Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Penicillium marneffei infection in a lung transplant recipient.

Penicillium marneffei is a thermally dimorphic fungus that can cause severe opportunistic infections in endemic regions of Southeast Asia, particularly in individuals infected with human immunodeficiency virus-1, but has rarely been reported in solid organ transplant recipients. Herein, we report the first case, to our knowledge, of P. marneffei infection in a lung transplant recipient, occurring in a 41-year-old woman 28 months post lung transplantation, after recent travel to Vietnam. We have reviewed the literature to derive some management principles for this rare infection in this clinical context. The number of P. marneffei infections in transplant recipients may increase, as a result of increasing rates of transplantation and travel to endemic areas.

Magnetic and thermodynamic properties of face-centered cubic Fe-Ni alloys.

A model lattice ab initio parameterized Heisenberg-Landau magnetic cluster expansion Hamiltonian spanning a broad range of alloy compositions and a large variety of chemical and magnetic configurations has been developed for face-centered cubic Fe-Ni alloys. The thermodynamic and magnetic properties of the alloys are explored using configuration and magnetic Monte Carlo simulations over a temperature range extending well over 1000 K. The predicted face-centered cubic-body-centered cubic coexistence curve, the phase stability of ordered Fe3Ni, FeNi, and FeNi3 intermetallic compounds, and the predicted temperatures of magnetic transitions simulated as functions of alloy composition agree well with experimental observations. Simulations show that magnetic interactions stabilize the face-centered cubic phase of Fe-Ni alloys. Both the model Hamiltonian simulations and ab initio data exhibit a particularly large number of magnetic configurations in a relatively narrow range of alloy compositions corresponding to the occurrence of the Invar effect.

A quinary WTaCrVHf nanocrystalline refractory high-entropy alloy withholding extreme irradiation environments.

In the quest of new materials that can withstand severe irradiation and mechanical extremes for advanced applications (e.g. fission & fusion reactors, space applications, etc.), design, prediction and control of advanced materials beyond current material designs become paramount. Here, through a combined experimental and simulation methodology, we design a nanocrystalline refractory high entropy alloy (RHEA) system. Compositions assessed under extreme environments and in situ electron-microscopy reveal both high thermal stability and radiation resistance. We observe grain refinement under heavy ion irradiation and resistance to dual-beam irradiation and helium implantation in the form of low defect generation and evolution, as well as no detectable grain growth. The experimental and modeling results-showing a good agreement-can be applied to design and rapidly assess other alloys subjected to extreme environmental conditions.

Evidence for separatrix formation and sustainment with steady inductive helicity injection.

The first sustainment of toroidal plasma current of 50 kA at up to 3 times the injected currents, added in quadrature, using steady inductive helicity injection is described. Separatrix currents-currents not linking the helicity injectors-are sustained up to 40 kA. Decreases in the n=1 toroidal mode of the poloidal magnetic field at higher current amplifications indicate more quiescent, direct toroidal current drive. Results are achieved in HIT-SI (with a spheromak of major radius 0.3 m) during deuterium operations immediately after helium operation. These results represent a breakthrough in the development of this new current drive method for magnetic confinement fusion.

Outstanding radiation resistance of tungsten-based high-entropy alloys.

A body-centered cubic W-based refractory high entropy alloy with outstanding radiation resistance has been developed. The alloy was grown as thin films showing a bimodal grain size distribution in the nanocrystalline and ultrafine regimes and a unique 4-nm lamella-like structure revealed by atom probe tomography (APT). Transmission electron microscopy (TEM) and x-ray diffraction show certain black spots appearing after thermal annealing at elevated temperatures. TEM and APT analysis correlated the black spots with second-phase particles rich in Cr and V. No sign of irradiation-created dislocation loops, even after 8 dpa, was observed. Furthermore, nanomechanical testing shows a large hardness of 14 GPa in the as-deposited samples, with near negligible irradiation hardening. Theoretical modeling combining ab initio and Monte Carlo techniques predicts the formation of Cr- and V-rich second-phase particles and points at equal mobilities of point defects as the origin of the exceptional radiation tolerance.

Origin of low Young modulus of multicomponent, biomedical Ti alloys - Seeking optimal elastic properties through a first principles investigation.

