Population pharmacokinetics of sevoflurane in conjunction with the AnaConDa: toward target-controlled infusion of volatiles into the breathing system

BACKGROUND: The Anesthetic Conserving Device (AnaConDa) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the AnaConDa, and retrospectively testing its performance (internal validation). MATERIALS AND METHODS: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated. RESULTS: In vitro studies assessed the contribution of the device to the pharmacokinetic model. In vivo, the sevoflurane concentration-time courses on the patient side of the AnaConDa were adequately described with a two-compartment model. The population median absolute prediction error was 27% (interquartile range 13-45%). CONCLUSION: The predictive performance of the two-compartment model was similar to that of models accepted for TCI administration of intravenous anesthetics, supporting open-loop administration of sevoflurane with the AnaConDa. Further studies will focus on prospective testing and external validation of the model implemented in a target-controlled infusion device.

Translocation and cellular entering mechanisms of nanoparticles in the respiratory tract

Anthropogenic nano-sized particles (NSP), ie, particles with a diameter of less than 100 nm, are generated with or without purpose as chemically and physically well-defined materials or as a consequence of combustion processes respectively. Inhalation of NSP occurs on a regular basis due to air pollution and is associated with an increase in respiratory and cardiovascular morbidity and mortality. Manufactured NSP may intentionally be inhaled as pharmaceuticals or unintentionally during production at the workplace. Hence the interactions of NSP with the respiratory tract are currently under intensive investigation. Due to special physicochemical features of NSP, its biological behaviour may differ from that of larger sized particles. Here we review two important themes of current research into the effects of NSP on the lungs: 1) The potential of NSP to cross the blood-air barrier of the lungs, thus gaining access to the circulation and extrapulmonary organs. It is currently accepted that a small fraction of inhaled NSP may translocate to the circulation. The significance of this translocation requires further research. 2) The entering mechanisms of NSP into different cell types. There is evidence that NSP are taken up by cells via well-known pathways of endocytosis but also via different mechanisms not well understood so far. Knowledge of the quantitative relationship between the different entering mechanisms and cellular responses is not yet available but is urgently needed in order to understand the effects of intentionally or unintentionally inhaled NSP on the respiratory tract.

Supplementary motor area (SMA) volume is associated with psychotic aberrant motor behaviour of patients with schizophrenia

We aimed to investigate whether aberrant motor behavior in schizophrenia was associated with structural alterations in the motor system. Whole brain voxel based morphometry of patients with different severity of motor symptoms identified altered gray matter volume in the supplementary motor area (SMA), a key region of the motor system.

Chemical and isotopic compositions of lavas from the Broken Ridge and Southern Kerguelen Plateau

Lavas from several major bathymetric highs in the eastern Indian Ocean that are likely to have formed as Early to Middle Cretaceous manifestations of the Kerguelen hotspot are predominantly tholeiitic; so too are glass shards from Eocene to Paleocene volcanic ash layers on Broken Ridge, which are believed to have come from eruptions on the Ninetyeast Ridge. The early dominance of tholeiitic compositions contrasts with the more recent intraplate, alkalic volcanism of the Kerguelen Archipelago. Isotopic and incompatible-element ratios of the plateau lavas are distinct from those of Indian mid-ocean ridge basalts; their Nd, Sr, 207Pb/204Pb and 2078b/204Pb isotopic ratios overlap with but cover a much wider range than measured for more recent oceanic products of the Kerguelen hotspot (including the Ninetyeast Ridge) or, indeed, oceanic lavas from any other hotspot in the world. Samples from the Naturaliste Plateau and ODP Site 738 on the southern tip of the Kerguelen Plateau are particularly noteworthy, with e-Nd(T) = -13 to -7, (87Sr/86Sr)T=0.7090 to 0.7130 and high 207Pb/204Pb relative to 206Pb/204Pb. In addition, the low-e-Nd(T) Naturaliste Plateau samples are elevated in SiO2 (>54 wt%). In contrast to "DUPAL" oceanic islands such as the Kerguelen Archipelago, Pitcairn and Tristan da Cunha, the plateau lavas with extreme isotopic characteristics also have relative depletions in Nb and Ta (e.g., Th/Ta, La Nb > primitive mantle values); the lowest e-Nd(T) and highest Th/Ta and La Nb values occur at sites located closest to rifted continental margins. Accepting a Kerguelen plume origin for the plateau lavas, these characteristics probably reflect the shallow-level incorporation of continental lithosphere in either the head of the early Kerguelen plume or in plume-derived magmas, and suggest that the influence of such material diminished after the period of plateau construction. Contamination of asthenosphere with the type of material affecting Naturaliste Plateau and Site 738 magmatism appears unlikely to be the cause of low-206Pb/204Pb Indian mid-ocean ridge basalts. Finally, because isotopic data for the plateaus do not cluster or form converging arrays in isotope-ratio plots, they provide no evidence for either a quickly evolving, positive ?Nd, relatively high-206Pb/204Pb plume composition, or a plume source dominated by mantle with e-Nd of -3 to ~0.

