bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of Linezolid Resistance among Coagulase-Negative Staphylococci Determined by Whole-Genome Sequencing
Authors: Tewhey Ryan , Gu Bing , Kelesidis Theodoros , Charlton Carmen , Bobenchik April , Hindler Janet , Schork Nicholas J. , Humphries Romney M.
Published: May 2014

Linezolid resistance is uncommon among staphylococci, but approximately 2% of clinical isolates of coagulase-negative staphylococci (CoNS) may exhibit resistance to linezolid (MIC, ≥8 µg/ml). We performed whole-genome sequencing (WGS) to characterize the resistance mechanisms and genetic backgrounds of 28 linezolid-resistant CoNS (21
Staphylococcus epidermidis
isolates and 7
Staphylococcus haemolyticus
isolates) obtained from blood cultures at a large teaching health system in California between 2007 and 2012. The following well-characterized mutations associated with linezolid resistance were identified in the 23S rRNA: G2576U, G2447U, and U2504A, along with the mutation C2534U. Mutations in the L3 and L4 riboproteins, at sites previously associated with linezolid resistance, were also identified in 20 isolates. The majority of isolates harbored more than one mutation in the 23S rRNA and L3 and L4 genes. In addition, the
cfr
methylase gene was found in almost half (48%) of
S. epidermidis
isolates.
cfr
had been only rarely identified in staphylococci in the United States prior to this study. Isolates of the same sequence type were identified with unique mutations associated with linezolid resistance, suggesting independent acquisition of linezolid resistance in each isolate.

IMPORTANCE
Linezolid is one of a limited number of antimicrobials available to treat drug-resistant Gram-positive bacteria, but resistance has begun to emerge. We evaluated the genomes of 28 linezolid-resistant staphylococci isolated from patients. Multiple mutations in the rRNA and associated proteins previously associated with linezolid resistance were found in the isolates investigated, underscoring the multifocal nature of resistance to linezolid in
Staphylococcus
. Importantly, almost half the
S. epidermidis
isolates studied harbored a plasmid-borne
cfr
RNA methylase gene, suggesting that the incidence of
cfr
may be higher in the United States than previously documented. This finding has important implications for infection control practices in the United States. Further,
cfr
is commonly detected in bacteria isolated from livestock, where the use of phenicols, lincosamides, and pleuromutilins in veterinary medicine may provide selective pressure and lead to maintenance of this gene in animal bacteria.
Pneumocystis jirovecii Can Be Productively Cultured in Differentiated CuFi-8 Airway Cells
Authors: Schildgen Verena , Mai Stephanie , Khalfaoui Soumaya , Lüsebrink Jessica , Pieper Monika , Tillmann Ramona L. , Brockmann Michael , Schildgen Oliver
Published: May 2014

Although
Pneumocystis jirovecii
is a well-known and serious pathogen, all previous attempts to isolate, cultivate, and propagate this fungus have failed. This serious challenge in microbiology was addressed in the present study. We examined whether
P. jirovecii
could be cultured in a permanent three-dimensional air-liquid interface culture system formed by CuFi-8 cells, a differentiated pseudostratified airway epithelial cell line. Cultured pseudostratified cells were inoculated with bronchoalveolar fluid that had been confirmed to be positive for
P. jirovecii
using PCR. Five days later, the cells and basal medium were harvested and tested for
P. jirovecii
using quantitative PCR (qPCR), commercially available immunofluorescence detection assays, and Grocott staining of formalin-fixed, paraffin-embedded thin sections of infected-cell cultures. We successfully productively cultivated and propagated
P. jirovecii
from these
P. jirovecii
-positive bronchoalveolar lavage fluid (BALF) samples. Furthermore, we provide evidence that
P. jirovecii
induced cytopathic effects on lung epithelial cells and was even invasive in cell culture. To the best of our knowledge, the cell culture system developed herein represents the first methodology to enable molecular analyses of this pathogen’s life cycle and further
in vitro
studies of
P. jirovecii
, such as assessments of drug sensitivity and resistance as well as investigations of the pathogen’s stability against environmental factors and disinfectants.

IMPORTANCE
This is the first report of the successful productive cultivation and propagation of
Pneumocystis jirovecii
, a human-pathogenic fungus of major clinical significance. These findings are groundbreaking because they will influence the field of diagnostic microbiology, facilitate the testing of antibiotics against
P. jirovecii
, and enable stability studies of this pathogen when exposed to the environmental factors and chemicals that hospitals are required to use for disinfection. Because productively culturing
P. jirovecii
has been attempted unsuccessfully for several decades, this study represents a breakthrough in this field.
Migration of intrauterine devices with radiological findings: report on two cases
Authors: Gunbey Hediye Pinar , Tanrivermis Sayit Asli , Sedakat Idilman Ilkay , Aksoy Onur
Published: May 2014