Multicomponent, biomedical ß-Ti alloys offer ultra-low Young modulus values that are related to a unique and poorly understood reduction of C44 and C' elastic constants in comparison with binary systems. The elastic properties of such materials are difficult to control due to the large variations occurring even for a small change in chemical composition, which cannot be explained using existing theories. In this article, we investigate the above issues through systematic ab initio elastic constants calculations for a series of binary, ternary and quaternary Ti alloys. Special attention is paid to examining the reliability of the methodology adopted and to clarifying the atomic scale mechanisms that affect the mechanical properties of the systems analysed. It was found that the lower boundary of the polycrystalline Young modulus of Ti-Nb-base ß phase is close to 50 GPa, and strongly depends on two specific electronic hybridisations related to niobium and simple metals addition that control C44 and C'. Based on the relationship established between electronic structure and mechanical properties, we propose several quaternary alloys whose directional <100> Young modulus values are equal or similar to that of human bones. Some electronic-based guidelines for designing new multicomponent ß-Ti alloys are also formulated.

A first-principles model for anomalous segregation in dilute ternary tungsten-rhenium-vacancy alloys.

The occurrence of segregation in dilute alloys under irradiation is a highly unusual phenomenon that has recently attracted attention, stimulated by the interest in the fundamental properties of alloys as well as by their applications. The fact that solute atoms segregate in alloys that, according to equilibrium thermodynamics, should exhibit full solubility, has significant practical implications, as the formation of precipitates strongly affects physical and mechanical properties of alloys. A lattice Hamiltonian, generalizing the so-called 'ABV' Ising model and including collective many-body inter-atomic interactions, has been developed to treat rhenium solute atoms and vacancies in tungsten as components of a ternary alloy. The phase stability of W-Re-vacancy alloys is assessed using a combination of density functional theory (DFT) calculations and cluster expansion (CE) simulations. The accuracy of CE parametrization is evaluated against the DFT data, and the cross-validation error is found to be less than 4.2 meV/atom. The free energy of W-Re-vacancy ternary alloys is computed as a function of temperature using quasi-canonical Monte Carlo simulations, using effective two, three and four-body interactions. In the low rhenium concentration range (<5 at.[Formula: see text]Re), solute segregation is found to occur in the form of voids decorated by Re atoms. These vacancy-rhenium clusters remain stable over a broad temperature range from 800 K to 1600 K. At lower temperatures, simulations predict the formation of Re-rich rhenium-vacancy clusters taking the form of sponge-like configurations that contain from 30 to 50 at.[Formula: see text]Re. The anomalous vacancy-mediated segregation of Re atoms in W can be rationalized by analyzing binding energy dependence as a function of Re to vacancy ratio as well as chemical Re-W and Re-vacancy interactions and short-range order parameters. DFT calculations show that rhenium-vacancy binding energies can be as high as 1.5 eV if the rhenium/vacancy ratio is in the range from 2.4 to 6.6. The predicted Re clustering agrees with experimental observations of precipitation in self-ion irradiated W-2[Formula: see text] Re alloys and neutron-irradiated alloys containing 1.4 at.[Formula: see text]Re.

The effects of anions, substrates, metal ions and sulfhydryl reagents on the proteolytic susceptibility of yeast phosphoglycerate kinase.

With the aim of confirming our previous spectrophotometric binding studies ((1978) Eur. J. Biochem. 85, 345-350 and (1980) Eur. J. Biochem. 104, 249-254) and of ascertaining the full physiological significance of ion binding, we investigated the effects of ions and thiol reagents on the proteolysis of yeast phosphoglycerate kinase (ATP: 3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.2.3). The single non-essential thiol of the enzyme was modified with 5,5'-dithiobis(2-nitrobenzoic acid) or 2-chloromercuri-4-nitrophenol. Both modifications greatly increased the susceptibility of the kinase to inactivation by trypsin or yeast proteinase A, when compared with that of the native kinase. Electrophoresis in sodium dodecyl sulfate (SDS) revealed that limited proteolysis had occurred. The time courses for the proteolysis and loss of catalytic activity were followed and the active and inactive fragments identified. The molecular masses of the major proteolytic fragments differed with the two endopeptidases. Substrate and non-substrate anions in a concentration-dependent fashion, protected the native and mercurial-labelled kinase from inactivation by trypsin or yeast proteinase A. However, Zn2+, in a concentration-dependent fashion, increased the susceptibility of the native kinase to inactivation by each endopeptidase. The time courses for the inactivation and for the proteolysis allowed the active and inactive fragments to be identified. Zn2+ decreased the rate of inactivation of the mercurial-labelled kinase by proteinase A. The effects of these ions were detected at concentrations compatible with occupancy of an anion binding site and a low affinity Zn2+ binding site, both of which have been indicated from our previous binding studies.

Geographic variation of lower-extremity major amputation in individuals with and without diabetes in the Medicare population.

OBJECTIVE: To describe geographic variation in rates of lower-limb major amputation in Medicare patients with and without diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional population-based study used national fee-for-service Medicare claims from 1996 through 1997. The unit of analysis was 306 hospital referral regions (HRRs) representing health care markets for their respective tertiary medical centers. Numerators were calculated using nontraumatic major amputations and the diabetes code (250.x) for individuals with diabetes. Denominators for individuals with diabetes were created by multiplying the regional prevalence of diabetes (as determined using a 5% sample of Medicare Part B data identifying at least two visits with a diabetes code for 1995-1996) by the regional Medicare population. Denominators for individuals without diabetes were the remaining Medicare beneficiaries. Rates of major amputations were adjusted for age, sex, and race. RESULTS: Rates of major amputations per year were 3.83 per 1,000 (95% CI 3.60-4.06) individuals with diabetes compared with 0.38 per 1,000 (95% C1 0.35-0.41) individuals without diabetes. Marked geographic variation was observed for individuals with and without diabetes; however, patterns were distinct between the two populations. Rates were high in the Southern and Atlantic states for individuals without diabetes. In contrast, rates for individuals with diabetes were widely varied. Variation across HRRs for individuals with diabetes was 8.6-fold compared with 6.7-fold in individuals without diabetes for major amputations. CONCLUSIONS: Diabetes-related amputation rates exhibit high regional variation, even after age, sex, and race adjustment. Future work should be directed to exploring sources of this variation.

Orally active aldose reductase inhibitors derived from bioisosteric substitutions on tolrestat.

A series of aldose reductase inhibitors was prepared in which structural modifications were made to three positions of the potent, orally active inhibitor tolrestat (1), namely, the 6-methoxy substituent, thioamide sulfur, and the N-methyl moiety. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated rat sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Bioisosteric replacement of the 6-methoxy group of 1 with a methylthio substituent gave 5, and replacement of the thioamide substituent of 1 with a cyanoamidine gave 7. Both 5 and 7 retained high in vitro potency but were less potent in vivo than 1. Replacement of the tolrestat N-methyl group by a carbomethoxy moiety gave 10 and led to a substantial reduction in activity in each of the three assays employed. However, this same structural modification on oxo-tolrestat (2) led to 11 and resulted in an enhancement of the intrinsic activity and a comparable in vivo potency. The isolated nerve data suggest that some compounds in these series do not readily penetrate into peripheral nerves, and this presumably is a factor in their lack of oral activity.

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as antihyperglycemic agents.

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.

Syntheses of tolrestat analogues containing additional substituents in the ring and their evaluation as aldose reductase inhibitors. Identification of potent, orally active 2-fluoro derivatives.

A series of aldose reductase inhibitors were prepared which were analogues of the potent, orally active inhibitor tolrestat (1). These compounds (5, 7, 9, and 10) have an extra substituent on one of the unoccupied positions on the naphthalene ring of 1. Primary amide prodrugs of several members from the series 5 and 7, namely 6 and 8, respectively, were also prepared. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. In general, compounds in series 5, 7, 9, and 10 were potent inhibitors of bovine lens aldose reductase. 2-Halo-substituted analogues from the series 5, 7, and 9 exhibited high activity in the nerve of the 4-day-galactose-fed rat, and in several instances, the primary amide prodrug 8 enhanced the in vivo potency of the respective carboxylic acid 7. Two 2-fluoro-derivatives, 8a and 9a, had especially high activity in vivo and were chosen for additional studies. These compounds were found to be approximately equipotent to tolrestat in the sciatic nerve of the galactose-fed rat and the STZ rat, as judged by their ED50's in these assays. Although primary amide analogue 8a did not have intrinsic inhibitory activity toward aldose reductase, it was metabolized to an active form in vivo and also in vitro within the sciatic nerve.

Novel spirosuccinimides with incorporated isoindolone and benzisothiazole 1,1-dioxide moieties as aldose reductase inhibitors and antihyperglycemic agents.

Compounds from two novel series of spirosuccinimides were prepared. Analogs of series 2 possessed a spiro-fused isoindolone moiety while those of series 3 contained a spiro-fused benzisothiazole S,S-dioxide group. These compounds were evaluated as aldose reductase inhibitors (ARI) in vitro by their ability to inhibit glyceraldehyde reduction using a partially purified bovine lens aldose reductase preparation and in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. Many members from the isoindolone series 2, particularly those containing an isoindolone N-methyl moiety, showed good in vitro and in vivo potency. The most potent member, the 6-chloro analog 32, was resolved, and aldose reductase activity was found to reside almost exclusively in the (+)-enantiomer. Compound 32 was approximately equipotent in the sciatic nerve of the galactose-fed rat to other cyclic imide ARI's of similar in vitro activity, namely sorbinil and ADN-138 and also to tolrestat, an acetic acid-based ARI (ED50's 4-8 mg/kg). Compounds from both series, 2 and 3, were also found to lower plasma glucose levels of genetically obese db/db and ob/ob mice with potency similar to that of ciglitazone. However, members from these series failed to lower insulin levels of the ob/ob mouse at the doses tested.

Analysis of HIV type 1 reverse transcriptase: comparing sequences of viral isolates with mutational data.

A result of the high level of mutagenesis during HIV-1 viral replication is that many, if not most, HIV-1 virions and proviruses are defective and are not infectious. There is a vast amount of HIV-1 sequence data available. Unless any particular sequence is shown to be from a stable DNA clone (e.g., lambda) that can transfect cells and produce virions, then it is not known if that sequence was from an infectious HIV-1. Most sequences have not been shown to be from infectious clones. We have reported a saturation mutagenesis of a 109-amino acid region of the HIV-1 reverse transcriptase, in which we assayed the effects of 366 single-amino acid substitutions. We examined a set of sequences in the Los Alamos HIV-1 sequence database. We found that none of the sequences derived from stable infectious clones had substitutions that produce an inactive reverse transcriptase. However, we found that other sequences in this database had substitutions that inactivate the reverse transcriptase. We predict that these sequences are not from infectious clones. This method may also be useful for evaluating the sequences of other viruses.

The effect of verapamil on intestinal calcium transport.

Verapamil (1.5 mM) completely inhibits active calcium transport by everted rat duodenum sacs and depresses oxygen consumption by duodenal rings. Increasing the Ca2+ concentration in the incubation medium from 0.4 mM 5.0 mM reverses the inhibition of oxygen consumption by verapamil but is without effect on the extent of inhibition of calcium active transport.

A recombinagenic effect of strychnine in Salmonella typhimurium.

The aroC321 allele in Salmonella typhimurium permits a positive selection for genetic duplications. Bacteria that contain a large genetic duplication are detected as tryptophan prototrophs in aroC321 strains and occur at a spontaneous frequency greater than 1/10(4) cells plated on the selection medium. Duplications originate by a recombinational mechanism, and the induction of duplications by chemicals or radiation may therefore be considered to be a recombinagenic effect. We have found that strychnine is a potent recombinagen in this system; it causes a dose-dependent increase in the frequency of genetic duplications, and very high frequencies of duplications are recovered at high doses. In contrast, brucine, the 2,3-dimethoxy derivative of strychnine, caused no increase in duplication frequencies under the identical conditions.

Effect of dietary calcium and photoperiod on the diurnal rhythm of active calcium transport in rat intestine.

1. The everted gut sac technique was used to study the diurnal pattern of active calcium transport along the small intestine of adult rat. 2. In animals maintained under artificial light-dark cycle (LD 12 : 12) and fed ad libitum diets containing from 0.02 to 1% calcium, calcium transport displayed distinct rhythmic changes: it was high in dark and low in light. 3. The decrease in dietary calcium level resulted in a rise of the rhythm amplitude, of the transport maximum in darkness, as well as the mean efficiency of transport during 24 h. The length of the intestinal region with the ability for calcium transport was also increased. 4. The phase of the transport rhythm was shifted on low-calcium diet (0.02%). 5. Diurnal periodicity of calcium transport persisted in rats adapted for 25 days to constant illumination. Similar exposure to constant darkness resulted in arhythmic transport fluctuations.

The effect of calcium restriction in the diet of calcium transport in rat small intestine.

1. The everted-sac technique has been used to study the time-dependent effect of low-calcium diet on calcium active transport along rat small intestine. 2. In animals maintained on standard diet active translocation of calcium was limited to proximal 10 cm of the intestine. 3. In response to calcium restriction, calcium transport in duodenum was highly stimulated after 3 days, then gradually declined and after 28 days almost disappeared. In proximal jejunum it was the highest between 7 and 21 days. In distal ileum, the transport appeared after 3 days and increased progressively until 21 days, but markedly decreased at the 28-th day. The normal pattern of calcium transport was reestablished on refeeding the animals with standard diet.