(Table 2) Foehn characteristics of station in the McMurdo Dry Valleys, Antarctica

Foehn winds resulting from topographic modification of airflow in the lee of mountain barriers are frequently experienced in the McMurdo Dry Valleys (MDVs) of Antarctica. Strong foehn winds in the MDVs cause dramatic warming at onset and have significant effects on landscape forming processes; however, no detailed scientific investigation of foehn in the MDVs has been conducted. As a result, they are often misinterpreted as adiabatically warmed katabatic winds draining from the polar plateau. Herein observations from surface weather stations and numerical model output from the Antarctic Mesoscale Prediction System (AMPS) during foehn events in the MDVs are presented. Results show that foehn winds in the MDVs are caused by topographic modification of south-southwesterly airflow, which is channeled into the valleys from higher levels. Modeling of a winter foehn event identifies mountain wave activity similar to that associated with midlatitude foehn winds. These events are found to be caused by strong pressure gradients over the mountain ranges of the MDVs related to synoptic-scale cyclones positioned off the coast of Marie Byrd Land. Analysis of meteorological records for 2006 and 2007 finds an increase of 10% in the frequency of foehn events in 2007 compared to 2006, which corresponds to stronger pressure gradients in the Ross Sea region. It is postulated that the intra- and interannual frequency and intensity of foehn events in the MDVs may therefore vary in response to the position and frequency of cyclones in the Ross Sea region.

How Continuous Monitoring Changes the Interaction of Patients with a Mobile Telemedicine System

The use of continuous glucose monitor changes the way patients manage their diabetes, as observed in the increased number of daily insulin bolus, the increased number of daily BG measurements, and the differences in the distribution of BG measurements throughout the day. Continuous monitoring also increases the interaction of patients with the information system and modifies their patterns of use.

Suspensor-derived polyembryony caused by altered expression of valyl-tRNA synthetase in the twn2 mutant of Arabidopsis

The twn2 mutant of Arabidopsis exhibits a defect in early embryogenesis where, following one or two divisions of the zygote, the decendents of the apical cell arrest. The basal cells that normally give rise to the suspensor proliferate abnormally, giving rise to multiple embryos. A high proportion of the seeds fail to develop viable embryos, and those that do, contain a high proportion of partially or completely duplicated embryos. The adult plants are smaller and less vigorous than the wild type and have a severely stunted root. The twn2-1 mutation, which is the only known allele, was caused by a T-DNA insertion in the 5′ untranslated region of a putative valyl-tRNA synthetase gene, valRS. The insertion causes reduced transcription of the valRS gene in reproductive tissues and developing seeds but increased expression in leaves. Analysis of transcript initiation sites and the expression of promoter–reporter fusions in transgenic plants indicated that enhancer elements inside the first two introns interact with the border of the T-DNA to cause the altered pattern of expression of the valRS gene in the twn2 mutant. The phenotypic consequences of this unique mutation are interpreted in the context of a model, suggested by Vernon and Meinke [Vernon, D. M. & Meinke, D. W. (1994) Dev. Biol. 165, 566–573], in which the apical cell and its decendents normally suppress the embryogenic potential of the basal cell and its decendents during early embryo development.

Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5

Chromosome 7q22 has been the focus of many cytogenetic and molecular studies aimed at delineating regions commonly deleted in myeloid leukemias and myelodysplastic syndromes. We have compared a gene-dense, GC-rich sub-region of 7q22 with the orthologous region on mouse chromosome 5. A physical map of 640 kb of genomic DNA from mouse chromosome 5 was derived from a series of overlapping bacterial artificial chromosomes. A 296 kb segment from the physical map, spanning Ache to Tfr2, was compared with 267 kb of human sequence. We identified a conserved linkage of 12 genes including an open reading frame flanked by Ache and Asr2, a novel cation-chloride cotransporter interacting protein Cip1, Ephb4, Zan and Perq1. While some of these genes have been previously described, in each case we present new data derived from our comparative sequence analysis. Adjacent unfinished sequence data from the mouse contains an orthologous block of 10 additional genes including three novel cDNA sequences that we subsequently mapped to human 7q22. Methods for displaying comparative genomic information, including unfinished sequence data, are becoming increasingly important. We supplement our printed comparative analysis with a new, Web-based program called Laj (local alignments with java). Laj provides interactive access to archived pairwise sequence alignments via the WWW. It displays synchronized views of a dot-plot, a percent identity plot, a nucleotide-level local alignment and a variety of relevant annotations. Our mouse–human comparison can be viewed at http://web.uvic.ca/~bioweb/laj.html. Laj is available at http://bio.cse.psu.edu/, along with online documentation and additional examples of annotated genomic regions.

The role of distinct p185neu extracellular subdomains for dimerization with the epidermal growth factor (EGF) receptor and EGF-mediated signaling

The extracellular domain of p185c-neu can be viewed as a complex structure of four subdomains, two of which are cysteine-rich subdomains. We have investigated the contribution of these distinct p185c-neu extracellular subdomains to p185/epidermal growth factor receptor (EGFR) heteromer formation and EGF-induced heteromeric signaling. Our studies indicate that at least two separate p185 subdomains, a region spanning subdomains I and II and subdomain IV are involved in association of p185 with the EGFR. We also demonstrated that subdomain IV reduced the heteromeric signaling and transforming activities induced by EGF after associating with EGFR. When 126 aa were deleted from subdomain IV, this small subdomain IV-derived fragment could still lead to heterodimers with EGFR and suppress EGF-induced mitogen-activated protein kinase activation and subsequent transformation abilities. These data provide information about trans-inhibitory mechanisms of mutant p185 species and also indicate that both the entire and a part of subdomain IV may represent a therapeutic target for erbB-overexpressing tumors. Finally, these studies define a basic feature of receptor-receptor associations that are determined by cystine-knot containing subdomains.

Protonation dynamics of the extracellular and cytoplasmic surface of bacteriorhodopsin in the purple membrane.

The dynamics of proton binding to the extracellular and the cytoplasmic surfaces of the purple membrane were measured by laser-induced proton pulses. Purple membranes, selectively labeled by fluorescein at Lys-129 of bacteriorhodopsin, were pulsed by protons released in the aqueous bulk from excited pyranine (8-hydroxy-1,3,6-pyrenetrisulfonate) and the reaction of protons with the indicators was measured. Kinetic analysis of the data imply that the two faces of the membrane differ in their buffer capacities and in their rates of interaction with bulk protons. The extracellular surface of the purple membrane contains one anionic proton binding site per protein molecule with pK = 5.1. This site is within a Coulomb cage radius (approximately 15 A) from Lys-129. The cytoplasmic surface of the purple membrane bears 4-5 protonable moieties (pK = 5.1) that, due to close proximity, function as a common proton binding site. The reaction of the proton with this cluster is at a very fast rate (3.10(10) M-1.s-1). The proximity between the elements is sufficiently high that even in 100 mM NaCl they still function as a cluster. Extraction of the chromophore retinal from the protein has a marked effect on the carboxylates of the cytoplasmic surface, and two to three of them assume positions that almost bar their reaction with bulk protons. The protonation dynamics determined at the surface of the purple membrane is of relevance both for the vectorial proton transport mechanism of bacteriorhodopsin and for energy coupling, not only in halobacteria, but also in complex chemiosmotic systems such as mitochondrial and thylakoid membranes.

Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1.

Ca2+ and its ubiquitous intracellular receptor calmodulin (CaM) are required in the nervous system, among a host of cellular responses, for the modulation of several important enzymes and ion channels involved in synaptic efficacy and neuronal plasticity. Here, we report that CaM can be replaced by the neuronal calcium sensor NCS-1 both in vitro and in vivo. NCS-1 is a calcium binding protein with two Ca(2+)-binding domains that shares only 21% of homology with CaM. We observe that NCS-1 directly activates two Ca2+/CaM-dependent enzymes (3':5'-cyclic nucleotide phosphodiesterase and protein phosphatase calcineurin). Co-activation of nitric oxide synthase by NCS-1 and CaM results in a higher activity than with CaM alone. Moreover, NCS-1 is coexpressed with calcineurin and nitric oxide synthase in several neuron populations. Finally, injections of NCS-1 into calmodulin-defective cam1 Paramecium partially restore wildtype behavioral responses. With this highly purified preparation of NCS-1, we have obtained crystals suitable for crystallographic structure studies. NCS-1, despite its very different structure, distribution, and Ca(2+)-binding affinity as compared with CaM, can substitute for or potentiate CaM functions. Therefore, NCS-1 represents a novel protein capable of mediating multiple Ca(2+)-signaling pathways in the nervous system.

