Implications of bio-efficacy and persistence of insecticides when indoor residual spraying and longlasting insecticide nets are combined for malaria prevention.

Bio-efficacy and residual activity of insecticides used for indoor residual spraying (IRS) and long-lasting insecticide nets (LLINs) were assessed against laboratory-reared and wild populations of the malaria vector, Anopheles arabiensis in south eastern Tanzania. Implications of the findings are examined in the context of potential synergies and redundancies where IRS and LLINs are combined. METHODS: Bioassays were conducted monthly for six months on three LLIN types (Olyset(R) PermaNet 2.0(R),and Icon Life(R)) and three IRS treatments (2 g/m2 pirimiphos-methyl, 2 g/m2 DDT and 0.03 g/m2 lambda-cyhalothrin, sprayed on mud walls and palm ceilings of experimental huts). Tests used susceptible laboratory-reared An. arabiensis exposed in cones (nets and IRS) or wire balls (nets only). Susceptibility of wild populations was assessed using WHO diagnostic concentrations and PCR for knock-down resistance (kdr) genes. IRS treatments killed [greater than or equal to] 85% of mosquitoes exposed on palm ceilings and [greater than or equal to] 90% of those exposed on mud walls, but up to 50% of this toxicity decayed within 1-3 months, except for DDT. By 6th month, only 7.5%, 42.5% and 30.0% of mosquitoes died when exposed to ceilings sprayed with pirimiphos-methyl, DDT or lambda-cyhalothrin respectively, while 12.5%, 36.0% and 27.5% died after exposure to mud walls sprayed with the same insecticides. In wire-ball assays, mortality decreased from 98.1% in 1st month to 92.6% in 6th month in tests on PermaNet 2.0(R), from 100% to 61.1% on Icon Life(R) and from 93.2% to 33.3% on Olyset(R) nets. In cone bioassays, mortality reduced from 92.8% in 1st month to 83.3% in 6th month on PermaNet 2.0(R), from 96.9% to 43.80% on Icon Life(R) and from 85.6% to 14.6% on Olyset(R). Wild An. arabiensis were 100% susceptible to DDT, 95.8% to deltamethrin, 90.2% to lambda cyhalothrin and 95.2% susceptible to permethrin. No kdr gene mutations were detected. CONCLUSIONS: In bioassays where sufficient contact with treated surfaces is assured, LLINs and IRS kill high proportions of susceptible An. arabiensis mosquitoes, though these efficacies decay gradually for LLINs and rapidly for IRS. It is, therefore, important to always add intact nets in sprayed houses, guaranteeing protection even after the IRS decays, and to ensure accurate timing, quality control and regular re-spraying in IRS programmes. By contrast, adding IRS in houses with intact LLINs is unlikely to improve protection relative to LLINs alone, since there is no guarantee that unfed vectors would rest long enough on the sprayed surfaces, and because of the rapid IRS decay. However, there is need to clarify these effects using data from observations of free flying mosquitoes in huts. Physiological susceptibility of An. arabiensis in the area remains 100% against DDT, but is slightly reduced against pyrethroids, necessitating caution over possible spread of resistance. The loss of LLIN toxicity, particularly Olyset(R) nets suggests that protection offered by these nets against An. arabiensis may be primarily due to physical bite prevention rather than insecticidal efficacy

Growth cycle signals as inflation indicators for major industrial nations

One of the issues of concern to forecasters is whether leading indicators of the real economy, which are now issued in many countries, have a bearing on the future of inflation. Doubtless a direct approach, which would involve the development of leading indicators specifically related to inflation, would be preferable. However, we are aware of only one such index currently available, the leading index of inflation compiled for the United States by the Center for International Business Cycle Research. Hence in this paper we explore whether leading and coincident indexes measuring real growth are useful for forecasting inflation in the U.S., the United Kingdom, West Germany and Japan. Section 2 shows how growth cycles and inflation cycles are related in these countries, using results from a recent study by Moore and Philip Klein for the World Bank. Section 3 explains the development of signals of turning points in inflation rate cycles using the growth rates in the leading and coincident indexes. It shows the leads and lags of the signal system at inflation cycle turns, and measures the magnitude of changes in the inflation rate between the growth signal dates. Section 4 discloses how the new signals could be of use in forecasting changes in interest rates. Section 5 provides a summary of the principal findings

Structural role of the tyrosine residues of cytochrome c

The tertiary structures of horse, tuna, Neurospora crassa, horse [Hse65,Leu67]- and horse [Hse65,Leu74]-cytochromes c were studied with high-resolution 1H n.m.r. spectroscopy. The amino acid sequences of these proteins differ at position 46, which is occupied by phenylalanine in the horse proteins but by tyrosine in the remaining two, and at positions 67, 74 and 97, which are all occupied by tyrosine residues in horse and tuna cytochrome c but in the other proteins are substituted by phenylalanine or leucine, though there is only one such substitution per protein. The various aromatic-amino-acid substitutions do not seriously affect the protein structure

Identification of a neurovascular signaling pathway regulating seizures in mice

ObjectiveA growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainate‐induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet‐derived growth factor receptor alpha (PDGFRα).ResultsCompared to wild‐type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure‐resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPA‐mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112290/1/acn3209.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/112290/2/acn3209-sup-0001-TableS1.pd

Population Pharmacokinetics of Lamivudine in Adult Human Immunodeficiency Virus-Infected Patients Enrolled in Two Phase III Clinical Trials

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4+ cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4+ cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

1964

Turf Management Club by John Traynor (page 1) Who Is Superintendent Here by H.E. Frenette (1) Good Turf Can Result from good Sodding (3) Golf Course Superintendent by Edwart Wiacek (4) Picture - Outstanding Senior Prof. Troll Picture - recognition for Blazers St. Andrew\u27s, Scotland by William Hynd (5) Analogy of a Turf Manager by James B. Cole (6) Fish Trouble by Peter A. Langelier and Dennis P. Leger (8) Square Rings by Robert P. McGuire (9) A Different Type of Course by Robert Hall (10) Literature by Pierre Coste (11) Weeds in Golf Course Turf and Their Control by John F. Cornman (A-1) The USe of Liquid Fertilizer by Anthony B. Longo (A-3) Fertilizing a Golf Course Through an Irrigation System by Herbert E. Berg (A-6) The Extent of Winter Injury on Golf Courses by James L. Holmes (A-11) The Problem of Winter Injury by James B. Beard (A-13) Establishing, Maintaining, and Selling Sod for Turf Areas in New England by George F. Stewart (A-20) Problems of Maintaining Turf Around Industrial Grounds by George Moore (A-22) Landscaping Industrial sites by A.W. Boicourt (A-25) Introduction to the panel Discussion on Grasses for Tees and Their Management by Alexander M. Radko (A-28) Building a Golf Tee by Phil Cassidy (A-29) Grasses for Tees and Their Management by Wm. Dest (A-31) Golf Course Tee maintenance by Jim Fulwider (A-32) Tees by F. Thompson (A-33) How to Draw up a Contract by Lawrence D. Rhoades (A-34) My Contract by Lucien E. Duval (A-37) The Golf Car Problem by Geoffrey S. Cornish (A-41) Golf Cars and Turfgrass by Lee Record (A-42) Course Design and Golf Cars by William F. Mitchell (A-42) Golf Cars and the Established Course by Sherwood Moore (A-45) Course Design and Golf Cars by Phil Wogan (a-52) Introduction of Cars to the New Course by M. Ovian (A-56

Near-complete backbone resonance assignments of acid-denatured human cytochrome c in dimethylsulfoxide: a prelude to studying interactions with phospholipids

Human cytochrome c plays a central role in the mitochondrial electron transfer chain and in the intrinsic apoptosis pathway. Through the interaction with the phospholipid cardiolipin, cytochrome c triggers release of pro-apoptotic factors, including itself, from the mitochondrion into the cytosol of cells undergoing apoptosis. The cytochrome c/cardiolipin complex has been extensively studied through various spectroscopies, most recently with high-field solution and solid-state NMR spectroscopies, but there is no agreement between the various studies on key structural features of cytochrome c in its complex with cardiolipin. In the present study, we report backbone 1H, 13C, 15N resonance assignments of acid-denatured human cytochrome c in the aprotic solvent dimethylsulfoxide. These have led to the assignment of a reference 2D 1H-15N HSQC spectrum in which out of the 99 non-proline residues 87% of the backbone amides are assigned. These assignments are being used in an interrupted H/D exchange strategy to map the binding site of cardiolipin on human cytochrome c

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses