bluuebunny/crossref_metadata_2025 huggingface dataset:
The human translational vestibulo‐ocular reflex in response to complex motion
Authors: Walker Mark , Liao Ke
Published: September 2011

We studied the translational vestibulo‐ocular reflex (tVOR) in four healthy human subjects during complex, unpredictable sum‐of‐sines head motion (combination of 0.73, 1.33, 1.93, and 2.93 Hz), while subjects viewed a target 15 cm away. Ideal eye velocity was calculated from recorded head motion; actual eye velocity was measured with scleral coils. The gain and phase for each frequency component was determined by least‐squares optimization. Gain averaged approximately 40% and did not change with frequency; phase lag increased with frequency to a maximum of 66°. Fitting actual to ideal eye velocity predicted a tVOR latency of 48 m/s for vertical and 38 m/s for horizontal translation. These findings provide further evidence that the normal tVOR is considerably undercompensatory, even at low frequencies if the stimulus is not predictable. The similarity of this behavior to that of pursuit suggests that these two eye movements may share some aspects of neural processing.
Sources of calretinin inputs to motoneurons of extraocular muscles involved in upgaze
Authors: Ahlfeld Julia , Mustari Michael , Horn Anja K.E.
Published: September 2011

Recent monkey studies showed that motoneurons of the oculomotor nucleus involved in upward eye movements receive a selective input from afferents containing calretinin (CR). Here, we investigated the sources of these CR‐positive afferents. After injections of tract‐tracers into the oculomotor nucleus (nIII) of two monkeys, the retrograde labeling was combined with CR‐immunofluorescence in frozen brainstem sections. Three sources of CR inputs to nIII were found: the rostral interstitial nucleus of the medial longitudinal fascicle (RIMLF), the interstitial nucleus of Cajal, and the y‐group. CR is not present in all premotor upward‐moving pathways. The excitatory secondary vestibulo‐ocular neurons in the magnocellular part of the medial vestibular nuclei contained nonphosphorylated neurofilaments, but no CR, and they received a strong supply of large CR‐positive boutons. In conclusion, the present study presents evidence that only specific premotor pathways for upward eye movements—excitatory upgaze pathways—contain CR, but not the up vestibulo‐ocular reflex pathways. This property may help to differentiate between premotor up‐ and downgaze pathways in correlative clinico‐anatomical studies in humans.
Do brainstem omnipause neurons terminate saccades?
Authors: Rucker Janet C. , Ying Sarah H. , Moore Willa , Optican Lance M. , Büttner‐Ennever Jean , Keller Edward L. , Shapiro Barbara E. , Leigh R. John
Published: September 2011

Saccade‐generating burst neurons (BN) are inhibited by omnipause neurons (OPN), except during saccades. OPN activity pauses before saccade onset and resumes at the saccade end. Microstimulation of OPN stops saccades in mid‐flight, which shows that OPN can end saccades. However, OPN pause duration does not correlate well with saccade duration, and saccades are normometric after OPN lesions. We tested whether OPN were responsible for stopping saccades both in late‐onset Tay–Sachs, which causes premature saccadic termination, and in individuals with cerebellar hypermetria. We studied gaze shifts between two targets at different distances aligned on one eye, which consist of a disjunctive saccade followed by vergence. High‐frequency conjugate oscillations during the vergence movements that followed saccades were present in all subjects studied, indicating OPN silence. Thus, mechanisms other than OPN discharge (e.g., cerebellar caudal fastigial nucleus–promoting inhibitory BN discharge) must contribute to saccade termination.
Liver involvement during influenza infection: perspective on the 2009 influenza pandemic
Authors: Papic Neven , Pangercic Ana , Vargovic Martina , Barsic Bruno , Vince Adriana , Kuzman Ilija
Published: September 2011

Please cite this paper as: Papic et al. (2011) Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza and Other Respiratory Viruses 6(3), e2–e5.

Elevation of liver transaminase levels is a frequent observation during systemic infections. The aim of our study was to investigate liver damage during pandemic 2009 influenza A/H1N1 infection in comparison with seasonal influenza. Serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma‐glutamyl transpeptidase (GGT) were significantly higher in patients with pandemic influenza compared to seasonal influenza, which was strongly correlated with hypoxia. Moreover, a positive correlation between C‐reactive protein and serum GGT, alkaline phosphatase, and lactate dehydrogenase was noticed. Our findings support the hypothesis that the pandemic 2009 influenza A/H1N1 is an illness with a significant immune response to infection leading to hepatocellular injury.
Pandemic influenza A (H1N1) virus in households with young children
Authors: Peltola Ville , Teros‐Jaakkola Tamara , Rulli Maris , Toivonen Laura , Broberg Eeva , Waris Matti , Mertsola Jussi
Published: September 2011

Please cite this paper as: Peltola et al. (2011) Pandemic influenza A (H1N1) virus in households with young children. Influenza and Other Respiratory Viruses 6(3), e21–e24.

Background  Influenza viruses may cause a severe infection in infants and young children. The transmission patterns of pandemic 2009 influenza A (H1N1) within households with young children are poorly characterized.

Methods  Household members of six children younger than 1·5 years with documented 2009 influenza A (H1N1) infection were studied by daily symptom diaries and serial parent‐collected nasal swab samples for detection of influenza A by reverse transcription polymerase chain reaction (RT‐PCR) assay.

Results  Laboratory‐confirmed, symptomatic influenza was documented in 11 of 15 household contacts of young children with pandemic influenza (73%; 95% CI, 48–99). In five contact cases symptoms started earlier, in three cases on the same day, and in three cases after the onset of symptoms in the youngest child. The first case with influenza A (H1N1) within the household was an elder sibling in two households, father in two households, the youngest child in one household, and the youngest child at the same time with a sibling in one household. The median copy number of influenza virus was higher in children than in adults (4·2 × 107 versus 4·9 × 104, P = 0·02).

Conclusions  This study demonstrates the feasibility of nasal swab sampling by parents in investigation of household transmission of influenza. The results support influenza vaccination of all household contacts of young children.
Overexpression of the Immunoreceptor CD300f Has a Neuroprotective Role in a Model of Acute Brain Injury
Authors: Peluffo Hugo , Alí‐Ruiz Daniela , Ejarque‐Ortíz Aroa , Heras‐Alvarez Victor , Comas‐Casellas Emma , Martínez‐Barriocanal Agueda , Kamaid Andres , Alvarez‐Errico Damiana , Negro Maria Luciana , Lago Natalia , Schwartz Jr Simó , Villaverde Antonio , Sayós Joan
Published: September 2011

It is well known that cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). We have analyzed the function of cluster of differentiation (CD)300f immunoreceptor in a model of excitotoxic rat brain damage. First, to explore the presence of endogenous ligand(s) for this receptor we used a human CD300f‐Ig soluble protein and confocal microscopy, showing specific staining mainly in CNS white matter and on the surface of oligodendrocytes and certain astrocytes. Next, we demonstrated in a model of in vivo rat brain excitotoxic damage that the overexpression of human CD300f induced a significant reduction in the lesion volume. To validate these results, we cloned the rat ortholog of CD300f protein (rCD300f). The overexpression of rCD300f receptor had a comparable neuroprotective effect after the acute brain injury and a similar CNS staining pattern when stained with the rCD300f‐Ig soluble protein. Interestingly, when we analyzed the expression pattern of rCD300f in brain cells by quantitative polymerase chain reaction and immunohistochemistry, we detected the expression of CD300f as expected in microglial cells, but also in oligodendrocytes and neurons. These data suggest that the neuroprotective role of CD300f would be the result of a complex network of cell interactions.
Amyloid Plaques Dissociate Pentameric to Monomeric C‐Reactive Protein: A Novel Pathomechanism Driving Cortical Inflammation in Alzheimer's Disease?
Authors: Strang Frederik , Scheichl Amelie , Chen Yung‐Chih , Wang Xiaowei , Htun Nay‐Min , Bassler Nicole , Eisenhardt Steffen U. , Habersberger Jonathon , Peter Karlheinz
Published: September 2011

Beta‐amyloid (Aβ) plaques and local inflammation are central to the pathogenesis of Alzheimer's disease. Although an association between circulating pentameric C‐reactive protein (pCRP) and Alzheimer's disease has been reported no pathomechanistic link has been established. We hypothesized that Aβ plaques induce the dissociation of pCRP to individual monomers (mCRP), which possess strong pro‐inflammatory properties not shared with pCRP and localizing inflammation to Alzheimer's plaques. pCRP was incubated with Aβ plaques generated in vitro and with non‐aggregated Aβ42 peptide. pCRP dissociation to mCRP was found only when co‐incubated with Aβ plaques. Furthermore, sections of frontal cortex from brains of patients with and without Alzheimer's disease were stained with antibodies specific for mCRP and pCRP. There was significantly more mCRP in the cortex of Alzheimer's disease patients (P ≤ 0.01). In contrast, there was no significant difference in pCRP staining. These findings establish that Aβ plaques possess a previously unrecognized potential to dissociate pentameric CRP to monomeric CRP. The existence of mCRP but not pCRP in the brains of Alzheimer's disease patients strongly indicates that this newly described biological effect of Aβ plaques is relevant in Alzheimer pathobiology; potentially localizing and amplifying inflammation via the strong pro‐inflammatory effects of locally generated mCRP.
Magmatic Nature of Mineralizing Fluids in the Solnechnoye Sn Deposit (Russia) Deduced from Isotopic (H, O) Compositions of Tourmaline
Authors: SUSHCHEVSKAYA Tatiana , IGNATIEV Alexander , VELIVETSKAYA Tatiana
Published: September 2011

In this paper, we present new isotopic (H, O) data of fluids in tourmalines from the large Sn deposit at Solnechnoye (Far East Russia). These data indicate that the deposit formed by fluid‐rock interactions in a hydrothermal system where the mineralizing fluid was mainly magmatic and to a lesser extent meteoric. This is in agreement with a magmatic fluid model. Our interpretation of the new isotopic data is consistent with earlier findings of the studies on fluid‐rock interactions that magmatic fluids form larger Sn deposits than exogenic fluids. We propose that isotopic (H, O) data of fluids in tourmaline, rather than those in quartz, muscovite, or chlorite, support robust interpretation on the nature of mineralizing fluids associated with Sn deposits.
Maladaptive schemas as a mediator between social defeat and positive symptoms in young people at clinical high risk for psychosis
Authors: Stowkowy Jacqueline , Addington Jean
Published: September 2011

Aim: Social defeat may be the mechanism that links past social adversities with the development of psychosis. In depression research, it is accepted that adverse early social experiences can lead to enduring cognitive vulnerabilities, characterized by negative schemas about the self and others. The aim of this study was to examine whether negative beliefs about the self and others link social defeat to early signs of psychosis.

Methods: Data from a sample of individuals at high risk for developing psychosis (n = 38) were assessed using measures of social defeat and schemas.

Results: High levels of social defeat and negative evaluations of the self and others were displayed. Negative beliefs mediated the relationship between social defeat and early symptoms, offering some support for the notion that maladaptive self‐beliefs play a role in the onset of psychosis.

Conclusions: These results have implications for prevention because these maladaptive schemas are malleable factors for which we have effective psychological interventions.
Use of allele‐specific sequencing primers is an efficient alternative to PCR subcloning of low‐copy nuclear genes
Authors: SCHEEN ANNE‐CATHRINE , PFEIL BERNARD E. , PETRI ANNA , HEIDARI NAHID , NYLINDER STEPHAN , OXELMAN BENGT
Published: September 2011

Direct Sanger sequencing of polymerase chain reaction (PCR)‐amplified nuclear genes leads to polymorphic sequences when allelic variation is present. To overcome this problem, most researchers subclone the PCR products to separate alleles. An alternative is to directly sequence the separate alleles using allele‐specific primers. We tested two methods to enhance the specificity of allele‐specific primers for use in direct sequencing: using short primers and amplification refractory mutation system (ARMS) technique. By shortening the allele‐specific primer to 15–13 nucleotides, the single mismatch in the ultimate base of the primer is enough to hinder the amplification of the nontarget allele in direct sequencing and recover only the targeted allele at high accuracy. The deliberate addition of a second mismatch, as implemented in the ARMS technique, was less successful and seems better suited for allele‐specific amplification in regular PCR rather than in direct sequencing.
Development and multiplexing of microsatellite markers using pyrosequencing in the clonal plant Comarum palustre (Rosaceae)
Authors: SOMME L. , RAABOVÁ J. , JACQUEMART A. L. , RASPÉ O.
Published: September 2011

Microsatellites represent one of the most commonly used genetic markers for population genetic studies. Traditionally, their development is quite time consuming, requiring construction of a genomic library enriched for repeated motifs. Using pyrosequencing, a fast and cost‐effective new generation sequencing technique, we produced 24 340 862 bases in 63 860 short fragment reads, including 1170 dinucleotide motifs with a minimum of six repeats and 1383 trinucleotide motifs with a minimum of four repeats for the Marsh Cinquefoil, Comarum palustre L., an endangered marsh pioneer species. We selected 58 loci with SSR (Short Sequence Repeat) segments (at least 10 repeats) for a preliminary screening. Out of them, we screened 29 loci on a capillary sequencer after ligation in a vector and PCR using T7 forward primer labelled with FAM fluorescent dye and the specific unlabeled reverse primers. This procedure allowed us to screen large number of candidate loci with the same labelled primer and unlabelled specific primers. Finally, we characterized 20 polymorphic microsatellite markers, nine dinucleotides and 11 trinucleotides. We used these markers to assess genetic diversity and clonal structure in two Belgian populations. All loci showed a maximum of two alleles per individual, suggesting that they are from a diploid genome. One genet was detected in a newly extending population while 53 different genets in a long‐term ecologically managed population. The number of alleles per locus ranged from 6 to 14 in this old population with an expected heterozygosity, ranging from 0.5964 to 0.8278. These preliminary results show a genet size up to 7.2 m.
The efficacy of optic nerve ultrasonography for differentiating papilloedema from pseudopapilloedema in eyes with swollen optic discs
Authors: Neudorfer Meira , Ben‐Haim Maytal Siegman , Leibovitch Igal , Kesler Anat
Published: September 2011

Purpose:  To evaluate the diagnostic yield of optic nerve ultrasonography (US) in distinguishing between papilloedema (swollen discs owing to raised intracranial pressure) and pseudopapilloedema.

Methods:  We prospectively evaluated all patients with bilateral optic disc swelling who underwent a complete neuro‐ophthalmological examination. Suitable patients were referred for neuroimaging (computerized tomography or magnetic resonance imaging) and lumbar puncture. They underwent optic nerve US (A‐mode and B‐mode), and the findings were compared with the final clinical assessment. Sensitivity, specificity and predictive values for US distinction between true papilloedema and pseudopapilloedema were calculated and compared with those of the other imaging tests.

Results:  Forty‐four patients were enrolled. Ultrasonography detected papilloedema with a high degree of sensitivity (85%) when the normal optic nerve width (ONW) was set at ≤3.3 mm, and with an even higher degree of sensitivity (95%) when the normal ONW was set at ≤3.0 mm. Ultrasonography had a high negative predictive value for detecting papilloedema: 83% when the normal ONW was set at ≤3.3 mm and 93% when it was set at ≤3.0 mm. There was a significant correlation between the US findings and the final diagnosis (p < 0.001) when the upper limit of the normal ONW was set at 3.0 mm.

Conclusions:  Ultrasonography findings of the ONW correlated well with the final diagnosis of papilloedema or pseudopapilloedema, especially when the upper limit of the normal ONW was set at 3.0 mm. Ultrasonography could be a useful non‐invasive technique for differentiating papilloedema from other causes for swollen discs, such as pseudopapilloedema.
Intravitreal bevacizumab versus ranibizumab for the treatment of retinal angiomatous proliferation
Authors: Parodi Maurizio B. , Iacono Pierluigi , Menchini Francesca , Sheth Saumil , Polini Giovanni , Pittino Raffaele , Bandello Francesco
Published: September 2011

Purpose:  To evaluate the effects of intravitreal bevacizumab and ranibizumab treatments in retinal angiomatous proliferation (RAP).

Methods:  Fifty patients affected by RAP were randomly assigned either to intravitreal bevacizumab injection (IVBI) or intravitreal ranibizumab injection (IVRI). After a loading phase including three consecutive monthly injections, the retreatment was administered in cases of persistent RAP. The primary outcome measures were the mean changes in BCVA between the two treatment groups, and the proportion of eyes gaining 1 and 3 lines at the end of the follow‐up. Secondary outcomes included central macular thickness (CMT) changes and progression to more advanced stages of RAP.

Results:  Fifty patients affected by stage 1 and 2 RAP were recruited. Twenty‐six and 24 patients received IVBI and IVRI, respectively. At the baseline, mean best corrected visual acuity (BCVA) values were 0.59 ± 0.21 (LogMAR ± SD, approximately corresponding to 20/80 Snellen Equivalent‐SE) in IVBI group and 0.66 ± 0.33 (approximately 20/90 SE) in IVRI group with no statistical difference. At 12‐month examination, both groups showed a statistically significant improvement in the BCVA, with a final mean value of 0.43 ± 0.24 (approximately 20/54 SE) in IVBI group and 0.50 ± 0.32 (approximately 20/63 SE) in the IVRI group. A BCVA gain of 1 and 3 lines was registered in 20 and 8 eyes, respectively, in the IVBI group. Similarly, 17 and 7 eyes showed an improvement of 1 or 3 lines, respectively, in the IVRI group. The CMT reduced significantly from baseline to 12‐month examination in both groups. A lower proportion of eyes with complete pigment epithelium detachment resolution was noted in the IVBI group than in the IVRI group (40% versus 90%).

Conclusions:  Our study shows that both IVBI and IVRI are equally effective in improving the BCVA over a 1‐year follow‐up in eyes affected by stage 1 and 2 RAP.
Homozygous carrier of the NOD2 1007fs frame‐shift mutation presenting with refractory community‐acquired spontaneous bacterial peritonitis and developing fatal pulmonary mucormycosis: A case report
Authors: Bruns Tony , Peter Jack , Hagel Stefan , Pfeifer Rüdiger , Prinz Peter , Stallmach Andreas
Published: September 2011

Genetic variants of the innate immune system contribute to episodes of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis. We herein report the case of a patient with the homozygous nucleotide‐binding oligomerization domain containing 2 (NOD2) frame‐shift mutation 1007fs presenting with sepsis and community‐acquired SBP by Escherichia coli. Secondary peritonitis, pancreatic ascites and malignant causes were excluded by extensive diagnostic work‐up. First‐line treatment with ceftriaxone was not successful despite in vitro sensitivity of the isolated strain. Despite prolonged second‐line treatment with imipenem/cilastatin and intermittent ascites drainage, the ascitic fluid neutrophil count remained markedly elevated in this patient. In the course of the disease the patient developed pneumonia with identification of the typical hyphae of mucormycosis in the bronchoalveolar lavage and died of sepsis with multi‐organ failure. On the basis of this observation, variants of the innate immunity have to be considered in therapy‐refractory SBP, even when they are community‐acquired and caused by cephalosporin‐sensitive Enterobacteriaceae.
Becoming and Remaining a ‘Force for Good’– Reforming the Police in Post‐conflict Sierra Leone
Authors: Chris Charley Joseph P. , M'Cormack Freida Ibiduni
Published: September 2011

The Sierra Leone Police Force has its origins in the British colonial administration of the country. After Independence and with the consolidation of one‐party rule the force slid into disrepute. The outbreak of civil conflict in 1991 largely decimated the force but the gradual restoration of peace provided an opportunity for police reform. This research report covers the aspects of the political and institutional environment that helped engender change, as well as constraints faced by the reform agenda. It considers how the officers actually carried out the task at hand, and shares lessons as to what reform tactics worked and which were less successful. While several challenges remain, the reform programme, centred around local needs policing has been largely successful, hinging on – among other factors – the appointment of a British Inspector General of Police, perceived to be neutral and above political machinations, supported by a core of reform‐minded officers; long‐term external technical and financial assistance; and a conducive political environment for change.
The analysis of zero‐inflated count data: Beyond zero‐inflated Poisson regression.
Authors: Loeys Tom , Moerkerke Beatrijs , De Smet Olivia , Buysse Ann
Published: September 2011

Infrequent count data in psychological research are commonly modelled using zero‐inflated Poisson regression. This model can be viewed as a latent mixture of an “always‐zero” component and a Poisson component. Hurdle models are an alternative class of two‐component models that are seldom used in psychological research, but clearly separate the zero counts and the non‐zero counts by using a left‐truncated count model for the latter. In this tutorial we revisit both classes of models, and discuss model comparisons and the interpretation of their parameters. As illustrated with an example from relational psychology, both types of models can easily be fitted using the R‐package pscl.
Anxious attachment may be a vulnerability factor for developing embitterment
Authors: Blom David , van Middendorp Henriët , Geenen Rinie
Published: September 2011

By predisposing to ego‐defensive strategies in social situations, a negative attachment history may promote embitterment. The present study identified attachment anxiety – more than attachment avoidance – as a possible vulnerability factor for the development and maintenance of embitterment. This factor should be considered in theories and in interventions of embitterment.

Practitioner Points

Interventions directed at embitterment should take anxious attachment into account.

Embittered individuals with high levels of attachment anxiety should be provided a secure therapeutic environment in which defensive tendencies are no longer needed.
Defined criteria for auxiliary subunits of glutamate receptors
Authors: Yan Dan , Tomita Susumu
Published: September 2011

Abstract  Pore‐forming subunits of ion channels show channel activity in heterologous cells. However, recombinant and native channels often differ in their channel properties. These discrepancies are resolved by the identification of channel auxiliary subunits. In this review article, an auxiliary subunit of ligand‐gated ion channels is defined using four criteria: (1) as a Non‐pore‐forming subunit, (2) direct and stable interaction with a pore‐forming subunit, (3) modulation of channel properties and/or trafficking in heterologous cells, (4) necessity in vivo. We focus particularly on three classes of ionotropic glutamate receptors and their transmembrane interactors. Precise identification of auxiliary subunits and reconstruction of native glutamate receptors will open new directions to understanding the brain and its functions.
E-Waste Stream Analysis and Design Implications
Authors: Kwak Minjung , Behdad Sara , Zhao Yuan , Kim Harrison , Thurston Deborah
Published: September 2011

The quantity and age of the incoming stream of “feedstock” from product take-back systems are known as the major sources of the uncertainty that complicates the e-waste recovery. This paper presents the results of an analysis of data from an incoming stream for an e-waste collection center and analyzes the quantity and age of e-waste by product type and brand. The analysis results point out receiving of outdated products and processing of multiple generations, and brands of products at the same time are among main obstacles to the e-waste recovery. The potential role of product design in overcoming those obstacles is discussed with emphasis on design for upgrade, repurpose, and commonality.
Near Valve Flows and Potential Blood Damage During Closure of a Bileaflet Mechanical Heart Valve
Authors: Herbertson L. H. , Deutsch S. , Manning K. B.
Published: September 2011

Blood damage and thrombosis are major complications that are commonly seen in patients with implanted mechanical heart valves. For this in vitro study, we isolated the closing phase of a bileaflet mechanical heart valve to study near valve fluid velocities and stresses. By manipulating the valve housing, we gained optical access to a previously inaccessible region of the flow. Laser Doppler velocimetry and particle image velocimetry were used to characterize the flow regime and help to identify the key design characteristics responsible for high shear and rotational flow. Impact of the closing mechanical leaflet with its rigid housing produced the highest fluid stresses observed during the cardiac cycle. Mean velocities as high as 2.4 m/s were observed at the initial valve impact. The velocities measured at the leaflet tip resulted in sustained shear rates in the range of 1500–3500 s−1, with peak values on the order of 11,000–23,000 s−1. Using velocity maps, we identified regurgitation zones near the valve tip and through the central orifice of the valve. Entrained flow from the transvalvular jets and flow shed off the leaflet tip during closure combined to generate a dominant vortex posterior to both leaflets after each valve closing cycle. The strength of the peripheral vortex peaked within 2 ms of the initial impact of the leaflet with the housing and rapidly dissipated thereafter, whereas the vortex near the central orifice continued to grow during the rebound phase of the valve. Rebound of the leaflets played a secondary role in sustaining closure-induced vortices.
Relationship between Vancomycin Trough Concentrations and Nephrotoxicity: a Prospective Multicenter Trial
Authors: Bosso John A. , Nappi Jean , Rudisill Celeste , Wellein Marlea , Bookstaver P. Brandon , Swindler Jenna , Mauldin Patrick D.
Published: September 2011

Several single-center studies have suggested that higher doses of vancomycin, aimed at producing trough concentrations of >15 mg/liter, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to trough concentration in patients with documented methicillin-resistant
Staphylococcus aureus
(MRSA) infections at seven hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 h with at least one vancomycin trough concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin trough concentrations of >15 mg/ml and the occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, gender, race, dose, length of therapy, use of other nephrotoxins (including contrast media), intensive care unit (ICU) residence, episodes of hypotension, and comorbidities. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a ≥50% increase from the baseline for two consecutive measurements. MICs of vancomycin for the MRSA isolates were also determined. A total of 288 patients were studied between February 2008 and June 2010, with approximately one-half having initial trough concentrations of ≥15 mg/ml. Nephrotoxicity was observed for 42 patients (29.6%) with trough concentrations >15 mg/ml and for 13 (8.9%) with trough concentrations of ≤15 mg/ml. Multivariate analysis revealed vancomycin trough concentrations of >15 mg/ml and race (black) as risk factors for nephrotoxicity in this population. Vancomycin trough concentrations of >15 mg/ml appear to be associated with a 3-fold increased risk of nephrotoxicity.
Meta-Analysis and Systematic Review of Procalcitonin-Guided Therapy in Respiratory Tract Infections
Authors: Li Hui , Luo Yi-Feng , Blackwell Timothy S. , Xie Can-Mao
Published: September 2011

Circulating procalcitonin (PCT) is a biomarker that can be used in diagnosing bacterial infections. We performed a quantitative meta-analysis of available randomized controlled trials to determine whether antibiotic therapy based on PCT measurements alters clinical outcomes and antibiotic use in patients with lower respiratory tract infections. We identified studies through MEDLINE (1996 to 2010), the ISI Web of Knowledge (1996 to 2010), and Ovid. Studies that met our criteria were prospective, randomized controlled trials involving patients with respiratory tract infections. Outcomes of mortality, intensive care unit (ICU) admission, length of hospital stay, number of antibiotic prescriptions, and duration of antibiotic treatment were evaluated. Eight studies randomizing 3,431 patients met our criteria for inclusion. Pooled analysis showed a significant reduction in number of antibiotic prescriptions and duration of antibiotic use in patients with PCT-guided antibiotic treatment compared to standard therapy. In addition, the use of PCT-guided antibiotic therapy did not impact mortality, ICU admission, or length of hospital stay in these studies. A high degree of heterogeneity was identified in 3 of 5 outcomes that were evaluated, and sensitivity analysis indicated that heterogeneity was decreased among studies using the same PCT-based treatment algorithm. In conclusion, PCT-guided antibiotic therapy in patients with respiratory tract infections appears to reduce antibiotic use without affecting overall mortality or length of stay in the hospital.
The Antibacterial Activity of Ga3+Is Influenced by Ligand Complexation as Well as the Bacterial Carbon Source
Authors: Rzhepishevska Olena , Ekstrand-Hammarström Barbro , Popp Maximilian , Björn Erik , Bucht Anders , Sjöstedt Anders , Antti Henrik , Ramstedt Madeleine
Published: September 2011

Gallium ions have previously been shown to exhibit antibacterial and antibiofilm properties. In this study, we report differential bactericidal activities of two gallium complexes, gallium desferrioxamine B (Ga-DFOB) and gallium citrate (Ga-Cit). Modeling of gallium speciation in growth medium showed that DFOB and citrate both can prevent precipitation of Ga(OH)3, but some precipitation can occur above pH 7 with citrate. Despite this, Ga-Cit 90% inhibitory concentrations (IC90) were lower than those of Ga-DFOB for clinical isolates ofPseudomonas aeruginosaand several reference strains of other bacterial species. Treatment with Ga compounds mitigated damage inflicted on murine J774 macrophage-like cells infected withP. aeruginosaPAO1. Again, Ga-Cit showed more potent mitigation than did Ga-DFOB. Ga was also taken up more efficiently byP. aeruginosain the form of Ga-Cit than in the form of Ga-DFOB. Neither Ga-Cit nor Ga-DFOB was toxic to several human cell lines tested, and no proinflammatory activity was detected in human lung epithelial cells after exposurein vitro. Metabolomic analysis was used to delineate the effects of Ga-Cit on the bacterial cell. Exposure to Ga resulted in lower concentrations of glutamate, a key metabolite forP. aeruginosa, and of many amino acids, indicating that Ga affects various biosynthesis pathways. An altered protein expression profile in the presence of Ga-Cit suggested that some compensatory mechanisms were activated in the bacterium. Furthermore, the antibacterial effect of Ga was shown to vary depending on the carbon source, which has importance in the context of medical applications of gallium.
Analysis of Genes Encoding Penicillin-Binding Proteins in Clinical Isolates of Acinetobacter baumannii
Authors: Cayô Rodrigo , Rodríguez María-Cruz , Espinal Paula , Fernández-Cuenca Felipe , Ocampo-Sosa Alain A. , Pascual Álvaro , Ayala Juan A. , Vila Jordi , Martínez-Martínez Luis
Published: September 2011

There is limited information on the role of penicillin-binding proteins (PBPs) in the resistance of
Acinetobacter baumannii
to β-lactams. This study presents an analysis of the allelic variations of PBP genes in
A. baumannii
isolates. Twenty-six
A. baumannii
clinical isolates (susceptible or resistant to carbapenems) from three teaching hospitals in Spain were included. The antimicrobial susceptibility profile, clonal pattern, and genomic species identification were also evaluated. Based on the six complete genomes of
A. baumannii
, the PBP genes were identified, and primers were designed for each gene. The nucleotide sequences of the genes identified that encode PBPs and the corresponding amino acid sequences were compared with those of ATCC 17978. Seven PBP genes and one monofunctional transglycosylase (MGT) gene were identified in the six genomes, encoding (i) four high-molecular-mass proteins (two of class A, PBP1a [
ponA
] and PBP1b [
mrcB
], and two of class B, PBP2 [
pbpA
or
mrdA
] and PBP3 [
ftsI
]), (ii) three low-molecular-mass proteins (two of type 5, PBP5/6 [
dacC
] and PBP6b [
dacD
], and one of type 7 (PBP7/8 [
pbpG
]), and (iii) a monofunctional enzyme (MtgA [
mtgA
]). Hot spot mutation regions were observed, although most of the allelic changes found translated into silent mutations. The amino acid consensus sequences corresponding to the PBP genes in the genomes and the clinical isolates were highly conserved. The changes found in amino acid sequences were associated with concrete clonal patterns but were not directly related to susceptibility or resistance to β-lactams. An insertion sequence disrupting the gene encoding PBP6b was identified in an endemic carbapenem-resistant clone in one of the participant hospitals.
Molecular Characterization of Resistance to Extended-Spectrum Cephalosporins in Clinical Escherichia coli Isolates from Companion Animals in the United States
Authors: Shaheen Bashar W. , Nayak Rajesh , Foley Steven L. , Kweon Ohgew , Deck Joanna , Park Miseon , Rafii Fatemeh , Boothe Dawn M.
Published: September 2011

Resistance to extended-spectrum cephalosporins (ESC) among members of the family
Enterobacteriaceae
occurs worldwide; however, little is known about ESC resistance in
Escherichia coli
strains from companion animals. Clinical isolates of
E. coli
were collected from veterinary diagnostic laboratories throughout the United States from 2008 to 2009.
E. coli
isolates (
n
= 54) with reduced susceptibility to ceftazidime or cefotaxime (MIC ≥ 16 μg/ml) and extended-spectrum-β-lactamase (ESBL) phenotypes were analyzed. PCR and sequencing were used to detect mutations in ESBL-encoding genes and the regulatory region of the chromosomal gene
ampC
. Conjugation experiments and plasmid identification were conducted to examine the transferability of resistance to ESCs. All isolates carried the
bla
CTX-M-1
-group β-lactamase genes in addition to one or more of the following β-lactamase genes:
bla
TEM
,
bla
SHV-3
,
bla
CMY-2
,
bla
CTX-M-14-like
, and
bla
OXA-1.
Different
bla
TEM
sequence variants were detected in some isolates (
n
= 40). Three isolates harbored a
bla
TEM-181
gene with a novel mutation resulting in an Ala184Val substitution. Approximately 78% of the isolates had mutations in promoter/attenuator regions of the chromosomal gene
ampC
, one of which was a novel insertion of adenine between bases −28 and −29. Plasmids ranging in size from 11 to 233 kbp were detected in the isolates, with a common plasmid size of 93 kbp identified in 60% of isolates. Plasmid-mediated transfer of β-lactamase genes increased the MICs (≥16-fold) of ESCs for transconjugants. Replicon typing among isolates revealed the predominance of IncI and IncFIA plasmids, followed by IncFIB plasmids. This study shows the emergence of conjugative plasmid-borne ESBLs among
E. coli
strains from companion animals in the United States, which may compromise the effective therapeutic use of ESCs in veterinary medicine.
Randomized, Double-Blind, Phase II, Multicenter Study Evaluating the Safety/Tolerability and Efficacy of JNJ-Q2, a Novel Fluoroquinolone, Compared with Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infection
Authors: Covington Paul , Davenport J. Michael , Andrae David , O'Riordan William , Liverman Lisa , McIntyre Gail , Almenoff June
Published: September 2011

JNJ-Q2 is a fluoroquinolone with broad coverage including methicillin-resistant
Staphylococcus aureus
(MRSA). A double-blind, multicenter, phase II noninferiority study treated 161 patients for 7 to 14 days, testing the efficacy of JNJ-Q2 (250 mg, twice a day [BID]) versus linezolid (600 mg, BID) in patients with acute bacterial skin and skin structure infections (ABSSSI). The prespecified criterion for noninferiority was 15%. Primary intent-to-treat analysis was unable to declare noninferiority, as the risk difference lower bound of the 95% confidence interval between treatments was 19% at 36 to 84 h postrandomization for the composite end point of lesion assessment and temperature. Prespecified clinical cure rates 2 to 14 days after completion of therapy were similar (83.1% for JNJ-Q2 versus 82.1% for linezolid).
Post hoc
analyses revealed that JNJ-Q2 was statistically noninferior to linezolid (61.4% versus 57.7%, respectively;
P
= 0.024) based on the 2010 FDA guidance, which defines treatment success as lack of lesion spread and afebrile status within 48 to 72 h postrandomization. Despite evidence of systemic disease, <5% of patients presented with fever, suggesting fever is not a compelling surrogate measure of systemic disease resolution for this indication. Nausea and vomiting were the most common adverse events. Of the patients, 86% (104/121) had
S. aureus
isolated from the infection site; 63% of these were MRSA. The results suggest JNJ-Q2 shows promise as an effective treatment for ABSSSI, demonstrating (i) efficacy for early clinical response (i.e., lack of spread of lesions and absence of fever at 48 to 72 h), and (ii) cure rates for ABSSSI pathogens (especially MRSA) consistent with the historical literature.
Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria
Authors: Rijken Marcus J. , McGready Rose , Phyo Aung Phae , Lindegardh Niklas , Tarning Joel , Laochan Natthapon , Than Hla Hla , Mu Oh , Win Aye Kyi , Singhasivanon Pratap , White Nicholas , Nosten François
Published: September 2011

Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (
P
= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (
P
= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (
P
= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days;
P
= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml,
P
= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
Role of Aspergillus lentulus 14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility
Authors: Mellado Emilia , Alcazar-Fuoli Laura , Cuenca-Estrella Manuel , Rodriguez-Tudela Juan L.
Published: September 2011

Recent studies have demonstrated that some morphologically atypical
Aspergillus fumigatus
strains are different species belonging to the section
Fumigati
.
Aspergillus lentulus
, one of these sibling species, is increasingly reported in patients under corticosteroid treatment. MICs of most antifungals in clinical use are elevated against
A. lentulus
, and it shows primary resistance to azole drugs. Two
A. lentulus
cytochrome P450 14-α sterol demethylases, encoded by
A. lentulus
c
yp51
A (Alc
yp51A
) and Al
cyp51B
genes, were identified. Targeted
cyp51A
gene knockout in
A. lentulus
showed that the intrinsic azole resistance of this species is
cyp51A
dependent. The Δ
cyp51A
strain was morphologically indistinguishable from the
A. lentulus
wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice. The heterologous expression of
A. lentulus
cyp51A
was performed in an
A. fumigatus
cyp51A
-deficient strain, confirming that Cyp51A is responsible for the differences in
A. lentulus
-azole drug interaction.
Production of Autoantibodies by Murine B-1a Cells Stimulated with Helicobacter pylori Urease through Toll-Like Receptor 2 Signaling
Authors: Kobayashi Fumiko , Watanabe Eri , Nakagawa Yohko , Yamanishi Shingo , Norose Yoshihiko , Fukunaga Yoshitaka , Takahashi Hidemi
Published: September 2011

Helicobacter pyloriinfection is associated with several autoimmune diseases, in which autoantibody-producing B cells must be activated. Among these B cells, CD5-positive B-1a cells from BALB/c mice were confirmed to secrete autoantibodies when cocultured with purifiedH. pyloriurease in the absence of T cells. To determine the mechanisms for autoantibody production, CD5-positive B-1a cells were sorted from murine spleen cells and stimulated with either purifiedH. pyloriurease orH. pyloricoated onto plates (referred to hereafter as plate-coatedH. pylori), and autoantibody production was measured by enzyme-linked immunosorbent assay (ELISA). Complete urease was not secreted fromH. pyloribut was visually expressed over the bacterium-like endotoxin. Urease-positive plated-coatedH. pyloristimulated B-1a cells to produce autoantibodies, although urease-deficient isotype-matchedH. pyloridid not. Autoantibody secretion by B-1a cells was inhibited when bacteria were pretreated with anti-H. pyloriurease-specific antibody having neutralizing ability against urease enzymatic activity but not with anti-H. pyloriurease-specific antibody without neutralizing capacity. The B-1a cells externally express various Toll-like receptors (TLRs): TLR1, TLR2, TLR4, and TLR6. Among the TLRs, blocking of TLR2 on B-1a cells with a specific monoclonal antibody (MAb), T2.5, inhibited autoantibody secretion when B-1a cells were stimulated with plate-coatedH. pyloriorH. pyloriurease. Moreover, B-1a cells from TLR2-knockout mice did not produce those autoantibodies. The present study provides evidence that functional urease expressed on the surface ofH. pyloriwill directly stimulate B-1a cells via innate TLR2 to produce various autoantibodies and may induce autoimmune disorders.
Infection with Conditionally Virulent Streptococcus pneumoniae Δ
pab
Strains Induces Antibody to Conserved Protein Antigens but Does Not Protect against Systemic Infection with Heterologous Strains
Authors: Chimalapati Suneeta , Cohen Jonathan , Camberlein Emilie , Durmort Claire , Baxendale Helen , de Vogel Corné , van Belkum Alex , Brown Jeremy S.
Published: September 2011

Avirulent strains of a bacterial pathogen could be useful tools for investigating immunological responses to infection and potentially effective vaccines. We have therefore constructed an auxotrophic TIGR4 Δ
pab
strain of
Streptococcus pneumoniae
by deleting the
pabB
gene Sp_0665. The TIGR4 Δ
pab
strain grew well in complete medium but was unable to grow in serum unless it was supplemented with
para
-aminobenzoic acid (PABA). The TIGR4 Δ
pab
strain was markedly attenuated in virulence in mouse models of
S. pneumoniae
nasopharyngeal colonization, pneumonia, and sepsis. Supplementing mouse drinking water with PABA largely restored the virulence of TIGR4 Δ
pab
. An additional Δ
pab
strain constructed in the D39 capsular serotype 2 background was also avirulent in a sepsis model. Systemic inoculation of mice with TIGR4 Δ
pab
induced antibody responses to
S. pneumoniae
protein antigens, including PpmA, PsaA, pneumolysin, and CbpD, but not capsular polysaccharide. Flow cytometry demonstrated that IgG in sera from TIGR4 Δ
pab
-vaccinated mice bound to the surface of TIGR4 and D39 bacteria but not to a capsular serotype 3 strain, strain 0100993. Mice vaccinated with the TIGR4 Δ
pab
or D39 Δ
pab
strain by intraperitoneal inoculation were protected from developing septicemia when challenged with the homologous
S. pneumoniae
strain. Vaccination with the TIGR4 Δ
pab
strain provided only weak or no protection against heterologous challenge with the D39 or 0100993 strain but did strongly protect against a TIGR4 capsular-switch strain expressing a serotype 2 capsule. The failure of cross-protection after systemic vaccination with Δ
pab
bacteria suggests that parenteral administration of a live attenuated vaccine is not an attractive approach for preventing
S. pneumoniae
infection.