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Interest in lifetime lung function trajectories has increased in the context of emerging evidence that chronic obstructive pulmonary disease (COPD) can arise from multiple disadvantaged lung function pathways, including those that stem from poor lung function in childhood. To our knowledge, no previous study has investigated both obstructive and restrictive lifetime patterns concurrently, while accounting for potential overlaps between them. We aimed to investigate lifetime trajectories of the FEVUsing z scores from spirometry measured at ages 7, 13, 18, 45, 50, and 53 years in the Tasmanian Longitudinal Health Study (n=2422), we identified six FEVThe prevalence of the four lifetime spirometry patterns was as follows: low FEVTo our knowledge, this is the first study to characterise lifetime phenotypes of obstruction and restriction simultaneously using objective data-driven techniques and unique life course spirometry measures of FEVNational Health and Medical Research Council of Australia, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, QueenslandTasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.

To sustain plant growth, development, and crop yield, sucrose must be transported from leaves to distant parts of the plant, such as seeds and roots. To identify genes that regulate sucrose accumulation and transport in maize (Zea mays), we isolated carbohydrate partitioning defective33 (cpd33), a recessive mutant that accumulated excess starch and soluble sugars in mature leaves. The cpd33 mutants also exhibited chlorosis in the leaf blades, greatly diminished plant growth, and reduced fertility. Cpd33 encodes a protein containing multiple C2 domains and transmembrane regions. Subcellular localization experiments showed the CPD33 protein localized to plasmodesmata (PD), the plasma membrane, and the endoplasmic reticulum. We also found that a loss-of-function mutant of the CPD33 homolog in Arabidopsis, QUIRKY, had a similar carbohydrate hyperaccumulation phenotype. Radioactively labeled sucrose transport assays showed that sucrose export was significantly lower in cpd33 mutant leaves relative to wild-type leaves. However, PD transport in the adaxial-abaxial direction was unaffected in cpd33 mutant leaves. Intriguingly, transmission electron microscopy revealed fewer PD at the companion cell-sieve element interface in mutant phloem tissue, providing a possible explanation for the reduced sucrose export in mutant leaves. Collectively, our results suggest that CPD33 functions to promote symplastic transport into sieve elements.

Detailed herein is the synthesis and characterization of [P,N]-ligated perfluoronickelacyclopentanes based on the bidentate ligand 2-(diphenylphosphino)phenyl-N-phenylaniline [P,NH]. A high-yielding substitution reaction between [P(O-o-tol)3]2Ni(C4F8) and [P,NH] gives the phosphine-amine-coordinated metallacycle [P,NH]Ni(C4F8). Alternatively, [P,NH]Ni(C4F8) is formed upon treatment of Ni[P(O-o-tol)3]4 with one equiv. of [P,NH] followed by tetrafluoroethylene. This product reacts quantitatively with base to give an anionic phosphine-amido-ligated nickelacycle. Reactivity studies of the new [P,NH]- and [P,N−]-ligated perfluoronickelacycles are presented and compared and contrasted with our previously reported [P,S] systems.

Conversion of renewable resources to the chemicals and materials needed for consumer products represents an exciting challenge for catalysis science. Here we discuss our initial progress on synthesizing C6 diacids from the sugar fermentation intermediate α-homo-citric acid lactone using supported heterogeneous catalysts in water. Using high-throughput catalysis testing we have identified several promising catalysts for this process that yield different amounts of the three C6 diacids: adipic, 2-methylglutaric and 2-ethylsuccinic. The process involves a relay of four different chemical reactions: dehydration, alkene isomerization, decarboxylation and alkene hydrogenation. DFT studies have been initiated in order to rationalize the activity and selectivity based on catalyst properties.

The fundamental reactivity leading to N-heterocyclic fluoroalkene adducts is explored in detail, featuring a total of 15 N-heterocyclic carbenes (NHCs) with various electronic and steric environments. The activity of these carbenes towards tetrafluoroethylene (TFE), hexafluoropropene (HFP), trifluoroethylene (HTFE) and vinylidene fluoride (VDF) is assessed in THF and toluene. Attempts were made to correlate the observed reactivity with electronic (Tolman Electronic Parameters) and steric (% buried volume) parameters unique to each NHC, but a trend has yet to be fully determined. However, the unique steric constraints of a cyclic (alkyl)(amino)carbene (CAAC) were shown to modify the initial point of nucleophilic attack on HTFE, providing selective transformation to a different adduct than has been observed to date with all reactions involving this fluoroalkene.

In this study, trifluoromethyl POCOP-type pincer complexes (iPrPOCOP)Ni(CF3) (1-CF3) and (iPrPOCOP)Pd(CF3) (2-CF3) are prepared. These complexes undergo Lewis acid-mediated fluoride abstraction to furnish cationic d8 difluorocarbene complexes of the type [(iPrPOCOP)M(=CF2)]+[X]-, which are characterized in solution and for M = Ni using single-crystal X-ray diffraction analysis. The electrophilic nature of these difluorocarbene complexes is discussed, including their reactivity with pyridines.

Highly efficient and selective production of levulinic acid has been achieved from D-fructose in the presence of polystyrene-based sulphonic acid resin catalyst, Dowex 50 × 8-100, at mild reaction conditions of 120 °C, over 24 h in a 50:50 mixture of water/GVL resulting in 72 mol% yield under optimized reaction conditions. Optimization of the effect of reaction temperature, time, pressure, catalyst to substrate ratio, fructose concentration and solvent was performed. Various polystyrene-based sulfonic acid resins were also investigated for quantitative production of LA from 5-hydroxymethylfurfural (5-HMF) in pure water. Catalyst recycling was carried out up to 6 cycles. Significant mechanistic information was obtained for the formation of “humins”, which are the primary cause of catalyst fouling, by the identification of soluble by-products and polymerization presursors using Q-Tof mass spectrometry based on accurate masses.

EXECUTIVE SUMMARYEXECUTIVE SUMMARYThe 2020-21 Professional Affairs Committee was charged to (1) Read all six reports from the 2019-20 AACP standing committees to identify elements of these reports that are relevant to the committee's work this year; (2) Identify opportunities and models of integration of pharmacist care services in physician and other health provider practices beyond primary care; (3) Differentiate and make the case for the integration of pharmacist care services from that of other mid-level providers; and (4) From the work on the aforementioned charges, identify salient activities for the Center To Accelerate Pharmacy Practice Transformation and Academic Innovation (CTAP) for consideration by the AACP Strategic Planning Committee and AACP staff. This report provides information on the committee's process to address the committee charges, describes the rationale for and the results from a call to colleges and schools of pharmacy to provide information on their integrating pharmacist care services in physician and other health provider practices beyond primary care practice, and discusses how pharmacist-provided patient care services differ from those provided by other healthcare providers. The committee offers a revision to a current association policy statement, a proposed policy statement as well as recommendations to CTAP and AACP and suggestions to colleges and schools of pharmacy pertaining to the committee charges.

