bluuebunny/crossref_metadata_2025 huggingface dataset:
Transferring Trust: Reciprocity Norms and Assignment of Contract
Authors: Wilkinson‐Ryan Tess
Published: July 2012

This article presents four experiments testing the prediction that assignment of contract rights erodes the moral obligation to perform. The first three studies used an experimental laboratory game designed to model contractual exchange. Players in the games were less selfish with a previously generous partner than with a third‐party player who had purchased the right to the original partner's expected return. The fourth study used a web‐based questionnaire, and found that subjects reported that they would require less financial incentive to breach an assigned contract than a contract held by the original promisee. The results of these four experiments provide support for the proposition that a permissible and apparently neutral transfer of a contractual right may nonetheless reduce the likelihood or quality of performance by weakening the norm of reciprocity.
Older people’s dependence on caregivers’ help in their own homes and their lived experiences of their opportunity to make independent decisions
Authors: Breitholtz Agneta , Snellman Ingrid , Fagerberg Ingegerd
Published: July 2012

Breitholtz A., Snellman I. & Fagerberg I. (2013) Older people’s dependence on caregivers’ help in their own homes and their lived experiences of their opportunity to make independent decisions. International Journal of Older People Nursing 8, 139–148 doi: 10.1111/j.1748‐3743.2012.00338.x

Aim.  The aim of this study was to illuminate the meaning of older people’s dependence on caregivers’ help, and of their opportunity to make independent decisions.

Background.  Throughout the world, the older population is growing, and in Sweden, the system of care for older people is currently undergoing change. Older people in the need of care are expected to live at home for as long as possible.

Design.  A qualitative and life world approach was used.

Methods.  Audio‐taped interviews were conducted with twelve older persons living at home, dependent on daily municipal home help service. A phenomenological hermeneutic method was utilised to disclose the meanings of lived experiences.

Finding.  The findings revealed three themes: being facilitated to make one’s own decisions, being hindered from making one’s own decisions, struggling for vs. resigning oneself to losing the opportunity to make one’s own decisions. The comprehensive understanding revealed that as older people become more dependent on caregivers’ help, their opportunity to self‐determine is challenged and this is stressful for them.

Conclusion.  The older persons assess their opportunity to self‐determine differently, depending on who they are as a person. The caregivers need an awareness of this, and further research is needed to gain knowledge and understanding of how caregivers can improve the way they support and enhance older people’s opportunity to decide for themselves.

Implications for practice.  The findings revealed older persons need to exercise more self‐determination and caregivers’ need for knowledge to enable this. Further, it indicates a move towards a person‐centred approach to focus on persons as individuals and see them as interdependent. The findings contribute to improvements in similar contexts worldwide.
Structure‐Dependent Demetalation Kinetics of Chlorophyll a Analogs under Acidic Conditions
Authors: Saga Yoshitaka , Hirai Yuki , Sadaoka Kana , Isaji Megumi , Tamiaki Hitoshi
Published: July 2012

Demetalation of chlorophyll (Chl) a and its analogs is an important reaction in oxygenic photosynthetic organisms, which produces the primary electron acceptors in photosystem II reaction centers and is crucial in the Chl degradation. From these viewpoints, demetalation reactions of four Chl a analogs, 3,8‐divinyl‐Chl a (DV‐Chl a), 3‐devinyl‐3‐ethyl‐Chl a (mesoChl a), 132‐demethoxycarbonyl‐Chl a (pyroChl a) and protochlorophyll a (PChl a), were kinetically analyzed under weakly acidic conditions, and were compared with that of Chl a. DV‐Chl a exhibited slower demetalation kinetics than did Chl a, whereas demetalation of mesoChl a was faster than that of Chl a. The difference in demetalation kinetics of the three chlorophyllous pigments originates from the electron‐withdrawing ability of the vinyl group as the peripheral substituent compared with the ethyl group. Removal of the electron‐withdrawing and homoconjugating 132‐methoxycarbonyl group in Chl a (Chl a → pyroChl a) accelerated demetalation kinetics by two‐fold. PChl a possessing the porphyrin‐type skeleton exhibited slower demetalation kinetics than Chl a. The structure‐dependent demetalation properties of Chl a analogs will be useful for understanding in vivo Chl demetalation reactions in oxygenic photosynthetic organisms.
Guidance for storing blood samples in laboratories performing complete blood count with differential
Authors: Cornet E. , Behier C. , Troussard X.
Published: July 2012

Introduction

The complete blood count (CBC) with differential leukocyte count (DIFF) is an important part of clinical laboratory analyses and provides crucial data for clinicians. Delivery time after blood collection and conditions of storage is known to affect the reliability of results of some hematologic parameters. The aim of this study was to assess the variations of hematologic parameters over time and the influence of storage temperature.

Methods

Blood samples were randomly selected from hospitalized patients and stored at room temperature and at 4 °C. CBC and DIFF were performed on an automated hematology analyzer and the results between the two groups were compared.

Results

Samples stored at room temperature showed an important increase in mean corpuscular volume and hematocrit and a decrease in mean corpuscular hemoglobin concentration. Neutrophil counts tended to increase, whereas monocyte counts tended to decrease.

