bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxygen‐conserving reflexes of the brain: the current molecular knowledge
Authors: Schaller B. , Cornelius J. F. , Sandu N. , Ottaviani G. , Perez‐Pinzon M. A.
Published: April 2009

The trigemino‐cardiac reflex (TCR) may be classified as a sub‐phenomenon in the group of the so‐called ‘oxygen‐conserving reflexes’. Within seconds after the initiation of such a reflex, there is neither a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF) with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently and gives substantial evidence that the TCR is an oxygen‐conserving reflex. This system, which mediates reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus which finally engage a small population of neurons in the cortex. This cortical centre appears to be dedicated to reflexively transduce a neuronal signal into cerebral vasodilatation and synchronization of electrocortical activity. Sympathetic excitation is mediated by cortical‐spinal projection to spinal pre‐ganglionic sympathetic neurons whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Better and more detailed knowledge of the cascades, transmitters and molecules engaged in such endogenous (neuro) protection may provide new insights into novel therapeutic options for a range of disorders characterized by neuronal death and into cortical organization of the brain.
Effects of a short behavioural intervention for dental flossing: randomized‐controlled trial on planning when, where and how
Authors: Schüz Benjamin , Wiedemann Amelie U. , Mallach Natalie , Scholz Urte
Published: April 2009

Aim: Regular dental flossing has been widely recommended to prevent periodontal diseases. Nevertheless, compliance is below a desirable level. This study evaluates the effects of a brief behavioural intervention on dental flossing and determines whether the effects of such an intervention are stronger in a specific subgroup of individuals (those intending to floss regularly=implemental mindset).

Materials and Method: Behavioural intervention (planning when, where and how to floss) trial was conducting with 194 participants assigned to an intervention or a control group by a random time schedule; the primary outcome was validated self‐report of flossing behaviour. Follow‐up data were collected 2 and 8 weeks post‐intervention.

Results: Individuals receiving the planning intervention significantly outperformed those in the control condition at both the 2‐ and the 8‐week follow‐up (4.24 times flossing/week versus 3.9 at 2 weeks; 4.02 versus 2.98 at 8 weeks). Intervention effects were stronger in individuals in the implemental mindset. Dropout rates were higher for participants who received the planning intervention but were not in the implemental mindset.

Conclusion: Planning interventions are an economic and effective way to change oral self‐care behaviour, and are more effective in individuals in an implemental mindset.
Aggressive periodontitis is likely influenced by a few small effect genes
Authors: De Carvalho Flavia M. , Tinoco Eduardo M. B. , Govil Manika , Marazita Mary L. , Vieira Alexandre R.
Published: April 2009

Aim: To evaluate the inheritance mode of aggressive periodontitis in a collection of families with a similar geographic origin.

Materials and Methods: Segregation analysis was performed in pedigree data from 74 families by the use of the SEGREG program of SAGE v.5.4.2. Homogeneous no transmission, homogeneous Mendelian transmission, homogeneous general transmission, semi‐general transmission and heterogeneous general transmission models were tested assuming the prevalence of aggressive periodontitis as 1% and no deviations from Hardy–Weinberg equilibrium. The parameters of the model were estimated by the method of maximum likelihood, which provides the overall ln (likelihood), ‐2ln and the AIC (Akaike's score) for each model. The likelihood ratio test (LRT) was used to compare each model against a fully general model (p>0.05).

Results: The most parsimonious mode of inheritance was the semi‐general transmission model that allows the heterozygote transmission probability to vary.

Conclusion: This result provides strong support for the hypothesis that genetic factors play a role in aggressive periodontitis and that a few loci, each with relatively small effects, contribute to aggressive periodontitis, with or without interaction with environmental factors.
ORIGINAL ARTICLE: Suppression of Mamu‐AG by RNA Interference
Authors: Drenzek Jessica G. , Vidiguriene Jolanta , Vidiguris Geminis , Grendell Richard L. , Dambaeva Svetlana V. , Durning Maureen , Golos Thaddeus G.
Published: April 2009

Problem  The role of placental major histocompatibility complex (MHC) class I molecules in pregnancy is not well understood. Mamu‐AG, the rhesus monkey homology of human leukocyte antigen (HLA)‐G expressed in the human placenta, was targeted for degradation by RNA interference (RNAi), a powerful tool to aid in determining gene function, to determine the effect that this knockdown has on NK cell function.

Method of study  A series of potential target short hairpin RNA (shRNA) sequences to suppress Mamu‐AG expression was screened, which identified an optimal sequence to use in transfection experiments. Knockdown in two different Mamu‐AG‐expressing cell lines was measured by flow cytometry. Cytotoxicity assays were performed to correlate Mamu‐AG expression with NK cell cytotoxicity.

Results  Decreased expression of Mamu‐AG by short interfering RNA (siRNA) (70–80%) in cell types tested was associated with increased lysis of Mamu‐AG target cells.

