bluuebunny/crossref_metadata_2025 huggingface dataset:
Responses to deviants are modulated by subthreshold variability of the standard
Authors: Daikhin Luba , Ahissar Merav
Published: September 2011

Auditory mechanisms automatically detect both basic features of sounds and the rules governing their presentation. In the oddball paradigm, the auditory system detects the sameness (or no‐variability) rule when the same reference tone is consistently repeated. We used two oddball protocols, the classical one with a fixed reference and a modified one with a jittered reference, to determine whether the auditory system can detect subthreshold violations of sameness. We found that the response to the repeated standard was not modified by the small jitter. However, the response to the frequency oddball was smaller under the jittered protocol, indicating hypersensitivity to sameness. The sensitivity to jitter was largest when the oddball deviated by 8%, was smaller for 40%, and disappeared at 100% deviation, indicating that sensitivity to sameness is context dependent; namely, it is scaled with respect to the overall range of stimuli.
A Historical Institutionalist Approach to Political Party Organization: The Case of South Korea
Authors: Hellmann Olli
Published: September 2011

The existing literature on party organization is deeply divided over the question of how much freedom of choice decision-makers in a party enjoy in relation to their environment. Although the resulting theoretical deadlock seriously weakens our understanding of party formation and change, no attempt has been made to reconcile the different approaches. This article aims to do just that by offering a historical institutionalist perspective on party organization. Studying the development of political parties in South Korea, it argues that party organizations are best understood as strategic responses to electoral markets. Party organizations reproduce and change, as advantaged factions defend the status quo, while disadvantaged factions work towards organizational reform.
Treatment of Helicobacter pylori Infection 2011
Authors: O’Connor Anthony , Gisbert Javier P. , McNamara Deirdre , O’Morain Colm
Published: September 2011

This article reviews the literature published pertaining to Helicobacter pylori eradication over the last year. The general perception among clinicians and academics engaged in research on H. pylori has been that eradication rates for first‐line therapies are falling, although some data published this year have cast doubt on this. The studies published this year have therefore focussed on developing alternative strategies for the first‐line eradication of H. pylori. In this regard, clear evidence now exists that both levofloxacin and bismuth are viable options for first‐line therapy. The sequential and “concomitant” regimes have also been studied in new settings and may have a role in future algorithms also. In addition, data have emerged that the probiotic Saccharomyces boulardii may be a useful adjunct to antibiotic therapy. Other studies promote individualized therapies based on host polymorphisms, age, and other such demographic factors.
Helicobacter pylori in Pediatrics
Authors: Sýkora Josef , Rowland Marion
Published: September 2011

This article reviewed the important publications on Helicobacter pylori research with children between April 2010 and March 2011. The most interesting studies in the last year lend further weight to the evidence for vertical transmission of H. pylori. The discovery of a potential role for jhp0562, the gene which encodes for the cell envelope protein glycosyltransferase, in the progression to peptic ulcer disease is also very interesting as it may provide a novel way to distinguish children at risk of peptic ulcer disease from those who are not, and so determine those who requires treatment to eradicate H. pylori. The rise in non‐H. pylori‐associated ulcers and erosions continues to be reported with no apparent risk factors for these ulcers identified to date. High levels of treatment failure continue to be reported, and there remains an urgent need for more effective treatment regimes for children.
String‐Of‐Pearls Locking Plate and Cerclage Wire Stabilization of Periprosthetic Femoral Fractures after Total Hip Replacement in Six Dogs
Authors: Fitzpatrick Noel , Nikolaou Christos , Yeadon Russell , Hamilton Michael
Published: September 2011

Objective

To report use of, and outcome after, string‐of‐pearls (SOP™) plate and multiple cerclage wire fixation for treatment of periprosthetic femoral fractures (PFF) associated with total hip replacement (THR) in dogs.

Study Design

Case series.

Animals

Dogs (n=6) with PFF after THR.

Methods

Clinical records (2005–2010) and radiographic evaluations of dogs that had PFF associated with THR, treated with a SOP™ plate and cerclage wires were retrospectively reviewed. Clinical and radiographic postoperative assessments were performed 4, 12, and 24 weeks postoperatively. Telephone follow‐up was performed >12 months postoperatively.

Results

Three fractures occurred intraoperatively and 3 occurred postoperatively. One SOP™ failed at 2 weeks necessitating revision using 2 parallel SOP™ implants. One dog was euthanatized because of quadriceps muscle tie‐down at 6 weeks. Other dogs were free of lameness with full range of motion of the stifle and hip joints at final clinical examination, and positive outcomes were maintained at >12 month telephone questionnaire. There was no evidence of implant failure and positive evidence of fracture healing at final radiographic follow‐up.

Conclusions

Stabilization resulted in bone healing in 5 dogs; failure in 1 dog may be attributable to technical error. Optimal technical guidelines for use of the SOP™ in this circumstance are unknown, particularly where fracture configuration varies.
Standing Ovariectomy in Mares Using a Transvaginal Natural Orifice Transluminal Endoscopic Surgery (NOTES®) Approach
Authors: Pader Karine , Lescun Timothy B. , Freeman Lynetta J.
Published: September 2011

Objective

To develop and assess the feasibility of standing transvaginal Natural Orifice Transluminal Endoscopic Surgery (NOTES®) ovariectomy in the mare.

Study Design

Descriptive study.

Animals

Mares (n=10).

Methods

The technique was developed in 6 mares and then evaluated in a short‐term study in 4 mares. Abdominal access was developed using controlled access vaginal cannula placement under endoscopic guidance. With viewing provided by a flexible endoscope, hemostasis, and transection of ovarian pedicles was performed using a customized bipolar vessel‐sealing device. The ovaries were retrieved and the colpotomy was sutured. Surgical time, intra‐, and postoperative complications were recorded. Necropsy was performed immediately after surgery in 6 mares and 15 days after surgery in 4 mares to assess short‐term complications.

Results

After the instruments and techniques were developed, transvaginal NOTES® ovariectomy was successfully performed. Analgesia during the procedure was adequate in all cases. The visual field provided by the endoscope was acceptable. The customized 60 cm vessel‐sealing device provided good hemostasis and a comfortable working length. Intraoperative complications included difficult viewing that prolonged operative time and inability to remove the second ovary in 1 mare. Postoperative recovery was excellent. Postmortem findings of 1 true positive microbial culture, elevated cell counts in abdominal fluid, and adhesion formation raise questions that must be addressed in future studies.

Conclusion

Using specialized instruments, transvaginal NOTES® ovariectomy is technically feasible in mares.
Reversible Vasoconstriction Syndrome with Bilateral Basal Ganglia Hemorrhages
Authors: Westover M. Brandon , Cohen Adam B.
Published: September 2011

Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized acute cerebrovascular condition that may produce myriad transient and sustained neurologic deficits as well as a host of radiologic features. We report the case of a woman with RCVS and a severe clinical syndrome with bilateral basal ganglia hemorrhages, cerebral infarctions, and marked vascular abnormalities. The patient made a near complete clinical recovery, representing an extreme and illustrative form of RCVS.
Receptor activator of nuclear factor kappa B ligand antagonists inhibit tissue inflammation and bone loss in experimental periodontitis
Authors: Yuan Huaiping , Gupte Rohit , Zelkha Sami , Amar Salomon
Published: September 2011

Aim

The purpose of this study was to assess the role of anti‐bone resorptive agents and an anti‐inflammatory compound in murine Porphyromonas gingivalis (P. gingivalis)‐induced periodontitis.

Material and Methods

Six randomly assigned groups were administered vehicle (saline, control) (n = 6), P. gingivalis infection only (untreated) (n = 6), human‐Fc (n = 4), Kavain (n = 6), OPG‐Fc (n = 6) and Receptor activator of nuclear factor‐kappa B (RANK)‐Fc (n = 6) intraperitoneally at day 0, 3 and 7. Animals were euthanized on day 10 and subjected to comprehensive histomorphometric analysis. To capture the progress of inflammation, serum samples were collected at days 0, 3, 7 and 10 for levels of pro‐inflammatory cytokines.

Results

Compared with control group, OPG‐Fc, RANK‐Fc and Kavain treatment showed significant bone loss reduction with OPG‐Fc performing better than RANK‐Fc or Kavain. Epithelial down‐growth showed significant reduction in treatment groups with OPG‐Fc performing better than RANK‐Fc or Kavain. Finally, Kavain, OPG‐Fc and RANK‐Fc‐treated mice displayed reduced inflammatory cell counts and cytokine expression particularly at day 7 postinfection.

Conclusions

RANKL antagonists and Kavain effectively reduced alveolar bone loss in P. gingivalis‐induced periodontitis in our mice model. Compared with RANK‐Fc, Kavain‐treated animals showed milder improvement of bone and connective tissue inflammation. Therapeutic implications in the prevention of periodontal bone loss are discussed.
Genitogluteal porokeratosis involving the scrotum: an unusual presentation of an uncommon disease
Authors: Wanat Karolyn A. , Gormley Rachel H. , Bennett Daniel D. , Kovarik Carrie L.
Published: September 2011

Porokeratosis represents a heterogeneous group of keratinization disorders typified by the presence of annular plaques with distinct, raised borders that include cornoid lamellae. Histopathologically, a cornoid lamella is a column of parakeratotic scale overlying an epidermal invagination that displays nearby dyskeratotic keratinocytes and loss of the granular layer. Porokeratosis ptychotropica constitutes a rare variant that classically presents as a plaque in the gluteal cleft that mimics a dermatitis and microscopically contains numerous cornoid lamellae. We report a 28 year‐old man with a two‐month history of scrotal burning and itching associated with the development of multiple thin red plaques with distinct elevated borders and a pebbled appearance. Histopathological examination revealed psoriasiform acanthosis and multiple cornoid lamellae, which is consistent with a diagnosis of porokeratosis ptychotropica. Our patient's presentation may represent a distinct variant with clinical features of verrucous porokeratosis and histopathological features of porokeratosis ptychotropica which may suggest that the finding of multiple cornoid lamellae is not unique to porokeratosis ptychotropica.

Wanat KA, Gormley RH, Bennett DD, Kovarik CL. Genitogluteal porokeratosis involving the scrotum: an unusual presentation of an uncommon disease.
Mangifera indica L. extract (Vimang) and mangiferin reduce the airway inflammation and Th2 cytokines in murine model of allergic asthma
Authors: Rivera Dagmar García , Hernández Ivones , Merino Nelson , Luque Yilian , Álvarez Alina , Martín Yanet , Amador Aylin , Nuevas Lauro , Delgado René
Published: September 2011

Objectives

The aim was to study the effects of Mangifera indica extract and its major component mangiferin on lung inflammation response and Th2 cytokine production using a murine experimental model of allergic asthma.

Methods

BALB/c mice were intraperitoneally sensitized with 10 µg of ovoalbumin (OVA) adsorbed on aluminium hydroxide on days 0, 7 and 14. Seven days after the last injection, the mice were challenged with 2% aerosolized OVA inhalation for 30 min beginning on day 21 and continuing until day 24. To evaluate the protective effect, mice were orally treated with M. indica extract (50, 100 or 250 mg/kg) or mangiferin (50 mg/kg) from days 0 to 24. Anti-OVA immunoglobulin E, interleukin (IL)-4 and IL-5 were determined by ELISA and lungs were analysed by histology.

Key findings

M. indica extract and mangiferin produced a marked reduction of airway inflammation around vessels and bronchi, inhibition of IL-4 and IL-5 cytokines in bronchoalveolar lavage fluid and lymphocyte culture supernatant, IgE levels and lymphocyte proliferation.

Conclusion

This is the first pre-clinical report of the anti-inflammatory properties of M. indica extract and mangiferin in experimental asthma and it could be an important part of pre-clinical requirement necessary for its use to complement the treatment of this complex disease.
Leadership and management research in Africa: A synthesis and suggestions for future research
Authors: Walumbwa Fred O. , Avolio Bruce J. , Aryee Samuel
Published: September 2011

Although we are aware of some positive cases of leadership and management emerging on the African continent, very little empirical or theoretical work has addressed leadership and management in Africa. This raises a challenge for African nations in that ultimately a country's economic performance is contingent on the effectiveness of its leadership and management practices that serve to unlock the potential of its workforce to effectively implement the strategic goals of organizations. Against the backdrop of an increasingly knowledge‐dependent global marketplace, the centrality of leadership and effective management systems as drivers of individual and organization performance has never been more critical. This special section brings together a compendium of papers that advances the science of leadership and management within the African context. Our principle goal was to examine what is unique, what generalizes, and what does not generalize from the West and East to Africa, as well as within different regions of Africa and then offer ideas to guide future research and practice. The papers in this section provide a broad and indeed innovative approach to studying leadership and management in Africa by including historical, philosophical, economic, and socio‐political perspectives, as part of the analyses of leadership and management in the African context. Our editorial provides an integration of this work and a launching point for some audacious goals for future leadership and management science and practice in Africa and beyond.
Reliability-Based Design Optimization With Confidence Level for Non-Gaussian Distributions Using Bootstrap Method
Authors: Noh Yoojeong , Choi Kyung K. , Lee Ikjin , Gorsich David , Lamb David
Published: September 2011

For reliability-based design optimization (RBDO), generating an input statistical model with confidence level has been recently proposed to offset inaccurate estimation of the input statistical model with Gaussian distributions. For this, the confidence intervals for the mean and standard deviation are calculated using Gaussian distributions of the input random variables. However, if the input random variables are non-Gaussian, use of Gaussian distributions of the input variables will provide inaccurate confidence intervals, and thus yield an undesirable confidence level of the reliability-based optimum design meeting the target reliability βt. In this paper, an RBDO method using a bootstrap method, which accurately calculates the confidence intervals for the input parameters for non-Gaussian distributions, is proposed to obtain a desirable confidence level of the output performance for non-Gaussian distributions. The proposed method is examined by testing a numerical example and M1A1 Abrams tank roadarm problem.
Optimization of Face Cone Element for Spiral Bevel and Hypoid Gears
Authors: Fan Qi
Published: September 2011

In the blank design of spiral bevel and hypoid gears, the face cone is defined as an imaginary cone tangent to the tops of the teeth. Traditionally, the face cone element or generatrix is a straight line. On the other hand, the tooth root lines, which are traced by the blade tips, are normally not straight lines. As a result, the tooth top geometry generally does not fit the mating member’s real root shape, providing an uneven tooth root-tip clearance; additionally, in some cases root-tip interference between the tooth tip and the root tooth surfaces of the mating gear members may be observed. To address this issue, this paper describes a method of determining an optimized face cone element for spiral bevel and hypoid gears. The method is based on the incorporation of calculation of tooth surface and root geometries, the conjugate relationship of the mating gear members, the ease-off topography, and the tooth contact analysis. The resulting face cone element may not be a straight line but generally an optimized curve that, in addition, to avoidance of the interference, offers maximized contact ratio and even tooth root-tip clearance. Manufacturing of bevel gear blanks with a curved face cone element can be implemented by using computer numerically controlled machines.
Decay Times and Quality Factors for a Resonance Apparatus
Authors: Stephens Heather , Tam Austin , Moloney Michael
Published: September 2011

The commercial resonance demonstration apparatus1 shown in Fig. 1 exhibits curious behavior. It consists of three pairs of slender spring-steel rods attached to a horizontal bar. When one of the rods is pulled aside and released, the rod of corresponding length is excited into visible motion, but the other rods remain apparently stationary. This may seem surprising because there is no noticeable motion of the bar or the base. The effect is achieved because each length of rod has its own frequency, and all of the rods are very lightly damped. A very lightly damped rod responds quite strongly when excited at its resonant frequency but barely responds at other frequencies (Fig. 2).
The St. Louis Motor
Authors: Greenslade Thomas B.
Published: September 2011

The St. Louis Motor, invented in 1909, is unique among physics apparatus for being named for a geographical place rather than a physicist. The sturdy little device (Fig. 1) has never been out of production. Any older school or physics department that has not done a catastrophic housecleaning in the last 20 years will certainly have a small flock of them in the back room.
Don't Erase that Whiteboard! Archiving Student Work on a Photo-Sharing Website
Authors: Price Edward , Tsui Stephen , Hart Alicia , Saucedo Lydia
Published: September 2011

Students in physics courses often use whiteboards to brainstorm, solve problems, and present results to the rest of the class, particularly in courses involving collaborative small group work and whole class discussions. The whiteboards contain a valuable record of students' collaborative work. Once a whiteboard is erased, however, its contents are lost and no longer accessible to students, instructors, or researchers and curriculum developers. We solve this problem using wireless-enabled digital cameras to create an archive of students' work on the photo-sharing website Flickr.com. This provides a persistent record of class activities that our students use frequently and find valuable. In this paper, we describe how this works in class and how students use the photos.
A School Experiment in Kinematics: Shooting from a Ballistic Cart
Authors: Kranjc T. , Razpet N.
Published: September 2011

Many physics textbooks start with kinematics. In the lab, students observe the motions, describe and make predictions, and get acquainted with basic kinematics quantities and their meaning. Then they can perform calculations and compare the results with experimental findings. In this paper we describe an experiment that is not often done, but is interesting and attractive to students—the ballistic cart,1 i.e., the shooting of a ball from a cart moving along a slope. For that, one has to be familiar with one-dimensional uniform motion and one-dimensional motion with constant acceleration, as well as curvilinear motion that is a combination of such motions.1,2 The experimental results confirm theoretical predictions.
A New Perspective on Eratosthenes' Measurement of the Earth
Authors: Brown Ronald A. , Kumar Alok
Published: September 2011

Around 240 B.C., Eratosthenes made what is considered to be the most famous and accurate of the ancient measurements of the circumference of the Earth.1 It was accomplished by making presumably simultaneous measurements of the angles of the shadows cast by a vertical stick at Syene (today known as Aswan) and another at Alexandria, at noon on the day of the summer solstice (about June 21 every year). From these measurements, and knowing the distance from Syene to Alexandria along the assumed same meridian of longitude, Eratosthenes was able to provide a remarkably accurate estimate of the radius of the Earth.
“Can You See Me Now?” Using a favorite haunted physics laboratory project to teach color theory
Authors: Donaldson Nancy
Published: September 2011

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Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab
Authors: Yonesaka Kimio , Zejnullahu Kreshnik , Okamoto Isamu , Satoh Taroh , Cappuzzo Federico , Souglakos John , Ercan Dalia , Rogers Andrew , Roncalli Massimo , Takeda Masayuki , Fujisaka Yasuhito , Philips Juliet , Shimizu Toshio , Maenishi Osamu , Cho Yonggon , Sun Jason , Destro Annarita , Taira Koichi , Takeda Koji , Okabe Takafumi , Swanson Jeffrey , Itoh Hiroyuki , Takada Minoru , Lifshits Eugene , Okuno Kiyotaka , Engelman Jeffrey A. , Shivdasani Ramesh A. , Nishio Kazuto , Fukuoka Masahiro , Varella-Garcia Marileila , Nakagawa Kazuhiko , Jänne Pasi A.
Published: September 2011

Several cancers become resistant to cetuximab by activating a bypass signaling pathway and preventing cetuximab inhibition of ERK1/2-stimulated growth.
Hidden Immunotherapy Targets Challenge Dogma
Authors: Ferrone Soldano
Published: September 2011

Intracellular tumor antigen–specific monoclonal antibodies inhibit tumor growth and metastasis and prolong survival of tumor-bearing mice.
Neurons Are Only Skin Deep
Authors: Gesty-Palmer Diane
Published: September 2011

Skin fibroblasts from patients with Alzheimer’s disease can be converted directly into neuronal cells that retain the cellular characteristics of the disease.
Coffee Perks Up Parkinson’s Disease Prevention
Authors: Nielson Carrie M.
Published: September 2011

Among heavy coffee drinkers, a glutamate receptor gene polymorphism halves the risk of developing Parkinson’s disease.
Thinking Globally About Asthma
Authors: Niewold Timothy B.
Published: September 2011

Genome-wide association studies reveal shared and unique risk factors for asthma in ethnically diverse North American populations.
Pharmacokinetic Mismatch Does Not Lead to Emergence of Isoniazid- or Rifampin-Resistant Mycobacterium tuberculosis but to Better Antimicrobial Effect: a New Paradigm for Antituberculosis Drug Scheduling
Authors: Srivastava Shashikant , Sherman Carleton , Meek Claudia , Leff Richard , Gumbo Tawanda
Published: September 2011

Multidrug resistant-tuberculosis is a pressing problem. One of the major mechanisms proposed to lead to the emergence of drug resistance is pharmacokinetic mismatch. Stated as a falsifiable hypothesis, the greater the pharmacokinetic mismatch between rifampin and isoniazid, the higher the isoniazid- and rifampin-resistant subpopulation sizes become with time. To test this, we performed hollow-fiber-system studies for both bactericidal and sterilizing effects in experiments of up to 42 days. We mimicked pharmacokinetics of 600-mg/day rifampin and 300-mg/day isoniazid administered to patients. Rifampin was administered first, followed by isoniazid 0, 6, 12, and 24 h later. The treatment was for drug-susceptible
Mycobacterium tuberculosis
in some experiments and hollow fiber systems with inoculum preseeded with isoniazid- and rifampin-resistant isogenic
Mycobacterium tuberculosis
strains in others. Analysis of variance revealed that the 12-h and 24-h-mismatched regimens always killed better than the matched regimens during both bactericidal and sterilizing effects (
P
< 0.05). This means that either the order of scheduling or the sequential administration of drugs in combination therapy may lead to significant improvement in microbial killing. Rifampin-resistant and isoniazid-resistant subpopulations were not significantly higher with increased mismatching in numerous analysis-of-variance comparisons. Thus, the pharmacokinetic mismatch hypothesis was rejected. Instead, sequential administration of anti-tuberculosis (TB) drugs (i.e., deliberate mismatch) following particular schedules suggests a new paradigm for accelerating
M. tuberculosis
killing. We conclude that current efforts aimed at better pharmacokinetic matching to decrease
M. tuberculosis
resistance emergence are likely futile and counterproductive.
Zanamivir Pharmacokinetics and Pulmonary Penetration into Epithelial Lining Fluid following Intravenous or Oral Inhaled Administration to Healthy Adult Subjects
Authors: Shelton Mark J. , Lovern Mark , Ng-Cashin Judith , Jones Lori , Gould Elizabeth , Gauvin Jennifer , Rodvold Keith A.
Published: September 2011

Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza.
Inhibition of HIV-1 by Octadecyloxyethyl Esters of (S)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl] Nucleosides and Evaluation of Their Mechanism of Action
Authors: Magee Wendy C. , Valiaeva Nadejda , Beadle James R. , Richman Douglas D. , Hostetler Karl Y. , Evans David H.
Published: September 2011

(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC [cidofovir]) and (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of a variety of DNA viruses. These drugs possess a 3′-hydroxyl equivalent which could support chain extension from an incorporated drug molecule. HPMPC and HPMPA were initially reported to lack activity against human immunodeficiency virus type 1 (HIV-1); more recent results have shown that the octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of HPMPA are potent inhibitors of the virus. We have synthesized the ODE esters of a series of (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides, including HPMPC, HPMP-guanine (HPMPG), HPMP-thymine (HPMPT), and HPMP-diaminopurine (HPMPDAP), as well as the ODE ester of the obligate chain terminator (S)-9-[3-methoxy-2-(phosphonomethoxy)-propyl]adenine (MPMPA). All compounds except ODE-HPMPT were inhibitors of HIV-1 replication at low nanomolar concentrations. These compounds were also inhibitors of the replication of HIV-1 variants that are resistant to various nucleoside reverse transcriptase (RT) inhibitors at concentrations several times lower than would be expected to be achievedin vivo. To investigate the mechanism of the antiviral activity, the active metabolites of HPMPC and HPMPA were studied for their effects on reactions catalyzed by HIV-1 RT. Incorporation of HPMPC and HPMPA into a DNA primer strand resulted in multiple inhibitory effects exerted on the enzyme and showed that neither compound acts as an absolute chain terminator. Further, inhibition of HIV-1 RT also occurred when these drugs were located in the template strand. These results indicate that HPMPC and HPMPA inhibit HIV-1 by a complex mechanism and suggest that this class of drugs has a broader spectrum of activity than previously shown.
Discovery of GAMA, a Plasmodium falciparum Merozoite Micronemal Protein, as a Novel Blood-Stage Vaccine Candidate Antigen
Authors: Arumugam Thangavelu U. , Takeo Satoru , Yamasaki Tsutomu , Thonkukiatkul Amporn , Miura Kazutoyo , Otsuki Hitoshi , Zhou Hong , Long Carole A. , Sattabongkot Jetsumon , Thompson Jennifer , Wilson Danny W. , Beeson James G. , Healer Julie , Crabb Brendan S. , Cowman Alan F. , Torii Motomi , Tsuboi Takafumi
Published: September 2011

One of the solutions for reducing the global mortality and morbidity due to malaria is multivalent vaccines comprising antigens of several life cycle stages of the malarial parasite. Hence, there is a need for supplementing the current set of malaria vaccine candidate antigens. Here, we aimed to characterize glycosylphosphatidylinositol (GPI)-anchored micronemal antigen (GAMA) encoded by the PF08_0008 gene in
Plasmodium falciparum
. Antibodies were raised against recombinant GAMA synthesized by using a wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that GAMA is a microneme protein of the merozoite. Erythrocyte binding assays revealed that GAMA possesses an erythrocyte binding epitope in the C-terminal region and it binds a nonsialylated protein receptor on human erythrocytes. Growth inhibition assays revealed that anti-GAMA antibodies can inhibit
P. falciparum
invasion in a dose-dependent manner and GAMA plays a role in the sialic acid (SA)-independent invasion pathway. Anti-GAMA antibodies in combination with anti-erythrocyte binding antigen 175 exhibited a significantly higher level of invasion inhibition, supporting the rationale that targeting of both SA-dependent and SA-independent ligands/pathways is better than targeting either of them alone. Human sera collected from areas of malaria endemicity in Mali and Thailand recognized GAMA. Since GAMA in
P. falciparum
is refractory to gene knockout attempts, it is essential to parasite invasion. Overall, our study indicates that GAMA is a novel blood-stage vaccine candidate antigen.
Conserved Mutations in the Pneumococcal Bacteriocin Transporter Gene,
blpA
, Result in a Complex Population Consisting of Producers and Cheaters
Authors: Son Matthew R. , Shchepetov Mikhail , Adrian Peter V. , Madhi Shabir A. , de Gouveia Linda , von Gottberg Anne , Klugman Keith P. , Weiser Jeffrey N. , Dawid Suzanne
Published: September 2011

All fully sequenced strains of
Streptococcus pneumoniae
possess a version of the
blp
locus, which is responsible for bacteriocin production and immunity. Activation of the
blp
locus is stimulated by accumulation of the peptide pheromone, BlpC, following its secretion by the ABC transporter, BlpA. The
blp
locus is characterized by significant diversity in
blpC
type and in the region of the locus containing putative bacteriocin and immunity genes. In addition, the
blpA
gene can represent a single large open reading frame or be divided into several smaller fragments due to the presence of frameshift mutations. In this study, we use a collection of strains with
blp
-dependent inhibition and immunity to define the genetic changes that bring about phenotypic differences in bacteriocin production or immunity. We demonstrate that alterations in
blpA
,
blpC
, and bacteriocin/immunity content likely play an important role in competitive interactions between pneumococcal strains. Importantly, strains with a highly conserved frameshift mutation in
blpA
are unable to secrete bacteriocins or BlpC, but retain the ability to respond to exogenous peptide pheromone produced by cocolonizing strains, stimulating
blp
-mediated immunity. These “cheater” strains can only coexist with bacteriocin-producing strains that secrete their cognate BlpC and share the same immunity proteins. The variable outcome of these interactions helps to explain the heterogeneity of the
blp
pheromone, bacteriocin, and immunity protein content.

IMPORTANCE
Streptococcus pneumoniae
resides in a polymicrobial environment and competes for limited resources by the elaboration of small antimicrobial peptides called bacteriocins. A conserved cluster of genes in the
S. pneumoniae
genome is involved in the production of bacteriocins and their associated protective immunity proteins through secretion of a signaling pheromone. In this study, we show that a significant number of strains have lost the ability to secrete bacteriocins and signaling pheromones due to a specific mutation in a dedicated transporter protein. Because the regulatory and immunity portion of the locus is retained, these “cheater” strains can survive in the face of invasion from a bacteriocin-producing strain without the cost of bacteriocin secretion. The outcome of such interactions depends on each strain’s repertoire of pheromone, immunity protein, and bacteriocin genes, such that intrastrain competition drives the diversity in bacteriocin, immunity protein, and pheromone content.
Passive smoking and chronic obstructive pulmonary disease: cross-sectional analysis of data from the Health Survey for England
Authors: Jordan Rachel E , Cheng Kar Keung , Miller Martin R , Adab Peymané
Published: September 2011

Objectives

There is increasing evidence that passive smoking is associated with chronic respiratory diseases, but its association with chronic obstructive pulmonary disease (COPD) requires more study. In this cross-sectional analysis of data from 3 years of the Health Survey for England, the association between passive smoking exposure and risk of COPD is evaluated.

Design

Cross-sectional analysis of the 1995, 1996 and 2001 Health Surveys for England including participants of white ethnicity, aged 40+ years with valid lung function data. COPD was defined using the lower limit of normal spirometric criteria for airflow obstruction. Standardised questions elicited self-reported information on demography, smoking history, ethnicity, occupation, asthma and respiratory symptoms (dyspnoea, chronic cough, chronic phlegm, wheeze). Passive smoking was measured by self-report of hours of exposure to cigarette smoke per week.

Results

Increasing passive smoke exposure was independently associated with increased risk of COPD, with adjusted OR 1.05 (95% CI 0.93 to 1.18) for 1–19 h and OR 1.18 (95% CI 1.01 to 1.39) for 20 or more hours of exposure per week. Similar patterns (although attenuated and non-significant) were observed among never smokers. More marked dose–response relationships were observed between passive smoking exposure and respiratory symptoms, but the most marked effects were on the development of clinically significant COPD (airflow obstruction plus symptoms), where the risk among never smokers was doubled (OR 1.98 (95% CI 1.03 to 3.79)) if exposure exceeded 20 h/week.

Conclusion

This analysis adds weight to the evidence suggesting an association between passive smoking exposure and COPD.
Open versus closed IV infusion systems: a state based model to predict risk of catheter associated blood stream infections
Authors: Graves Nicholas , Barnett Adrian G , Rosenthal Victor D
Published: September 2011

Objectives

To quantify the change in risk of central line associated blood stream infection (CLABSI) following the introduction of a closed infusion container in intensive care units (ICUs) in two Latin American cities.

Design

A state-space model was used to describe the flow of admissions through the ICU. This approach correctly treats infection as a time-dependent covariate.

Results

A closed system reduced the risk of CLABSI. The hazard ratios for the closed versus open container were between 0.15 and 0.31 (p values<0.001), indicating a clinically significant reduction in the risk of admissions having a CLABSI. A simulation study showed that a closed system reduced the number of infections, costs and deaths.

Conclusions

The data reveal costs are saved and health benefits gained from fewer cases of CLABSI after adoption of a closed infusion system. Information is required on the costs of implementing the closed system widely in these settings.
Development of a primary care physician task list to evaluate clinic visit workflow: Table 1
Authors: Wetterneck Tosha B , Lapin Jamie A , Krueger Daniel J , Holman G Talley , Beasley John W , Karsh Ben-Tzion
Published: September 2011

Background

Interventions designed to improve the delivery of primary care, including Patient-Centered Medical Homes and electronic health records, require an understanding of clinical workflow to be successfully implemented. However, there is a lack of tools to describe and study primary care physician workflow. We developed a comprehensive list of primary care physician tasks that occur during a face-to-face patient visit.

Methods

A validated list of tasks performed by primary care physicians during patient clinic visits was developed from a secondary data analysis of observation data from two studies evaluating primary care workflow. Thirty primary care physicians participated from a convenience sample of 17 internal medicine and family medicine clinics in Wisconsin and Iowa across rural and urban settings and community and academic settings.

Results

The final task list has 12 major tasks, 189 subtasks, and 191 total tasks. The major tasks are: Enter Room, Gather Information from Patient, Review Patient Information, Document Patient Information, Perform, Recommend / Discuss Treatment Options, Look Up, Order, Communicate, Print / Give Patient (advice, instructions), Appointment Wrap-up, and Leave Room. Additional subcodes note use of paper or EHR and the presence of a caregiver or medical student.

Conclusions

The task list presented here is a tool that will help clinics study their workflows so they can plan for changes that will take place because of EHR implementation and/or transformation to a patient centered medical home.
Tandem mass spectrometry findings at autopsy for detection of metabolic disease in infant deaths: postmortem changes and confounding factors
Authors: Pryce J W , Weber M A , Heales S , Malone M , Sebire N J
Published: September 2011

Aim

Tandem mass spectrometry (MS/MS) is a recommended investigation for sudden unexpected death in infancy (SUDI), but there are limited data regarding yield and potential influencing factors. This study investigates postmortem acylcarnitine profiles in a large cohort of infant deaths from a single centre, including those with metabolic disease.

Methods

Acylcarnitine results obtained by MS/MS from routine blood/bile spot samples during the standard autopsy investigation were identified from infant deaths over a 14-year period. Results were categorised as normal or abnormal according to the clinical report by a specialist paediatric biochemist. Possible interdependent variables were assessed, multiple linear regression models were constructed and residual comparison was undertaken.

Results

397 blood and 268 bile MS/MS results were identified from infant cases, including 255 matched blood–bile pairs. There was significant association between blood acylcarnitine findings and postmortem interval (PMI), body mass index and liver weight. A probable cause of death was identified in 40% of sudden death cases, including 18 (2%) with a definite or highly likely cause of death as underlying metabolic disease; this represented 12 (12%) unexpected deaths in the first week of life and six (<1%) aged 7–365 days. Fatty acid oxidation disorders identified included very long chain acyl-CoA dehydrogenase deficiency, medium chain acyl-CoA dehydrogenase deficiency and carnitine transporter defects.

Conclusion

Postmortem blood and bile acylcarnitine profiles are influenced by several variables, and PMI can influence MS/MS acylcarnitine results. Metabolic disease may present as SUDI and may be identified from postmortem samples.
Canine breeds at high risk of developing inflammatory bowel disease in the south‐eastern UK
Authors: Kathrani A. , Werling D. , Allenspach K.
Published: September 2011

Genetics are an important factor in the development of human inflammatory bowel disease (IBD); however, there is very little information available regarding the role of genetics in canine IBD. The purpose of this study was to gather information about which canine breeds in the south‐eastern UK are at a high risk for developing IBD. Determination of such breeds may help further genetic research in this complex disease. The computer medical records at the Queen Mother Hospital for Animals, Royal Veterinary College dating from August 1, 2003 to December 31, 2009 were retrospectively searched for cases diagnosed with IBD. Five hundred and forty‐six dogs with IBD were identified, representing 86 different breeds. The comparison group consisted of all dogs from these same 86 breeds without IBD admitted to the hospital during the same period that amounted to 27,463 dogs. The breeds at significantly higher risk of developing IBD compared with mixed‐breed dogs consisted of weimaraner (odds ratio [OR]=3.6797, 95 per cent confidence interval [CI]=2.0167 to 6.7141, P<0.0001), rottweiler (OR=2.9697, 95 per cent CI=1.7569 to 5.0196, P<0.0001), German shepherd dog (GSD) (OR=2.4101, 95 per cent CI=1.5826 to 3.36705, P<0.0001), border collie (OR=1.9936, 95 per cent CI=1.1655 to 3.4101, P=0.0118) and boxer (OR=1.6961, 95 per cent CI=1.0441 to 2.755, P=0.0328). This study demonstrates for the first time canine breeds in the south‐eastern UK that are highly susceptible to developing IBD. Identification of such breeds may allow for a more focused investigation of genetic mutations associated with canine IBD.
Inhibition of Endoplasm Reticulum Stress by Anisodamine Protects Against Myocardial Injury After Cardiac Arrest and Resuscitation in Rats
Authors: Yin Xue-Lian , Shen Hong , Zhang Wei , Yang Yang
Published: September 2011

Anisodamine is a multi-functional bio-alkaloid with vascular activity. Our previous studies have revealed that anisodamine protects the heart from ischemia/reperfusion (I/R) injury induced by cardiac arrest (CA) and resuscitation. This study aimed to explore whether the protective effect of anisodamine is mediated by inhibition of the endoplasmic reticulum stress (ERS) response, which has been demonstrated to implicate in various I/R injuries. After 5 min of CA induced by electric stimulation, Wistar rats were randomly selected to receive cardiopulmonary resuscitation (CPR, including chest compression and epinephrine infusion) with or without anisodamine injection (n = 50/group). Hearts were harvested 24 h after the return of spontaneous circulation (ROSC). Sham-operated animals served as non-ischemic controls (n = 10). The survival rate, cardiomyocyte apoptosis, and the protein expression of ERS markers were detected. Thirty-three of the 50 rats in the Ani + CA/R group were successfully resuscitated, whereas only 18 of the 50 rats in the CA/R group gained ROSC. Survival to 24 h was significantly improved in the anisodamine treatment group (Ani + CA/R, n = 22/50) compared to the group with standard CPR (CA/R, n = 8/50). Anisodamine markedly decreased the number of apoptotic cardiomyocytes, the protein expression of GRP78, CHOP, and the active form of Caspase3 compared to the CA/R group. Our data suggest that anisodamine protects against cellular damage in rat hearts after CA and resuscitation, at least in part, by inhibiting myocardial ERS.
Vasorelaxant Effect ofCinnamomi RamulusEthanol Extract via Rho-Kinase Signaling Pathway
Authors: Kang Yun Hwan , Shin Heung Mook
Published: September 2011

The Rho-kinase (ROCK) signaling pathway is substantially involved in vascular contraction. This study investigated the vasodilatory effects and possible mechanisms of Cinnamomi ramulus ethanol extract (CRE), with the hypothesis that the CRE vasodilatory effect involves RhoA and the ROCK signaling pathway in rat aortic preparations. CRE (0.05–1 mg/ml) dose-dependently relaxed the vascular contraction induced by phenylephrine and calpeptin in an endothelium-independent manner. Measurement of the expression levels of ROCK-related signaling molecules in response to calpeptin revealed that CRE completely inhibited RhoA and ROCK2 protein expressions. Furthermore, CRE dephosphorylated the subsequent downstream targets myosin phosphatase targeting subunit 1 (MYPT-1), protein kinase C potentiated phosphatase inhibitor protein-17 kDa (CPI-17) and myosin light chain 20 kDa (MLC20). We conclude that the vasorelaxation effect of CRE occurs via downregulation of ROCK signal molecules.
Effect ofCuscuta chinensison Renal Function in Ischemia/Reperfusion-Induced Acute Renal Failure Rats
Authors: Shin Sun , Lee Yun Jung , Kim Eun Ju , Lee An Sook , Kang Dae Gill , Lee Ho Sub
Published: September 2011

The kidneys play a central role in regulating water, ion composition and excretion of metabolic waste products in the urine. Cuscuta chinensis has been known as an important traditional Oriental medicine for the treatment of liver and kidney disorders. Thus, we studied whether an aqueous extract of Cuscuta chinensis (ACC) seeds has an effect on renal function parameters in ischemia/reperfusion-induced acute renal failure (ARF) rats. Administration of 250 mg/kg/day ACC showed that renal functional parameters including urinary excretion rate, osmolality, Na+, K+, Cl-, creatinine clearance, solute-free water reabsorption were significantly recovered in ischemia/reperfusion-induced ARF. Periodic acid Schiff staining showed that administration of ACC improved tubular damage in ischemia/reperfusion-induced ARF. In immunoblot and immunohistological examinations, ischemia/reperfusion-induced ARF decreased the expressions of water channel AQP 2, 3 and sodium potassium pump Na , K -ATPase in the renal medulla. However, administration of ACC markedly incremented AQP 2, 3 and Na , K -ATPase expressions. Therefore, these data indicate that administration of ACC ameliorates regulation of the urine concentration and renal functions in rats with ischemia/reperfusion-induced ARF.