Conclusion

Storing samples at 4 °C improved reproducibility over time of all quantitative and qualitative parameters. We also observed that NEUT‐X, a routine parameter useful in detecting myelodysplastic syndrome, became unreliable when analyzed 24 h after sample collection. Our results led us to recommend that samples should be analyzed within 6 h, particularly if samples are transported at room temperature. We also recommend storing samples at 4 °C in case of remote CBC analysis, especially in the context of clinical trials.
Diagnostic overlap of depressive, anxiety, stress and somatoform disorders in primary care
Authors: Bener Abdulbari , Al‐Kazaz Mohammed , Ftouni Darine , Al‐Harthy Munjid , Dafeeah Elnour E.
Published: July 2012

Introduction

The aim of the present study was to determine the prevalence of somatization, anxiety, depression and stress in a primary care population, explore their association to psychosocial stressors and determine the diagnostic overlap of these four mental disorders.

Methods

This is a prospective cross‐sectional study. A representative sample of 2,150 patients was approached, of whom 1,762 patients agreed to participate and responded to the questionnaire (81.9%). Anxiety was assessed with the Generalized Anxiety Disorder Scale (GAD‐7). Depression was assessed with the depression module Patients Health Questionnaire‐8. Somatization was measured with the somatic symptom module PHQ‐15. The Perceived Stress Scale (PSS) instrument was used to identify the stress cases.

Results

Of the study sample, 23.8% of the total cases were identified as probable cases. The prevalence of somatization, depression, anxiety and stress was 11.7%, 11.3%, 8.3% and 18.6%, respectively. The specific gender prevalence of these four psychological disorders was very similar in men and women: depression (11.3% versus 11.3%), anxiety (7.7% versus 8.9%), somatization (12.5% versus 10.7%) and stress disorders (19.3% versus 17.8%). A significant difference was observed in nationality and marital status for depression and anxiety (P < 0.05). The age‐specific prevalence rate showed a higher prevalence in the age group 45–54 years: depression (13.3%), anxiety (9.5%), somatization (12.8%) and stress (20.4%). Unable to control worries (69.2%) was the worst symptom for anxiety disorders, while the majority of the depressed patients wanted to hurt themselves (71.9%). Stomach pain (46.1%) was the most common symptom in somatic patients. Most of the patients experiencing stress could not cope with their daily duties (65.9%). There was a high comorbidity rate of depression, anxiety, somatization and stress observed in the studied population (9.3%).

Conclusion

The prevalence of somatization and depression was similar, but the prevalence of stress was higher in inpatient patients. Somatization, depression, anxiety and stress disorders co‐occurred at higher rate in the study sample.
Impact of Part D on previously uninsured Medicare beneficiaries with hypertension
Authors: Shoemaker J. Samantha , Stuart Bruce , Davidoff Amy , Zacker Christopher
Published: July 2012

Objectives

US Medicare Part D began in January 2006, but beneficiaries could wait until May to sign up without being assessed a premium penalty. The availability of this penalty-free period offers a unique opportunity to study selection patterns and demand response to Part D coverage. The objective is to examine factors associated with early and late Part D enrolment and assess impact of enrolment timing on changes in drug use.

Methods

Nationally representative sample of community-dwelling Medicare beneficiaries with hypertension and no drug coverage in 2005 (n = 641).We used 2005 and 2006 Medicare Current Beneficiary Survey data with a multinomial logistic model to predict Part D enrolment and a difference-in-difference (DID) model to compare changes in monthly antihypertensive drug fills pre- and post-enrolment.

Key findings

Of the sample enrolled in Part D in 2006, 63.3% (23.5% by January and 39.8% late). Early enrolees had higher antihypertensive use prior to Part D (1.6 monthly fills) compared to late enrolees (1.2) and non-enrolees (0.9). Post-Part D monthly antihypertensive use averaged 2.2 fills for early enrolees, 1.4 for late enrolees and 1.0 for non-enrolees. The estimated DID programme effect was 0.54 additional monthly antihypertensive prescription fills for early enrolees (P < 0.01) and 0.26 fills for late enrolees (P < 0.01).

Conclusions

The estimated Part D demand response from early enrolees was unrealistically high suggesting selection bias. The price elasticity for late enrolees (−0.29 to −0.43) was consistent with best evidence in the literature. Failure to consider selection can lead to overestimating the impact of Part D on drug use.
Microvascular reconstruction of the mouth, face and jaws. Oromandibular reconstruction – free fibula flap
Authors: Hoffman GR , Islam S , Eisenberg RL
Published: July 2012

Dental surgeons may encounter in their clinical practice patients who present with aggressive pathologies that require early diagnosis and prompt treatment. This action may limit the extent of tissue damage and, where relevant, improve survival outcome. Clinicians should therefore be aware of the range of resective, reconstructive and rehabilitative options that are available in the management of these patients. We present our experience with the free fibula flap used for oromandibular reconstruction; this was undertaken in 21 patients following resective surgery for malignant pathology, cytologically benign but biologically aggressive odontogenic pathology and radiation induced osteonecrosis. We also review the history, surgical anatomy, surgical assessment and potential complications that are relevant to the free fibula flap.
Duodenal Endoscopic Findings and Histopathologic Confirmation of Intestinal Lymphangiectasia in Dogs
Authors: Larson R.N. , Ginn J.A. , Bell C.M. , Davis M.J. , Foy D.S.
Published: July 2012

Background

The diagnosis of intestinal lymphangiectasia (IL) has been associated with characteristic duodenal mucosal changes. However, the sensitivity and specificity of the endoscopic duodenal mucosal appearance for the diagnosis of IL are not reported.

