bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restricted diffusion of calretinin in cerebellar granule cell dendrites implies Ca2+‐dependent interactions via its EF‐hand 5 domain
Authors: Arendt Oliver , Schwaller Beat , Brown Edward B. , Eilers Jens , Schmidt Hartmut 
Published: June 2013

Key points
The dynamics of the second messenger Ca2+ are tightly controlled by Ca2+‐binding proteins (CaBPs).
The diffusional mobility of a given CaBP, such as calretinin (CR), defines how it affects the range‐of‐action of Ca2+ but, if unexpectedly low, may also indicate that the CaBP acts as a Ca2+ sensor, undergoing specific protein interactions.
Here we quantified the diffusional mobility of CR in dendrites of cerebellar granule cells using microscopic methods.
We find that CR diffuses unexpectedly slow, that its mobility is further reduced when Ca2+ levels are elevated and that a distinct region of CR interacts with specific targets in a Ca2+‐dependent manner.
Our findings indicate a new ‘sensor’ role for CR, which may allow for Ca2+‐dependent feedback control of neuronal excitability.
Abstract  Ca2+‐binding proteins (CaBPs) are important regulators of neuronal Ca2+ signalling, acting either as buffers that shape Ca2+ transients and Ca2+ diffusion and/or as Ca2+ sensors. The diffusional mobility represents a crucial functional parameter of CaBPs, describing their range‐of‐action and possible interactions with binding partners. Calretinin (CR) is a CaBP widely expressed in the nervous system with strong expression in cerebellar granule cells. It is involved in regulating excitability and synaptic transmission of granule cells, and its absence leads to impaired motor control. We quantified the diffusional mobility of dye‐labelled CR in mouse granule cells using two‐photon fluorescence recovery after photobleaching. We found that movement of macromolecules in granule cell dendrites was not well described by free Brownian diffusion and that CR diffused unexpectedly slow compared to fluorescein dextrans of comparable size. During bursts of action potentials, which were associated with dendritic Ca2+ transients, the mobility of CR was further reduced. Diffusion was significantly accelerated by a peptide embracing EF‐hand 5 of CR. Our results suggest long‐lasting, Ca2+‐dependent interactions of CR with large and/or immobile binding partners. These interactions render CR a poorly mobile Ca2+ buffer and point towards a Ca2+ sensor function of CR.
Prevalence and Genetic Characterization of Second-Line Drug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in Rural China
Authors: Hu Yi , Hoffner Sven , Wu Linlin , Zhao Qi , Jiang Weili , Xu Biao 
Published: June 2013

ABSTRACT

This study aimed to investigate the prevalence of resistance to second-line antituberculosis (anti-TB) drugs and its association with resistance-related mutations in
Mycobacterium tuberculosis
isolated in China. In the present study, we collected 380 isolates from a population-based study in China and tested the drug susceptibility to first- and selected second-line drugs. These results were compared with polymorphisms in the DNA sequences of genes associated with drug resistance and MIC values of the studied second-line drugs. Of 43 multidrug-resistant
M. tuberculosis
isolates, 13 showed resistance to fluoroquinolones or injectable second-line drugs (preextensively drug-resistant TB [pre-XDR-TB]), and 4 were resistant to both and thus defined as extensively drug-resistant TB (XDR-TB). Age and previous TB therapy, including use of second-line drugs, were two independent factors associated with increased resistance to both first- and second-line drugs. Molecular analysis identified the most frequent mutations in the resistance-associated genes: D94G in
gyrA
(29.1%) and A1401G in
rrs
(30.8%). Meanwhile, all 4 XDR-TB isolates had a mutation in
gyrA
, and 3 of them carried the A1401G mutation in
rrs
. Mutations in
gyrA
and
rrs
were associated with high-level resistance to fluoroquinolones and the second-line injectable drugs. In addition to the identification of resistance-associated mutations and development of a rapid molecular test to diagnose the second-line drug resistance, it should be a priority to strictly regulate the administration of second-line drugs to maintain their efficacy to treat multidrug-resistant TB.
Pharmacokinetics of Caspofungin in Critically Ill Patients on Continuous Renal Replacement Therapy
Authors: Weiler Stefan , Seger Christoph , Pfisterer Hartwig , Stienecke Eva , Stippler Florian , Welte René , Joannidis Michael , Griesmacher Andrea , Bellmann Romuald 
Published: June 2013

ABSTRACT
Caspofungin pharmacokinetics was assessed in 27 critically ill patients, including 7 on continuous venovenous hemofiltration (CVVH), 8 on continuous venovenous hemodialysis (CVVHD), and 13 not requiring continuous renal replacement therapy (CRRT). Caspofungin exposure during CRRT was very similar to that of the control group and comparable to that in healthy volunteers. Caspofungin clearance by CRRT was very low. Therefore, the standard dosage of caspofungin is probably adequate for critically ill patients undergoing CVVH or CVVHD.
Electronic Estimations of Renal Function Are Inaccurate in Solid-Organ Transplant Recipients and Can Result in Significant Underdosing of Prophylactic Valganciclovir
Authors: Trevillyan J. , Angus P. , Shelton E. , Whitlam J. , Ierino F. , Pavlovic J. , Gregory D. , Urbancic K. , Torresi J. , Testro A. , Grayson M. L. 
Published: June 2013

ABSTRACT

In a prospective study of solid-organ transplant recipients (
n
= 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft-Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (≤0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter).
Azithromycin Attenuates Lung Inflammation in a Mouse Model of Ventilator-Associated Pneumonia by Multidrug-Resistant Acinetobacter baumannii
Authors: Yamada Koichi , Yanagihara Katsunori , Kaku Norihito , Harada Yosuke , Migiyama Yohei , Nagaoka Kentaro , Morinaga Yoshitomo , Nakamura Shigeki , Imamura Yoshifumi , Miyazaki Taiga , Izumikawa Koichi , Kakeya Hiroshi , Hasegawa Hiroo , Mikamo Hiroshige , Kohno Shigeru 
Published: June 2013

ABSTRACT

Acinetobacter baumannii
is one of the main pathogens that cause ventilator-associated pneumonia (VAP) and is associated with a high rate of mortality. Little is known about the efficacy of macrolides against
A. baumannii
. In order to confirm the efficacy of azithromycin (AZM) against VAP caused by multidrug-resistant
A. baumannii
(MDRAB), we used a mouse model that mimics VAP by placement of a plastic tube in the bronchus. AZM (10 and 100 mg/kg of body weight) was administered subcutaneously every 24 h beginning at 3 h after inoculation. Phosphate-buffered saline was administered as the control. Survival was evaluated over 7 days. At 48 h postinfection, mice were sacrificed and the numbers of viable bacteria in lungs and bronchoalveolar lavage fluid were compared. Histopathological analysis of lung specimens was also performed. The treatment groups displayed significantly longer survival than the control group (
P
< 0.05). AZM did not have an antimicrobial effect. Histopathological examination of lung specimens indicated that the progression of lung inflammation was prevented in the AZM-treated groups. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in bronchoalveolar lavage fluid were significantly decreased (
P
< 0.05) in the AZM-treated groups. AZM may have a role for the treatment of VAP with MDRAB because of its anti-inflammatory effects.
Cell Wall Perturbation Sensitizes Fungi to the Antimalarial Drug Chloroquine
Authors: Islahudin Farida , Khozoie Combiz , Bates Steven , Ting Kang-Nee , Pleass Richard J. , Avery Simon V. 
Published: June 2013

ABSTRACT

Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model
Saccharomyces cerevisiae
. A genomewide yeast deletion strain collection was screened against CQ, revealing that
bck1
Δ and
slt2
Δ mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall-targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in
bck1
Δ and
slt2
Δ mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen
Candida albicans
was decreased 2-fold by 250 μM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in
Candida glabrata
and
Aspergillus fumigatus
. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment.
Evaluation of a Nisin-Eluting Nanofiber Scaffold To Treat Staphylococcus aureus-Induced Skin Infections in Mice
Authors: Heunis Tiaan D. J. , Smith Carine , Dicks Leon M. T. 
Published: June 2013

ABSTRACTStaphylococcus aureusis a virulent pathogen and a major causative agent of superficial and invasive skin and soft tissue infections (SSSTIs). Antibiotic resistance inS. aureus, among other bacterial pathogens, has rapidly increased, and this is placing an enormous burden on the health care sector and has serious implications for infected individuals, especially immunocompromised patients. Alternative treatments thus need to be explored to continue to successfully treat infections caused byS. aureus, including antibiotic-resistant strains ofS. aureus. In this study, an antimicrobial nanofiber wound dressing was generated by electrospinning nisin (Nisaplin) into poly(ethylene oxide) and poly(d,l-lactide) (50:50) blend nanofibers. Active nisin diffused from the nanofiber wound dressings for at least 4 daysin vitro, as shown by consecutive transfers onto plates seeded with strains of methicillin-resistantS. aureus(MRSA). The nisin-containing nanofiber wound dressings significantly reducedS. aureusXen 36 bioluminescencein vivoand viable cell numbers in a murine excisional skin infection model. The bacterial burden of wounds treated with nisin-containing nanofiber wound dressings was 4.3 × 102CFU/wound, whereas wounds treated with control nanofiber wound dressings had 2.2 × 107CFU/wound on the last day of the trial (day 7). Furthermore, the wound dressings stimulated wound closure of excisional wounds, and no adverse effects were observed by histological analysis. Nisin-containing nanofiber wound dressings have the potential to treatS. aureusskin infections and to potentially accelerate wound healing of excisional wounds.
First Report of the Multiresistance Gene
cfr
in Streptococcus suis
Authors: Wang Yang , Li Dexi , Song Li , Liu Yang , He Tao , Liu Hebing , Wu Congming , Schwarz Stefan , Shen Jianzhong 
Published: June 2013

ABSTRACT

The multiresistance gene
cfr
was identified for the first time in streptococci, namely, in porcine
Streptococcus suis
isolate S10. The
cfr
gene was detected on the ∼100-kb plasmid pStrcfr, where it was bracketed by two copies of the novel insertion sequence IS
Enfa5
, located in the same orientation. The detection of a
cfr
- and IS
Enfa5
-containing amplicon by inverse PCR suggests that IS
Enfa5
may play a role in the dissemination of
cfr
.
Patient-Derived Tumor Xenografts: Transforming Clinical Samples into Mouse Models
Authors: Siolas Despina , Hannon Gregory J. 
Published: June 2013

Abstract
Tumor graft models (also known as patient-derived xenografts or PDX) are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse. Because PDX mice are derived from human tumors, they offer a tool for developing anticancer therapies and personalized medicine for patients with cancer. In addition, these models can be used to study metastasis and tumor genetic evolution. This review examines the development, challenges, and broad use of these attractive preclinical models. Cancer Res; 73(17); 5315–9. ©2013 AACR.
Primary hrHPV DNA Testing in Cervical Cancer Screening: How to Manage Screen-Positive Women? A POBASCAM Trial Substudy
Authors: Dijkstra Maaike G. , van Niekerk Dirk , Rijkaart Dorien C. , van Kemenade Folkert J. , Heideman Daniëlle A.M. , Snijders Peter J.F. , Meijer Chris J.L.M. , Berkhof Johannes 
Published: June 2013

Abstract
Background: High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening.
Methods: A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n = 44,938; 29–61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3+) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3+ after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3+ risk after positive triage (positive predictive value, PPV) was at least 20%.
Results: Triage at baseline with cytology only yielded an NPV of 94.3% [95% confidence interval (CI), 92.0–96.0] and a PPV of 39.7% (95% CI, 34.0–45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5% and PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8% and PPV 28.5%). The inclusion of both HPV16/18 genotyping at baseline and repeat cytology testing provided a high NPV (99.6%) and a moderately high PPV (25.6%).
Conclusions: Triaging hrHPV-positive women by cytology at baseline and after 6 to 12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening.
Impact: Implementable triage strategies are provided for primary hrHPV screening in an organized setting. Cancer Epidemiol Biomarkers Prev; 23(1); 55–63. ©2013 AACR.
VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians
Authors: Shahin Mohamed Hossam A. , Cavallari Larisa H. , Perera Minoli A. , Khalifa Sherief I. , Misher Anne , Langaee Taimour , Patel Shitalben , Perry Kimberly , Meltzer David O. , McLeod Howard L. , Johnson Julie A. 
Published: June 2013

SummaryThe VKORC1 Asp36Tyr single nucleotide polymorphism (SNP) is one of the most promising predictors of high warfarin dose, but data on its population prevalence is incomplete. We determined the frequency of this SNP in participants from seven countries on four continents and investigated its effect on warfarin dose requirement. One thousand samples were analysed to define the population prevalence of this SNP. Those samples included individuals from Egypt, Ghana, Sudan, Kenya, Saudi Arabia, Peru and African Americans from the United States. A total of 206 Egyptian samples were then used to investigate the effect of this SNP on warfarin dose requirements. This SNP was most frequent among Kenyans and Sudanese, with a minor allele frequency (MAF) of 6% followed by Saudi Arabians and Egyptians with a MAF of 3% and 2.5%, respectively. It was not detected in West Africans, based on our data from Ghana, and a large cohort of African Americans. Egyptian carriers of the VKORC1 Tyr36 showed higher warfarin dose requirement (57.1 ± 29.4 mg/week) than those with the Asp36Asp genotype (35.8 ± 16.6 mg/week; p=0.03). In linear regression analysis, this SNP had the greatest effect size among the genetic factors (16.6 mg/week increase in dose per allele), and improved the warfarin dose variability explained in Egyptians (model R2 from 31% to 36.5%). The warfarin resistant VKORC1 Asp36Tyr appears to be confined to north-eastern Africa and nearby Middle-Eastern populations, but in those populations where it is present, it has a significant influence on warfarin dose requirement and the percent of warfarin dose variability that can be explained.
Subepicardial Action Potential Characteristics Are a Function of Depth and Activation Sequence in Isolated Rabbit Hearts
Authors: Kelly Allen , Ghouri Iffath A. , Kemi Ole J. , Bishop Martin J. , Bernus Olivier , Fenton Flavio H. , Myles Rachel C. , Burton Francis L. , Smith Godfrey L. 
Published: June 2013

Background—
Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface.

Methods and Results—

Two-photon excitation of di-4-aminonaphthenyl-pyridinum-propylsulfonate was used to measure electric activity at discrete epicardial layers of isolated Langendorff-perfused rabbit hearts to a depth of 500 μm. Endo-to-epicardial wavefronts were studied during right atrial or ventricular endocardial pacing. Similar measurements were made with epi-to-endocardial, transverse, and longitudinal pacing protocols. Results were compared with data from a bidomain model of 3-dimensional (3D) electric propagation within ventricular myocardium. During right atrial and endocardial pacing, AP rise time (10%–90% of upstroke) decreased by ≈50% between 500 and 50 μm from the epicardial surface, whereas conduction velocity increased and AP duration was only slightly shorter (≈4%). These differences were not observed with other conduction patterns. The depth-dependent changes in rise time were larger at higher pacing rates. Modeling data qualitatively reproduced the behavior seen experimentally and demonstrated a parallel reduction in peak
I
Na
and electrotonic load as the wavefront approaches the epicardial surface.

Conclusions—
Decreased electrotonic load at the epicardial surface results in more rapid AP upstrokes and higher conduction velocities compared with the bulk myocardium. Combined effects of tissue depth and pacing rate on AP rise time reduce conduction safety and myocardial excitability within the ventricular wall.
Evaluation of the Role of Endomyocardial Biopsy in 851 Patients With Unexplained Heart Failure From 2000–2009
Authors: Bennett Mosi K. , Gilotra Nisha A. , Harrington Colleen , Rao Shaline , Dunn Justin M. , Freitag Tasha B. , Halushka Marc K. , Russell Stuart D. 
Published: June 2013

Background—
Endomyocardial biopsy (EMB) is often considered when the pathogenesis of heart failure cannot be determined by noninvasive testing. Uncertainty remains about the diagnostic and clinical use of EMB in various clinical scenarios.

Methods and Results—
We examined the characteristics of a cohort of patients with unexplained heart failure who underwent EMB at a tertiary care medical center. We categorized each patient into a clinical scenario as outlined by the 2007 AHA/ACC/ESC guidelines and determined the number of times EMB provided a diagnosis or altered the clinical course. A total of 851 patients underwent EMB from 2000–2009. Overall, 25.5% of EMBs provided a diagnosis and 22.7% of EMBs changed clinical course. Heart failure associated with unexplained restrictive cardiomyopathy was the most common clinical scenario, comprising 33.6% (286/851) of EMBs, and 84 (29.4%) of these EMBs were diagnostic. EMB for unexplained heart failure of <2 weeks duration had a diagnostic yield at 35% (39/109). There were 4 uncommon scenarios where EMB had a high diagnostic and clinical yield. There were 16 complications for an overall rate of 1.9%.

Conclusions—
We confirm that EMB is useful in acute onset unexplained cardiomyopathy. We demonstrate a role for EMB in suspected infiltrative disease and in the management of rare clinical scenarios, such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Our results suggest low use of EMB in chronic heart failure that responds to usual care.
Mechanistic Features Associated With Improvement in Mitral Regurgitation After Cardiac Resynchronization Therapy and Their Relation to Long-Term Patient Outcome
Authors: Onishi Tetsuari , Onishi Toshinari , Marek Josef J. , Ahmed Mohamed , Haberman Stephanie C. , Oyenuga Olusegun , Adelstein Evan , Schwartzman David , Saba Samir , Gorcsan John 
Published: June 2013

Background—
Mechanisms of mitral regurgitation (MR) reduction with cardiac resynchronization therapy (CRT) are complex, and their association with long-term outcome is unclear. We sought to elucidate mechanistic features of reduction in MR with CRT, which impact long-term patient survival.

Methods and Results—

A prospective longitudinal study of 277 patients with heart failure with QRS width ≥120 ms and ejection fraction ≤35% for CRT was performed. Quantitative echocardiography, including dyssynchrony analysis, was performed at baseline. MR was quantified by color Doppler before and 6 months after CRT. Predefined end points of death, transplant, or left ventricular assist device were tracked during 4 years. There were 114 (48%) patients with CRT with significant MR (≥moderate) at baseline; of whom 48 (42%) patients had MR improvement, and 24 (19%) patients had MR worsening after CRT. The 66 events (47 deaths, 10 transplantations, and 9 left ventricular assist devices) were strongly associated with significant MR after CRT (hazard ratio, 3.58; 95% confidence interval, 2.18–5.87;
P
<0.0001). Three echocardiographic features were independently associated with amelioration of significant MR after CRT by multivariable analysis: anteroseptal to posterior wall radial strain dyssynchrony >200 ms, lack of severe left ventricular dilatation (end-systolic dimension index <29 mm/m
2
), and lack of echocardiographic scar at papillary muscle insertion sites (all
P
<0.05) and, when combined, were additively associated with long-term survival (
P
=0.0001).

Conclusions—
Significant MR after CRT was strongly associated with less favorable long-term survival. Echocardiographic mechanistic features were identified that were associated with improvement in MR after CRT and favorable long-term survival.