Integration of speech with natural language understanding.

The integration of speech recognition with natural language understanding raises issues of how to adapt natural language processing to the characteristics of spoken language; how to cope with errorful recognition output, including the use of natural language information to reduce recognition errors; and how to use information from the speech signal, beyond just the sequence of words, as an aid to understanding. This paper reviews current research addressing these questions in the Spoken Language Program sponsored by the Advanced Research Projects Agency (ARPA). I begin by reviewing some of the ways that spontaneous spoken language differs from standard written language and discuss methods of coping with the difficulties of spontaneous speech. I then look at how systems cope with errors in speech recognition and at attempts to use natural language information to reduce recognition errors. Finally, I discuss how prosodic information in the speech signal might be used to improve understanding.

The first extrasolar planet discovered with a new-generation high-throughput Doppler instrument

We report the detection of the first extrasolar planet, ET-1 (HD 102195b), using the Exoplanet Tracker (ET), a new-generation Doppler instrument. The planet orbits HD 102195, a young star with solar metallicity that may be part of the local association. The planet imparts radial velocity variability to the star with a semiamplitude of 63.4 ± 2.0 m s^-1 and a period of 4.11 days. The planetary minimum mass (m sin i) is 0.488MJ ± 0.015M_J. The planet was initially detected in the spring of 2005 with the Kitt Peak National Observatory (KPNO) 0.9 m coudé feed telescope. The detection was confirmed by radial velocity observations with the ET at the KPNO 2.1 m telescope and also at the 9 m Hobby-Eberly Telescope (HET) with its High Resolution Spectrograph. This planetary discovery with a 0.9 m telescope around a V = 8.05 magnitude star was made possible by the high throughput of the instrument: 49% measured from the fiber output to the detector. The ET's interferometer-based approach is an effective method for planet detection. In addition, the ET concept is adaptable to multiple-object Doppler observations or very high precision observations with a cross-dispersed echelle spectrograph to separate stellar fringes over a broad wavelength band. In addition to spectroscopic observations of HD 102195, we obtained brightness measurements with one of the automated photometric telescopes at Fairborn Observatory. Those observations reveal that HD 102195 is a spotted variable star with an amplitude of ~0.015 mag and a 12.3 ± 0.3 day period. This is consistent with spectroscopically observed Ca II H and K emission levels and line-broadening measurements but inconsistent with rotational modulation of surface activity as the cause of the radial velocity variability. Our photometric observations rule out transits of the planetary companion.

Clinical pathway intervention compliance and effectiveness when used in the treatment of patients with severe sepsis and septic shock at an Intensive Care Unit in Spain

The purpose of this quasi-experimental study was to assess levels of compliance with the intervention bundles contained in a clinical pathway used in the treatment of patients with severe sepsis and septic shock, and to analyze the pathway’s impact on survival and duration of hospital stays. We used data on 125 patients in an Intensive Care Unit, divided into a control group (N=84) and an intervention group (N=41). Levels of compliance increased from 13.1% to 29.3% in 5 resuscitation bundle interventions and from 14.3% to 22% in 3 monitoring bundle interventions. In-hospital mortality at 28 days decreased by 11.2% and the duration of hospital stay was reduced by 5 days. Although compliance was low, the intervention enhanced adherence to the instructions given in the clinical pathway and we observed a decline in mortality at 28 days and shorter hospital stays.

Ecclesiastical memorials, relating chiefly to religion, and the reformation of it and the emergencies of the Church of England under King Henry VIII., King Edward VI., and Queen Mary I., with large appendixes, containing original papers, records, [etc.]

v.1,pt.1. Ecclesiastical memorials... under King Henry VIII.-v.1,pt.2. Appendix, containing records, letters and other original writings referred to in the Memorials under the reign of Kin Henry VIII.-v.2, pt.1-2. Historical memorials, chiefly ecclesiastical...under the reign and influence of King Edward the Sixth.-v.3, pt.1-2. Historical memorials, ecclesiastical and civil of events under the reign of Queen Mary I.