Hypothesis/Objectives

To evaluate the utility of endoscopic images of the duodenum for diagnosis of IL. Endoscopic appearance of the duodenal mucosal might predict histopathologic diagnosis of IL with a high degree of sensitivity and specificity.

Animals

51 dogs that underwent upper gastrointestinal (GI) endoscopy and endoscopic biopsies.

Methods

Retrospective review of images acquired during endoscopy. Dogs were included if adequate biopsies were obtained during upper GI endoscopy and digital images were saved during the procedure. Images were assessed for the presence and severity of IL. Using histopathology as the gold standard, the sensitivity and specificity of endoscopy for diagnosing IL were calculated.

Results

Intestinal lymphangiectasia (IL) was diagnosed in 25/51 dogs. Gross endoscopic appearance of the duodenal mucosa had a sensitivity and specificity (95% confidence interval) of 68% (46%, 84%) and 42% (24%, 63%), respectively for diagnosis of IL. Endoscopic images in cases with lymphopenia, hypocholesterolemia, and hypoalbuminemia had a sensitivity of 80%.

Conclusions and Clinical Importance

Endoscopic duodenal mucosa appearance alone lacks specificity and has only a moderate sensitivity for diagnosis of IL. Evaluation of biomarkers associated with PLE improved the sensitivity; however, poor specificity for diagnosis of IL supports the need for histopathologic confirmation.
Argirein alleviates corpus cavernosum dysfunction by suppressing pro-inflammatory factors p66Shc and ER stress chaperone Bip in diabetic rats
Authors: Cheng Yu-Si , Cong Xiao-Dong , Dai De-Zai , Zhang Yun , Dai Yin
Published: July 2012

Objectives

The aim was to investigate whether argirein, which releases rhein and l-arginine after medication, could improve erectile dysfunction (ED) in diabetic rats through normalising the abnormalities of nitric oxide synthase (NOS), p66Shc and immunoglobulin heavy-chain binding protein (Bip), in the corpus cavernosum (CC).

Methods

SD rats were randomly divided into six groups. Except for the control group, rats were injected with streptozotocin (STZ) (60 mg/kg, i.p.) once. During weeks 5–8 following STZ injection, except for STZ-injected untreated rats, others were treated with aminoguanidine (AMG; 100 mg/kg/day, i.g.), or argirein at three doses (50, 100 and 200 mg/kg/day, i.g.). The vascular activity and biomarkers of the cavernosum were examined.

Key findings

Constrictive and dilative activity was abnormal in the CC, associated with decreased nitric oxide (NO) in serum in the diabetic (DM) group. Increased expression of p66Shc, Bip and inducible nitric oxide synthase (iNOS) and decreased endothelial nitric oxide synthase (eNOS) in the CC were significant in DM rats. Argirein and AMG improved these abnormities significantly.

Conclusions

We concluded that vascular activity of the cavernosal tissue was impaired due to upregulated p66Shc and Bip in the diabetic CC. Argirein alleviates the vascular dysfunction of the CC by suppressing these upregulated pro-inflammatory proteins caused by diabetic lesions.
Long‐term facilitation of ventilation following acute continuous hypoxia in awake humans during sustained hypercapnia
Authors: Griffin Harry S. , Pugh Keith , Kumar Prem , Balanos George M.
Published: July 2012

Key points

In awake humans, when CO2 is maintained above normal levels, exposure to acute intermittent hypoxia causes a sustained elevation in ventilation that persists when normoxic breathing is resumed.

In this study we have demonstrated that when CO2 is maintained above normal levels, exposure to acute continuous hypoxia also causes a sustained elevation in ventilation when normoxic breathing is resumed.

This sustained elevation in ventilation following both acute intermittent hypoxia and acute continuous hypoxia is maintained by mechanisms other than increased activity of the carotid body.

These results help develop our understanding of respiratory control in humans and may aid future development of treatments for respiratory control disorders, such as obstructive sleep apnoea.

Abstract  In awake humans, long‐term facilitation of ventilation (vLTF) following acute intermittent hypoxia (AIH) is only expressed if CO2 is maintained above normocapnic levels. vLTF has not been reported following acute continuous hypoxia (ACH) and it is not known whether this might be unmasked by elevated CO2. Twelve healthy participants completed three trials. In all trials end‐tidal pressure of CO2 was elevated 4–5 mmHg above normocapnic levels. During Trial 1 (AIH) participants were exposed to eight 4 min episodes of hypoxia. During Trial 2 (ACH) participants were exposed to continuous hypoxia for 32 min. In Trial 3 (Control) participants were exposed to euoxia throughout. To assess the contribution of the carotid body (CB) in observed ventilatory responses, CB afferent discharge before and after each trial was transiently inhibited with hyperoxia. Minute ventilation () increased following all trials, but was significantly greater in Trials 1 and 2 when compared with Trial 3 (Trial 1: 4.96 ± 0.87, Trial 2: 5.07 ± 0.7, Trial 3: 2.55 ± 0.98 l min−1, P < 0.05). Hyperoxia attenuated to a similar extent in baseline and recovery in all trials (Trial 1: 3.0 ± 0.57 vs. 3.27 ± 0.68, Trial 2: 1.97 ± 0.62 vs. 2.56 ± 0.62, Trial 3: 2.23 ± 0.49 vs. 2.15 ± 0.55 l min−1, P > 0.05). Data are means ± SEM. In awake humans with elevated CO2, ACH evokes a sustained increase in ventilation that is comparable to that evoked by AIH. However, a gradual positive drift in ventilation in response to elevated CO2 accounts for approximately half of this apparent vLTF. Additionally, our data support the view that the CB is not directly involved in maintaining vLTF.
Parametric Study of Meshing Characteristics With Respect to Different Meshing Rollers of the Antibacklash Double-Roller Enveloping Worm Gear
Authors: Deng Xingqiao , Wang Jinge , Horstemeyer M. F. , Solanki K. N. , Zhang Junfu
Published: July 2012

Roller shapes play a very critical role in the performance of antibacklash double-roller enveloping hourglass worm (ADEHW) gears; however, their influence is seldom reported in the literature. Based on the theories of differential geometry and gear meshing, this paper presents generic models of meshing characteristics for ADEHW gears, including both the contact curve and the tooth profile. We present different meshing functions and their derivatives with respect to each drive type and their associated roller shapes. We also compare the effects of contact curve, tooth profile, tooth undercutting, lubrication angle, induced normal curvature, and autorotation angle in order to design the most optimal tooth profile for the ADEHW gear. Finite element analysis was also conducted in order to minimize the contact stresses as a function of the roller type. Our results show that a spherical roller has the smallest value among the three available meshing roller shapes but is the most difficult design to procure. A cylindrical roller, however, incurs the greatest contact stress.
Thermal Assessment of Naturally Cooled Electronic Enclosures With Rectangular Fins
Authors: Tamayol A. , McGregor F. , Bahrami M.
Published: July 2012

Passive heat transfer from enclosures with rectangular fins is studied both experimentally and theoretically. Several sample enclosures with various lengths are prepared and tested. To calibrate the thermal measurements and the analyses, enclosures without fins (“bare” enclosures) are also prepared and tested. Surface temperature distribution is determined for various enclosure lengths and heat generation rates. Existing relationships for natural convection and radiation heat transfer are used to calculate the heat transfer rate from the tested samples. The theoretical results successfully predict the trends observed in the experimental data. It is observed that the contribution of the radiation heat transfer is on the order of 50% of the total heat transfer for the tested enclosures. As such, a new correlation is reported for calculating an optimum fin spacing for vertically-mounted uniformly finned surfaces, with rectangular straight fins that takes into account both natural convection and radiation.
Hypervelocity Cavity Expansion in Porous Elastoplastic Solids
Authors: Cohen Tal , Durban David
Published: July 2012

Dynamic steady-state spherical cavitation fields are examined with emphasis on material porosity at large strain. Cavity expansion is driven by constant internal pressure in presence of remote tension or compression. The plastic branch of constitutive relations is described by the Gurson model, with arbitrary strain hardening. The mathematical model is reduced to a system of four ordinary nonlinear coupled differential equations. Numerical examples show that a plastic shock wave builds up as expansion velocity approaches a critical value and jump conditions across the shock are accounted for. At critical levels of remote tension, quasi-static cavitation of all internal voids is induced before dynamic cavity expansion occurs.
A Single Progenitor Population Switches Behavior to Maintain and Repair Esophageal Epithelium
Authors: Doupé David P. , Alcolea Maria P. , Roshan Amit , Zhang Gen , Klein Allon M. , Simons Benjamin D. , Jones Philip H.
Published: July 2012

Epithelial Defense Force

The nature of the cells that maintain and heal the epithelium lining the esophagus has been controversial.

Doupé
et al.

(p.
1091
, published online 19 July; see the Perspective by

Kushner

) show that, unlike many other tissues, mouse esophagus is devoid of slow cycling stem cells. Instead, the epithelium is maintained and repaired by a single population of proliferating cells that can switch rapidly from homeostatic behavior into “repair mode” in the vicinity of a wound.
TLR13 Recognizes Bacterial 23
S
rRNA Devoid of Erythromycin Resistance–Forming Modification
Authors: Oldenburg Marina , Krüger Anne , Ferstl Ruth , Kaufmann Andreas , Nees Gernot , Sigmund Anna , Bathke Barbara , Lauterbach Henning , Suter Mark , Dreher Stefan , Koedel Uwe , Akira Shizuo , Kawai Taro , Buer Jan , Wagner Hermann , Bauer Stefan , Hochrein Hubertus , Kirschning Carsten J.
Published: July 2012

A Double Escapee

Toll-like receptors (TLRs)—TLR2 and TLR7—are thought to contribute to the sensing of Gram-positive bacteria like
Staphylococcus aureus
and
Streptococcus pneumoniae
by the immune system. Mice deficient in these receptors, however, are still sensitive to infection with these bacteria.

