sc). An alpha 2-adrenergic agonist can be used to model gastroparesis in dogs by inhibiting antroduodenal motility and can also be used to examine the actions of motor stimulants, such as renzapride, which promote gastric emptying.

Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs.

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid pH enhances the effects of taurodeoxycholate on water and solute transport in the human and rat jejunum.

The relative rate of unspecific binding of bile acids to brush border membrane vesicles resembles their relative potencies as intestinal secretagogues. This interaction of bile acids with brush border membranes is enhanced in an acid environment. We, therefore, studied the effects of taurodeoxycholate and taurocholate on water and solute transport at pH 7.6 and pH 4.0 in the human and rat jejunum. Five mM taurodeoxycholate induced significantly greater fluid secretion in the human jejunum at pH 4.0 than at pH 7.6 (p less than 0.02; n = 5), 10 mM taurocholate (n = 4) had no effect at either pH. In the rat 15 mM taurodeoxycholate at pH 4.0 induced greater fluid secretion (p less than 0.01; n = 6), released more phospholipid (p less than 0.001; n = 4) and enhanced absorption of mannitol more than at pH 7.6 (p less than 0.05; n = 6). In contrast fluid secretion and release of phospholipids induced by Triton X-100 were not affected by pH (n = 6), nor was fluid secretion induced by cholera toxin (n = 8). The data suggest that the enhancement of the secretory effect of taurodeoxycholate in an acid environment is due to its increased interaction with the mucosal surface, and support the concept that the ability of detergents to interact with the intestinal brush border membrane determines their effectiveness as intestinal secretagogues.

Effects of auranofin and myochrysine on intestinal transport and morphology in the rat.

Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy.

Effects of taurodeoxycholate on in vivo water and solute transport in rat jejunum in absence and presence of calcium.

Bile acids and fatty acids enhance the permeability of brush-border membrane vesicles for calcium. It has been postulated that increased influx of calcium into the enterocyte might be responsible for the fluid secretion induced by dihydroxy bile acids and fatty acids. During in vivo perfusion studies of the rat jejunum, 15 mM taurodeoxycholate induced secretion of electrolytes and water (P less than 0.001), reduced glucose absorption (P less than 0.001), and enhanced the absorption of mannitol (P less than 0.0125) and calcium (P less than 0.001). Calcium absorption continued to be enhanced during perfusion of a CaCl2-containing solution following the perfusion with taurodeoxycholate (P less than 0.05). In view of the previously demonstrated enhanced permeability of the apical brush-border membrane in the presence of bile acids, it is very likely that some calcium enters the enterocyte along the steep concentration gradient in the presence of taurodeoxycholate. In spite of enhanced calcium absorption, 15 mM CaCl2 had no effect on control absorption rates or on fluid secretion induced by taurodeoxycholate. The data indicate that the effects of bile acids on intestinal transport are not mediated by an influx of calcium into the enterocyte.