Intrauterine devices (IUDs) are one of the most reliable and cheapest contraception methods. Our aims are to evaluate misplaced IUDs with radiological findings and to emphasise the importance of radiological imaging. We report two cases with radiological findings, one of complete migration to the abdomen without colonic perforation and one of partial migration to the bladder lumen with pregnancy. Uterine perforation and migration of IUDs are rare and undesirable complications. Suspected intra-abdominal IUDs can be evaluated with CT for precise localisation and possible complications without pregnancy.
Nintendo Wii related Achilles tendon rupture: first reported case and literature review of motion sensing video game injuries
Authors: Singh Rohit , Manoharan Gopikanthan , Moores Thomas Steven , Patel Amit
Published: May 2014

Achilles tendon ruptures tend to occur more commonly in healthy men between the ages of 30 and 50 years who have had no previous injury or problem reported in the affected leg. The injury is usually due to sudden forced plantar flexion of the foot, unexpected dorsiflexion of the foot and violent dorsiflexion of a plantar flexed foot, all of which occur during high impact activities. We present the first reported case of interactive activity with Nintendo Wii games that have resulted in Achilles tendon rupture in a 46-year-old man. There have been no previous reports of Achilles tendon rupture with Nintendo Wii usage; it is a relatively uncommon mode of injury and is rare in terms of epidemiology of motion sensing video game injuries.
Mesenchymal phosphaturic tumour: early detection of recurrence
Authors: Allevi Fabiana , Rabbiosi Dimitri , Mandalà Marco , Colletti Giacomo
Published: May 2014

The case of a recurrent phosphaturic mesenchymal tumour of the maxillary sinus 10 years after the first surgical excision is reported. The neoplasm first presented with paraneoplastic osteomalacia causing a pathological femur fracture. A right maxillary sinus tumour was identified and treated thereafter. The patient had no local symptoms and serum electrolytes returned to normal after surgical removal of the tumour. However, 10 years later, the patient's urine Ca and P levels increased and an octreoscan detected a new tumour in the right maxillary sinus. Early diagnosis prevented the effects of the paraneoplastic activity of the neoplasm. This case emphasises the importance of specific, close follow-up, because the neoplasm rarely produces local signs indicating its position. To our knowledge, this is the first reported case of a late relapse presenting without relevant symptoms (local pain or swelling or pathological fractures).
A ‘picturesque’ case of transition from subcutaneous to oral treatment in neonatal diabetes
Authors: Verstappen Stephanie , Mul Dick
Published: May 2014

We report a case of a 6-week-old infant with diabetes mellitus based on a genetic defect in the sulfonylurea receptor 1 (SUR1), an ATP-sensitive potassium (KATP) channel protein. A spectacular improvement in glucose regulation was shown by real-time continuous glucose monitoring when switching her from insulin to oral glibenclamide. Children with neonatal onset of diabetes deserve genetic testing in order to replace insulin with oral medication.
Primary lymphoma of the gallbladder accompanied by cirrhosis: CT and MRI findings
Authors: Batur Abdussamed , Odev Kemal
Published: May 2014

A 60-year-old patient with cirrhosis due to chronic hepatitis B was admitted to the hospital for routine controls. An ultrasonographic examination demonstrated a soft tissue mass originating from the gallbladder. A CT scan and after 3 months a dynamic liver MRI were performed for the possible diagnosis. Based on these imaging studies, laparoscopic cholecystectomy was performed. The histopathological examination diagnosed non-Hodgkin's lymphoma.
An incidental finding of a calcified right-atrial mass in a young patient treated with chemotherapy 20 years ago
Authors: Rathod Krishnaraj Sinhji , Westwood Mark , Uppal Rakesh , Deaner Andrew
Published: May 2014

We describe a case of a young woman presenting with lethargy and pleuritic chest pain. She had a medical history of leukaemia treated successfully 20 years ago with chemotherapy via a long line. Although initial investigations suggested a diagnosis of pulmonary embolism (PE; on CT pulmonary angiogram (CTPA)) and a possible thrombus in the right atrium, her symptoms appeared out of proportion in relation to this diagnosis. Further imaging using transthoracic echocardiography suggested the presence of a calcified mass in the right atrium. She underwent successful surgical resection of the mass which was found to be attached to the lateral wall of the right atrium. She made an uneventful recovery and continued on warfarin therapy for 6 months in view of the diagnosis of PE on CTPA. We believe the calcified mass was probably caused by the presence of a long line at the time of her chemotherapy.
Vascular hamartoma of the parotid gland
Authors: Al Omran Yasser , George Sara Mathew , Zonoozi Shahrzad , Al-Omran Mohammed-kamal
Published: May 2014

Hamartomas of the parotid gland are highly unusual. We present a case of a vascular hamartoma of the parotid gland arising as a 1.5 cm mass in a 5-year-old girl. As far as we are aware, no other case with the same features has been reported. We present this case to generate greater consideration of hamartomas as part of the differential diagnosis of parotid lesions, and to reflect over the criteria used to identify a hamartoma from other parotid lesions, as there appears to be some confusion in the literature.
Adductor longus muscle metastasis of transitional cell carcinoma of the urinary bladder
Authors: Koca Irfan , Ucar Mehmet , Bozdag Zehra , Alkan Samet
Published: May 2014

Bladder cancer most commonly spreads to the lymph nodes, lungs, bones and adrenal glands. Metastasis of bladder cancer to the skeletal muscle is extremely rare, as is the case in other malignancies. We report a case of a 62-year-old male patient who presented with pain and swelling in the right lower extremity and had difficulty walking, and who was later found to have metastasis in the adductor longus muscle 3 months after the initial diagnosis of transitional cell carcinoma of the urinary bladder. The study also provides a review of the current literature.
Transanal protrusion of ventriculoperitoneal shunt reflecting asymptomatic perforation of the large bowel
Authors: Plummer Nicholas Russell , Tokala Ajay , Date Ravindra S
Published: May 2014

Perforation into the gastrointestinal tract is a rare complication of ventriculoperitoneal shunt insertion. We present a case of transanal protrusion of the shunt catheter in an otherwise asymptomatic patient, with only transient signs of shunt failure some 2 months prior to presentation, and discuss treatment options to rationalise our decision to treat with laparotomy and preservation of the shunt.
Mitral valve prolapse and electrolyte abnormality: a dangerous combination for ventricular arrhythmias
Authors: Rajani Ali Raza , Murugesan Vagishwari , Baslaib Fahad Omar , Rafiq Muhammad Anwer
Published: May 2014

A 27-year-old woman with a history of bileaflet mitral valve prolapse and moderate mitral regurgitation presented to our emergency with untractable polymorphic wide complex tachycardia and unstable haemodynamics. After cardiopulmonary resuscitation, return of spontaneous circulation was achieved 30 min later. Her post-resuscitation ECG showed a prolonged QT interval which progressively normalised over the same day. Her laboratory investigations revealed hypocalcaemia while other electrolytes were within normal limits. A diagnosis of ventricular arrhythmia secondary to structural heart disease further precipitated by hypocalcaemia was made. Further hospital stay did not reveal a recurrence of prolonged QT interval or other arrhythmias except for an episode of non-sustained ventricular tachycardia. However, the patient suffered diffuse hypoxic brain encephalopathy secondary to prolonged cardiopulmonary resuscitation.
Responsiveness of motion sensors to detect change in sedentary and physical activity behaviour
Authors: Swartz Ann M , Rote Aubrianne E , Cho Young Ik , Welch Whitney A , Strath Scott J
Published: May 2014

Background

The purpose of this study was to determine the responsiveness of two motion sensors to detect change in sedentary behaviour (SB) and physical activity (PA) during an occupational intervention to reduce sitting time.

Methods

SB and PA were assessed using a hip-worn Actigraph GTX3 (AG) and a thigh-worn activPAL (AP) during three consecutive workdays throughout baseline and intervention periods. Mean scores at baseline and intervention were estimated by hierarchical linear models (HLM) with robust SEs, adjusting for random variance of average scores between participants. Change scores (mean baseline minus mean intervention) were calculated for each device. Response to change was assessed for each device using the standardised response mean.

Results

67 adults (45±11 years; 29.3±7.7 kg/m2) wore the acceleration-based motion sensors for 8.3 (SD=1.2) and 8.3 (SD=1.1) h during the baseline and intervention periods, respectively. HLM showed that AP sitting/lying time (−16.5 min, −5%), AP stepping (+7.5 min, 19%), AP steps/day (+838 steps/day, +22%), AP sit-to-stand transitions (+3, +10%), AG SB (−14.6 min, −4%), AG lifestyle moderate-intensity PA (LMPA, +4 min, +15%) and AG MPA (+3 min, 23%) changed significantly between the baseline and the intervention period. Standardised response means for AP sitting/lying time, stepping, steps/day, sit-to-stand transitions and AG SB, LMPA and MPA were above 0.3, indicating a small but similar responsiveness to change.

Conclusions

Responsiveness to change in SB and PA was similar and comparable for the AP and AG, indicating agreement across both measurement devices.
The CEA Second-Look Trial: a randomised controlled trial of carcinoembryonic antigen prompted reoperation for recurrent colorectal cancer
Authors: Treasure Tom , Monson Kathryn , Fiorentino Francesca , Russell Christopher
Published: May 2014

Objective

In patients who have undergone a potentially curative resection of colorectal cancer, does a ‘second-look’ operation to resect recurrence, prompted by monthly monitoring of carcinoembryonic antigen, confer a survival benefit?

Design

A randomised controlled trial recruiting patients from 1982 to 1993 was recovered under the Restoring Invisible and Abandoned Trials (RIAT) initiative.

Setting

58 hospitals in the UK.

Participants

From 1982 to 1993, 1447 patients were enrolled. Of these 216 met the criteria for carcinoembryonic antigen (CEA) elevation and were randomised to ‘Aggressive’ or ‘Conventional’ arms.

Interventions

‘Second-look’ surgery with intention to remove any recurrence discovered.

Primary outcome measure

Survival.

Results

By February 1993, 91/108 patients had died in the ‘Aggressive arm’ and 88/108 in the ‘Conventional’ arm (relative risk=1.16, 95% CI 0.87 to 1.37). By 2011 a further 25 randomised patients had died. Kaplan-Meier analysis showed no difference in long-term survival.

Conclusions

The trial was closed in 1993 following a recommendation from the Data Monitoring Committee that it was highly unlikely that any survival advantage would be demonstrated for CEA prompted second-look surgery. This conclusion was confirmed by repeat analysis of survival times after 20 years.

Trial registration number

ISRCTN76694943.
Impact of anaemia on clinical outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention: insights from the AFCAS registry
Authors: Puurunen Marja , Kiviniemi Tuomas , Nammas Wail , Schlitt Axel , Rubboli Andrea , Nyman Kai , Karjalainen Pasi , Kirchhof Paulus , Lip Gregory Y H , Airaksinen Juhani K E
Published: May 2014

Objectives

Anaemia has an adverse impact on the outcome in the general patient population undergoing percutaneous coronary intervention (PCI). The aim of this study was to analyse the impact of anaemia on the 12-month clinical outcome of patients with atrial fibrillation (AF) undergoing PCI and therefore requiring intense antithrombotic treatment. We hypothesised that anaemia might be associated with a worse outcome and more bleeding in these anticoagulated patients.

Setting

Data were collected from 17 secondary care centres in Europe.

Participants

Consecutive patients with AF undergoing PCI were enrolled in the prospective, multicenter AFCAS (Atrial Fibrillation undergoing Coronary Artery Stenting) registry. Altogether, 929 patients participated in the study. Preprocedural haemoglobin concentration was available for 861 (92.7%; 30% women). The only exclusion criteria were inability or unwillingness to give informed consent. Anaemia was defined as a haemoglobin concentration of <12 g/dL for women and <13 g/dL for men.

Outcome measures

The primary endpoint was occurrence of major adverse cardiac and cerebrovascular events (MACCE) or bleeding events.

Results

258/861 (30%) patients had anaemia. Anaemic patients were older, more often had diabetes, higher CHA2DS2-VASc scores, prior history of heart failure, chronic renal impairment and acute coronary syndrome. Anaemic patients had more MACCE than non-anaemic (29.1% vs 19.4%, respectively, p=0.002), and minor bleeding events (7.0% vs 3.3%, respectively, p=0.028), with a trend towards more total bleeding events (25.2% vs 21.7%, respectively, p=0.059). No difference was observed in antithrombotic regimens at discharge. In multivariate analysis, anaemia was an independent predictor of all-cause mortality at 12-month follow-up (hazard ratio 1.62, 95% CI 1.05 to 2.51, p=0.029).

Conclusions

Anaemia was a frequent finding in patients with AF referred for PCI. Anaemic patients had a higher all-cause mortality, more thrombotic events and minor bleeding events. Anaemia seems to be an identification of patients at risk for cardiovascular events and death.

Trial registration

ClinicalTrials.gov numberNCT00596570.
Cosmological constant from the emergent gravity perspective
Authors: Padmanabhan T. , Padmanabhan Hamsa
Published: May 2014

Observations indicate that our universe is characterized by a late-time accelerating phase, possibly driven by a cosmological constant Λ, with the dimensionless parameter [Formula: see text], where LP= (Għ/c3)1/2is the Planck length. In this review, we describe how the emergent gravity paradigm provides a new insight and a possible solution to the cosmological constant problem. After reviewing the necessary background material, we identify the necessary and sufficient conditions for solving the cosmological constant problem. We show that these conditions are naturally satisfied in the emergent gravity paradigm in which (i) the field equations of gravity are invariant under the addition of a constant to the matter Lagrangian and (ii) the cosmological constant appears as an integration constant in the solution. The numerical value of this integration constant can be related to another dimensionless number (called CosMIn) that counts the number of modes inside a Hubble volume that cross the Hubble radius during the radiation and the matter-dominated epochs of the universe. The emergent gravity paradigm suggests that CosMIn has the numerical value 4π, which, in turn, leads to the correct, observed value of the cosmological constant. Further, the emergent gravity paradigm provides an alternative perspective on cosmology and interprets the expansion of the universe itself as a quest towards holographic equipartition. We discuss the implications of this novel and alternate description of cosmology.
Output-Only Structural Health Monitoring for Deepwater Risers: Experimental Study of Wavelet Modified SOBI and Distributed Force Index Algorithm
Authors: Huang Chaojun , Nagarajaiah Satish
Published: May 2014

Risers are the conduits between the subsea wellhead and the drilling/production platform for development, production, gas lift or water injection purposes, which are also one of the most important and the most vulnerable components for deepwater floating platforms. To address the lack of appropriate global structural health monitoring (SHM) system for deepwater risers, this paper proposes a time-frequency domain approach using a wavelet modified second order blind identification (WMSOBI) method and combined distributed force change (CDFC) index. WMSOBI provides a reliable time-frequency domain identified modal properties of riser systems, even with large damping and under-determinate conditions. In addition, CDFC index generated from modal properties extracted by WMSOBI can accurately identify the damage location and damage level for both single and multiple crack scenarios. Details of experiments conducted on suspended pipe are presented. Both numerical and experimental verification are presented to validate the effectiveness of the proposed WMSOBI/CFDC algorithm and SHM system.
Nonlinear Transient Thermal Stress Analysis of Temperature-Dependent Hollow Cylinders Using a Finite Element Model
Authors: Zenkour Ashraf M. , Abbas Ibrahim A.
Published: May 2014

In this paper, the nonlinear transient thermal stress analysis is conducted for temperature-dependent hollow cylinders subjected to a decaying-with-time thermal field. By the finite element method, the highly nonlinear governing equations are solved. The time histories of temperature, displacement, and stress due to the decaying-with-time thermal load are computed. A sensitivity analysis includes the effects of exponent of the decayed heat flux and temperature-dependency of density and material properties is carried out. Numerical results show some interesting characteristics of the thermoelastic behaviors of the hollow cylinders studied. In particular, the effect of temperature-dependency of the material properties on the thermoelastic parameters was demonstrated to be significant.
Do Electromagnetic Waves Exist in a Short Cable at Low Frequencies? What Does Physics Say?
Authors: Chen Hsien-Pu , Kish Laszlo B. , Granqvist Claes-Göran , Schmera Gabor
Published: May 2014

We refute a physical model, recently proposed by Gunn, Allison and Abbott (GAA) [ http://arxiv.org/pdf/1402.2709v2.pdf ], to utilize electromagnetic waves for eavesdropping on the Kirchhoff-law–Johnson-noise (KLJN) secure key distribution. Their model, and its theoretical underpinnings, is found to be fundamentally flawed because their assumption of electromagnetic waves violates not only the wave equation but also the second law of thermodynamics, the principle of detailed balance, Boltzmann's energy equipartition theorem, and Planck's formula by implying infinitely strong blackbody radiation. We deduce the correct mathematical model of the GAA scheme, which is based on impedances at the quasi-static limit. Mathematical analysis and simulation results confirm our approach and prove that GAA's experimental interpretation is incorrect too.
EFFECTIVENESS OF OPINION INFLUENCE APPROACHES IN HIGHLY CLUSTERED ONLINE SOCIAL NETWORKS
Authors: FALETRA MELISSA , PALMER NATHAN , MARSHALL JEFFREY S.
Published: May 2014

A mathematical model was developed for opinion propagation on online social networks using a scale-free network with an adjustable clustering coefficient. Connected nodes influence each other when the difference between their opinion values is less than a threshold value. The model is used to examine effectiveness of three different approaches for influencing public opinion. The approaches examined include (1) a "Class", defined as an approach (such as a class or book) that greatly influences a small, randomly selected portion of the population, (2) an "Advertisement", defined as an approach (such as a TV or online advertisement) that has a small influence at each viewing on a large randomly selected portion of the population, and (3) an "App", defined as an approach (such as a Facebook game or smartphone "App") that spreads via the online social network (rather than randomly) and has a small influence at each viewing on the affected population. The Class and Advertisement approaches result in similar overall influence on the population, despite the fact that these approaches are highly different. In contrast, the App approach has a much more significant effect on opinion values of users occupying clusters within the social network compared to the overall population.
The Influence of Perceived Innovation and Brand Awareness on Purchase Intention of Innovation Product — An Example of iPhone
Authors: Wu Shwu-Ing , Ho Li-Pang
Published: May 2014

As the number of mobile phone users has increased steadily in recent years, mobile phone manufacturers continuously compete to be the first to introduce innovative products to the market in the hope of gaining a larger market share. Currently, the innovation product has become the target of competition in the mobile phone industry. Thus, this study uses 3G mobile phone as an example, through literature review and empirical research to examine whether perceived innovation and brand awareness have a significant impact on the perceived quality, perceived value, and purchase intention toward innovation products. An analysis of 595 effective questionnaires produced five main findings: (i) consumer-perceived innovation has significant and positive impact on the perceived quality and purchase intention; (ii) brand awareness has significant and positive impact on the consumer-perceived quality; (iii) perceived quality has significant and positive impact on perceived value; (iv) consumer-perceived value has significant and positive impact on purchase intention; however, (v) consumer-perceived quality has significant and negative impact on purchase intention. Moreover, this study evidences that consumer-perceived innovation has higher effect on purchase intention than brand awareness. These results can provide useful information to mobile phone industry to carry out innovation planning and marketing strategy.
Nanocomposite multilayer capacitors comprising BaTiO3@TiO2 and poly(vinylidene fluoride-hexafluoropropylene) for dielectric-based energy storage
Authors: Rahimabady Mojtaba , Lu Li , Yao Kui
Published: May 2014

Multilayer dielectric capacitors were fabricated from nanocomposite precursor comprised of BaTiO 3@ TiO 2 core–shell nanosized particles and poly(vinylidene fluoride–hexafluoropropylene) (P(VDF–HFP)) polymer matrix (20 vol%). The multilayer capacitors showed very high discharge speed and high discharged energy density of around 2.5 J/cm3 at its breakdown field (~ 166 MV/m). The energy density of the nanocomposite multilayer capacitors was substantially higher than the energy density of commercially used power capacitors. Low cost, flexible structure, high discharge rate and energy density suggest that the nanocomposite multilayer capacitors are promising for energy storage applications in many power devices and systems.
Geochemical record of fluid flow and dolomitization of carbonate platforms: ascending freshwater–mesohaline mixing, Miocene of Spain
Authors: Li Zhaoqi , Goldstein Robert H. , Franseen Evan K.
Published: May 2014

This paper constrains fluid flow and chemistry in Miocene dolomites of Spain, where dolomitization has been ascribed to ascending freshwater–mesohaline mixing. End-Miocene dolomite formed as replacement and cement with the same widespread cathodoluminescence. Fluid inclusion final melting temperatures of ice (
T
m ice
: −0.2 to −2.3 °C) indicate mixing of freshwater and evaporated seawater. δ
18
O and δ
13
C data mostly show positive covariation, and only some have variable δ
13
C and invariant δ
18
O, arguing that mixing was more important than sulphate reduction. Data range from +0.9 to +6.0‰ for δ
18
O and from −4.5 to +3.0‰ for δ
13
C (VPDB (Vienna Pee Dee Belemnite)). Lower stratigraphic units are more depleted isotopically than upper units, suggesting upwards flow of freshwater.
87
Sr/
86
Sr values (0.70866–0.70904) range from less than to greater than late Miocene seawater. δ
18
O, δ
13
C and Sr analyses show that freshwater interacted with basement, confirming injection of freshwater from below. Upwards flow of freshwater, driven by low density and hydraulic head, created fluid mixing and CO
2
degassing. Comparison of La Molata dolomite to other dolomites of the western Mediterranean suggests that ascending freshwater–mesohaline mixing may be widespread, and that local composition of basement is not the primary driver of dolomitization. The model is broadly applicable to carbonates adjacent to highs, where freshwater discharged into slightly evaporated seawater.
Citrulline does not enhance blood flow, microvascular circulation, or myofibrillar protein synthesis in elderly men at rest or following exercise
Authors: Churchward-Venne Tyler A. , Cotie Lisa M. , MacDonald Maureen J. , Mitchell Cameron J. , Prior Todd , Baker Steven K. , Phillips Stuart M.
Published: May 2014

Aging is associated with anabolic resistance, a reduced sensitivity of myofibrillar protein synthesis (MPS) to postprandial hyperaminoacidemia, particularly with low protein doses. Impairments in postprandial skeletal muscle blood flow and/or microvascular perfusion with hyperaminoacidemia and hyperinsulinemia may contribute to anabolic resistance. We examined whether providing citrulline, a precursor for arginine and nitric oxide synthesis, would increase arterial blood flow, skeletal muscle microvascular perfusion, MPS, and signaling through mTORC1. Twenty-one elderly males (65–80 yr) completed acute unilateral resistance exercise prior to being assigned to ingest a high dose (45 g) of whey protein (WHEY) or a low dose (15 g) of whey protein with 10 g of citrulline (WHEY + CIT) or with 10 g of nonessential amino acids (WHEY + NEAA). A primed, continuous infusion of l-[ ring-13C6] phenylalanine with serial muscle biopsies was used to measure MPS and protein phosphorylation, whereas ultrasound was used to measure microvascular circulation under basal and postprandial conditions in both a rested (FED) and exercised (EX-FED) leg. Argininemia was greater in WHEY + CIT vs. WHEY and WHEY + NEAA from 30 to 300 min postexercise ( P < 0.001), but there were no treatment differences in blood flow or microvascular perfusion (all P > 0.05). Phosphorylation of p70S6K-Thr389was greater in WHEY vs. WHEY + NEAA ( P = 0.02). Postprandial MPS was greater in WHEY vs. WHEY + CIT and WHEY + NEAA under both FED (WHEY: ∼128%; WHEY + CIT: ∼56%; WHEY + NEAA: ∼38%) and EX-FED (WHEY: ∼251%; WHEY + CIT: ∼124%; WHEY + NEAA: ∼108%) conditions ( P = 0.003). Citrulline coingestion with a low quantity of protein was ineffective in augmenting the anabolic properties of protein compared with nonessential amino acids.
Mediobasal hypothalamic PTEN modulates hepatic insulin resistance independently of food intake in rats
Authors: Sumita Takashi , Ono Hiraku , Suzuki Tokuko , Sakai Gota , Inukai Kouichi , Katagiri Hideki , Asano Tomoichiro , Katayama Shigehiro , Awata Takuya
Published: May 2014

Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.
FFA-induced hepatic insulin resistance in vivo is mediated by PKCδ, NADPH oxidase, and oxidative stress
Authors: Pereira Sandra , Park Edward , Mori Yusaku , Haber C. Andrew , Han Ping , Uchida Toyoyoshi , Stavar Laura , Oprescu Andrei I. , Koulajian Khajag , Ivovic Alexander , Yu Zhiwen , Li Deling , Bowman Thomas A. , Dewald Jay , El-Benna Jamel , Brindley David N. , Gutierrez-Juarez Roger , Lam Tony K. T. , Najjar Sonia M. , McKay Robert A. , Bhanot Sanjay , Fantus I. George , Giacca Adria
Published: May 2014

Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-l-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47phox(marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling.
miR-24 regulates menin in the endocrine pancreas
Authors: Vijayaraghavan Jyothi , Maggi Elaine C. , Crabtree Judy S.
Published: May 2014

Menin, the product of the MEN1 gene, functions as a tumor suppressor and was first identified in 1997 due to its causative role in the endocrine tumor disorder multiple endocrine neoplasia, type 1 (MEN1). More recently, menin has been identified as a key player in pancreatic islet biology with the observation of an inverse relationship between menin levels and pancreatic islet proliferation. However, the factors regulating menin and the MEN1 gene in the pancreas are poorly understood. Here, we describe the regulation of menin by miR-24 and demonstrate that miR-24 directly decreases menin levels and impacts downstream cell cycle inhibitors in MIN6 insulinoma cells and in βlox5 immortalized β-cells. This regulation of menin impacts cell viability and proliferation in βlox5 cells. Furthermore, our data show a feedback regulation between miR-24 and menin that is present in the pancreas, suggesting that miR-24 regulates menin levels in the pancreatic islet.
Targeted metabolomics and mathematical modeling demonstrate that vitamin B-6 restriction alters one-carbon metabolism in cultured HepG2 cells
Authors: da Silva Vanessa R. , Ralat Maria A. , Quinlivan Eoin P. , DeRatt Barbara N. , Garrett Timothy J. , Chi Yueh-Yun , Frederik Nijhout H. , Reed Michael C. , Gregory Jesse F.
Published: May 2014

Low vitamin B-6 nutritional status is associated with increased risk for cardiovascular disease and certain cancers. Pyridoxal 5′-phosphate (PLP) serves as a coenzyme in many cellular processes, including several reactions in one-carbon (1C) metabolism and the transsulfuration pathway of homocysteine catabolism. To assess the effect of vitamin B-6 deficiency on these processes and associated pathways, we conducted quantitative analysis of 1C metabolites including tetrahydrofolate species in HepG2 cells cultured in various concentrations of pyridoxal. These results were compared with predictions of a mathematical model of 1C metabolism simulating effects of vitamin B-6 deficiency. In cells cultured in vitamin B-6-deficient medium (25 or 35 nmol/l pyridoxal), we observed >200% higher concentrations of betaine ( P < 0.05) and creatinine ( P < 0.05) and >60% lower concentrations of creatine ( P < 0.05) and 5,10-methenyltetrahydrofolate ( P < 0.05) compared with cells cultured in medium containing intermediate (65 nmol/l) or the supraphysiological 2,015 nmol/l pyridoxal. Cystathionine, cysteine, glutathione, and cysteinylglycine, which are components of the transsulfuration pathway and subsequent reactions, exhibited greater concentrations at the two lower vitamin B-6 concentrations. Partial least squares discriminant analysis showed differences in overall profiles between cells cultured in 25 and 35 nmol/l pyridoxal vs. those in 65 and 2,015 nmol/l pyridoxal. Mathematical model predictions aligned with analytically derived results. These data reveal pronounced effects of vitamin B-6 deficiency on 1C-related metabolites, including previously unexpected secondary effects on creatine. These results complement metabolomic studies in humans demonstrating extended metabolic effects of vitamin B-6 insufficiency.
Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML
Authors: Vachhani Pankit , Bose Prithviraj , Rahmani Mohamed , Grant Steven
Published: May 2014

Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.
Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment
Authors: Wood Charles E. , Rabaglino Maria Belen , Richards Elaine , Denslow Nancy , Zarate Miguel A. , Chang Eileen I. , Keller-Wood Maureen
Published: May 2014

Estradiol (E2) is a well-known modulator of fetal neuroendocrine activity and has been proposed as a critical endocrine signal readying the fetus for birth and postnatal life. To investigate the modulatory role of E2 on fetal stress responsiveness and the response of the fetal brain to asphyxic stress, we subjected chronically catheterized fetal sheep to a transient (10 min) brachiocephalic artery occlusion (BCO) or sham occlusion. Half of the fetuses received subcutaneous pellets that increased plasma E2 concentrations within the physiological range. Hypothalamic mRNA was analyzed using the Agilent 8x15k ovine array (019921), processed and annotated as previously reported by our laboratory. Analysis of the data by ANOVA revealed that E2 differentially regulated (DR) 561 genes, and BCO DR 894 genes compared with control and E2+BCO DR 1,153 genes compared with BCO alone (all P < 0.05). E2 upregulated epigenetic pathways and downregulated local steroid biosynthesis but did not significantly involve genes known to directly respond to the estrogen receptor. Brachiocephalic occlusion upregulated kinase pathways as well as genes associated with lymphocyte infiltration into the brain and downregulated neuropeptide synthesis. E2 upregulated immune- and apoptosis-related pathways after BCO and reduced kinase and epigenetic pathway responses to the BCO. Responses to BCO are different from responses to hypoxic hypoxia suggesting that mechanisms of responses to these two forms of brain hypoxia are distinct. We conclude that cerebral ischemia caused by BCO might stimulate lymphocyte infiltration into the brain and that this response appears to be modified by estradiol.
VDR Activity Is Differentially Affected by Hic-5 in Prostate Cancer and Stromal Cells
Authors: Solomon Joshua D. , Heitzer Marjet D. , Liu Teresa T. , Beumer Jan H. , Parise Robert A. , Normolle Daniel P. , Leach Damien A. , Buchanan Grant , DeFranco Donald B.
Published: May 2014

Patients with prostate cancer treated with androgen deprivation therapy (ADT) eventually develop castrate-resistant prostate cancer (CRPC). 1,25-Dihydroxyvitamin D3 (1,25D3/calcitriol) is a potential adjuvant therapy that confers antiproliferative and pro-differentiation effects in vitro, but has had mixed results in clinical trials. The impact of the tumor microenvironment on 1,25D3 therapy in patients with CRPC has not been assessed. Transforming growth factor β (TGFβ), which is associated with the development of tumorigenic “reactive stroma” in prostate cancer, induced vitamin D3 receptor (VDR) expression in the human WPMY-1 prostate stromal cell line. Similarly, TGFβ enhanced 1,25D3-induced upregulation of CYP24A1, which metabolizes 1,25D3 and thereby limits VDR activity. Ablation of Hic-5, a TGFβ-inducible nuclear receptor coregulator, inhibited basal VDR expression, 1,25D3-induced CYP24A1 expression and metabolism of 1,25D3 and TGFβ-enhanced CYP24A1 expression. A Hic-5–responsive sequence was identified upstream (392–451 bp) of the CYP24A1 transcription start site that is occupied by VDR only in the presence of Hic-5. Ectopic expression of Hic-5 sensitized LNCaP prostate tumor cells to growth-inhibitory effects of 1,25D3 independent of CYP24A1. The sensitivity of Hic-5–expressing LNCaP cells to 1,25D3-induced growth inhibition was accentuated in coculture with Hic-5–ablated WPMY-1 cells. Therefore, these findings indicate that the search for mechanisms to sensitize prostate cancer cells to the antiproliferative effects of VDR ligands needs to account for the impact of VDR activity in the tumor microenvironment.

Implications: Hic-5 acts as a coregulator with distinct effects on VDR transactivation, in prostate cancer and stromal cells, and may exert diverse effects on adjuvant therapy designed to exploit VDR activity in prostate cancer. Mol Cancer Res; 12(8); 1166–80. ©2014 AACR.
Happy and Sad Judgements in Dependence on Mode and Note Density in Patients with Mild Cognitive Impairment and Early-Stage Alzheimer's Disease
Authors: Kerer Manuela , Marksteiner Josef , Hinterhuber Hartmann , Kemmler Georg , Bliem Harald R. , Weiss Elisabeth M.
Published: May 2014

Background: In Western cultures it has often been assumed that the experience of happy or sad emotions while listening to music is clearly correlated to the key (mode) and the tempo of the musical piece. Recent studies point towards more complex dependencies, but knowledge in this line of research is still very limited, especially regarding the experience of music for persons with memory-related disorders such as dementia. Objective: This pilot study explores the emotional content of music for patients with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD) and compares them to healthy subjects. Methods: A new test was specifically designed for this study and presented to 10 patients with MCI diagnosis, 10 with AD diagnosis and 23 controls. The test comprised musical stimuli consisting of chords and short musical pieces in major and minor mode with variable note density (number of notes per second). Results: In the current study no significant correlation between key and the attribution of ‘happy' or ‘sad' judgements to a musical piece could be found in all groups. Note density, however, was shown to exhibit a strong influence on happy/sad judgements in all groups. Conclusion: Our findings indicate that the note density of a musical piece is much more important for happy/sad judgements than the key. Furthermore, the diagnosis MCI and early AD had no influence on the attribution of emotional expressions to musical pieces, corroborating recent findings of spared memory for music in these patient groups.
Association between Serum 25-Hydroxyvitamin D Levels and TTN
Authors: Konca Capan , Kahramaner Zelal , Bulbul Mehmet , Erdemir Aydin , Tekin Mehmet , Ercan Sumeyye , Yilmaz Sedat , Arpaci Abdullah , Turgut Mehmet
Published: May 2014

Aim: To investigate the association between serum 25-hydroxyvitamin D (25(OH)D3) levels and transient tachypnea of the newborn (TTN). Methods: Calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathormone (PTH) and serum 25(OH)D3 levels were measured in 51 infants diagnosed with TTN and 59 healthy control infants for comparison. Demographic factors including gestational age, birth weight, gender, delivery mode, parity, vitamin D supplementation during pregnancy and severity of TTN were recorded. Results: The serum levels of 25(OH)D3 were significantly lower in infants with TTN compared to infants with no respiratory distress (p < 0.01). There was no statistically significant difference in serum Ca, P and ALP levels between the groups while the serum levels of PTH were significantly higher in the study group (p < 0.01). No correlation was found between the serum 25(OH)D3 levels and severity of TTN. Vitamin D supplementation (400 IU/day) during pregnancy did not affect the serum levels of newborns. Conclusion: Our data suggests that lower 25(OH)D3 serum levels are associated with an increased risk of TTN and vitamin D may have a role in the pathogenesis of TTN.