Oldenburg
et al.

(p.
1111
, published online 19 July) demonstrate that TLR13 also plays a role in detecting Gram-positive bacteria. TLR13 recognized a conserved region in the peptidyl transferase loop of bacterial 23S ribosomal RNA. Intriguingly, this same sequence is modified by specific methyltransferases that confer resistance to erythromycin. Indeed, erythromycin-resistant bacteria were no longer detectible by TLR13.
Strategy-Dependent Encoding of Planned Arm Movements in the Dorsal Premotor Cortex
Authors: Pearce Thomas M. , Moran Daniel W.
Published: July 2012

Coding Complex Movements

The dorsal premotor cortex is a critical area for planning reaching movements.
Pearce and Moran
(p.
984
, published online 19 July) trained two macaques to reach around randomly placed objects in a virtual reality task while simultaneously recording neuronal activity in the premotor cortex. Neurons in the premotor cortex coded for the direction of the hand movement and at the same time also coded other variables, including the position of the hand and the final location of the target. Population vector analyses were able to decode multiple kinematic variables from the neural activity. In one monkey, the population vector was first directed to the target but when the obstacle appeared the population vector rotated. However, the other monkey waited until the obstacle appeared. The differences in the neural planning between these two monkeys suggest different optimization strategies.
DrosophilaDosage Compensation Involves Enhanced Pol II Recruitment to Male X-Linked Promoters
Authors: Conrad Thomas , Cavalli Florence M. G. , Vaquerizas Juan M. , Luscombe Nicholas M. , Akhtar Asifa
Published: July 2012

Promoting the Male X Chromosome

In mammals and fruit flies, females have a double dose of the X chromosome compared to males, and to compensate for this imbalance, in fruit flies, transcription from across most of the male X chromosome is boosted by twofold.Conradet al.(p.742, published online 19 July) measured the binding of RNA polymerase II, responsible for the majority of the transcription on the X chromosome, and found a consistent increase at the promoters of genes on the male X chromosome. Thus, the increase in transcription on the male X chromosome is not driven by increased rates of transcriptional elongation, as has been suggested previously, but must involve up-regulation of transcription initiation.
A Reversible and Higher-Rate Li-O
2
Battery
Authors: Peng Zhangquan , Freunberger Stefan A. , Chen Yuhui , Bruce Peter G.
Published: July 2012

Improving Lithium Batteries

Lithium-oxygen batteries have similar volumetric energy densities to lithium-ion batteries, but, because the oxygen part of the battery can be extracted from the air, they have a significant advantage in their gravimetric energy densities. One of the fundamental problems plaguing the nonaqueous Li-O
2
system is that the Li
2
O
2
that forms on discharge must be completely reversed on charging, but for most systems, a range of side products form instead of Li
2
O
2
.

Peng
et al.

(p.
563
, published online 19 July) show that by using dimethyl sulfoxide as the electrolyte, and a porous gold cathode, they can get reversible production and removal of Li
2
O
2
during discharge and charge cycles. Furthermore, the electrolyte-electrode system operates with much faster kinetics than carbon electrodes.
Earthquake in a Maze: Compressional Rupture Branching During the 2012
M
w
8.6 Sumatra Earthquake
Authors: Meng L. , Ampuero J.-P. , Stock J. , Duputel Z. , Luo Y. , Tsai V. C.
Published: July 2012

Earthquake in a Maze

The 11 April 2012 magnitude 8.6 earthquake offshore of Sumatra was the largest measured earthquake along a strike-slip boundary that modern seismological instruments have ever recorded. Despite its size and proximity to a large population, there was no subsequent tsunami and there were no reported fatalities.

Meng
et al.

(p.
724
, published online 19 July) used teleseismic data from seismological networks in Japan and Europe to image the source of high-frequency radiation generated by the earthquake to understand the mechanics of this unique event. The resultant back projections showed that the earthquake slowly ruptured along a complex series of faults. The deeper-than-usual rupture path and large stress drop are both features that may not be unique to this earthquake, suggesting that regions in a similar tectonic environment may have the potential for more complex—or larger—intraplate earthquakes than might have been expected.
Connecting Stress to Viral Reactivation
Authors: VanHook Annalisa M.
Published: July 2012

Local axonal signaling through mTORC1 maintains herpes virus latency in neurons.
Opioid Receptor Satiety Signal
Authors: Gough Nancy R.
Published: July 2012

In nerves of the portal vein, antagonism of μ-opioid receptors by peptide products of digestion signals the brain to reduce food intake.
SHARP1 Keeps Breast Cancer Cells from Metastasizing
Authors: Andrianantoandro Ernesto
Published: July 2012

SHARP1 mediates ubiquitin-independent targeting of hypoxia-inducible factors to the proteasome, thus reducing breast cancer metastasis.
Temsirolimus Activates Autophagy and Ameliorates Cardiomyopathy Caused by Lamin A/C Gene Mutation
Authors: Choi Jason C. , Muchir Antoine , Wu Wei , Iwata Shinichi , Homma Shunichi , Morrow John P. , Worman Howard J.
Published: July 2012

Cardiomyopathy arising from lamin A/C mutations in mice can be corrected by enhancing autophagy through blockade of mTOR with temsirolimus.
Overcoming Drug Resistance with Alginate Oligosaccharides Able To Potentiate the Action of Selected Antibiotics
Authors: Khan Saira , Tøndervik Anne , Sletta Håvard , Klinkenberg Geir , Emanuel Charlotte , Onsøyen Edvar , Myrvold Rolf , Howe Robin A. , Walsh Timothy R. , Hill Katja E. , Thomas David W.
Published: July 2012

The uncontrolled, often inappropriate use of antibiotics has resulted in the increasing prevalence of antibiotic-resistant pathogens, with major cost implications for both United States and European health care systems. We describe the utilization of a low-molecular-weight oligosaccharide nanomedicine (OligoG), based on the biopolymer alginate, which is able to perturb multidrug-resistant (MDR) bacteria by modulating biofilm formation and persistence and reducing resistance to antibiotic treatment, as evident using conventional and robotic MIC screening and microscopic analyses of biofilm structure. OligoG increased (up to 512-fold) the efficacy of conventional antibiotics against important MDR pathogens, including
Pseudomonas
,
Acinetobacter
, and
Burkholderia
spp., appearing to be effective with several classes of antibiotic (i.e., macrolides, β-lactams, and tetracyclines). Using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), increasing concentrations (2%, 6%, and 10%) of alginate oligomer were shown to have a direct effect on the quality of the biofilms produced and on the health of the cells within that biofilm. Biofilm growth was visibly weakened in the presence of 10% OligoG, as seen by decreased biomass and increased intercellular spaces, with the bacterial cells themselves becoming distorted and uneven due to apparently damaged cell membranes. This report demonstrates the feasibility of reducing the tolerance of wound biofilms to antibiotics with the use of specific alginate preparations.
Effect of Reduced Vancomycin Susceptibility on Clinical and Economic Outcomes in Staphylococcus aureus Bacteremia
Authors: Han Jennifer H. , Mascitti Kara B. , Edelstein Paul H. , Bilker Warren B. , Lautenbach Ebbing
Published: July 2012

Reduced vancomycin susceptibility (RVS) may lead to poor clinical outcomes in
Staphylococcus aureus
bacteremia. The objective of this study was to evaluate the clinical and economic impact of RVS in patients with bacteremia due to
S. aureus
. A cohort study of patients who were hospitalized from December 2007 to May 2009 with
S. aureus
bacteremia was conducted within a university health system. Multivariable logistic regression and zero-truncated negative binomial regression models were developed to evaluate the association of RVS with 30-day in-hospital mortality, length of stay, and hospital charges. One hundred thirty-four (34.2%) of a total of 392 patients had bacteremia due to
S. aureus
with RVS as defined by a vancomycin Etest MIC of >1.0 μg/ml. Adjusted risk factors for 30-day in-hospital mortality included the all patient refined-diagnosis related group (APRDRG) risk-of-mortality score (odds ratio [OR], 7.11; 95% confidence interval [CI], 3.04 to 16.6), neutropenia (OR, 13.4; 95% CI, 2.46 to 73.1), white blood cell count (OR, 1.05; 95% CI, 1.01 to 1.09), immunosuppression (OR, 6.31; 95% CI, 1.74 to 22.9), and intensive care unit location (OR, 3.51; 95% CI, 1.65 to 7.49). In multivariable analyses, RVS was significantly associated with increased mortality in patients with
S. aureus
bacteremia as a result of methicillin-susceptible (OR, 3.90; 95% CI, 1.07 to 14.2) but not methicillin-resistant (OR, 0.53; 95% CI, 0.19 to 1.46) isolates. RVS was associated with greater 30-day in-hospital mortality in patients with bacteremia due to methicillin-susceptible
S. aureus
but not methicillin-resistant
S. aureus
. Further research is needed to identify optimal treatment strategies to reduce mortality associated with RVS in
S. aureus
bacteremia.
In Vitro
and
In Vivo
Biological Activities of Iron Chelators and Gallium Nitrate against Acinetobacter baumannii
Authors: de Léséleuc Louis , Harris Greg , KuoLee Rhonda , Chen Wangxue
Published: July 2012

We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of
Acinetobacter baumannii
. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited
A. baumannii
growth
in vitro
. Gallium nitrate alone was moderately effective at reducing
A. baumannii
growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistant
A. baumannii
.
The Combination of Sulfamethoxazole, Trimethoprim, and Isoniazid or Rifampin Is Bactericidal and Prevents the Emergence of Drug Resistance in Mycobacterium tuberculosis
Authors: Vilchèze Catherine , Jacobs William R.
Published: July 2012

