bluuebunny/crossref_metadata_2025_split huggingface dataset:
Laparoscopic Closure of the Nephrosplenic Space in Horses with Nephrosplenic Colonic Entrapment: Factors Associated with Survival and Colic Recurrence
Authors: Nelson Brad B. , Ruple‐Czerniak Audrey A. , Hendrickson Dean A. , Hackett Eileen S. 
Published: September 2016

Objectives1) To identify factors associated with short‐term survival and time to death after hospital discharge in horses with nephrosplenic entrapment (NSE). 2) To compare the frequency of recurrent colic episodes in horses with and without laparoscopic closure of the nephrosplenic space.Study DesignHistorical cohort with a nested case control.AnimalsClient‐owned horses.MethodsMedical records of horses treated for NSE from January 1, 2002 to June 1, 2014 were reviewed. Data collected included signalment, physical examination parameters, laboratory results, diagnostic findings, and treatments. Factors associated with short‐term survival to discharge were analyzed with a multivariable logistic regression model and time to death after hospital discharge was analyzed with a Cox proportional hazards model.ResultsDuring the study period, 211 horses had 231 NSE events and 192/211 (91%) horses survived to discharge. A positive difference in packed cell volume (PCV at admission – PCV after treatment) was associated with reduced odds of nonsurvival with each increment (OR: 0.899, 95% CI 0.816–0.991,P=.03) while the presence of concurrent alimentary lesions (OR: 8.47, 95% CI 1.42–50.4,P=.02) were significantly associated with increased odds of nonsurvival in the short term. Of 156 horses that survived to discharge for which follow‐up was available, 152 (97%) were alive for ≥1 year. Increasing age (incremental years) at hospital admission was significantly associated with death after discharge (hazard ratio 1.078, 95% CI 1.002–1.16,P=.049). Recurrence of NSE was documented in 49/211 (23%) horses. The overall change in colic score indicated a reduction in colic in horses following laparoscopic closure of the nephrosplenic space compared with horses that did not have closure of the nephrosplenic space (P<0.001).ConclusionAn increase in PCV from admission to after treatment and concurrent abdominal lesions were associated with increased odds of nonsurvival to discharge in horses with NSE. Horses that underwent laparoscopic closure had reduced colic episodes compared with horses without laparoscopic closure.
Assessing Risk of Falling in Older Adults—A Comparison of Three Methods
Authors: Strupeit Steve , Buss Arne , Wolf‐Ostermann Karin 
Published: September 2016

ABSTRACTBackgroundVarious risk assessment methods have been developed to assess fall risk. Diagnostic accuracy of fall risk assessments is low and there is a scarcity of evidence regarding clinical effectiveness.AimsThe aim of this study was to evaluate the diagnostic accuracy and clinical effectiveness of a standardized fall risk assessment relative to clinical and self‐report assessment.MethodsA single‐site, prospective, longitudinal study was performed in a group of geriatric patients. Participants were patients being admitted to a geriatric rehabilitation hospital. The St. Thomas's risk assessment tool (STRATIFY), clinical assessment, and a self‐report assessment (fear of falling) were used to assess fall risk at two time points (at baseline and 3‐week follow‐up). The primary outcome was fall events. Contingency tables were used to calculate sensitivity, specificity, positive predictive values, and negative predictive values. Fisher's exact test was used to test the association between assessments and fall events.ResultsA total of 124 patients participated in the study. The self‐report technique demonstrated the highest sensitivity and negative predictive validity. The STRATIFY tool showed the highest specificity but the lowest sensitivity. The self‐report technique was associated with a lower number of fall events.DiscussionGiven the lack of diagnostic accuracy of all three assessment techniques and the lack of evidence regarding clinical effectiveness, the usefulness of these fall risk assessments can be challenged.Implications for PracticeAt least in settings in which fall prevention programs are a part of standard care, additional time consuming assessments may not be required.Linking Evidence to ActionIt is questionable whether time‐consuming assessments examined in this study are necessary. Further studies are needed to examine the diagnostic accuracy and clinical effectiveness of fall risk assessments.
Hepatitis E Virus Antibodies in Finnish Veterinarians
Authors: Kantala T. , Kinnunen P. M. , Oristo S. , Jokelainen P. , Vapalahti O. , Maunula L. 
Published: September 2016

SummaryWe investigated hepatitis E virus (HEV) infections in Finnish veterinarians engaged in different practice specialties and evaluated the effect of different background factors on HEV exposure by examining total HEV antibodies in samples collected from the participants of the 2009 National Veterinary Congress in Helsinki, Finland. Finnish veterinarians commonly have total HEV antibodies with seroprevalence of 10.2%. Of the non‐veterinarians, 5.8% were seropositive. Increasing age was associated with HEV seropositivity, and, surprisingly, the highest HEV seroprevalence (17.8%) among veterinarians was detected among small animal practitioners. Although no positive correlation between swine contacts and HEV seropositivity was found, 22.7% of veterinarians who had had needle stick by a needle that had previously been injected into a pig versus 9.0% of those who had not were seropositive, even though the finding was statistically non‐significant (P = 0.07). Our results suggest that, although contact with swine is a known risk factor for HEV infection, the sources of HEV infections are probably numerous, including travelling abroad and possibly also other reservoirs of HEV than pigs.
Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians
Authors: Spendiff Sally , Vuda Madhusudanarao , Gouspillou Gilles , Aare Sudhakar , Perez Anna , Morais José A. , Jagoe Robert T. , Filion Marie‐Eve , Glicksman Robin , Kapchinsky Sophia , MacMillan Norah J. , Pion Charlotte H. , Aubertin‐Leheudre Mylène , Hettwer Stefan , Correa José A. , Taivassalo Tanja , Hepple Russell T. 
Published: September 2016

Key points
Mitochondria are frequently implicated in the ageing of skeletal muscle, although the role of denervation in modulating mitochondrial function in ageing muscle is unknown.
We show that increased sensitivity to apoptosis initiation occurs prior to evidence of persistent denervation and is thus a primary mitochondrial defect in ageing muscle worthy of therapeutic targeting.
However, at more advanced age, mitochondrial function changes are markedly impacted by persistent sporadic myofibre denervation, suggesting the mitochondrion may be a less viable therapeutic target.
AbstractExperimental denervation modulates mitochondrial function, where changes in both reactive oxygen species (ROS) and sensitivity to permeability transition are implicated in the resultant muscle atrophy. Notably, although denervation occurs sporadically in ageing muscle, its impact on ageing muscle mitochondria is unknown. Because this information has important therapeutic implications concerning targeting the mitochondrion in ageing muscle, we examined mitochondrial function in skeletal muscle from four groups of humans, comprising two active (mean ± SD age: 23.7 ± 2.7 years and 71.2 ± 4.9 years) and two inactive groups (64.8 ± 3.1 years and 82.5 ± 4.8 years), and compared this with a murine model of sporadic denervation. We tested the hypothesis that, although some alterations of mitochondrial function in aged muscle are attributable to a primary organelle defect, mitochondrial dysfunction would be impacted by persistent denervation in advanced age. Both ageing in humans and sporadic denervation in mice increased mitochondrial sensitivity to permeability transition (humans, P = 0.004; mice, P = 0.01). To determine the contribution of sporadic denervation to mitochondrial function, we pharmacologically inhibited the denervation‐induced ROS response. This reduced ROS emission by 60% (P = 0.02) in sporadically denervated mouse muscle, which is similar to that seen in humans older than 75 years (–66%, P = 0.02) but not those younger than 75 years. We conclude that an increased sensitivity to permeability transition is a primary mitochondrial defect in ageing muscle. However, at more advanced age, when muscle atrophy becomes more clinically severe, mitochondrial function changes are markedly impacted by persistent sporadic denervation, making the mitochondrion a less viable therapeutic target.
Phosphorylation regulates the sensitivity of voltage‐gated Kv7.2 channels towards phosphatidylinositol‐4,5‐bisphosphate
Authors: Salzer Isabella , Erdem Fatma Asli , Chen Wei‐Qiang , Heo Seok , Koenig Xaver , Schicker Klaus W. , Kubista Helmut , Lubec Gert , Boehm Stefan , Yang Jae‐Won 
Published: September 2016

Key points
Phosphatidylinositol‐4,5‐bisphosphate (PIP2) is a key regulator of many membrane proteins, including voltage‐gated Kv7.2 channels.
In this study, we identified the residues in five phosphorylation sites and their corresponding protein kinases, the former being clustered within one of four putative PIP2‐binding domains in Kv7.2.
Dephosphorylation of these residues reduced the sensitivity of Kv7.2 channels towards PIP2.
Dephosphorylation of Kv7.2 affected channel inhibition via M1 muscarinic receptors, but not via bradykinin receptors.
Our data indicated that phosphorylation of the Kv7.2 channel was necessary to maintain its low affinity for PIP2, thereby ensuring the tight regulation of the channel via G protein‐coupled receptors.
AbstractThe function of numerous ion channels is tightly controlled by G protein‐coupled receptors (GPCRs). The underlying signalling mechanisms may involve phosphorylation of channel proteins and participation of phosphatidylinositol‐4,5‐bisphosphate (PIP2). Although the roles of both mechanisms have been investigated extensively, thus far only little has been reported on their interaction in channel modulation. GPCRs govern Kv7 channels, the latter playing a major role in the regulation of neuronal excitability by determining the levels of PIP2 and through phosphorylation. Using liquid chromatography‐coupled mass spectrometry for Kv7.2 immunoprecipitates of rat brain membranes and transfected cells, we mapped a cluster of five phosphorylation sites in one of the PIP2‐binding domains. To evaluate the effect of phosphorylation on PIP2‐mediated Kv7.2 channel regulation, a quintuple alanine mutant of these serines (S427/S436/S438/S446/S455; A5 mutant) was generated to mimic the dephosphorylated state. Currents passing through these mutated channels were less sensitive towards PIP2 depletion via the voltage‐sensitive phosphatase Dr‐VSP than were wild‐type channels. In vitro phosphorylation assays with the purified C‐terminus of Kv7.2 revealed that CDK5, p38 MAPK, CaMKIIα and PKA were able to phosphorylate the five serines. Inhibition of these protein kinases reduced the sensitivity of wild‐type but not mutant Kv7.2 channels towards PIP2 depletion via Dr‐VSP. In superior cervical ganglion neurons, the protein kinase inhibitors attenuated Kv7 current regulation via M1 receptors, but left unaltered the control by B2 receptors. Our results revealed that the phosphorylation status of serines located within a putative PIP2‐binding domain determined the phospholipid sensitivity of Kv7.2 channels and supported GPCR‐mediated channel regulation.
Continuous leaf optimization for IMRT leaf sequencing
Authors: Long Troy , Chen Mingli , Jiang Steve , Lu Weiguo 
Published: September 2016

PurposeConventional step‐and‐shoot intensity modulated radiation therapy leaf sequencing methods, where a nonhomogeneous fluence map is converted to a set of apertures and associated intensities, assume that target fluence is stratified into a fixed number of discrete levels and/or aperture leaf positions are restricted to a discrete set of locations. These assumptions induce a deviation from the planned fluence map and/or reduce the feasible region of potential plans, respectively. A continuous leaf optimization (CLO) framework is developed as a postprocessing methodology to improve upon conventional leaf sequencing so that the resulting plan avoids these two main drawbacks.MethodsThe CLO model directly represents leaf positions and aperture intensities with continuous variables with the goal of reproducing some target fluence profile. Fluence through leaf edges is modeled using the error function, and continuous fluence is approximated using a 0.1 mm discretization across the aperture opening. Conventional leaf sequencing methods provide feasible solutions to the CLO model, and a first‐order descent algorithm is used to converge onto a locally optimal solution.ResultsAs a proof‐of‐concept, the authors test this framework on 1D (single leaf pair) fluence maps. The CLO model was applied to conventional leaf sequencing and direct aperture optimization solutions. Consistent improvements to existing leaf sequencing methods were found when tested on 232 generated instances of potential target fluence. In addition to improvements in matching the target fluence, the CLO model was able to keep MUs at similar values to the initial conventional sequence.ConclusionsThe CLO model can improve upon existing leaf sequencing methods by avoiding the restrictions of fluence stratification and discretized leaf positions. This study lays the foundation for future models and solution methodologies that can incorporate continuous leaf positions explicitly into the treatment planning model.
Automatic multiorgan segmentation in CT images of the male pelvis using region‐specific hierarchical appearance cluster models
Authors: Li Dengwang , Zang Pengxiao , Chai Xiangfei , Cui Yi , Li Ruijiang , Xing Lei 
Published: September 2016

PurposeAccurate segmentation of pelvic organs in CT images is of great importance in external beam radiotherapy for prostate cancer. The aim of this studying is to develop a novel method for automatic, multiorgan segmentation of the male pelvis.MethodsThe authors’ segmentation method consists of several stages. First, a pretreatment includes parameterization, principal component analysis (PCA), and an established process of region‐specific hierarchical appearance cluster (RSHAC) model which was executed on the training dataset. After the preprocessing, online automatic segmentation of new CT images is achieved by combining the RSHAC model with the PCA‐based point distribution model. Fifty pelvic CT from eight prostate cancer patients were used as the training dataset. From another 20 prostate cancer patients, 210 CT images were used for independent validation of the segmentation method.ResultsIn the training dataset, 15 PCA modes were needed to represent 95% of shape variations of pelvic organs. When tested on the validation dataset, the authors’ segmentation method had an average Dice similarity coefficient and mean absolute distance of 0.751 and 0.371 cm, 0.783 and 0.303 cm, 0.573 and 0.604 cm for prostate, bladder, and rectum, respectively. The automated segmentation process took on average 5 min on a personal computer equipped with Core 2 Duo CPU of 2.8 GHz and 8 GB RAM.ConclusionsThe authors have developed an efficient and reliable method for automatic segmentation of multiple organs in the male pelvis. This method should be useful for treatment planning and adaptive replanning for prostate cancer radiotherapy. With this method, the physicist can improve the work efficiency and stability.
DNA Targeting as a Likely Mechanism Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics
Authors: Opperman Timothy J. , Kwasny Steven M. , Li Jessica Bo , Lewis Mark A. , Aiello Daniel , Williams John D. , Peet Norton P. , Moir Donald T. , Bowlin Terry L. , Long Eric C. 
Published: September 2016

ABSTRACT

We previously reported the synthesis and biological activity of a series of cationic bis-indoles with potent, broad-spectrum antibacterial properties. Here, we describe mechanism of action studies to test the hypothesis that these compounds bind to DNA and that this target plays an important role in their antibacterial outcome. The results reported here indicate that the bis-indoles bind selectively to DNA at A/T-rich sites, which is correlated with the inhibition of DNA and RNA synthesis in representative Gram-positive (
Staphylococcus aureus
) and Gram-negative (
Escherichia coli
) organisms. Further, exposure of
E. coli
and
S. aureus
to representative bis-indoles resulted in induction of the DNA damage-inducible SOS response. In addition, the bis-indoles were found to be potent inhibitors of cell wall biosynthesis; however, they do not induce the cell wall stress stimulon in
S. aureus
, suggesting that this pathway is inhibited by an indirect mechanism. In light of these findings, the most likely basis for the observed activities of these compounds is their ability to bind to the minor groove of DNA, resulting in the inhibition of DNA and RNA synthesis and other secondary effects.
Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin
Authors: Ong Voon , Hough Grayson , Schlosser Michael , Bartizal Ken , Balkovec James M. , James Kenneth D. , Krishnan B. Radha 
Published: September 2016

ABSTRACT

Fungal infections pose a significant public health burden with high morbidity and mortality. CD101 is a novel echinocandin under development for the treatment and prevention of systemic
Candida
infections. Preclinical studies were conducted to evaluate the metabolic stability, plasma protein binding, pharmacokinetics, toxicity, and efficacy of CD101 at various dose levels. CD101 was stable to biotransformation in rat, monkey, and human liver microsomes and rat, monkey, dog, and human hepatocytes.
In vitro
studies suggest minimal interaction with recombinant cytochrome P450 enzymes (50% inhibitory concentrations [IC
50
s] of >10 μM). Similar to anidulafungin, CD101 bound avidly (>98%) to human, mouse, rat, and primate plasma proteins. In a 2-week repeat-dose comparison study, CD101 was well tolerated in rats (no effects on body weight, hematology, coagulation, or urinalysis). In contrast, administration of anidulafungin (at comparable exposure levels) resulted in reduced body weight, decreases in red blood cell, hemoglobin, hematocrit, mean cell volume, mean corpuscular hemoglobin, platelet, and reticulocyte counts, increases in neutrophil and eosinophil counts, polychromasia, and decreased activated partial thromboplastin time. Elevated plasma transaminases, total bilirubin, cholesterol, and globulin, dark and enlarged spleens, and single-cell hepatocyte necrosis were also observed for anidulafungin but not CD101. Hepatotoxicity may be due to the inherent chemical lability of anidulafungin generating potentially reactive intermediates. A glutathione trapping experiment confirmed the formation of a reactive species from anidulafungin, whereas CD101 did not exhibit instability or reactive intermediates. CD101 showed antifungal activity against
Candida
and
Aspergillus
infections in neutropenic mice. These preclinical studies demonstrated that CD101 is chemically and metabolically stable, well tolerated with no hepatotoxicity, and efficacious as an antifungal agent.
A Modified P1 Moiety Enhances
In Vitro
Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and
In Vitro
Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413
Authors: Amano Masayuki , Salcedo-Gómez Pedro Miguel , Zhao Rui , Yedidi Ravikiran S. , Das Debananda , Bulut Haydar , Delino Nicole S. , Sheri Venkata Reddy , Ghosh Arun K. , Mitsuya Hiroaki 
Published: September 2016

ABSTRACT

We report here that GRL-10413, a novel nonpeptidic HIV-1 protease inhibitor (PI) containing a modified P1 moiety and a hydroxyethylamine sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC
50
] of 0.00035 to 0.0018 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC
50
] = 35.7 μM). GRL-10413 blocked the infectivity and replication of HIV-1
NL4-3
variants selected by use of atazanavir, lopinavir, or amprenavir (APV) at concentrations of up to 5 μM (EC
50
= 0.0021 to 0.0023 μM). GRL-10413 also maintained its strong antiviral activity against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to various antiviral regimens after long-term antiretroviral therapy. The development of resistance against GRL-10413 was significantly delayed compared to that against APV. In addition, GRL-10413 showed favorable central nervous system (CNS) penetration properties as assessed with an
in vitro
blood-brain barrier (BBB) reconstruction system. Analysis of the crystal structure of HIV-1 protease in complex with GRL-10413 demonstrated that the modified P1 moiety of GRL-10413 has a greater hydrophobic surface area and makes greater van der Waals contacts with active site amino acids of protease than in the case of darunavir. Moreover, the chlorine substituent in the P1 moiety interacts with protease in two distinct configurations. The present data demonstrate that GRL-10413 has desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants, with favorable CNS penetration capability, and that the newly modified P1 moiety may confer desirable features in designing novel anti-HIV-1 PIs.
Dietary Composition Influences Incidence of Helicobacter pylori-Induced Iron Deficiency Anemia and Gastric Ulceration
Authors: Beckett Amber C. , Piazuelo M. Blanca , Noto Jennifer M. , Peek Richard M. , Washington M. Kay , Algood Holly M. Scott , Cover Timothy L. 
Published: September 2016

ABSTRACT

Epidemiologic studies have provided conflicting data regarding an association between
Helicobacter pylori
infection and iron deficiency anemia (IDA) in humans. Here, a Mongolian gerbil model was used to investigate a potential role of
H. pylori
infection, as well as a possible role of diet, in
H. pylori-
associated IDA. Mongolian gerbils (either
H. pylori
infected or uninfected) received a normal diet or one of three diets associated with increased
H. pylori
virulence: high-salt, low-iron, or a combination of a high-salt and low-iron diet. In an analysis of all infected animals compared to uninfected animals (independent of diet),
H. pylori-
infected gerbils had significantly lower hemoglobin values than their uninfected counterparts at 16 weeks postinfection (
P
< 0.0001). The mean corpuscular volume (MCV) and serum ferritin values were significantly lower in
H. pylori-
infected gerbils than in uninfected gerbils, consistent with IDA. Leukocytosis and thrombocytosis were also detected in infected gerbils, indicating the presence of a systemic inflammatory response. In comparison to uninfected gerbils,
H. pylori
-infected gerbils had a higher gastric pH, a higher incidence of gastric ulcers, and a higher incidence of fecal occult blood loss. Anemia was associated with the presence of gastric ulceration but not gastric cancer. Infected gerbils consuming diets with a high salt content developed gastric ulcers significantly more frequently than gerbils consuming a normal-salt diet, and the lowest hemoglobin levels were in infected gerbils consuming a high-salt/low-iron diet. These data indicate that
H. pylori
infection can cause IDA and that the composition of the diet influences the incidence and severity of
H. pylori-
induced IDA.