Conclusion  Target sequences have been identified that knocked down Mamu‐AG expression by RNAi and increased lysis by NK cells. This supports the concept that NK cell receptors recognize this placental non‐classical MHC class I molecule.
The endogenous retinoid metaboliteS‐4‐oxo‐9‐cis‐13,14‐dihydro‐retinoic acid activates retinoic acid receptor signalling bothin vitroandin vivo
Authors: Schuchardt Jan P. , Wahlström David , Rüegg Joëlle , Giese Norbert , Stefan Madalina , Hopf Henning , Pongratz Ingemar , Håkansson Helen , Eichele Gregor , Pettersson Katarina , Nau Heinz
Published: April 2009

Retinoic acid receptor (RAR) and retinoid X receptor are ligand‐induced transcription factors that belong to the nuclear receptor family. The receptors are activated by small hydrophobic compounds, such as all‐trans‐retinoic acid and 9‐cis‐retinoic acid, respectively. Interestingly, these receptors are also targets for a number of exogenous compounds. In this study, we characterized the biological activity of the 9‐cis‐substituted retinoic acid metabolite,S‐4‐oxo‐9‐cis‐13,14‐dihydro‐retinoic acid (S‐4o9cDH‐RA). The endogenous levels of this metabolite in wild‐type mice and rats were found to be higher than those of all‐trans‐retinoic acid, especially in the liver. Using cell‐based luciferase reporter systems, we showed thatS‐4o9cDH‐RA activates the transcription of retinoic acid response element‐containing genes in several cell types, both from a simple 2xDR5 element and from the promoter of the natural retinoid target geneRARβ2. In addition, quantitative RT‐PCR analysis demonstrated thatS‐4o9cDH‐RA treatment significantly increases the endogenous mRNA levels of the RAR target geneRARβ2. Utilizing a limited proteolytic digestion assay, we showed thatS‐4o9cDH‐RA induces conformational changes to both RARα and RARβ in the same manner as does all‐trans‐retinoic acid, suggesting thatS‐4o9cDH‐RA is indeed an endogenous ligand for these receptors. Thesein vitroresults were corroborated in anin vivosystem, whereS‐4o9cDH‐RA induced morphological changes similar to those of all‐trans‐retinoic acid in the developing chicken wing bud. When locally applied to the wing bud,S‐4o9cDH‐RA induced digit pattern duplications in a dose‐dependent fashion. The results illustrate thatS‐4o9cDH‐RA closely mimics all‐trans‐retinoic acid with regard to pattern respecification. Finally, using quantitative RT‐PCR analysis, we showed thatS‐4o9cDH‐RA induces the transcription of several retinoic acid‐regulated genes in chick wing buds, includingHoxb8,RARβ2,shh,Cyp26andbmp2. Although S‐4o9cDH‐RA was less potent when compared with all‐trans‐retinoic acid, the findings clearly demonstrate thatS‐4o9cDH‐RA has the capacity to bind and activate nuclear retinoid receptors and regulate gene transcription bothin vitroandin vivo.
Perturbation of membranes by the amyloid β‐peptide – a molecular dynamics study
Authors: Lemkul Justin A. , Bevan David R.
Published: April 2009

The etiology of Alzheimer’s disease is considered to be linked to interactions between amyloid β‐peptide (Aβ) and neural cell membranes. Membrane disruption and increased ion conductance have been observed in vitro in the presence of Aβ, and it is assumed that these same phenomena occur in the brain of an individual afflicted with Alzheimer’s. The effects of Aβ on lipid behavior have been characterized experimentally, but details are lacking regarding how Aβ induces these effects. Simulations of Aβ in a bilayer environment can provide the resolution necessary to explain how the peptide interacts with the surrounding lipids. In the present study, we present an extensive analysis of lipid parameters for a model dipalmitoylphosphatidylcholine bilayer in the presence of the 40‐residue Aβ peptide (Aβ40). The simulated systems examine the effects of the insertion depth of the peptide, temperature, the protonation state of the peptide, and ionic strength on the features of the lipid bilayer. The results show that Aβ40 is capable of disordering nearby lipids, as well as decreasing bilayer thickness and area per lipid headgroup. These phenomena arise as a result of the unfolding process of the peptide, which leads to a disordered, extended conformation that is capable of extensive electrostatic and hydrogen‐bonding interactions between the peptide and the lipid headgroups. Comparisons are made using melittin‐dipalmitoylphosphatidylcholine systems as positive controls of a membrane‐disrupting peptide because these systems have previously been characterized experimentally as well as in molecular dynamics simulations.
Nondestructive Evaluation of Thermal Barrier Coatings Using Impedance Spectroscopy
Authors: Yang Fan , Xiao Ping
Published: April 2009

This article reviews previous studies on nondestructive evaluation of thermal barrier coatings (TBCs) using impedance spectroscopy (IS). IS or electrochemical impedance spectroscopy has been widely used to measure the electrical properties of materials and electrochemical behavior at electrode/electrolyte interfaces. TBCs, which comprise metallic and ceramic multilayers, have been widely used in the hot section of aeroturbine engines to increase turbine efficiency and to extend the life of metallic components. Since 1999, IS has been developed to examine degradation of the TBCs as a nondestructive evaluation tool, which is critical for prediction of TBCs lifetime during service. IS has been used both at high temperature in dry environments and in aqueous solutions. Impedance spectra of TBCs reflect change in TBC thickness, porosity, cracks, sintering, and yttria‐stabilized zirconia phase transformation. Meanwhile, impedance measurements indicate the thermally grown oxide growth and the failure in TBCs. In addition, the thermal conductivity of TBCs can be correlated to impedance measurement results.
Genetic mutations associated with chemical resistance in the cytochrome P450 genes of invasive and native Bemisia tabaci (Hemiptera: Aleyrodidae) populations in China
Authors: Qiu Bao‐Li , Liu Li , Li Xiao‐Xi , Mathur Vartika , Qin Zhen‐Qiang , Ren Shun‐Xiang
Published: April 2009

Abstract  Bemisia tabaci (Gennadius) is a species complex, and its two most damaging biotypes B and Q are globally distributed pests. Despite increasing biological and economic impacts, little is known about the evolutionary mechanisms that favor their competition with native populations. Here, we investigated the genetic mutations in the P450 gene of the invasive B, Q biotypes and the native Cv population. Four mutations associated with chemical resistance, Pro‐Leu, Ala‐Ser, Ser‐Phe and Trp‐Leu, were found in the cytochrome P450 CYP6C and CYP9F genes of the B and Q biotypes. Bioassay results also revealed that both the B and Q biotypes have about 12–47 times more resistance to acephate, beta‐cypermethrin, methomyl, and 5–7 times more resistance to imidacloprid insecticide than Cv population. Our results provide a molecular approach for better understanding and monitoring the pesticide resistances of invasive and native B. tabaci populations in China.
Differential levels of mite infestation of wheat and barley in Czech grain stores
Authors: Hubert Jan , Kucerova Zuzana , Aulicky Radek , Nesvorna Marta , Stejskal Vaclav
Published: April 2009

Abstract  While mites are able to utilize numerous food sources, the suitability of the food strongly influences population growth. The different suitabilities of various stored agricultural products will thus affect the level of infestation. In this study, we compared field mite infestation rates in two stored cereals: wheat and barley. We analyzed mite abundance, frequency and species composition in samples of grain obtained from 79 selected Czech grain stores. Stored barley seemed to be more vulnerable to mite attack than wheat, as we consistently found more infested samples, more species and higher mean and median mite abundance per sample in barley as compared to wheat. The mean mite abundance per sample were 55 and 506 individuals for wheat and barley, respectively. In barley, 10% of samples exceeded allergen risk threshold (i.e., 1 000 individuals per kg of grain). Altogether, 25 species were identified from approximately 35 000 individuals. The most frequently identified species were the same in wheat and barley, that is, Tydeus interruptus Sig Thor, Acarus siro L., Tarsonemus granarius Lindquist, Lepidoglyphus destructor (Schrank) and Tyrophagus putrescentiae (Schrank). Based on principal components analysis, we found a closer association of T. interruptus, T. putrescentiae, L. destructor and Cheyletus eruditus (Schrank) with barley samples, corresponding to the high frequency and abundance values of these mites. The probable reasons for the higher infestation, especially mite abundance in barley, are discussed in relation to the higher proportion of crushed parts, which may release favorable nutrient sources and amplify the abundance values.
“Greatly Changed for the Better”: Free Kindergartens as Transatlantic Reformance
Authors: Nawrotzki Kristen D.
Published: April 2009

Historians such as Seth Koven and Carolyn Steedman have shown how visual and literary depictions of children helped move late-nineteenth-century middle- and upper-class audiences to join in child-saving philanthropy aimed at the deserving poor. This was certainly true of the promotional literature of the free kindergartens, an analysis of which forms the focus of this essay. Starting from the concepts of fact, truth, and intertextuality utilized by Koven in his analyses of nineteenth-century representations of child-saving, this essay analyzes texts written by free kindergartners (that is, teachers in free kindergartens) Kate Douglas Wiggin in San Francisco and Lileen Hardy in Edinburgh during the 1880s and 1910s, respectively. It contends that we can better understand the purposes, messages, and relatedness of Anglo-American free kindergartners' accounts—and the movements of which they were a part—if we read them as contemporary readers might have; that is, as “artistic fictions” in the mold of the late-Victorian evangelical “true narratives” and as depictions of how child-saving was consciously performed for and presented to multiple audiences.
The Passion for Educating the “New Man”: Debates about Preschooling in Soviet Russia, 1917–1925
Authors: Valkanova Yordanka
Published: April 2009

The Russian Revolution of February 1917 displaced the autocracy of the Romanov royal family and aimed to establish a liberal republican Russia. The Bolsheviks, who came to power a few months later in the revolution of October 1917, announced that their new policy in education “had no analogy in history.” Their reforms sought to establish a Marxist-based education system, in an attempt to raise new citizens for a new, communist society. Above all, the Bolsheviks regarded education as a means to engineer the ideal human being, the “new man” and the “new woman.”
An optimized method to separate reticulocytes from peripheral blood for molecular analysis
Authors: PETRUZZELLI R. , PALUMBO I. , GAUDINO S. , SCALIA G. , DEL VECCHIO L. , IZZO P. , GROSSO M.
Published: April 2009