The challenges of developing new drugs to treat tuberculosis (TB) are indicated by the relatively small number of candidates entering clinical trials in the past decade. To overcome these issues, we reexamined two FDA-approved antibacterial drugs, sulfamethoxazole (SMX) and trimethoprim (TMP), for use in TB treatment. SMX and TMP inhibit folic acid biosynthesis and are used in combination to treat infections of the respiratory, urinary, and gastrointestinal tracts. The MICs of SMX and TMP, alone and in combination, were determined for drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistant
Mycobacterium tuberculosis
strains. While TMP alone was not effective against
M. tuberculosis
, the combination of TMP and SMX was bacteriostatic against
M. tuberculosis
. Surprisingly, the combination of SMX and TMP was also active against a subset of MDR
M. tuberculosis
strains. Treatment of
M. tuberculosis
with TMP-SMX and a first-line anti-TB drug, either isoniazid or rifampin, was bactericidal, demonstrating that the combination of TMP and SMX with isoniazid or rifampin was not antagonistic. Moreover, the addition of SMX-TMP in combination with either isoniazid or rifampin also prevented the emergence of drug resistance
in vitro
. In conclusion, this study further illustrates the opportunity to reevaluate the activity of TMP-SMX
in vivo
to prevent the emergence of drug-resistant
M. tuberculosis
.
Reduced Expression of the
rplU-rpmA
Ribosomal Protein Operon in
mexXY
-Expressing Pan-Aminoglycoside-Resistant Mutants of Pseudomonas aeruginosa
Authors: Lau Calvin Ho-Fung , Fraud Sebastien , Jones Marcus , Peterson Scott N. , Poole Keith
Published: July 2012

Pan-aminoglycoside-resistant
Pseudomonas aeruginosa
mutants expressing the
mexXY
components of the aminoglycoside-accommodating MexXY-OprM multidrug efflux system but lacking mutations in the
mexZ
gene encoding a repressor of this efflux system and in the
mexXY
promoter have been reported (S. Fraud and K. Poole, Antimicrob. Agents Chemother. 55:1068–1074, 2011). Genome sequencing of one of these mutants, K2966, revealed the presence of a mutation within the predicted promoter region of the
rplU-rpmA
operon encoding ribosomal proteins L21 and L27, consistent with an observed 2-fold decrease in expression of this operon in the mutant relative to wild-type
P. aeruginosa
PAO1. Moreover, correction of the mutation restored
rplU-rpmA
expression and, significantly, reversed the elevated
mexXY
expression and pan-aminoglycoside resistance of the mutant. Reduced
rplU-rpmA
expression was also observed in a second
mexXY
-expressing pan-aminoglycoside-resistant mutant, K2968, which, however, lacked a mutation in the
rplU-rpmA
promoter region. Restoration of
rplU-rpmA
expression in the K2968 mutant following chromosomal integration of the
rplU-rpmA
operon derived from wild-type
P. aeruginosa
failed, however, to reverse the elevated
mexXY
expression and pan-aminoglycoside resistance of this mutant, although it did so for K2966, suggesting that the mutation impacting
rplU-rpmA
expression in K2968 also impacts other
mexXY
-related genes. Increased
mexXY
expression owing to reduced
rplU-rpmA
expression in K2966 and K2968 was dependent on PA5471, whose expression was also elevated in these mutants. Thus, mutational disruption of ribosome function, by limiting expression of ribosomal constituents, promotes recruitment of
mexXY
and does so via PA5471, reminiscent of
mexXY
induction by ribosome-disrupting antimicrobial agents. Interestingly, reduced
rplU-rpmA
expression was also observed in a
mexXY
-expressing pan-aminoglycoside-resistant clinical isolate, suggesting that ribosome-perturbing mutations have clinical relevance in the recruitment of the MexXY-OprM aminoglycoside resistance determinant.
Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in an
In Vitro
Model of Invasive Pulmonary Aspergillosis
Authors: Jeans Adam R. , Howard Susan J. , Al-Nakeeb Zaid , Goodwin Joanne , Gregson Lea , Warn Peter A. , Hope William W.
Published: July 2012

Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of
A. fumigatus
strains with elevated voriconazole MICs. We used an
in vitro
model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.
The WalKR System Controls Major Staphylococcal Virulence Genes and Is Involved in Triggering the Host Inflammatory Response
Authors: Delauné Aurélia , Dubrac Sarah , Blanchet Charlène , Poupel Olivier , Mäder Ulrike , Hiron Aurélia , Leduc Aurélie , Fitting Catherine , Nicolas Pierre , Cavaillon Jean-Marc , Adib-Conquy Minou , Msadek Tarek
Published: July 2012

The WalKR two-component system is essential for the viability ofStaphylococcus aureus, playing a central role in controlling cell wall metabolism. We produced a constitutively active form of WalR inS. aureusthrough a phosphomimetic amino acid replacement (WalRc, D55E). The strain displayed significantly increased biofilm formation and alpha-hemolytic activity. Transcriptome analysis was used to determine the full extent of the WalKR regulon, revealing positive regulation of major virulence genes involved in host matrix interactions (efb,emp,fnbA, andfnbB), cytolysis (hlgACB,hla, andhlb), and innate immune defense evasion (scn,chp, andsbi), through activation of the SaeSR two-component system. The impact on pathogenesis of varying cell envelope dynamics was studied using a murine infection model, showing that strains producing constitutively active WalRcare strongly diminished in their virulence due to early triggering of the host inflammatory response associated with higher levels of released peptidoglycan fragments. Indeed, neutrophil recruitment and proinflammatory cytokine production were significantly increased when the constitutively activewalRcallele was expressed, leading to enhanced bacterial clearance. Taken together, our results indicate that WalKR play an important role in virulence and eliciting the host inflammatory response by controlling autolytic activity.
Intracellular Trafficking of Clostridium perfringens Iota-Toxin b
Authors: Nagahama Masahiro , Umezaki Mariko , Tashiro Ryo , Oda Masataka , Kobayashi Keiko , Shibutani Masahiro , Takagishi Teruhisa , Ishidoh Kazumi , Fukuda Mitsunori , Sakurai Jun
Published: July 2012

Clostridium perfringens
iota-toxin is composed of an enzymatic component (Ia) and a binding component (Ib). Ib binds to a cell surface receptor, undergoes oligomerization in lipid rafts, and binds Ia. The resulting complex is then endocytosed. Here, we show the intracellular trafficking of iota-toxin. After the binding of the Ib monomer with cells at 4°C, oligomers of Ib formed at 37°C and later disappeared. Immunofluorescence staining of Ib revealed that the internalized Ib was transported to early endosomes. Some Ib was returned to the plasma membrane through recycling endosomes, whereas the rest was transported to late endosomes and lysosomes for degradation. Degraded Ib was delivered to the plasma membrane by an increase in the intracellular Ca
2+
concentration caused by Ib. Bafilomycin A1, an endosomal acidification inhibitor, caused the accumulation of Ib in endosomes, and both nocodazole and colchicine, microtubule-disrupting agents, restricted Ib's movement in the cytosol. These results indicated that an internalized Ia and Ib complex was delivered to early endosomes and that subsequent delivery of Ia to the cytoplasm occurs mainly in early endosomes. Ib was either sent back to the plasma membranes through recycling endosomes or transported to late endosomes and lysosomes for degradation. Degraded Ib was transported to plasma membranes.
Coagulases as Determinants of Protective Immune Responses against Staphylococcus aureus
Authors: McAdow Molly , DeDent Andrea C. , Emolo Carla , Cheng Alice G. , Kreiswirth Barry N. , Missiakas Dominique M. , Schneewind Olaf
Published: July 2012

During infection,Staphylococcus aureussecretes two coagulases (Coa and von Willebrand factor binding protein [vWbp]), which, following an association with host prothrombin and fibrinogen, form fibrin clots and enable the establishment of staphylococcal disease. Within the genomes of differentS. aureusisolates, coagulase gene sequences are variable, and this has been exploited for a classification of types. We show here that antibodies directed against the variable prothrombin binding portion of coagulases confer type-specific immunity through the neutralization ofS. aureusclotting activity and protection from staphylococcal disease in mice. By combining variable portions of coagulases from North American isolates into hybrid Coa and vWbp proteins, a subunit vaccine that provided protection against challenge with different coagulase-typeS. aureusstrains in mice was derived.
Increased Chain Length Promotes Pneumococcal Adherence and Colonization
Authors: Rodriguez Jesse L. , Dalia Ankur B. , Weiser Jeffrey N.
Published: July 2012

Streptococcus pneumoniaeis a mucosal pathogen that grows in chains of variable lengths. Short-chain forms are less likely to activate complement, and as a consequence they evade opsonophagocytic clearance more effectively during invasive disease. When grown in human nasal airway surface fluid, pneumococci exhibited both short- and long-chain forms. Here, we determined whether longer chains provide an advantage during colonization when the organism is attached to the epithelial surface. Chain-forming mutants and the parental strain grown under conditions to promote chain formation showed increased adherence to human epithelial cells (A549 cells)in vitro. Additionally, adherence to A549 cells selected for longer chains within the wild-type strain.In vivoin a murine model of colonization, chain-forming mutants outcompeted the parental strain. Together, our results demonstrate that morphological heterogeneity in the pneumococcus may promote colonization of the upper respiratory tract by enhancing the ability of the organism to bind to the epithelial surface.
Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production
Authors: Allen Rebecca G. , Lafuse William P. , Powell Nicole D. , Webster Marketon Jeanette I. , Stiner-Jones La'Tonia M. , Sheridan John F. , Bailey Michael T.
Published: July 2012

Exposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1α (IL-1α) and IL-1β, and increased reactivity of splenic CD11b+macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to killEscherichia colibothin vitroandin vivo, through a Toll-like receptor 4-dependent mechanism. The present study tested the hypothesis that stressor-enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation withE. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing ofE. colidemonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing.