Pathway to the piezoelectronic transduction logic device.

The piezoelectronic transistor (PET) has been proposed as a transduction device not subject to the voltage limits of field-effect transistors. The PET transduces voltage to stress, activating a facile insulator-metal transition, thereby achieving multigigahertz switching speeds, as predicted by modeling, at lower power than the comparable generation field effect transistor (FET). Here, the fabrication and measurement of the first physical PET devices are reported, showing both on/off switching and cycling. The results demonstrate the realization of a stress-based transduction principle, representing the early steps on a developmental pathway to PET technology with potential to contribute to the IT industry.

Giant piezoresistive on/off ratios in rare-earth chalcogenide thin films enabling nanomechanical switching.

Sophisticated microelectromechanical systems for device and sensor applications have flourished in the past decade. These devices exploit piezoelectric, capacitive, and piezoresistive effects, and coupling between them. However, high-performance piezoresistivity (as defined by on/off ratio) has primarily been observed in macroscopic single crystals. In this Letter, we show for the first time that rare-earth monochalcogenides in thin film form can modulate a current by more than 1000 times due to a pressure-induced insulator to metal transition. Furthermore, films as thin as 8 nm show a piezoresistive response. The combination of high performance and scalability make these promising candidates for nanoscale applications, such as the recently proposed piezoelectronic transistor (PET). The PET would mechanically couple a piezoelectric thin film with a piezoresistive switching layer, potentially scaling to higher speeds and lower powers than today's complementary metal-oxide-semiconductor technology.

Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial.

OBJECTIVES: Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. METHODS: In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. RESULTS: 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups. CONCLUSIONS: Treatment with rituximab 2×1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA. ClinicalTrials.gov identifier NCT00299104.

Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients.

OBJECTIVE: To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab. METHODS: RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected. RESULTS: Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred. CONCLUSIONS: In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

Growth of high aspect ratio nanometer-scale magnets with chemical vapor deposition and scanning tunneling microscopy.

A combination of chemical vapor deposition and scanning tunneling microscopy techniques have been used to produce nanometer-scale, iron-containing deposits with high aspect ratios from an iron pentacarbonyl precursor both on a substrate and on the tunneling tip itself. The structure and composition of the resulting nanodeposits were determined by transmission electron microscopy and high spatial resolution Auger electron spectroscopy. Either polycrystalline, relatively pure, body-centered-cubic iron or disordered carbon-rich material can be deposited, depending on the bias conditions of the tip sample junction and the precursor pressure. Two mechanisms of decomposition are inferred from the growth phenomenology.

Autoradiographical detection of cholecystokinin-A receptors in primate brain using 125I-Bolton Hunter CCK-8 and 3H-MK-329.

In vitro autoradiography was performed in order to visualize cholecystokinin-A (CCK-A) receptors in sections of Cynomolgus monkey brain. CCK-A receptors were defined as those which displayed high affinity for the selective non-peptide antagonist MK-329 (L-364,718) and were detected in several regions by selective inhibition of 125I-Bolton Hunter CCK using MK-329 or direct labeling with 3H-MK-329. In the caudal medulla, high densities of CCK-A sites were present in the nucleus tractus solitarius, especially the caudal and medial aspects, and also the dorsal motor nucleus of the vagus. CCK-A sites were localized to a number of hypothalamic nuclei such as the supraoptic and paraventricular nuclei, the dorsomedial and infundibular nuclei as well as the neurohypophysis. The mammillary bodies and supramammillary nuclei also contained CCK-A receptor sites. High concentrations of CCK-A receptors were present in the substantia nigra zona compacta and also the ventral tegmental area and may be associated with dopamine cell bodies. Binding of 3H-MK-329 was also detected in parts of the caudate nucleus and ventral putamen. The detection, by autoradiographical means, of CCK-A receptors throughout the Cynomolgus monkey brain contrasts with similar studies performed using rodents and suggests differences in the density and, perhaps, the importance of CCK-A receptors in the primate as opposed to the rodent. The data suggest the possibility that CCK-A receptors may be involved in a number of important brain functions as diverse as the processing of sensory information from the gut, the regulation of hormone secretion, and the activity of dopamine cell activity.

CCK-A receptors in the rat interpeduncular nucleus: evidence for a presynaptic location.

Using autoradiography, 'peripheral type' or cholecystokinin-A (CCK-A) receptor binding was measured in the interpeduncular nucleus (IPN) of rats which had received electrolytic lesions of the habenular nucleus. Presynaptic GABAB receptor binding was also determined in the IPN in order to verify the loss of input to the nucleus. In animals which showed almost total loss of GABAB receptors. 125I-Bolton Hunter CCK binding in the IPN was reduced from 1.83 +/- 0.28 pmol/g wet weight to 0.87 +/- 0.16 pmol/g wet weight. This was not significantly different from non-specific levels, determined in the same region using 10(-7) M L-365,031 (0.97 +/- 0.14 pmol/g wet weight). These data suggest that CCK-A receptors in rat IPN are localized on presynaptic terminals within the nucleus.

Binding sites for 125I-cholecystokinin in primate spinal cord are of the CCK-A subclass.

Cholecystokinin (CCK) receptor binding was measured in sections of human, monkey and rat spinal cord using autoradiographical techniques. In each species, high levels of specific 125I-Bolton-Hunter CCK binding were detected in the superficial layers of the dorsal horn (the substantia gelatinosa). In monkey and human but not rat spinal cord, 125I-CCK binding was dose-dependently inhibited by low concentrations of the selective CCK-A antagonist L-364,718. Binding of [3H]L-364,718, which was saturable (Bmax = 29.0 +/- 0.95 pmol/g wet wt.) and of high affinity (pKd) = 9.92 +/- 0.16) was also detected in sections of monkey spinal cord and had a similar localization to that of specific 125I-CCK binding. These data indicate that in striking contrast to CCK receptors in rat spinal cord, those in the primate cord are of the CCK-A receptor subclass.

Evaluation of high-resolution electron microscopy as a method for studying Y-Ba-Cu-O superconductors.

High-resolution transmission electron microscopes operating at 300 and 400 kV were used to investigate the crystallography and microstructure of the perovskitelike YBa2Cu3O7-x. In this paper, we evaluate the performance attainable with these microscopes both empirically and by computer modelling. Based upon the assumption that oxygen may be a key to superconductivity properties, we have also investigated the visibility of the oxygen sites as well as the heavier yttrium and barium ion positions and the lighter Cu atom positions. We propose a scheme for observing different twin orientations in these structures and hence the oxygen atom positions seen in projection for the [100] and [010]. Our observations of both thick and thin regions of Y-Ba-Cu-O materials are reported as well as the problems of adjusting microscope parameters and specimen alignment to obtain interpretable images. We also give a preliminary report on the effects of heat treatment as seen in high-resolution micrographs to assess disorder of the heavy atoms and oxygen vacancies.

Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists.

Two potent and highly selective nonpeptide antagonists, L-365,031 [1-methyl-3-(4-bromobenzoyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] and 3H-L-364,718 [1-methyl-3-(2-indoloyl)amino-5-phenyl-3H-1,4 benzodiazepin-2-one] were used to localize "peripheral" CCK receptors in rat brain. In autoradiographic experiments, L-365,031 displaced 125I-Bolton Hunter CCK-8 binding from the interpeduncular nucleus (IPN) (IC50 = 7 X 10(-8) M), the area postrema (AP), and the nucleus tractus solitarius (NTS) without influencing specific binding to other areas, such as the cerebral cortex or the spinal tract of the trigeminal nerve. Desulfated CCK preferentially inhibited 125I-CCK binding to cerebral cortex (IC50 = 7 X 10(-8) M) rather than IPN (IC50 greater than 1 X 10(-6) M) or AP-NTS. In the medulla the localization of 3H-L-364,718 binding was similar to L-365,031-sensitive 125I-CCK-8 binding and was found in the AP and medial, but not lateral, aspects of the NTS. In membranes prepared from IPN, NTS, and AP, 3H-364,718 binding was of high affinity (Kd = 0.14 nM), saturable (Bmax = 20 fmol/mg protein), and inhibited by compounds previously shown to act at pancreatic CCK receptors. The receptors labeled by 3H-364,718 were modulated by guanyl nucleotide, which reduced agonist affinity 10-fold without affecting antagonist binding. The localization and high density of CCK receptors in AP and NTS suggest that these receptors may play an important role in processing sensory afferent information.

Species differences in the localization of 'peripheral' type cholecystokinin receptors in rodent brain.

A comparison of cholecystokinin (CCK) receptor binding to sections of rat, mouse and guinea pig brain has been performed using 125I-Bolton Hunter CCK and the selective peripheral CCK receptor antagonist L-365,031. In both rat and mouse, 125I-Bolton Hunter CCK binding in the region of the interpeduncular nucleus (IPN) was inhibited by L-365,031 indicating that these receptors resemble CCK receptors found in peripheral tissues. In the mouse especially, dense regions of peripheral CCK receptors were detected either side of the IPN. By contrast, in the guinea pig IPN no evidence of L-365,031-sensitive binding could be found. The present reports shows that in different species, regional variations in brain CCK receptor binding occur not only in the case of classical 'brain' receptors, but also for the more discretely localised 'peripheral' type CCK receptors.

Transmission electron microscopy: direct observation of crystal structure in refractory ceramics.

Using high-resolution multibeam interference techniques in the transmission electron microscope, images have been obtained that make possible a real-space structure analysis of a beryllium-silicon-nitrogen compound. The results illustrate the usefulness of lattice imaging in the analysis of local crystal structure in these technologically promising ceramic materials.