A nickel catalyzed Suzuki coupling of arylboronic acids and novel bromodifluoromethyl(arylsulfonyl) compounds is described, providing an example of direct Csp2-CF2SO2Ar bond formation. High-throughput experimentation (HTE) was utilized for identifying the catalyst and reaction conditions.

Herein, we report the aerobic oxidation of several bio-oils (pyrolysis and microwave) derived from Kraft lignin using oxovanadium complex catalyst, (HQ) 2 V v (O)(O i Pr) (HQ = 8-oxyquinoline) ( 2 ), ionic liquid (IL)-tagged oxovanadium complex, PF 6 -IL-salen-V IV (O) ( 3 ) (PF 6 = hexafluorophosphate) and copper catalyst CuX/TEMPO/2,6-lutidine ( 4 ) [X = OTf, trifluoro-methanesulfonate), Cl; TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl]. Cleavage of some lignin linkages and reduced phenolic content were observed by multinuclear NMR spectroscopy, FT-IR and 1D/2D GC/MS analysis. Catalyst 2 oxidized chloroform extracts of the microwave bio-oil more extensively than those from the pyrolysis bio-oil although reactivity trends were similar. With catalyst 3 in [MMIM][MeOSO 3 ], the phenolic conversion was modest compared with the increase in carboxyl and decrease in aliphatic OH groups. IR spectra were consistent with phenol oxidation to quinone-type structures. In contrast, copper catalyst 4 showed formation of high molecular weight compounds after oxidation, likely resulting from radical recombination. Comparison of reactivity between the different types of lignin-derived bio-oils is also discussed.

An intelligent EWOD top plate control system is proposed in this study. The dynamic top plate is controlled by a piezoelectric (PZT) cantilever structure. A High resolution laser displacement sensor is used to monitor the deflection of the top plate. The gap height optimization and the top plate vibration significantly improve the droplet velocity and decrease the droplet minimum threshold actuation voltage. The top plate vibration induced actuation velocity improvement is magnitude and frequency dependent. 100 μm and 200 μm vibrations are tested at 25 Hz. Vibration frequencies at 5 Hz, 10 Hz, and 20 Hz are tested while the magnitude is 200 μm. Results show greater improvements are achieved at larger vibration magnitudes and higher vibration frequencies. With a vibrated top plate, the largest reduction of the actuation voltage is 76 V RMS for a 2.0 μl DI water droplet. The maximum droplet instantaneous velocity is around 9.3 mm/s, which is almost 3 times faster than the droplet velocity without top plate vibration under insufficient driving voltages. Liquid that has different hysteresis such as acetonitrile with various concentrations are used as a control to show its compatibility with the proposed DMF chip. Contact line depinning under top plate vibration is observed, which indicates the underlying mechanism for the improvements in actuation velocity and threshold voltage. The top plate control technique reported in this study makes EWOD DMF chips more reliable when used for the clinical point-of-care diagnostic applications.

Prosthetic valve replacement options in children lack the ability to grow with the patient and often require multiple reoperations. Adverse events are also magnified in the pediatric population, in whom the need for a functional valve is decades longer and the issue of growth leading to body–size

The hydrodimerization of C2 fluoroalkenes to saturated C4 hydrofluorocarbons proceeds via hydrogenolysis of M-C bonds in perfluorometallacyclopentanes. In previous work, hydrogenolysis of Fe[κ2-(CF2)4-](CO)4 (1) was shown to yield expected product H(CF2)4H as well as H2CF(CF2)3H, presumably due to Cα-F bond activation. In this work we investigate ligand-substituted analogs of 1 with regard to their propensity to undergo Cα-F bond activation to give perfluoroferracyclocarbenes. Specifically, reaction of 1 with triphos affords Fe=[CF(CF2)3-](F)(triphos) (5) which reacts further with NaBPh4 in acetonitrile to afford {Fe=[CF(CF2)3-](NCMe)(triphos)}+(BPh4)− (6; triphos = bis(2-diphenylphosphinoethyl)-phenylphosphine). In contrast, reaction of 1 with terpy’ followed by Me3SiOTf gives [Fe=[CF(CF2)3-](terpy’)(CO)]+(OTf)− (9; terpy’ = 4′-(4-methylphenyl)-2,2′:6′,2′′-terpyridine; OTf = SO3CF3). While 5 does not react readily with H2, 6 is readily converted to [FeH(triphos)(NCMe)]+(BPh4)− (10) and H2CF(CF2)3H whereas 9 undergoes a complex reaction with H2, affording HF and a mixture of uncharacterized Fe organofluorine complexes.

The 2019-2020 Professional Affairs Committee was charged to (1) Describe the leadership role of schools of pharmacy in advancing interprofessional practice, with an emphasis on physician-pharmacist collaborative relationships; (2) Establish an inventory of resources that can support school efforts to grow collaborative partnerships between pharmacists and physicians; (3) Determine gaps that exist in the resources required to support schools in efforts to facilitate expansion of interprofessional partnerships; and (4) Define strategies and draft an action plan for AACP’s role in facilitating member school efforts to accelerate the development of interprofessional practices within their geography of influence. This report provides information on the committee’s process to address the committee charges as well as background and resources pertaining to the charges, describes the rationale for and the results from the focus groups conducted at the 2020 AACP Interim Meeting, communicates the results of an initial inventory of models that integrate pharmacists with primary care practices, and provides an overview on issues to continue the work to integrate pharmacists with primary care practices. The committee offered several revisions to current association policy statements and provided a proposed policy statement and several recommendations to AACP pertaining to the committee charges.

