bluuebunny/crossref_metadata_2025 huggingface dataset:
Body composition, metabolic syndrome and type 2 diabetes in Klinefelter syndrome
Authors: Gravholt Claus H , Jensen Anne S , Høst Christian , Bojesen Anders
Published: February 2011

Klinefelter syndrome (KS) affects 1:660 men, making it the most common sex‐chromosome disorder in man, and is a common cause of infertility, hypogonadism and learning disability. Men with KS are described as tall, slim, narrow shouldered, broad hipped, with hypergonadotropic hypogonadism and small testes, and recently the description has been expanded to include increased risk of the metabolic syndrome, type 2 diabetes and an unfavourable change in body composition, with accumulation of body fat and decreased muscle mass and a concomitant decrease in insulin sensitivity, muscle strength and oxygen consumption capacity. Here, we review the data on body composition, bone turnover, liver function, insulin resistance and metabolic syndrome in relation to testosterone in both patients with KS and normal men. Treatment with testosterone in hypogonadal men (other than KS) improves body composition in both clinical and experimental studies. Despite the lack of such studies in KS, we recommend testosterone treatment to patients with KS with low serum testosterone or increased LH and change in body composition and thus possibly prevent common diseases like type 2 diabetes, osteoporosis and heart disease.

Conclusion:  Preventable causes of the increased morbidity and mortality, such as osteoporosis, chronic obstructive airway disease or type 2 diabetes, should be screened for. Despite the lack of randomized controlled studies, we recommend testosterone treatment in case of increased LH or low serum testosterone, and weight reduction programmes if overweight.
Anthropometric changes in Sweden during the obesity epidemic – increased overweight among adolescents of non‐Nordic origin
Authors: Sjöberg () Agneta , Hulthén Lena
Published: February 2011

Aim:  To compare overweight, obesity and thinness prevalences in adolescents born in 1979 and 1985 and to evaluate the influence of parental migration background.

Methods:  A total of 2306 15‐ to 16‐year‐old girls and boys in Gothenburg, Sweden, participated in two cross‐sectional surveys (1994 and 2000). Height and weight were measured and interviews about parental origin were conducted. Overweight and obesity were classified according to International Obesity Task Force (IOTF) and WHO. Thinness was classified according to Cole.

Results:  Among girls, the prevalence of thinness decreased, 8.4% vs. 4.7%. The prevalence of overweight, including obesity, according to IOTF criteria, was 11.8% and 13.7% in 1994 and 2000, respectively. The corresponding figures according to WHO criteria were 14.5% and 17.5%. No significant changes occurred between cohorts in prevalences of overweight and obesity. However, when interaction between survey year and origin was tested, there was a significant difference in overweight according to WHO criteria (p = 0.022).

Conclusion:  A shift entailing increased risk for overweight in adolescents of non‐Nordic origin was observed, while no changes occurred in the general population. Individual background factors are important to consider both for correct conclusions about health development in the population and for identification of target groups for health‐promoting interventions.
COMPARATIVE POPLITEAL AND MESENTERIC COMPUTED TOMOGRAPHY LYMPHANGIOGRAPHY OF THE CANINE THORACIC DUCT
Authors: MILLWARD IAN R. , KIRBERGER ROBERT M. , THOMPSON PETER N.
Published: February 2011

Thoracic duct computed tomography (CT) lymphangiograms were performed on seven clinically normal dogs. The appearance of the thoracic duct system was compared following administration of contrast medium through a mesenteric lymphatic vessel vs. ultrasound guided percutaneous injection into a popliteal lymph node using helical and sequential CT acquisition modes. The number of visible thoracic duct branches and the largest thoracic duct branch cross‐sectional area and mean Hounsfield units (HU) were determined from thoracic vertebra 9 to lumbar vertebra 1. Procedural time and patient discomfort were also assessed. Popliteal administration produced a successful thoracic duct lymphangiogram in eight of 11 dogs (73%) after two attempts, while mesenteric administration was successful in eight of 10 dogs (80%) after a single attempt. Popliteal lymphography required 46% of the time and was associated with less patient discomfort than mesenteric lymphangiography. The number of thoracic duct branches seen was not significantly different for either administration technique (P=0.256) or CT acquisition mode (P=0.417). However, the cross‐sectional area and mean HU of the largest thoracic duct branch were greater with mesenteric administration (P<0.001), and helical image acquisition (P<0.001). The thoracic duct branch number, size, and location were highly variable between dogs. Percutaneous popliteal lymphography appears to be an acceptable alternative to mesenteric lymphangiography for the detection of thoracic duct branches in the dog when using either helical or sequential CT acquisition modes.
TOTAL SKIN ELECTRON THERAPY TECHNIQUE FOR THE CANINE PATIENT
Authors: RECHNER KERENSA N. , WEEKS KENNETH J. , PRUITT AMY F.
Published: February 2011

Cutaneous epitheliotropic T‐cell lymphoma in canine patients is a radiation sensitive tumor but total skin electron therapy is used only rarely. Our purpose was to evaluate dose distribution from a total skin electron therapy technique using 6 MeV electron beams. The treatment was comprised of 12 fields, with the dog in lateral recumbency in a stride position at an extended distance from the source. Uniformity, flatness and symmetry were determined for each beam. The composite percent depth dose profile for all beams was measured in solid water phantoms and skin dose was determined on a canine cadaver using thermoluminescent dosimeters. The resulting dmax of the composite beams was 1 mm and dose variation over the skin was 6.8%, with the extremities having the most uneven dose distribution. Dimensions of the fields were adequate to obtain an effective treatment profile for the entire thickness of canine epidermis and the technique was feasible for clinical application. Individual tailoring of the protocol to deal with hot and cold spots may be necessary and set up will likely involve a significant time commitment for the therapy team.
IDENTIFICATION AND PREVALENCE OF ERRORS AFFECTING THE QUALITY OF RADIOGRAPHS SUBMITTED TO AUSTRALIAN THOROUGHBRED YEARLING SALE REPOSITORIES
Authors: JACKSON MELISSA A. , VIZARD ANDREW L. , ANDERSON GARRY A. , MATTOON JOHN S. , LAVELLE ROGER B. , SMITHENSON BRYAN T. , LESTER NOLA V. , CLARKE ANDREW F. , WHITTON ROBERT C.
Published: February 2011

We aimed to identify common mistakes made when radiographing yearling sale horses. Radiographic examinations from repositories at eight yearling sales held in Australia in 2003 were assessed by one of four veterinary radiology specialists. Each radiographic examination consisted of a maximum of 34 radiographs. Each radiograph was assessed for errors associated with movement, exposure, positioning, labeling or marker placement, and processing, and categorized as either ideal, less than ideal or nondiagnostic. In addition, from the first 800 sets catalogued, 167 were selected randomly and read twice by the four radiologists for agreement analysis. A total of 81,297 radiographs were examined for errors affecting quality. Positioning errors were the most common reason for radiographs to be considered nondiagnostic (2432/81,297; 3%), with the flexed lateromedial (LM) metacarpophalangeal joint, LM metatarsophalangeal joint, and the dorsomedial palmarolateral (DMPaLO) carpal views being the most frequently involved. Overexposure (14,357/81,297; 17.7%) was the most common reason for radiographs being categorized as less than ideal with the LM stifle view the most represented. Agreement within and between radiologists for reporting errors in positioning of the flexed LM metacarpophalangeal joint, LM metatarsophalangeal joint, and DMPaLO carpal views varied from slight to almost perfect. The low repeatability within radiologists on some views suggests that before declaring a radiograph nondiagnostic it is worth considering rereading it at another time. Care should be taken in positioning of the flexed LM metacarpophalangeal, LM metatarsophalangeal, and DMPaLO carpus views to maximize radiograph quality.
Systematic Review and Meta‐Analysis of the Correlates of Cancer‐Related Fatigue
Authors: Oh Hyun Soo , Seo Wha Sook
Published: February 2011

Background: Fatigue is one of the most common problems experienced by cancer patients. The factors most frequently reported to correlate with cancer‐related fatigue are symptom distress (pain, nausea/vomiting, dyspnea, and lack of appetite) and psychological distress (depression and anxiety).

Aims: This study was performed to examine the overall association of symptom and psychological distress with cancer‐related fatigue using systematic literature review and meta‐analysis. This study also aimed to determine which factors have a higher correlation with fatigue, and therefore should receive nursing priority.

Methods: A meta‐analysis of 30 primary studies identified by searching computer databases, which included MEDLINE, PubMed, and CINAHL.

Results: Results showed that all symptoms (pain, dyspnea, nausea/vomiting, and lack of appetite) and psychological distress (depression and anxiety) included had a significant association with cancer‐related fatigue with medium‐to‐large effect sizes, which were estimated using correlation coefficients. The overall correlations of psychological distress with cancer‐related fatigue were found to be higher than those of symptom distress. The correlation of nausea/vomiting with cancer‐related fatigue was higher than those of pain and dyspnea.

Conclusions and Implications: Our findings highlight the importance of psychological distress in dealing with cancer‐related fatigue in addition to the need to be attentive to a patient's symptom distress. Of the symptom distress, nausea/vomiting should be prioritized by nurses when managing cancer‐related fatigue. This study provides sound empirical evidence that can be used to draft guidelines for the management of cancer‐related fatigue.
Familial Isolated Pituitary Adenomas: From Genetics to Therapy
Authors: Guaraldi Federica , Salvatori Roberto
Published: February 2011

According to autopsy and radiological data, pituitary adenomas (PAs) develop in approximately 15% to 20% of the population. The great majority of PAs arise sporadically and affect adults. Rarely they are diagnosed in children and adolescents. Approximately 5% of cases are thought to be familial. Inherited conditions associated with pituitary tumors include multiple endocrine neoplasia type 1 (MEN‐1) and type 4 (MEN‐4), (CNC) Carney Complex, and familial isolated PA (FIPA) syndrome. FIPA is an autosomal dominant condition, defined by the presence of two or more patients affected by PAs in the same kindred, and no other associated condition. Germline mutations of the aryl hydrocarbon receptor interacting protein gene located on chromosome 11q13 have been reported in 15%–40% of FIPA cases. In the remaining cases, genetic defect are unidentified. This article focuses on FIPA clinical, pathological, genetic features, and therapeutic management. Clin Trans Sci 2011; Volume 4: 55–62
The peasant within: agrarian life in New Zealand and Canada
Authors: HEDLEY M.J.
Published: February 2011

Cette communication analyse les tentatives des membres des families ďagriculteurs de vouloir imposer leurs propres modèles sur le processes de production et sur la création et la reproduction de leur existence sociale. Cette communication souligne aussi ľimportance ďune reformulation des approches traditionnelles envers la culture rurale en reconnaissant ľinfluence importante ďune histoire de domination. Les arguents sont basés sur les résultats de recherches entreprises sur place dans le nord de la Nouvelle Zélande et en Alberta central.

This paper examines the concern of the members of farm households to impose their own designs on the productive process, and on the creation and reproduction of their social existence. It also points to the importance of rethinking conventional approaches to rural culture by recognizing the pervasive influence of a history of domination. The arguments draw upon the results of field work conducted in northern New Zealand and central Alberta, Canada.
Half Empty or Half Full
Authors: Olsen Gregg M.
Published: February 2011

Peu d'États‐providence dans le monde occidental n'ont pas fait l'expérience de compressions budgétaires et de restructurations au cours des dix dernières années, même si l'ampleur et l'intensité de ces ajustements ont varié considérablement selon les pays. Toutefois, les comptes rendus sur la restructuration de l'État‐providence en Suède ‐ longtemps considéré comme un modèle du genre ‐ ont été quelque peu contradictoires. En prenant comme exemple 1) le chô‐mage et la politique du marché du travail et 2) le système de soins aux personnes âgées et le régime de retraite, deux domaines impor‐tants de la politique sociale qui reflètent largement l'approche suédoise en matière de politique sociale, cette étude suggère que l'État‐providence suédois n'a pas été immunisé contre les diverses pressions et contraintes endogènes et exogènes qui sont en jeu dans le monde capitaliste moderne d'aujourd'hui. Dans la dernière partie de l'article, les changements apportés à la politique sociale sont abordés dans une perspective de mondialisation.

Few welfare states in the Western world have not experienced some retrenchment and restructuring over the past decade, even if the magnitude and intensity of these adjustments have varied considerably across nations. However, accounts of the restructuring of Sweden's welfare state—long considered the quintessential welfare model—have been somewhat contradictory. Primarily focussing on 1) unemployment and labour market policy, and 2) old‐age care and the pension system, two major social policy areas which broadly reflect the Swedish approach to social policy, the present study suggests that Sweden's welfare state has not been immune to the various endogenous and exogenous pressures and strains in play across the advanced capitalist world today. Changes in Swedish social policy are discussed in relation to globalization in the latter part of the paper.
Zoonotic Disease Awareness in Animal Shelter Workers and Volunteers and the Effect of Training
Authors: Steneroden K. K. , Hill A. E. , Salman M. D.
Published: February 2011

Animal shelter workers are a vulnerable population whose exposure to zoonotic disease may be greater compared with the general population. The aim of this project was to identify baseline zoonotic disease knowledge of animal shelter workers and to develop and evaluate zoonotic disease awareness training. Ten animal shelters in six western states were randomly selected. One hundred and eleven trainees were evaluated by identical pre‐ and post‐training tests. Training topics included identification of clinical signs, susceptible species, and transmission of disease to animals and to humans. Zoonotic diseases included rabies, plague, leptospirosis, internal parasites, methicillin‐resistant Staphylococcus aureus (MRSA) and salmonella. A statistically significant difference in overall total scores between pre‐test (58.5%) and post‐test (69.5%) was observed (P = 0.0001). No association was observed between test scores and length of time working in animal shelters, or with the participants’ role at the animal shelter. Overall test scores were raised by 11%. The lowest baseline levels of knowledge were found with leptospirosis, MRSA, plague and rabies, emerging diseases with increasing prevalence and high consequence. Zoonotic disease awareness training is a valuable service to animal shelters. In the current study, training was modestly successful in transferring short‐term knowledge to animal shelter workers. To understand and evaluate the effectiveness of training completely, observable or measureable behaviours should be compared before and after training. Long‐term assessment with measureable outcomes is needed.
Serological and Virological Surveillance of Swine H1N1 and H3N2 Influenza Virus Infection in Two Farms Located in Hubei Province, Central China
Authors: Wu R. , Liu Z. , Liang W. , Yang K. , Deng J. , Duan Z. , Zhou D. , Xu D.
Published: February 2011

Swine influenza viruses H1N1 and H3N2 have been reported in the swine population worldwide. From June 2008 to June 2009, we carried out serological and virological surveillance of swine influenza in the Hubei province in central China. The serological results indicated that antibodies to H1N1 swine influenza virus in the swine population were high with a 42.5% (204/480) positive rate, whereas antibodies to H3N2 swine influenza virus were low with a 7.9% (38/480) positive rate. Virological surveillance showed that only one sample from weanling pigs was positive by RT‐PCR. Phylogenetic analysis of the hemagglutinin and neuraminidase genes revealed that the A/Sw/HB/S1/2009 isolate was closely related to avian‐like H1N1 viruses and seemed to be derived from the European swine H1N1 viruses. In conclusion, H1N1 influenza viruses were more dominant in the pig population than H3N2 influenza viruses in central China, and infection with avian‐like H1N1 viruses persistently emerged in the swine population in the area.
Characteristic Analysis of VIV-Induced Fatigue Damage of Top Tensioned Risers Based on Simplified Model
Authors: Xue Hongxiang , Guo Jinting , Tang Wenyong , Zhang Shengkun
Published: February 2011

In this study, a simplified empirical model for fatigue analysis of top-tensioned risers due to vortex-induced vibration (VIV) in a nonuniform current is presented. Compared with previous studies on this subject, this model is able to take into account the main intrinsic nature of VIV for low mass ratio structures in lock-in regions, added mass, and nonlinear fluid damping. Based on the simplified model, a closed-form solution of fatigue damage is suggested for the case of a riser with uniform mass and cross-section oscillating in a uniform flow. Fatigue damage characteristics of the top-tensioned risers due to VIV are investigated to determine the effects of various ocean conditions and riser dimensions on fatigue damage.
The Specificity of Innate Immune Responses Is Enforced by Repression of Interferon Response Elements by NF-κB p50
Authors: Cheng Christine S. , Feldman Kristyn E. , Lee James , Verma Shilpi , Huang De-Bin , Huynh Kim , Chang Mikyoung , Ponomarenko Julia V. , Sun Shao-Cong , Benedict Chris A. , Ghosh Gourisankar , Hoffmann Alexander
Published: February 2011

Binding of NF-κB p50 homodimers to an interferon response element restricts interferon signaling and antiviral responses to only the appropriate stimuli.
ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor
Authors: Chen Chien-Hung , Shaikenov Tattym , Peterson Timothy R. , Aimbetov Rakhan , Bissenbaev Amangeldy K. , Lee Szu-Wei , Wu Juan , Lin Hui-Kuan , Sarbassov Dos D.
Published: February 2011

Cellular stress attenuates growth factor signaling through a phosphorylation event that blocks substrate access to the kinase complex mTORC2.
Science Signaling
Podcast: 22 February 2011
Authors: Hoffmann Alexander , VanHook Annalisa M.
Published: February 2011

A transcriptional repressor acts as a gatekeeper to restrict the innate immune response to specific stimuli.
Pump-Probe Imaging Differentiates Melanoma from Melanocytic Nevi
Authors: Matthews Thomas E. , Piletic Ivan R. , Selim M. Angelica , Simpson Mary Jane , Warren Warren S.
Published: February 2011

Multiphoton imaging reveals chemical changes in melanoma compared to benign nevi and could enhance current clinical diagnostic protocols.
Tuberculosis Immunopathology: The Neglected Role of Extracellular Matrix Destruction
Authors: Elkington Paul T. , D’Armiento Jeanine M. , Friedland Jon S.
Published: February 2011

Compounds that inhibit matrix metalloproteinases should be tested for their ability to limit tuberculosis morbidity and mortality.
Mutant Prevention Concentration-Based Pharmacokinetic/Pharmacodynamic Indices as Dosing Targets for Suppressing the Enrichment of Levofloxacin-Resistant Subpopulations of Staphylococcus aureus
Authors: Liang Beibei , Bai Nan , Cai Yun , Wang Rui , Drlica Karl , Zhao Xilin
Published: February 2011

MIC- and mutant prevention concentration (MPC)-based pharmacokinetic/pharmacodynamic (PK/PD) indices were compared for suitability as attainment targets for restricting amplification of levofloxacin-resistant mutant subpopulations. When three
Staphylococcus aureus
strains were examined with a hollow-fiber PK/PD model, area under the concentration-time curve over 24 h (AUC
24
)/MPC values of >25 and maximum concentration of drug in serum (
C
max
)/MPC values of >2.2 predicted resistance outcome among different isolates with an interisolate kappa coefficient of 1. MIC-based mutant-restrictive PK/PD values varied >8-fold and exhibited only a moderate interisolate agreement (kappa coefficient of 0.5). Thus, MPC-based PK/PD indices are more suitable than MIC-based indices for predicting mutant-restricting fluoroquinolone doses when multiple bacterial isolates are considered.
Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection
Authors: Pirrone Vanessa , Thakkar Nina , Jacobson Jeffrey M. , Wigdahl Brian , Krebs Fred C.
Published: February 2011

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4
+
T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development,
in vitro
and
in vivo
efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.
In Vitro
Antimicrobial Activity of Razupenem (SMP-601, PTZ601) against Anaerobic Bacteria
Authors: Tran Chau Minh , Tanaka Kaori , Yamagishi Yuka , Goto Takatsugu , Mikamo Hiroshige , Watanabe Kunitomo
Published: February 2011

We evaluated the
in vitro
antianaerobic activity of razupenem (SMP-601, PTZ601), a new parenterally administered carbapenem, against 70 reference strains and 323 clinical isolates. Razupenem exhibited broad-spectrum activity against anaerobes, inhibiting most of the reference strains when used at a concentration of ≤1 μg/ml. Furthermore, it exhibited strong activity, comparable to those of other carbapenems (meropenem and doripenem), against clinically isolated non
-fragilis Bacteroides
spp. (MIC
90
s of 2 μg/ml), with MIC
90
values of 0.06, 0.03, and 0.5 μg/ml against
Prevotella
spp.,
Porphyromonas
spp., and
Fusobacterium
spp., respectively. Clinical isolates of anaerobic Gram-positive cocci,
Eggerthella
spp., and
Clostridium
spp. were highly susceptible to razupenem (MIC
90
s, 0.03 to 1 μg/ml).
Efficacy of Topically Delivered Moxifloxacin against Wound Infection by Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus
Authors: Jacobsen F. , Fisahn C. , Sorkin M. , Thiele I. , Hirsch T. , Stricker I. , Klaassen T. , Roemer A. , Fugmann B. , Steinstraesser L.
Published: February 2011

Wound infection is a common risk for patients with chronic nonhealing wounds, causing high morbidity and mortality. Currently, systemic antibiotic treatment is the therapy of choice, despite often leading to several side effects and the risk of an insufficient tissue penetration due to impaired blood supply. If systemically delivered, moxifloxacin penetrates well into inflammatory blister fluid, muscle, and subcutaneous adipose tissues and might therefore be a possible option for the topical treatment of skin and infected skin wounds. In this study, topical application of moxifloxacin was investigated in comparison to mupirocin, linezolid, and gentamicin using a porcine wound infection and a rat burn infection model. Both animal models were performed either by an inoculation with methicillin-resistantStaphylococcus aureus(MRSA) orPseudomonas aeruginosa. Wound fluid, tissue, and blood samples were taken, and bacterial counts as well as the moxifloxacin concentration were determined for a 14-day follow-up. A histological comparison of the rat burn wound tissues was performed. Both strains were susceptible to moxifloxacin and gentamicin, whereas mupirocin and linezolid were effective only against MRSA. All antibiotics showed efficient reduction of bacterial counts, and except with MRSA, infected burn wounds reached bacterial counts below 105CFU/g tissue. Additionally, moxifloxacin was observed to promote wound healing as determined by histologic analysis, while no induction of bacterial resistance was observed during the treatment period. The use of topical antibiotics for the treatment of infected wounds confers many benefits. Moxifloxacin is therefore an ideal candidate, due to its broad antibacterial spectrum, its high efficiency, and its potential to promote wound healing.
Nitric Oxide Protects Bacteria from Aminoglycosides by Blocking the Energy-Dependent Phases of Drug Uptake
Authors: McCollister Bruce D. , Hoffman Matthew , Husain Maroof , Vázquez-Torres Andrés
Published: February 2011

Our investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protect
Salmonella
spp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellular
Salmonella
against the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressed
Salmonella
respiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen in
Salmonella
, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogens
Pseudomonas aeruginosa
and
Staphylococcus aureus
. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria.
4′-
C
-Methyl-2′-Deoxyadenosine and 4′-
C
-Ethyl-2′-Deoxyadenosine Inhibit HIV-1 Replication
Authors: Vu B. Christie , Boyer Paul L. , Siddiqui Maqbool A. , Marquez Victor E. , Hughes Stephen H.
Published: February 2011

It is important to develop new anti-HIV drugs that are effective against the existing drug-resistant mutants. Because the excision mechanism is an important pathway for resistance to nucleoside analogs, we are preparing analogs that retain a 3′-OH and can be extended after they are incorporated by the viral reverse transcriptase. We show that 4′-
C
-alkyl-deoxyadenosine (4′-
C
-alkyl-dA) compounds can be phosphorylated in cultured cells and can inhibit the replication of HIV-1 vectors: 4′-
C
-methyl- and 4′-
C
-ethyl-dA show both efficacy and selectivity against HIV-1. The compounds are also effective against viruses that replicate using reverse transcriptases (RTs) that carry nucleoside reverse transcriptase inhibitor resistance mutations, with the exception of the M184V mutant. Analysis of viral DNA synthesis in infected cells showed that viral DNA synthesis is blocked by the incorporation of either 4′-
C
-methyl- or 4′-
C
-ethyl-2′-deoxyadenosine.
In vitro
experiments with purified HIV-1 RT showed that 4′-
C
-methyl-2′-dATP can compete with dATP and that incorporation of the analog causes pausing in DNA synthesis. The 4′-
C
-ethyl compound also competes with dATP and shows a differential ability to block DNA synthesis on RNA and DNA templates. Experiments that measure the ability of the compounds to block DNA synthesis in infected cells suggest that this differential block to DNA synthesis also occurs in infected cells.
Integrase Inhibitors Effective against Human T-Cell Leukemia Virus Type 1
Authors: Seegulam Muhammad Esa , Ratner Lee
Published: February 2011

Drugs targeting the viral enzyme integrase have been in use for several years as part of the treatment regimen for patients with human immunodeficiency virus type 1 (HIV-1), and similar classes of compounds have been shown to inhibit human T-cell leukemia virus type 1 (HTLV-1) integration
in vitro
. The current study shows that the clinically approved HIV-1 integrase inhibitor, raltegravir, as well as the more recent diketo acid derivative, MK-2048, are active inhibitors of HTLV-1 infection
in vitro
. These agents were effective in inhibiting cell-free and cell-to-cell transmission of HTLV-1 in lymphoid and nonlymphoid cells. The drugs also inhibited HTLV-1 immortalization of human peripheral blood mononuclear cells. A novel adaptation of the
Alu
assay for viral integration was used to show that the drugs inhibit viral integration without affecting reverse transcription. These data support the administration of raltegravir and other integrase inhibitors as treatments for patients with HTLV-1-associated diseases.
Association of Composite IS
26-sul3
Elements with Highly Transmissible IncI1 Plasmids in Extended-Spectrum-β-Lactamase-Producing Escherichia coli Clones from Humans
Authors: Curiao Tânia , Cantón Rafael , Garcillán-Barcia M. Pilar , de la Cruz Fernando , Baquero Fernando , Coque Teresa M.
Published: February 2011

The association of an IS
440-sul3
platform with Tn
21
class 1 integrons carried by IncI1 plasmids encoding extended-spectrum β-lactamases (ESBLs; mainly SHV-12 and CTX-M-14) among worldwide
Escherichia coli
clones of phylogroups A (ST10, ST23, and ST46), B1 (ST155, ST351, and ST359), and D/B2 (ST131) is reported. An
in silico
comparative analysis of
sul3
elements available in the GenBank database shows the evolution of
sul3
platforms by hosting different transposable elements facilitating the potential genesis of IS
26
composite transposons and further insertion element-mediated promoted arrangements.
Outbreak of OXA-48-Positive Carbapenem-Resistant Klebsiella pneumoniae Isolates in France
Authors: Cuzon Gaelle , Ouanich Jocelyne , Gondret Remy , Naas Thierry , Nordmann Patrice
Published: February 2011

Seventeen
Klebsiella pneumoniae
isolates producing the OXA-48 carbapenemase, obtained from 10 patients hospitalized from April to June 2010, mostly in the medical intensive care unit of the Villeneuve-Saint-Georges Hospital in a suburb of Paris, France, were analyzed. Seven patients were infected, of whom five were treated at least with a carbapenem, and five patients died. Molecular analysis showed that the isolates belonged to a single clone that harbored a 70-kb plasmid carrying the
bla
OXA-48
gene and coproduced CTX-M-15 and TEM-1 β-lactamases. This is the first reported outbreak of OXA-48-producing
K. pneumoniae
isolates in France.
In Vitro
Activity of Proveblue (Methylene Blue) on Plasmodium falciparum Strains Resistant to Standard Antimalarial Drugs
Authors: Pascual Aurélie , Henry Maud , Briolant Sébastien , Charras Serge , Baret Eric , Amalvict Rémy , Huyghues des Etages Emilie , Feraud Michel , Rogier Christophe , Pradines Bruno
Published: February 2011

The geometric mean 50% inhibitory concentration (IC
50
) for Proveblue, a methylene blue complying with the European Pharmacopoeia, was more active on 23
P. falciparum
strains than chloroquine, quinine, mefloquine, monodesethylamodiaquine, and lumefantrine. We did not find significant associations between the Proveblue IC
50
and polymorphisms in the
pfcrt
,
pfmdr1
,
pfmdr2
,
pfmrp
, and
pfnhe-1
genes or the copy numbers of the
pfmdr1
and
pfmdr2
genes, all of which are involved in antimalarial resistance.
Evolution of Clonal and Susceptibility Profiles of Serotype 19A Streptococcus pneumoniae among Invasive Isolates from Children in Spain, 1990 to 2008
Authors: Tarragó David , Aguilar Lorenzo , García Raquel , Gimenez María-José , Granizo Juan-José , Fenoll Asunción
Published: February 2011

The genetic structure and antibiotic nonsusceptibility of all serotype 19A
Streptococcus pneumoniae
pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (
n
= 471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (
R
2
= 0.872;
P
= 0.001). Decreasing trends (
P
< 0.03) were found for ST202 (
R
2
= 0.774) and ST81 (
R
2
= 0.559), and increasing trends (
P
< 0.03) for ST878 (
R
2
= 0.544) and ST320 (
R
2
= 0.530), both belonging to the clonal complex (CC) Denmark
14
-32 and first detected in 2003 and 2007, respectively, and ST2013 (
R
2
= 0.704) and ST4461 (
R
2
= 0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC
50
/MIC
90
= 8/8 μg/ml) and 43.5% cefotaxime (MIC
50
/MIC
90
= 1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (
P
< 0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008;
R
2
= 0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008;
R
2
= 0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.
Effect of Ceftobiprole Treatment on Growth of and Toxin Production by Clostridium difficile in Cecal Contents of Mice
Authors: Nerandzic Michelle M. , Donskey Curtis J.
Published: February 2011

Ceftobiprole and ceftobiprole medocaril did not promote growth of or toxin production by
Clostridium difficile
in mouse cecal contents, whereas ceftazidime, cefoxitin, ceftriaxone, cefotaxime, and ertapenem did. The relatively low propensity of ceftobiprole to promote
C. difficile
was attributable to inhibitory activity against
C. difficile
and sparing of anaerobic microflora.
CTX-M-93, a CTX-M Variant Lacking Penicillin Hydrolytic Activity
Authors: Djamdjian Laura , Naas Thierry , Tandé Didier , Cuzon Gaelle , Hanrotel-Saliou Catherine , Nordmann Patrice
Published: February 2011

Extended-spectrum β-lactamases (ESBLs) of the CTX-M type are increasingly being reported worldwide, with more than 90 known variants. Clinical
Escherichia coli
isolate Bre-1 was isolated in 2009 and displayed an unusual ESBL phenotype, made of a synergy image between expanded cephalosporins and clavulanic acid discs and susceptibility to penicillins.
E. coli
Bre-1 harbored a novel CTX-M-encoding gene, designated
bla
CTX-M-93
. CTX-M-93 differed from CTX-M-27 by only a single L169Q substitution. Compared to CTX-M-27, CTX-M-93 conferred higher MICs of ceftazidime for
E. coli
(MIC of 8 versus 1.5 μg/ml) and decreased MICs of other expanded-cephalosporins (MIC of cefotaxime of 1 versus 32 μg/ml) and penicillins (MIC of ticarcillin of 0.5 versus >256 μg/ml). A comparison of enzymatic properties revealed that the L169Q substitution led to a decreased

K
m

for ceftazidime (25.5 versus 330 μM) but decreased hydrolytic activity against good substrates, such as cefotaxime (
k
cat
of 0.6 versus 113 s
−1
), probably owing to the alteration of the omega loop positioning during the catalytic process. The
bla
CTX-M-93
gene was surrounded by the IS
Ecp1
and IS
903
elements and inserted onto a 150-kb non-self-transferrable IncF-type plasmid.
E. coli
Bre-1 belongs to phylogroup D and is of multilocus sequence type (MLST) 624, a sequence type found only in rare Spanish CTX-M-14-producing
E. coli
isolates. We have characterized a novel CTX-M variant, CTX-M-93, lacking significant penicillin hydrolysis but with increased ceftazidime hydrolysis.
Case Report of a Successful Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia and MRSA/Vancomycin-Resistant Enterococcus faecium Cholecystitis by Daptomycin
Authors: Tascini Carlo , Di Paolo Antonello , Polillo Marialuisa , Ferrari Mauro , Lambelet Paola , Danesi Romano , Menichetti Francesco
Published: February 2011

A 72-year-old man, receiving 8 mg daptomycin/kg body weight/day for methicillin-resistant
Staphylococcus aureus
(MRSA) bacteremia, was diagnosed with MRSA/vancomycin-resistant
Enterococcus faecium
(VRE) cholecystitis (daptomycin MIC values, 1 and 2 mg/liter, respectively). After the fifth drug dose, the bile concentration of daptomycin was 66 mg/liter 5 min after drug administration, with the biliary concentration/MIC values higher than 30 for both bacterial strains. Therefore, daptomycin achieved therapeutic levels in bile, hence suggesting a role for the drug in the treatment of MRSA/VRE cholecystitis.
Trypanosoma cruzi Infection Induces a Global Host Cell Response in Cardiomyocytes
Authors: Manque Patricio A. , Probst Christian , Pereira Mirian C. S. , Rampazzo Rita C. P. , Ozaki L. Shozo , Pavoni Daniela P. , Silva Neto Dayse T. , Carvalho M. Ruth , Xu Ping , Serrano Myrna G. , Alves João M. P. , Meirelles Maria de Nazareth S. L. , Goldenberg Samuel , Krieger Marco A. , Buck Gregory A.
Published: February 2011

Chagas' disease, caused by the hemoflagellate protozoan
Trypanosoma cruzi
, affects millions of people in South and Central America. Chronic chagasic cardiomyopathy, the most devastating manifestation of this disease, occurs in approximately one-third of infected individuals. Events associated with the parasite's tropism for and invasion of cardiomyocytes have been the focus of intense investigation in recent years. In the present study, we use murine microarrays to investigate the cellular response caused by invasion of primary murine cardiomyocytes by
T. cruzi
trypomastigotes. These studies identified 353 murine genes that were differentially expressed during the early stages of invasion and infection of these cells. Genes associated with the immune response, inflammation, cytoskeleton organization, cell-cell and cell-matrix interactions, apoptosis, cell cycle, and oxidative stress are among those affected during the infection. Our data indicate that
T. cruzi
induces broad modulations of the host cell machinery in ways that provide insight into how the parasite survives, replicates, and persists in the infected host and ultimately defines the clinical outcome of the infection.
Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia
Authors: Shi Xin , Zhang Ping , Sempowski Gregory D. , Shellito Judd E.
Published: February 2011

CD4+T cells play a key role in host defense againstPneumocystisinfection. To define the role of naïve CD4+T cell production through the thymopoietic response in host defense againstPneumocystisinfection,Pneumocystis murinainfection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy.Pneumocystisinfection caused a significant increase in the number of CCR9+multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+cells was increased at 5 weeks post-Pneumocystisinfection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+T cells in all tissues examined were markedly reduced followingPneumocystisinfection. This deficiency of naïve and central memory CD4+T cells was associated with delayed pulmonary clearance ofPneumocystis. Extracts ofPneumocystisresulted in an increase in the number of CCR9+MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense againstPneumocystisinfection.
Involvement of Epidermal Growth Factor Receptor-Linked Signaling Responses in Pseudomonas fluorescens-Infected Alveolar Epithelial Cells
Authors: Choi Hye Jin , Seo Chan Hee , Park Seong Hwan , Yang Hyun , Do Kee Hun , Kim Juil , Kim Hyung-Kab , Chung Duk-Hwa , Ahn Jung Hoon , Moon Yuseok
Published: February 2011

Pseudomonas fluorescensis an opportunistic indoor pathogen that can cause severe airway proinflammatory responses. Pulmonary epithelium, like other mucosal epithelial linings of the body, constitutes the first line of defense against airway microbial pathogens. Mucosal epithelial cells can be a sentinel of pathogenic bacteria via stimulation of specific cell surface receptors, including the epidermal growth factor receptor (EGFR) and Toll-like receptor (TLR). This study addressed the involvement of EGFR in airway epithelial pathogenesis byP. fluorescens. Human A549 pneumocytes showed prolonged production of proinflammatory interleukin-8 (IL-8) in response to infection withP. fluorescens, which was via the nuclear factor-kappa B (NF-κB) signaling pathway. Production of proinflammatory cytokine IL-8 was not mediated byP. fluorescenslipopolysaccharide, a representative TLR4 agonist, but was mediated through EGFR-linked signals activated by the opportunistic bacteria. Moreover, EGFR signals were involved in NF-κB signal-mediated production of proinflammatory cytokines. Along with persistent NF-κB activation,P. fluorescensenhanced the EGFR phosphorylation and subsequent activation of downstream mediators, including protein kinase B or extracellular-signal-regulated kinases 1/2. Blocking of EGFR-linked signals increased epithelial susceptibility to pathogen-induced epithelial cell death, suggesting protective roles of EGFR signals. Thus, airway epithelial exposure toP. fluorescenscan trigger antiapoptotic responses via EGFR and proinflammatory responses via TLR4-independent NF-κB signaling pathway in human pneumocytes.
Pneumocystis Infection in an Immunocompetent Host Can Promote Collateral Sensitization to Respiratory Antigens
Authors: Swain Steve D. , Meissner Nicole , Han Soo , Harmsen Allen
Published: February 2011

Infection with the opportunistic fungal pathogenPneumocystisis assumed to pass without persistent pathology in immunocompetent hosts. However, when immunocompetent BALB/c mice were inoculated withPneumocystis, a vigorous Th2-like pulmonary inflammation ensued and peaked at 14 days postinfection. This coincided with a 10-fold increase in the number of antigen-presenting cells (APCs) in the lung, and these cells were capable of presenting antigenin vitro, as well as greater uptake of antigenin vivo. When mice were presented with exogenous antigen at the 14-day time point of the infection, they developed respiratory sensitization to that antigen, in the form of increased airway hyperresponsiveness upon a later challenge, whereas mice not infected but presented with antigen did not. Like other forms of collateral sensitization, this response was dependent on interleukin-4 receptor signaling. This ability to facilitate sensitization to exogenous antigen has been previously reported for other infectious disease agents; however,Pneumocystisappears to be uniquely capable in this respect, as a single intranasal dose without added adjuvant, when it was administered at the appropriate time, was sufficient to initiate sensitization.Pneumocystisinfection probably occurs in most humans during the first few years of life, and in the vast majority of cases, it fails to cause any overt direct pathology. However, as we show here,Pneumocystiscan be an agent of comorbidity at this time by facilitating respiratory sensitization that may relate to the later development or exacerbation of obstructive airway disease.