A method based on immunomagnetic sorting of reticulocytes from peripheral blood was set up and combined to a commercial extraction kit for the isolation of total RNA from whole blood. This procedure resulted in high‐quality RNA samples suitable for molecular analysis. We used this procedure to analyse erythroid‐specific transcripts, starting from peripheral blood samples, to search for differently expressed mRNAs in patients with hereditary persistence of foetal haemoglobin. After erythrocyte lysis, CD15+and CD45+ peripheral cells were negatively sorted to remove leucocyte populations that could have affected the subsequent screening procedure. The cell sorting and RNA extraction procedure was completed within 1–2 h of erythrocyte lysis, which represents a consistent saving of time compared with other procedures. Moreover, it produced 1 μg of total RNA per ml of blood samples, which is sufficient for molecular analysis. Therefore, our method is a reliable and efficient tool to isolate RNA from specific cell subpopulations poorly represented in peripheral blood, particularly when accurate detection and characterization of highly unstable and poorly expressed molecules is required.
Features of hemolysis due to Clostridium perfringens infection
Authors: BOYD S. D. , MOBLEY B. C. , REGULA D. P. , ARBER D. A.
Published: April 2009

Infection by Clostridium perfringens can be an unsuspected cause of hemolysis in emergency room patients. Historically, this condition has been associated with wound contamination and other tissue infections. We report the case of an autistic patient who presented to our emergency department with a distended abdomen and hemolysis of unknown etiology. The patient had no history of recent surgery. Exploration of the abdomen revealed a hepatic abscess. Blood cultures tested culture positive for C. perfringens. We present images demonstrating the salient features of the peripheral blood smear in cases of this uncommon but deadly cause of hemolysis.
“Some of These Words I Can't Pronounce”: A Qualitative Exploration of the Readability of Generic and Tailored Self‐help Material for Quitting Smoking
Authors: Gilbert Hazel , Nazareth Irwin , Sutton Stephen
Published: April 2009

Smoking remains the leading preventable cause of disease and death. A proliferation of health information is available to educate and aid in smoking cessation, a disparity between reading levels of patients and reading estimates of health promotion literature exists. The aim of the study was to adapt computer‐tailored feedback reports to different levels of readability, and to meet the needs of smokers from all social backgrounds. Focus groups were used to explore the perception of the adaptations. Results confirmed the importance of producing health promotion literature at an appropriate level of reading. However, it is essential that materials offer information and support using language that can be understood by smokers of all reading levels without being patronizing.
Associations of Sexual Victimization, Depression, and Sexual Assertiveness with Unprotected Sex: A Test of the Multifaceted Model of HIV Risk Across Gender
Authors: Morokoff Patricia J. , Redding Colleen A. , Harlow Lisa L. , Cho Sookhyun , Rossi Joseph S. , Meier Kathryn S. , Mayer Kenneth H. , Koblin Beryl , Brown‐Peterside Pamela
Published: April 2009

This study examined whether the Multifaceted Model of HIV Risk (MMOHR) would predict unprotected sex based on predictors including gender, childhood sexual abuse (CSA), sexual victimization (SV), depression, and sexual assertiveness for condom use. A community‐based sample of 473 heterosexually active men and women, aged 18–46 years completed survey measures of model variables. Gender predicted several variables significantly. A separate model for women demonstrated excellent fit, while the model for men demonstrated reasonable fit. Multiple sample model testing supported the use of MMOHR in both men and women, while simultaneously highlighting areas of gender difference. Prevention interventions should focus on sexual assertiveness, especially for CSA and SV survivors, as well as targeting depression, especially among men.
Impacts of the summer 2007 floods on agriculture in England
Authors: Posthumus H. , Morris J. , Hess T.M. , Neville D. , Phillips E. , Baylis A.
Published: April 2009

Exceptional rainfall during the summer of 2007 caused widespread flooding in parts of England. While the focus of attention has been correctly placed on the impact on densely populated urban areas, large tracts of rural land were seriously affected by flooding. Summer flooding is particularly damaging to farming. This paper presents the results from an evaluation of the impacts of the summer 2007 flood events on agriculture. High financial losses were incurred in the horticultural sector. Arable farmers incurred direct losses in the form of crop loss or yield reduction due to flooding and associated waterlogging of fields. Livestock farmers incurred indirect losses in the form of additional housing and feeding costs for livestock. Although total costs to agriculture were small compared with urban flood costs, they were typically large at the individual farm scale. Such impacts should be properly acknowledged in future strategies for flood risk management.
DNA barcoding of stygofauna uncovers cryptic amphipod diversity in a calcrete aquifer in Western Australia’s arid zone
Authors: BRADFORD T. , ADAMS M. , HUMPHREYS W. F. , AUSTIN A. D. , COOPER S. J. B.
Published: April 2009

The arid Yilgarn region of Western Australia contains numerous subterranean calcrete aquifers with unique assemblages of obligate groundwater invertebrates (stygofauna). We aimed to establish a DNA barcoding framework for the macro‐invertebrates present in a single calcrete, as a basis for future assessment of biodiversity of the Yilgarn calcretes and for investigating food webs. Intense sampling of a bore field grid in the Sturt Meadows calcrete was undertaken to obtain representatives of the entire macro‐invertebrate ecosystem. A 623‐bp fragment of the mitochondrial cytochromecoxidase 1 (COI) gene was used to provide DNA barcodes for stygobiont macro‐invertebrates plus terrestrial organisms that are found in the calcrete. Phylogenetic analyses revealed the existence of 12 divergent monophyletic groups of haplotypes. Subterranean amphipods (Chiltoniidae) showed three groups ofCOIhaplotypes with sequence divergences between them of >11%. Allozyme analyses found a large number of fixed allelic differences between these three amphipod groups, indicating that there are three morphologically cryptic species within the Sturt Meadows calcrete. Unlike the sister triplet of dytiscid beetles present, the amphipods are not sister clades and are more closely related to other Yilgarn and non‐Yilgarn amphipods than to each other. Our results show that the aquifer contains at least 12 macro‐invertebrate species and DNA barcoding provides a useful means for discriminating species in this system.
Affordable Housing: Concepts and Policies*
Authors: Abelson Peter
Published: April 2009

This article discusses the concepts of housing affordability and policies for increasing housing affordability. Most current measures of housing affordability used in Australia are based on the acquisition costs of housing. They define housing costs in nominal rather than in real terms and include mortgage repayments that are properly regarded as savings. Moreover, they do not account for household choice over type of house or household composition. The first part of this article proposes that measures of housing affordability should be based on real housing user costs or rents. Turning to policy issues, this article argues that housing affordability is essentially a household income problem made worse by government restrictions on housing supply. High housing costs do not reflect housing market failures. To reduce housing costs, the government should allow more housing in established and Greenfield areas. The government may also improve housing affordability by subsidising housing for low‐income households. However, subsidies to urban infrastructure nearly always raise the price of land rather than reduce the price of housing. Also, the Australian government’s proposed national housing and rental affordability funds are poorly defined and likely to be ineffective.
The Boom We Didn’t Really Have: Australian Economics Degree Enrolments, 1990–2007*
Authors: Millmow Alex
Published: April 2009

This paper revisits the matter of attracting students to study economics, an issue that faces every Australian university economics department. While the Australian economy has been in a boom phase for some period it has not led to a relative increase in economic degree enrolments for local universities. While some of the Go8 universities have seen a steady increase in economics degree enrolments between 1995 and 2007, the national picture, taken over a longer period, reveals that economic degree enrolments as a percentage of the overall student population is still falling. The paper concludes with the shy hope that, apart from improvement to the syllabus and teaching methodologies, the marked economic slowdown might elicit an increase in student interest in economics. The paper closes by suggesting that now might be an appropriate time for the regimen of the ideal economics degree offered by Australian universities to be re‐examined.
Comments on the Productivity Commission’s Modelling of the Economy‐Wide Effects of Future Automotive Assistance*
Authors: Dixon Peter B.
Published: April 2009

The Productivity Commission claims on the basis of computable general equilibrium modelling that a seemingly small reduction in assistance to the Australian Automotive industry (a cut in tariffs from 10 per cent to 5 per cent and elimination of the ACIS scheme) would generate an annual welfare benefit of about $500 million. I explain that this implausible result rests on an implicit manna‐from‐heaven assumption. Using results published by the Commission, I rework their welfare calculations. With parameter values favoured by them, the corrected annual welfare gain is $66 million. With what I consider more realistic parameter values, the welfare effect is negative.
Port Botany’s Landside: Market Pricing to Address Congestion
Authors: Cox James , Mahoney Dennis , Smart Mike
Published: April 2009

Endemic congestion at the road landside interface at Port Botany, Sydney results from coordination problems within the supply chain. These problems cannot be solved through the vertical integration of participants in the supply chain because of competition law considerations, and other non‐price solutions are unworkable. Government intervention is warranted, but in a minimal form targeted at the facilitation of slot pricing. This limited intervention would allow market dynamics to achieve an efficient solution.
The Victorian Competition and Efficiency Commission after Four Years*
Authors: Evans Graham
Published: April 2009

This paper reviews the performance of the Victorian Competition and Efficiency Commission since it was set up in July 2004 as an independent advisor to the Victorian Government on regulation reform and business competitiveness. The Commission undertakes inquiries into issues that the government refers to it; reviews regulatory impact statements and business impact assessments; and administers competitive neutrality policy. There is evidence that the Commission is contributing to improvements in the regulatory and competitive environment in Victoria, but there are opportunities for further improvements.
Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1
Authors: Szczech G. M. , Furman P. , Painter G. R. , Barry D. W. , Borroto-Esoda K. , Grizzle T. B. , Blum M. R. , Sommadossi J.-P. , Endoh R. , Niwa T. , Yamamoto M. , Moxham C.
Published: April 2009

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [14C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.
Chemical Specificity of thePDR5Multidrug Resistance Gene Product ofSaccharomyces cerevisiaeBased on Studies with Tri-n-Alkyltin Chlorides
Authors: Golin John , Barkatt Alisa , Cronin Susan , Eng George , May Leopold
Published: April 2009

To understand the chemical basis of action for thePDR5-encoded multidrug resistance transporter ofSaccharomyces cerevisiae, we compared the relative hypersensitivities of the wild-type (RW2802) and null mutant strains toward a series of tri-n-alkyltin compounds. These compounds differ from each other in a systematic fashion—either by hydrocarbon chain length or by anion composition. Using zone-of-inhibition and fixed-concentration assays, we found that the ethyl, propyl, and butyl compounds are strongPDR5substrates, whereas the methyl and pentyl compounds are weak. We conclude that hydrophobicity and anion makeup are relatively unimportant factors in determining whether a tri-n-alkyltin compound is a goodPDR5substrate but that the dissociation of the compound and the molecular size are significant.
Effect of Zinc-Reversible Growth-Inhibitory Activity in Human Empyema Fluid on Antibiotic Microbicidal Activity
Authors: Sohnle Peter G. , Hahn Beth L.
Published: April 2009

Abscess fluid supernatants have zinc-reversible microbial growth-inhibitory activity that is mediated by calprotectin, a zinc-binding protein. Because it inhibits microbial growth, this activity might interfere with killing by antibiotics that require their target organisms to be proliferating. In the present study, we cultured bacteria in human empyema fluid and used zinc to overcome the growth-inhibitory effect of calprotectin. We then compared the effect of zinc on killing by the beta-lactams ampicillin and cefazolin with that of the fluoroquinolone trovafloxacin, since the latter may be better able to kill nonproliferating organisms. In empyema fluid diluted 1:5 in normal saline, addition of zinc (30 μM) increased growth of two strains of
Staphyloccocus aureus
and two strains of
Escherichia coli
but did not affect the MICs or MBCs of the three antibiotics in Mueller-Hinton broth. For one strain of
S. aureus
, no effect of zinc was found on killing by either ampicillin or cefazolin. However, with the other strain of
S. aureus
and both strains of
E. coli
, significant enhancement of killing by both drugs was observed with zinc addition. On the other hand, no effect on the killing of any of the organisms was observed for trovafloxacin when zinc was added. These results suggest that the zinc-reversible growth-inhibitory activity of abscess fluid may interfere with the microbicidal activity of antibiotics requiring proliferating target organisms, although antibiotics better able to kill nonproliferating organisms may be less affected by this phenomenon.
Immunosuppressive and Nonimmunosuppressive Cyclosporine Analogs Are Toxic to the Opportunistic Fungal PathogenCryptococcus neoformansvia Cyclophilin-Dependent Inhibition of Calcineurin
Authors: Cruz M. Cristina , Del Poeta Maurizio , Wang Ping , Wenger Roland , Zenke Gerhard , Quesniaux Valerie F. J. , Movva N. Rao , Perfect John R. , Cardenas Maria E. , Heitman Joseph
Published: April 2009

Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found thatCryptococcus neoformansgrowth is resistant to CsA at 24°C but sensitive at 37°C and that calcineurin is required for growth at 37°C and pathogenicity. Here CsA analogs were screened for toxicity againstC. neoformansin vitro. In most cases, antifungal activity was correlated with cyclophilin A binding in vitro and inhibition of the mixed-lymphocyte reaction and interleukin 2 production in cell culture. Two unusual nonimmunosuppressive CsA derivatives, (γ-OH) MeLeu4-Cs (211-810) and D-Sar (α-SMe)3Val2-DH-Cs (209-825), which are also toxic toC. neoformanswere identified. These CsA analogs inhibitC. neoformansvia fungal cyclophilin A and calcineurin homologs. Our findings identify calcineurin as a novel antifungal drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as antifungal agents.
Activities of the Triazole Derivative SCH 56592 (Posaconazole) against Drug-Resistant Strains of the Protozoan Parasite
Trypanosoma
(
Schizotrypanum
)
cruzi
in Immunocompetent and Immunosuppressed Murine Hosts
Authors: Molina Judith , Martins-Filho Olindo , Brener Zigman , Romanha Alvaro J. , Loebenberg David , Urbina Julio A.
Published: April 2009

We have studied the in vivo activity of the new experimental triazole derivative SCH 56592 (posaconazole) against a variety of strains of the protozoan parasite
Trypanosoma
(
Schizotrypanum
)
cruzi
, the causative agent of Chagas' disease, in both immunocompetent and immunosuppressed murine hosts. The
T. cruzi
strains used in the study were previously characterized as susceptible (CL), partially resistant (Y), or highly resistant (Colombiana, SC-28, and VL-10) to the drugs currently in clinical use, nifurtimox and benznidazole. Furthermore, all strains are completely resistant to conventional antifungal azoles, such as ketoconazole. In the first study, acute infections with the CL, Y, and Colombiana strains in both normal and cyclophosphamide-immunosuppressed mice were treated orally, starting 4 days postinfection (p.i.), for 20 consecutive daily doses. The results indicated that in immunocompetent animals SCH 56592 at 20 mg/kg of body weight/day provided protection (80 to 90%) against death caused by all strains, a level comparable or superior to that provided by the optimal dose of benznidazole (100 mg/kg/day). Evaluation of parasitological cure revealed that SCH 56592 was able to cure 90 to 100% of the surviving animals infected with the CL and Y strains and 50% of those which received the benznidazole- and nifurtimox-resistant Colombiana strain. Immunosuppression markedly reduced the mean survival time of untreated mice infected with any of the strains, but this was not observed for the groups which received SCH 56592 at 20 mg/kg/day or benznidazole at 100 mg/kg/day. However, the overall cure rates were higher for animals treated with SCH 56592 than among those treated with benznidazole. The results were confirmed in a second study, using the same model but a longer (43-dose) treatment period. Finally, a model for the chronic disease in which oral treatment was started 120 days p.i. and consisted of 20 daily consecutive doses was investigated. The results showed that SCH 56592 at 20 mg/kg/day was able to induce a statistically significant increase in survival of animals infected with all strains, while benznidazole at 100 mg/kg/day was able to increase survival only in animals infected with the Colombiana strain. Moreover, the triazole was able to induce parasitological cures in 50 to 60% of surviving animals, irrespective of the infecting strain, while no cures were obtained with benznidazole. Taken together, the results demonstrate that SCH 56592 has in vivo trypanocidal activity, even against
T. cruzi
strains naturally resistant to nitrofurans, nitroimidazoles, and conventional antifungal azoles, and that this activity is retained to a large extent in immunosuppressed hosts.
Ciprofloxacin, Lomefloxacin, or Levofloxacin as Treatment for Chronic Osteomyelitis
Authors: Greenberg Richard N. , Newman Michael T. , Shariaty Saeed , Pectol Richard W.
Published: April 2009

The efficacy and safety of three oral fluoroquinolones (lomefloxacin, levofloxacin, and ciprofloxacin) for the treatment of chronic osteomyelitis were analyzed. Twenty-seven patients had documented infections with quinolone-sensitive organisms and received either lomefloxacin, levofloxacin, or ciprofloxacin. Levofloxacin was effective therapy for 9 of 15 (60%) patients. Lomefloxacin was effective therapy for five of seven (71%) patients, and ciprofloxacin was effective therapy for two of five patients (40%). Average follow-up was 11.8 months for patients who completed the course of therapy, and the average duration of therapy was 60.6 days. Gram-positive bacteria were isolated from 18 patients, and 11 patients were cured. Oral fluoroquinolones can be safe, effective therapy if they are given for a prolonged course as treatment for infections caused by susceptible gram-positive as well as gram-negative organisms and in combination with adequate surgical debridement.
Successful Treatment with Nitazoxanide of
Enterocytozoon bieneusi
Microsporidiosis in a Patient with AIDS
Authors: Bicart-Sée Alain , Massip Patrice , Linas Marie-Denise , Datry Annick
Published: April 2009

A patient with AIDS and chronic diarrhea caused by
Enterocytozoon bieneusi
was successfully treated with nitazoxanide, producing a complete clinical and parasitological response, while off of antiviral therapy. This suggests that nitazoxanide may be effective in treating microsporidiosis caused by
E. bieneusi
, a disease for which there is no established treatment.
Role of Penicillin-Binding Proteins in the Initiation of the AmpC β-Lactamase Expression in
Enterobacter cloacae
Authors: Pfeifle Dieter , Janas Eva , Wiedemann Bernd
Published: April 2009

Penicillin-binding proteins (PBPs) are involved in the regulation of β-lactamase expression by determining the level of anhydromuramylpeptides in the periplasmatic space. It was hypothesized that one or more PBPs act as a sensor in the β-lactamase induction pathway. We have performed induction studies with
Escherichia coli
mutants lacking one to four PBPs with
dd
-carboxypeptidase activity. Therefore, we conclude that a strong β-lactamase inducer must inhibit all
dd
-carboxypeptidases as well as the essential PBPs 1a, 1b, and/or 2.
Activities of Masked 2′,3′-Dideoxynucleoside Monophosphate Derivatives against Human Immunodeficiency Virus in Resting Macrophages
Authors: Aquaro Stefano , Wedgwood Orson , Yarnold Christopher , Cahard Dominique , Pathinara Ranjith , McGuigan Christopher , Calio' Raffaele , de Clercq Erik , Balzarini Jan , Perno Carlo Federico
Published: April 2009

The anti-human immunodeficiency virus (HIV) activity of aryloxyphosphoramidate protides of a number of anti-HIV nucleoside analogues was assessed in resting primary monocyte-macrophages (M/M). While 2′,3′-dideoxythymidine (d4T), 2′,3′-dideoxyadenosine (ddA), and 2′,3′-dideoxy-2′,3′-didehydroadenosine (d4A) protides showed an anti-HIV activity that was 25- to 625-fold greater than the parent nucleotides d4T, ddA, and d4A, respectively, other aryloxyphosphoramidate protides showed similar or even lower anti-HIV activities than their parent compounds. This variable anti-HIV effect is most likely related to the different dynamics of intracellular nucleoside monophosphate release from the protides. Our results indicate the potential advantage of therapeutic use of this approach for some nucleotide analogues to affect HIV replication in M/M, one of the major reservoirs of HIV in vivo.
Trovafloxacin Concentrations in Airway Fluids of Patients with Severe Community-Acquired Pneumonia
Authors: Peleman R. A. , Van De Velde V. , Germonpré P. R. , Fleurinck C. , Rosseel M. T. , Pauwels R. A.
Published: April 2009

The penetration of trovafloxacin (TVA), 200 mg once daily, into the airways of 17 patients with severe pneumonia was studied. The mean (standard deviations are given in parentheses) steady-state TVA concentrations, 2 h after the last intake, were 3.1 (0.3) mg/liter in induced sputum (n= 8), 3.2 (1.1) mg/liter in bronchial secretions (n= 9), 3.2 (0.9) mg/liter in bronchoalveolar lavage fluid (n= 10), and 4.9 (1.4) mg/liter in epithelial lining fluid (n= 11).
A Nine-Codon Deletion Mutation in the Cytomegalovirus UL97 Phosphotransferase Gene Confers Resistance to Ganciclovir
Authors: Chou Sunwen , Meichsner Camie L.
Published: April 2009

A deletion mutation (codons 595 to 603) in the cytomegalovirus (CMV) UL97 gene was recently reported after sequence analysis of leukocyte DNA from a patient receiving ganciclovir. The corresponding viral phenotype was examined by transfer of this mutation to a laboratory CMV strain (strain Towne). The recombinant virus was resistant to ganciclovir (8.4-fold increase in the 50% inhibitory concentration), was sensitive to foscarnet, and replicated normally in cell culture.
Susceptibilities of
Neisseria gonorrhoeae
Isolates Containing Amino Acid Substitutions in GyrA, with or without Substitutions in ParC, to Newer Fluoroquinolones and Other Antibiotics
Authors: Tanaka Masatoshi , Nakayama Hiroshi , Haraoka Masashi , Saika Takeshi , Kobayashi Intetsu , Naito Seiji
Published: April 2009

We examined the antimicrobial susceptibilities of 85
Neisseria gonorrhoeae
isolates, classified according to the presence of amino acid substitutions in the GyrA and ParC proteins, to 12 fluoroquinolones and 7 other antibiotics. Sitafloxacin and HSR-903 showed excellent activity against
N. gonorrhoeae
, including strains with both GyrA and ParC substitutions. Among the strains with various GyrA substitutions, strains with a serine-91-to-phenylalanine mutation required the highest MICs of all of the fluoroquinolones tested and were cross-resistant to structurally unrelated β-lactams.
Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP
Authors: Vaccaro Joseph A. , Parnell K. Mark , Terezakis Stephanie A. , Anderson Karen S.
Published: April 2009

Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2′,3′-didehydro-2′,3′-dideoxythymidine-5′-triphosphate (d4TTP) with the enzyme · primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3′-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.
MICs of Mutacin B-Ny266, Nisin A, Vancomycin, and Oxacillin against Bacterial Pathogens
Authors: Mota-Meira Marilaine , Lapointe Gisèle , Lacroix Christophe , Lavoie Marc C.
Published: April 2009

Peptide antibiotics, particularly lantibiotics, are good candidates for replacing antibiotics to which bacteria have become resistant. In order to compare two such lantibiotics with two antibiotics, the MICs of nisin A, mutacin B-Ny266, vancomycin, and oxacillin against various bacterial pathogens were determined. The results indicate that nisin A and mutacin B-Ny266 are as active as vancomycin and oxacillin against most of the strains tested. Furthermore, mutacin B-Ny266 remains active against strains that are resistant to nisin A, oxacillin, or vancomycin. The wide spectrum of activity of mutacin B-Ny266, its low MICs against bacterial pathogens, and its activity against bacteria resistant to other inhibitors support the development of this substance for therapeutic use.
Efficacies of Topical Formulations of Foscarnet and Acyclovir and of 5-Percent Acyclovir Ointment (Zovirax) in a Murine Model of Cutaneous Herpes Simplex Virus Type 1 Infection
Authors: Piret Jocelyne , Désormeaux André , Gourde Pierrette , Juhász Julianna , Bergeron Michel G.
Published: April 2009

The topical efficacies of foscarnet and acyclovir incorporated into a polyoxypropylene-polyoxyethylene polymer were evaluated and compared to that of 5% acyclovir ointment (Zovirax) by use of a murine model of cutaneous herpes simplex virus type 1 infection. All three treatments given three times daily for 4 days and initiated 24 h after infection prevented the development of the zosteriform rash in mice. The acyclovir formulation and the acyclovir ointment reduced the virus titers below detectable levels in skin samples from the majority of mice, whereas the foscarnet formulation has less of an antiviral effect. Reducing the number of treatments to a single application given 24 h postinfection resulted in a significantly higher efficacy of the formulation of acyclovir than of the acyclovir ointment. Acyclovir incorporated within the polymer was also significantly more effective than the acyclovir ointment when treatment was initiated on day 5 postinfection. The higher efficacy of the acyclovir formulation than of the acyclovir ointment is attributed to the semiviscous character of the polymer, which allows better penetration of the drug into the skin.