Treatment of complex bone defects places a significant burden on the US health care system. Current strategies for treatment include grafting and stabilization using internal metal plates/screws, intramedullary rods, or external fixators. Here, we introduce the use of shape memory polymer (SMP) materials for grafting and adjunct stabilization of segmental defects. Self-deploying SMP grafts and SMP sleeves capable of expanding and contracting, respectively, under intraoperative conditions were developed and evaluated in a mouse segmental defect model in vivo. Integration between grafts/sleeves and native bone was assessed using x-ray radiography, microcomputed tomography, and torsional mechanical testing. We found that SMP grafts were able to integrate with the native bone after 12 weeks, maintain defect stability, and provide torsional mechanical properties comparable to an allograft alone treatment; however no gross de novo bone formation was observed. SMP sleeves did not inhibit bony bridging at the margins, and limbs treated with a sleeve/allograft combination had torsional mechanical properties comparable to limbs treated with an allograft alone. In vitro torsional and bending tests suggest sleeves may provide additional torsional stability to defects. Incorporation of shape memory into synthetic bone graft substitutes and adjunct stabilization devices is anticipated to enhance functionality of synthetic materials employed in both applications.

Background Prosthetic valves currently used in children lack the ability to grow with the patient and often require multiple reoperations. Small intestinal submucosa-derived extracellular matrix (SIS-ECM) has been used successfully as a patch for repair in various tissues, including vessels, valves, and myocardium. Objectives This study sought to assess the remodeling potential of a tubular tricuspid valve (TV) bioprosthesis made of SIS-ECM by evaluating its growth, structure, and function in a growing ovine model. Methods A total of 12 3-month-old lambs were studied for a period of 3 or 8 months. SIS-ECM TVs were placed in 8 lambs; conventional bioprosthetic valves and native valves (NV) were studied as controls. All lambs underwent serial echocardiography, measuring annulus diameter and valve and right ventricular function. Results The SIS-ECM valves demonstrated an incremental increase in annular diameter similar to NV. SIS-ECM valve function was normal in 7 of 8; 1 valve had severe regurgitation due to a flail leaflet. Explanted SIS-ECM valves approximated native tissue in gross appearance. Histopathology demonstrated migration of resident mesenchymal cells into the scaffold and trilaminar ECM organization similar to an NV, without inflammation or calcification at 8 months. Ex vivo mechanical testing of SIS-ECM valve tissue showed normalization of the elastic modulus by 8 months. Conclusions In an ovine model, tubular SIS-ECM TV bioprostheses demonstrate “growth” and a cell-matrix structure similar to mature NVs while maintaining normal valve function. The SIS-ECM valve may provide a novel solution for TV replacement in children and adults.

The title compound was prepared by catalytic hydrogenation of the 4πs + 4πs photochemical cycloadduct between anthracene and cyclopentadiene to confirm the structure of the cycloadduct. Two different crystal morphologies were obtained. Bond distances and angles for the P21/c modification, which contains one molecule in the asymmetric unit, agree with ab initio calculations. Relative to typical C–C single bonds, the interannular bonds between the bridgehead carbons of the anthracene- and cyclopentane-derived fragments are elongated (observed to average 1.581 A and calculated to be 1.585 A and 1.583 A by RHF and MP2 theories, respectively), but other bond parameters are unexceptional. The C2/c structure contains one-half of a molecule disordered about an axis of pseudosymmetry. Bonding parameters in this structure are distorted due to the disorder which is only partially resolved. The origin of the disorder is considered in light of the crystallographic packing interactions.

The Neutron Induced Fission Fragment Tracking Experiment (NIFFTE) collaboration is developing a Time Projection Chamber (TPC) to measure neutron-induced fission cross sections with unprecedented accuracy. Modifying TPC technology for nuclear physics applications is a challenging endeavor, and frequent testing and evaluation is required to ensure that all components are behaving as expected. In-beam tests of the NIFFTE TPC at the Los Alamos Neutron Science Center (LAN-SCE) commenced in 2010. An overview of the NIFFTE TPC experiments performed at LANSCE will be presented, along with preliminary performance results.

The history and geography of sports in nineteenth- and twentieth-century France have been studied intensively during the last thirty years but one sport – that of pigeon racing – has received virtually no attention. This paper ventures into a largely unexplored field. After describing briefly the general history of homing pigeons and the specific geography of pigeon racing clubs in France in 1890, it focuses on the departement of Pas-de-Calais in northern France. Pas-de-Calais and the adjacent departement of Nord together accounted for more than half of the just over 400 pigeon racing clubs identified in France in 1890. Within the context of the rapid development between 1870 and 1914 of its population, society and economy (and especially its coalmining industry), Pas-de-Calais saw the creation of more than one thousand recreational societies, especially sports clubs, among them numerous pigeon racing clubs. Three hundred pigeon racing clubs in one of the departement's six arrondissements – that of Bethune – are examined closely from surviving but fragmentary sources. The aims, names, membership and racing activities of these societies are studied from their unpublished records. They are shown to have developed in close association with the growth of coalmining communities and in particular with the role of Belgian immigrants in those communities.

The oxidation and nitration of unsaturated fatty acids transforms cell membrane and lipoprotein constituents into mediators that regulate signal transduction. The formation of 9-NO2-octadeca-9,11-dienoic acid and 12-NO2-octadeca- 9,11-dienoic acid stems from peroxynitrite- and myeloperoxidase-derived nitrogen dioxide reactions as well as secondary to nitrite disproportionation under the acidic conditions of digestion. Broad anti-inflammatory and tissue-protective responses are mediated by nitro-fatty acids. It is now shown that electrophilic fatty acid nitroalkenes are present in the urine of healthy human volunteers (9.9 + 4.0 pmol/mg creatinine); along with electrophilic 16- and 14-carbon nitroalkenyl β-oxidation metabolites. High resolution mass determinations and co-elution with isotopically-labeled metabolites support renal excretion of cysteine-nitroalkene conjugates. These products of Michael addition are in equilibrium with the free nitroalkene pool in urine and are displaced by thiol reaction with HgCl2. This reaction increases the level of free nitroalkene fraction >10-fold and displays a KD of 7.5x10-6 M. In aggregate, the data indicates that formation of Michael adducts by electrophilic fatty acids is favored under biological conditions and that reversal of these addition reactions is critical for detecting both parent nitroalkenes and their metabolites. The measurement of this class of mediators can constitute a sensitive non-invasive index of metabolic and inflammatory status. Fil: Salvatore, Sonia Rosana. University of Pittsburgh; Estados Unidos Fil: Vitturi, Dario A.. University of Pittsburgh; Estados Unidos Fil: Baker, Paul R. S.. University of Pittsburgh; Estados Unidos Fil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Koenitzer, Jeffrey R.. University of Pittsburgh; Estados Unidos Fil: Woodcock, Steven R.. University of Pittsburgh; Estados Unidos Fil: Freeman, Bruce A.. University of Pittsburgh; Estados Unidos Fil: Schopfer, Francisco J.. University of Pittsburgh; Estados Unidos

Laser Doppler imaging (LDI) has been investigated and used since 1993 for the assessment of burn wounds. Here we describe tests that validate use of the dedicated colour palette, derived in Part 1, for a standardised interpretation of LDI images for prediction of healing time (14 days, 14-21 days or21 days). We also describe clinical and technical factors to be taken into account during LDI imaging and during image interpretation.(1) A cohort of images, selected at random, were assessed, according to strict rules of interpretation, by 6 clinicians against photographs of healing, for accuracy of healing time prediction and clinical usefulness using five-point scales. (2) All images were assessed technically in a similar way for accuracy and the accuracy was further studied by analysing the data by ordinal logistic regression to predict the dependence of burn healing time on demographic variables (age, sex, race, %TBSA, burn cause and site). (3) Where average LDI blood flow could be determined, regression analysis was used to assess the potential accuracy of the technique.(1) Clinical accuracy was found to be 93% and usefulness was 89%; (2) technical accuracy was found to be 96%; (3) regression analysis found that a potential accuracy of 90.9% could be achieved using LDI results alone, increasing to 92% if gender was also considered; no other parameters had an influence on healing time prediction.LDI can be used in a standardised way as a valid tool for improving on clinical assessment of burn wounds. This can enable earlier appropriate management.

A fission TPC is being developed to measure the energy-dependent neutron induced fission cross sections of the major and minor actinides to an accuracy of better than 1%. Achieving such an accuracy will depend in part, on the ability of the TPC to provide precise tracking and identification of charged particles. A measurement of the α -decay to spontaneous fission branching ratio of 252 Cf used to benchmark the performance of the TPC will be discussed.

The NIFFTE collaboration has developed a time projection chamber to study neutron-induced fission events in actinide targets by tracking and identifying fission fragments in three dimensions as they traverse a gas volume. This paper will provide an overview of the analysis software that has been developed by the NIFFTE collaboration, as well as examples of its success in analyzing data.

When fully instrumented, the NIFFTE Time Projection Chamber will consist of nearly 6000 channels, each of which requires a preamplifier, ADC, and digital readout. To minimize channel cost and size, the EtherDAQ data acquisition system utilizes off-the-shelf FPGA and Ethernet fiber technology. This application of commercially-available components made it possible to meet the requirements of the DAQ system with considerably less development cost and time than the a customized ASIC solution, and provides considerable flexibility in the final design. The detailed design and current status of the preamplifier and EtherDAQ boards will be discussed.

The general properties needed in targets (sources) for high precision, high accuracy measurements are reviewed. The application of these principles to the problem of developing targets for the Fission TPC is described. Longer term issues, such as the availability of actinide materials, improved knowledge of energy losses and straggling and the stability of targets during irradiation are also discussed.

The 2017-2018 AACP Professional Affairs Committee addressed the charges of (1) developing a self-reflection/self-assessment tool for pharmacy faculty and preceptors to allow them to assess their capability and confidence with Center for the Advancement of Pharmacy Education (CAPE) Educational Outcomes, the Pharmacists' Patient Care Process (PPCP), and the Entrustable Professional Activities (EPAs) for New Pharmacy Graduates and (2) creation of a plan for AACP to utilize in the development of preceptor continuing education and training programs. This report describes the framework, rationale and process for the development of the Preceptor Self-Assessment Tool for Entrustable Professional Activities for New Pharmacy Graduates (PSAE Tool), the pre-test for the PSAE tool, and the online pilot test and its results for the PSAE Tool. The committee provides recommendations for AACP in the continued development and distribution of the PSAE Tool to the schools of pharmacy. Considerations for AACP and the schools of pharmacy to consider in the continuing professional development (CPD) for all preceptors are also discussed. The committee provides a policy statement, adopted by the AACP House of Delegates, regarding the commitment of AACP regarding the CPD for all preceptors. The committee also provides several recommendations to AACP and suggestions to schools of pharmacy and other stakeholder groups pertaining to the committee charges.

The peroxisome proliferator-activated receptor-γ (PPARγ) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARγ include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPARγ ligands are intermediates of lipid metabolism and oxidation that bind PPARγ with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO2-FA) are endogenous products of nitric oxide (•NO) and nitrite (NO2−)-mediated redox reactions that activate PPARγ at nanomolar concentrations. We report that NO2-FA act as partial agonists of PPARγ and covalently bind PPARγ at Cys-285 via Michael addition. NO2-FA show selective PPARγ modulator characteristics by inducing coregulator protein interactions, PPARγ-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO2-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.

The signaling mediators nitric oxide ( NO) and oxidized lipids, once viewed to transduce metabolic and inflammatory information via discrete and independent pathways, are now appreciated as interdependent regulators of immune response and metabolic homeostasis. The interactions between these two classes of mediators result in reciprocal control of mediator synthesis that is strongly influenced by the local chemical environment. The relationship between the two pathways extends beyond coregulation of NO and eicosanoid formation to converge via the nitration of unsaturated fatty acids to yield nitro derivatives (NO(2)-FA). These pluripotent signaling molecules are generated in vivo as an adaptive response to oxidative inflammatory conditions and manifest predominantly anti-inflammatory signaling reactions. These actions of NO(2)-FA are diverse, with these species serving as a potential chemical reserve of NO, reacting with cellular nucleophiles to posttranslationally modify protein structure, function, and localization. In this regard these species act as potent endogenous ligands for peroxisome proliferator-activated receptor gamma. Functional consequences of these signaling mechanisms have been shown in multiple model systems, including the inhibition of platelet and neutrophil functions, induction of heme oxygenase-1, inhibition of LPS-induced cytokine release in monocytes, increased insulin sensitivity and glucose uptake in adipocytes, and relaxation of preconstricted rat aortic segments. These observations have propelled further in vitro and in vivo studies of mechanisms of NO(2)-FA signaling and metabolism, highlighting the therapeutic potential of this class of molecules as anti-inflammatory drug candidates.

Background. We previously showed cyclic guanosine 3’,5’-monophosphate (cGMP) levels increase with fetal cardiac bypass despite derangements in the placental nitric oxide pathway. The natriuretic peptides, atrial (ANP), brain (BNP), and c-type (CNP), are common indicators of cardiac distress, and an alternative pathway for cGMP generation. We hypothesized that these natriuretic peptides may account for the paradoxic rise in cGMP seen with fetal bypass. Methods. Six ovine fetuses, 106 to 118 days’ gestation, underwent cardiac bypass for 30 minutes and were followed for 120 minutes after bypass. Fetal plasma samples were collected before bypass, during bypass, and 30 and 120 minutes after bypass for natriuretic peptide analysis. Results were compared with 6 sham bypass fetuses and cGMP values from another 14 bypass fetuses (to avoid confounding effects of excess blood sampling). Fetal hemodynamics and metabolics were correlated to ANP, BNP, and CNP values. Statistical analysis was by analysis of variance, Student=s t test, and best-fit correlations, with significance set at p 0.05 or less. Results. The ANP, BNP, and CNP increased with fetal bypass (674 133 pg/mL, 151 52 pg/mL, and 295 45 pg/mL, respectively), remaining elevated after bypass, whereas sham concentrations remained stable at prebypass levels. Changes in ANP, BNP, and CNP positively correlated with rising cGMP. There was positive correlation between ANP and CNP and rising fetal lactate levels, but not to other physiologic parameters associated with placental dysfunction. Conclusions. There is a substantial rise in natriuretic peptides seen with fetal bypass, likely in part a reflection of myocardial dysfunction. Further, the natriuretic peptide pathway may account for the paradoxic rise in cGMP seen with fetal bypass.

Objective Fluid shifts have been suggested to occur with fetal bypass. The degree or mechanisms behind these volume changes (or location) have not been defined. We characterized the preceding and correlated the findings to plasma vasopressin concentrations, the critical peptide of osmoregulation. Methods Seventeen ovine fetuses (105–111 days' gestation) were started on bypass and followed 2 hours after bypass. Hemodynamics and volume replacements needed to maintain minimum reservoir volume during bypass and normal physiologic parameters after bypass were recorded. Serial blood samples were collected to assess gas exchange and vasopressin levels. Changes in total tissue water content were measured for several organs and the placenta. Plasma volume, fluid shifts, and osmolarity were calculated. Results Hematocrit values decreased by 15 minutes of bypass to 28% from 33% and then increased to 34% by 120 minutes after bypass, corresponding to a decreased fetal plasma volume of 79 to 72 mL/kg by 120 minutes after bypass. The majority of volume shifts (approximately 100 mL/kg) occurred during bypass, but additional volume replacements were required after bypass to maintain normal hemodynamics, resulting in overall losses of 0.8 mL · kg −1 · min −1 . Losses were not accounted for by placental or organ edema. Vasopressin levels increased dramatically with bypass (39–51.5 pg/mL) and were strongly predicted by increased fetal plasma volumes ( R 2 = 0.90), whereas osmolarity was not significantly associated with plasma volumes. Conclusion Fetal bypass leads to significant fluid shifts that correlate strongly with increasing vasopressin levels (but not changes in osmolarity). The placenta is not the primary site of volume loss. Rehydration of the fetus is necessary after bypass.

It has been proposed that disruption of normal vitreous humor may permit O(2) to travel more easily from the retina to the center of the lens where it may cause nuclear cataract (Barbazetto, I.A., Liang, J., Chang, S., Zheng, L., Spector, A., Dillon, J.P., 2004. Oxygen tension in the rabbit lens and vitreous before and after vitrectomy. Exp. Eye Res. 78, 917-924; Harocopos, G.J., Shui, Y.B., McKinnon, M., Holekamp, N.M., Gordon, M.O., Beebe, D.C., 2004. Importance of vitreous liquefaction in age-related cataract. Invest. Ophthalmol. Vis. Sci. 45, 77-85). In the present study, we injected enzymes intravitreally into guinea pigs (which possess an avascular retina) and rats (which possess a vascular retina) to produce either vitreous humor liquefaction plus a posterior vitreous detachment (PVD) (with use of microplasmin) or vitreous humor liquefaction only (with use of hyaluronidase), and 1-2 weeks later measured lens nuclear pO(2) levels in vivo using a platinum-based fluorophore O(2) sensor (Oxford-Optronix, Ltd.). Experiments were also conducted in which the animals were allowed to breathe 100% O(2) following intravitreal injection with either microplasmin or hyaluronidase in order to investigate possible effects on O(2) exchange within the eye. Injection of guinea pigs with either of the two enzymes produced no significant differences in lens pO(2) levels 1-2 weeks later, compared to controls. However, for the rat, injection of microplasmin produced a 68% increase in O(2) level in the center of the lens, compared to the controls (5.6mm Hg increasing to 9.4mm Hg, p0.05), with no corresponding effect observed following similar use of hyaluronidase. Treatment of guinea pigs with microplasmin dramatically accelerated movement of O(2) across the vitreal space when the animals were later allowed to breathe 100% O(2) (for example, O(2) traveled to a location directly behind the lens 5x faster than control; p0.01); however, the effect following treatment with hyaluronidase was significantly less. When microplasmin-injected rats breathed 100% O(2), the time required for O(2) to reach the center of the lens was 3x faster than control (0.4 min compared to 1.4 min, p0.01). The results have implication with regard to the occurrence of age-related PVD in the human, and a possible acceleration of maturity-onset nuclear cataract. In addition, enzymatic creation of a PVD to increase the rate of O(2) exchange within the vitreal space may have potential application for treatment of retinal ischemic disease.

Fatty acid nitration by nitric oxide-derived species yields electrophilic products that adduct protein thiols, inducing changes in protein function and distribution. Nitro-fatty acid adducts of protein and reduced glutathione (GSH) are detected in healthy human blood. Kinetic and mass spectrometric analyses reveal that nitroalkene derivatives of oleic acid (OA-NO2) and linoleic acid (LNO2) rapidly react with GSH and Cys via Michael addition reaction. Rates of OA-NO2 and LNO2 reaction with GSH, determined via stopped flow spectrophotometry, displayed second-order rate constants of 183 M(-1)S(-1) and 355 M(-1)S(-1), respectively, at pH 7.4 and 37 degrees C. These reaction rates are significantly greater than those for GSH reaction with hydrogen peroxide and non-nitrated electrophilic fatty acids including 8-iso-prostaglandin A2 and 15-deoxy-Delta(12,14)-prostaglandin J2. Increasing reaction pH from 7.4 to 8.9 enhanced apparent second-order rate constants for the thiol reaction with OA-NO2 and LNO2, showing dependence on the thiolate anion of GSH for reactivity. Rates of nitroalkene reaction with thiols decreased as the pKa of target thiols increased. Increasing concentrations of the detergent octyl-beta-d-glucopyranoside decreased rates of nitroalkene reaction with GSH, indicating that the organization of nitro-fatty acids into micellar or membrane structures can limit Michael reactivity with more polar nucleophilic targets. In aggregate, these results reveal that the reversible adduction of thiols by nitro-fatty acids is a mechanism for reversible post-translational regulation of protein function by nitro-fatty acids.

The hydroboration of phenyl vinyl sulfide with catecholborane (HBcat) and pinacolborane (HBpin) has been examined with a number of rhodium complexes, all of which proceed with excellent regiocontrol in favour of the branched product PhSCH(B(OR)2)CH3. The corresponding linear product can be obtained exclusively in reactions employing [Cp*IrCl2]2 and HBcat. Catalysed hydroborations of (E)-2-(p-toluenethio)styrene with HBcat using Rh(acac)(dppp) gave predominant formation of one product while reactions using HBpin afforded several products arising from a competing C–S bond cleavage (acac = acetylacetonato, dppp = 1,3-bis(diphenylphosphino)propane). Although reactions of phenyl vinyl sulfoxide were complicated by a competing deoxygenation reaction, hydroborations of phenyl vinyl sulfone using HBcat once again gave regioselective formation of either the branched or linear products, depending on the choice of catalyst used to effect this transformation. Catalysed hydroborations of phenyl vinyl sulfonate were less chemo- and regioselective, yielding hydrogenation and diboration products in addition to the two hydroboration product isomers. © 2007 Elsevier B.V. All rights reserved.

Mass spectrometric analysis of human plasma and urine revealed abundant nitrated derivatives of all principal unsaturated fatty acids. Nitrated palmitoleic, oleic, linoleic, linolenic, arachidonic and eicosapentaenoic acids were detected in concert with their nitrohydroxy derivatives. Two nitroalkene derivatives of the most prevalent fatty acid, oleic acid, were synthesized (9- and 10-nitro-9-cis-octadecenoic acid; OA-NO2), structurally characterized and determined to be identical to OA-NO2 found in plasma, red cells, and urine of healthy humans. These regioisomers of OA-NO2 were quantified in clinical samples using 13C isotope dilution. Plasma free and esterified OA-NO2 concentrations were 619 +/- 52 and 302 +/- 369 nm, respectively, and packed red blood cell free and esterified OA-NO2 was 59 +/- 11 and 155 +/- 65 nm. The OA-NO2 concentration of blood is approximately 50% greater than that of nitrated linoleic acid, with the combined free and esterified blood levels of these two fatty acid derivatives exceeding 1 microm. OA-NO2 is a potent ligand for peroxisome proliferator activated receptors at physiological concentrations. CV-1 cells co-transfected with the luciferase gene under peroxisome proliferator-activated receptor (PPAR) response element regulation, in concert with PPARgamma, PPARalpha, or PPARdelta expression plasmids, showed dose-dependent activation of all PPARs by OA-NO2. PPARgamma showed the greatest response, with significant activation at 100 nm, while PPARalpha and PPARdelta were activated at approximately 300 nm OA-NO2. OA-NO2 also induced PPAR gamma-dependent adipogenesis and deoxyglucose uptake in 3T3-L1 preadipocytes at a potency exceeding nitrolinoleic acid and rivaling synthetic thiazo-lidinediones. These data reveal that nitrated fatty acids comprise a class of nitric oxide-derived, receptor-dependent, cell signaling mediators that act within physiological concentration ranges.

A new probabilistic paradigm for calculating the uncertainty in casualty area of randomly reentering debris from orbital objects is presented with exemplar calculations of casualty area associated with elements of a reentering Delta II launch vehicle second stage. Sensitivity studies using a probabilistic paradigm for simulation of spacecraft random reentry disassembly have shown the importance of including uncertainties. The sensitivity of casualty area to spacecraft orientation and consequent free-flying ballistic element orientation is extreme. The notion of inherently stochastic processes during reentry is supported by recent data on recovered debris from the Space Shuttle Columbia. Casualty area standards for spacecraft that rely on deterministic estimates may not be providing the level of safety assurance that was intended.

The aqueous decay and concomitant release of nitric oxide (*NO) by nitrolinoleic acid (10-nitro-9,12-octadecadienoic acid and 12-nitro-9,12-octadecadienoic acid; LNO2) are reported. Mass spectrometric analysis of reaction products supports a modified Nef reaction as the mechanism accounting for the generation of *NO by the aqueous reactions of fatty acid nitroalkene derivatives. Nitrolinoleic acid is stabilized by an aprotic milieu, with LNO2 decay and *NO release strongly inhibited by phosphatidylcholine/cholesterol liposome membranes and detergents when present at levels above their critical micellar concentrations. The release of *NO from LNO2 was induced by UV photolysis and triiodide-based ozone chemiluminescence reactions currently used to quantify putative protein nitrosothiol and N-nitrosamine derivatives. This reactivity of LNO2 complicates the qualitative and quantitative analysis of biological oxides of nitrogen when applying UV photolysis and triiodide-based analytical systems to biological preparations typically abundant in nitrated fatty acids. The results reveal that nitroalkene derivatives of linoleic acid are pluripotent signaling mediators that act not only via receptor-dependent mechanisms, but also by transducing the signaling actions of *NO via pathways subject to regulation by the relative distribution of LNO2 to hydrophobic versus aqueous microenvironments.

The formation of products derived from competing reactions in Rh-catalyzed alkene hydroborations prompted us to study in situ interactions of several hydroborating reagents with unsaturated phosphinorhodium complexes. The reaction of [Rh(μ-H)(DiPPE)]2 (1) with borane–dimethylsulfide gave several rhodium–boron containing products including the structurally characterized metallaborane [RhH(DiPPE)]2B3H7 (2) [DiPPE=1,2-bis(diisopropylphosphino)ethane]. Addition of thexylborane and 9-H-BBN dimers, containing alkyl groups, to 1 gave the corresponding mononuclear substituted borohydride complexes Rh(η2-H2BRR′)(DiPPE) (4: R=H, R′=C(CH3)2CH(CH3)2; 5: R,R′=bicyclo-[3.3.1]-nonane [C8H14]). The analogous monodentate phosphine complex Rh(η2-H2BC8H14)(PPri3)2 (6) was isolated and structurally characterized. Addition of catecholborane (HBcat; cat=1,2-O2C6H4) to 1 gave the unusual dinuclear species Rh(DiPPE)(μ-H)2(μ-Bcat)RhH(DiPPE) (7) containing a semi-bridging Bcat group, confirmed by single-crystal X-ray diffraction, and zwitterionic Rh(η6-catBcat)(DiPPE) (8). Implications for rhodium-catalyzed hydroborations are addressed.

The addition of catecholborane (HBcat; cat = 1,2-O2C6H4) to a wide range of sulfoxides affords the corresponding sulfides, dihydrogen, and catBOBcat. The diboron compound catBOBcat acts like a Lewis acid and will coordinate one molecule of the starting sulfoxide. Although deoxygenations with bulky or electron withdrawing sulfoxides are slow, these reactions can be greatly accelerated with the use of excess HBcat or by employing a rhodium catalyst.

Objective This study was undertaken to determine whether Viagra (Pfizer, New York, NY), a type 5 phosphodiesterase (PDE-5) inhibitor, increases baseline coronary and uterine blood flow or potentiates estrogen-induced increases in blood flow. Study design Seven nonpregnant ovariectomized ewes were chronically instrumented to measure blood pressure, heart rate, cardiac output, and coronary and uterine blood flow. Estradiol-17β (E2, 0.3 μg/kg) (Sigma Chemical Co, St Louis, Mo) and Viagra (50 mg) were intravenously administered separately or together and hemodynamic responses monitored. Results Viagra alone rapidly decreased mean arterial pressure and cardiac output while increasing heart rate and uterine blood flow. Viagra tended to decrease coronary blood flow but not significantly. E2 by itself increased coronary and uterine blood flow over a 2-hour time course, whereas mean arterial pressure, cardiac output, and heart rate remained unchanged. Administration of E2 to animals pretreated with Viagra reversed Viagra-related decrease in cardiac output and coronary blood flow, resulting in a time-related increase in both parameters over baseline values. Viagra significantly augmented estradiol-related increases in uterine blood flow. Conclusion In our surgically menopausal ovine model, Viagra alone has a tendency to decrease baseline coronary blood flow, but the reduction does not reach statistical significance. The presence of estradiol reverses this Viagra-related negative trend and results in a net increase in coronary blood flow and cardiac output. Furthermore, Viagra significantly augments baseline and estrogen-induced increases in uterine blood flow suggesting the presence of PDE-5 in the ovine uterine vasculature.

An adequate increase of uterine blood flow throughout gestation is essential for uterine, placental and fetal growth. Maternal cardiovascular adaptation has to provide the uterine perfusion that is necessary to meet the requirements of the developing and growing fetus by providing transport of nutrients and oxygen to the placenta and the fetus. Thus, uterine blood flow is inextricably linked to fetal growth and survival. Reductions of uterine blood flow can occur under acute or chronic conditions or in a combination of both. Chronic reductions of uterine blood flow can be observed in pregnancy-induced hypertension (PIH), diabetes mellitus in pregnancy and intrauterine growth restriction (IUGR). Chronic restrictions in uterine blood flow will elicit a placental and fetal response in the form of growth adaptation to the reduced supply of oxygen and nutrients to the conceptus. If compensatory growth restriction reaches its limits intrauterine fetal distress can ensue. Among the great number of experimental models of intrauterine growth restriction, those involving a generalized reduction in the uteroplacental blood supply are of significance to questions relating to human pregnancy. Despite physiological differences, particularly with regard to maternal metabolism and placentation, the occlusion model in the pregnant sheep is suitable for investigating questions about fetal and placental growth.

Photosynthesis leads to the fixation of carbon in leaves and to the accumulation of carbohydrates (e.g., sucrose, starch). This assimilated carbon must be transported from the leaves (source tissues) to non-photosynthetic organs (sink tissues), such as roots and seeds. Despite the essentiality of this process in plants, a complete understanding of the actors involved in sucrose export from leaves is lacking. SWEET proteins are a newly identified class of sugar transporters that facilitate diffusion of sugars across cell membranes down a concentration gradient.

Objective: Hormone replacement therapy has been implicated in the increased incidence of breast cancer, although selective estrogen receptor modulators have been shown to be effective in the prevention of breast cancer. Breast cancers are associated with increased mammary blood flow compared to benign breast lesions. However, few studies have examined the hemodynamic effects of hormonal agents on the mammary circulation that promote or reduce the risk of breast cancers. Although estradiol-17β has been shown to increase mammary blood flow, the effect of selective estrogen receptor modulators remains undetermined. We therefore compared the vascular effects of selective estrogen receptor modulators and estrogens on mammary blood flow. Study Design: Fourteen nonpregnant ovariectomized ewes were instrumented to measure mean arterial pressure, heart rate, and uterine and mammary blood flows. Compounds were administered intravenously on separate days, and responses were monitored up to 4 hours. Compounds that were studied included estradiol-17β (1 μg/kg), conjugated equine estrogens (0.625 and 1.25 mg), tibolone (2.5 and 5 mg), raloxifene (10 μg/kg), and tamoxifen (300 μg/kg). Results: None of these compounds significantly affected mean arterial pressure or heart rate, but all of the compounds significantly increased uterine blood flow. Estradiol-17β increased mammary blood flow by 98% ± 25%; conjugated equine estrogen increased mammary blood flow by 46% ± 6% and 68% ± 13% at the 0.625 and 1.25 mg doses, respectively. Tibolone increased mammary blood flow by 37% ± 13% at the 2.5-mg dose and by only 14% ± 4% at the 5-mg dose. Neither raloxifene nor tamoxifen significantly altered mammary blood flow. Conclusion: Although estrogens and selective estrogen receptor modulators induced similar increases in uterine blood flow, they had differential effects on mammary blood flow. (Am J Obstet Gynecol 2002;187:1555-60.)

MgATP substantially inhibited 1-alkyl-sn-glycero-3-phosphate (AGP) acetyltransferase found in neuronal nuclei. Other nucleotides and the ATP analogue AMP-PNP did not show a comparable inhibition. MgATP inhibition decreased in the presence of bovine serum albumin or the fatty acyl CoA synthetase inhibitor, Triacsin C. MgATP inhibition increased when nuclei were preincubated in 50 mM Tris-HCl (pH 7.4)/1 mM MgCl(2) at 37 degrees C, and preincubations elevated levels of nuclear free fatty acid. Exogenous free fatty acid, added to the acetylation incubations, increased the inhibition seen in the presence of MgATP. Oleoyl CoA, in the absence of MgATP, also inhibited AGP acetylation. These results suggested that MgATP supported the conversion of nuclear free fatty acids to fatty acyl CoA. Fatty acyl CoA may directly inhibit nuclear AGP acetyltransferase, but inhibition brought about by MgATP was competitive for the AGP substrate, suggesting an inhibitor close in structure to AGP. 1-Hexadecyl-2-arachidonoyl-sn-glycero-3-phosphate was identified as a competitive inhibitor for AGP in the acetylation reaction. Neuronal nuclei can convert AGP to 1-alkyl-2-acyl-sn-glycero-3-phosphate (AAcylGP), a reaction dependent upon MgATP and the presence of acetyl CoA or free CoA. This nuclear acylation was increased by free fatty acid addition and was seen using oleoyl CoA in the absence of MgATP. Nuclear AAcylGP formation was inhibited by bovine serum albumin and by Triacsin C. Thus, nuclear AGP acetyltransferase may be regulated by AGP acyltransferase activity and the availability of MgATP, a nucleotide that is rapidly lost during brain ischemia.

We prove that the Segre variety I1,3 of PG(7,q>) can be partitioned into caps of size (q4- 1)/(q- 1). It can also be partitioned into three-dimensional elliptic quadrics or into twisted cubics.

Objective. To provide an update to the 2007 ASHP-AACP survey by examining the current capacity of hospitals/health systems’ ability to conduct experiential education for doctor of pharmacy students.Methods. Pharmacists identified as pharmacy directors were sent an invitation to participate in an online survey tool. The survey tool asked IPPE- and APPE-specific questions, the nature of support provided by colleges/schools of pharmacy, the types of experiences available for students, and the factors influencing the quality, value, and challenges of experiential education.Results. Four hundred sixty five of the 2,911 surveys sent were completed yielding a response rate of 16%. Respectively, 45.1% and 28.5% of respondents believe that the capacity for APPE and IPPE will increase in the next five years. Overall, respondents believe that students receive a high-quality experiential education (91.4%).Conclusion. The results of this survey provide insight to the capacity, benefits and challenges of experiential e...

Objective: Endothelin-1 is reportedly elevated in preeclampsia, and studies in our laboratory have shown that infusion of endothelin-1 produces increased mean arterial pressure, hemoconcentration, and proteinuria, while decreasing uterine blood flow. If a role in preeclampsia is confirmed for endothelin-1, therapeutic intervention may involve selective endothelin-A receptor blockers. Thus, this study was designed to determine the effects of Ro 61-1790, a selective endothelin-A receptor inhibitor, on mean arterial pressure, heart rate, and uteroplacental blood flow in pregnant and nonpregnant sheep. Study Design: Seven pregnant and seven nonpregnant sheep were instrumented with indwelling femoral artery and vein catheters and bilateral uterine artery flow probes, allowing determination of mean arterial pressure, heart rate, and uteroplacental blood flow. After baseline administration, animals received intravenous Ro 61-1790 either 1 mg/kg or 3 mg/kg, and hemodynamic responses were monitored for 120 minutes. Results: Intravenous administration of Ro 61-1790 at 1 mg/kg had no effect on the parameters measured in either group studied. However, at 3 mg/kg, Ro 61-1790 caused an increase in total uterine blood flow in nonpregnant sheep from 22 ± 6 mL/min to 51 ± 15 mL/min. This occurred in the absence of significant changes in mean arterial pressure. In pregnant animals, administration of 3 mg/kg Ro 61-1790 decreased mean (± SEM) uteroplacental blood flow by 20% (from 771 ± 130 mL/min to 621 ± 110 mL/min) and increased uterine vascular resistance transiently. Administration of Ro 61-1790 had no significant effect on fetal mean arterial pressure, heart rate, or oxygenation. Conclusions: These data suggest that endogenous endothelin-1 may play an important role in regulating uterine vascular tone in pregnant and nonpregnant sheep and that inhibition of endogenous endothelin-1 may lead to reductions in uteroplacental perfusion in pregnant animals. (Am J Obstet Gynecol 2002;186:55-60.)

Objective: We sought to determine the hemodynamic effects of tibolone in reproductive and nonreproductive tissues in the nonpregnant ovariectomized sheep. Study Design: Six ewes were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, and coronary and uterine blood flow. A dose response curve was generated for intravenous tibolone (1.25, 2.5, and 5 mg) and compared with intravenous 17β-estradiol (1 μg/kg body weight). To determine whether tibolone-related cardiovascular responses were estrogen receptor mediated and produced by nitric oxide, animals were treated on separate days with either estrogen receptor antagonist ICI 182,780 or the nitric oxide synthase inhibitor, L -nitroarginine methyl ester. Results: Tibolone significantly increased coronary blood flow in a dose-related fashion by 5% ± 3%, 9% ± 2%, and 11% ± 2% for the 1.25, 2.5, and 5 mg doses, respectively. Uterine blood flow was also increased significantly in a dose-dependent manner by 98 ± 15, 216 ± 59, and 303 ± 56 mL/min, for the 1.25, 2.5, and 5 mg doses, respectively. L -Nitroarginine methyl ester attenuated tibolone-induced increases in uterine blood flow by 84% ± 4% and abolished the increase in coronary blood flow. ICI 182,780 inhibited all tibolone-induced cardiovascular responses. Conclusion: Tibolone significantly increases coronary and uterine blood flow in ovariectomized ewes. The coronary and uterine vascular responses are mediated via an estrogen receptor–dependent mechanism and are produced mainly by nitric oxide. (Am J Obstet Gynecol 2001;184:544-51.)

The latest meeting in the series of International Conferences of Historical Geographers was held in Kyoto in 2009. The series originated in a meeting of Canadian and British historical geographers held in Kingston, Ontario, in 1975. Four subsequent meetings held in Britain, Canada and the USA saw an increasingly international participation and the sixth meeting, held in 1986, was accorded the title of the Sixth International Conference of Historical Geographers. Eight further such conferences have been held since then, some in locations well beyond Britain and North America. This paper records the basic historical and geographical characteristics of all of the meetings between 1975 and 2009.