bluuebunny/crossref_metadata_2025 huggingface dataset:
Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs
Authors: Farrell Helen E. , Lawler Clara , Oliveira Martha T. , Davis-Poynter Nick , Stevenson Philip G.
Published: December 2015

Cytomegaloviruses (CMVs) infect the lungs and cause pathological damage there in immunocompromised hosts. How lung infection starts is unknown. Inhaled murine CMV (MCMV) directly infected alveolar macrophages (AMs) and type 2 alveolar epithelial cells (AEC2s) but not type 1 alveolar epithelial cells (AEC1s). In contrast, herpes simplex virus 1 infected AEC1s and murid herpesvirus 4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from a human CMV IE1 promoter; but most IE1-positive cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched the fluorochrome expression of <5% of floxed MCMV in the lungs. In contrast, CD11C-cre mice exhibited fluorochrome switching in >90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion increased MCMV titers in the lung during the acute phase of infection. Thus, the influence of AMs was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly; infection occurred mainly via AEC2s. Mice infected with an MCMV mutant lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed levels of lung infection equivalent to those of wild-type MCMV-infected mice. The level of lung infiltration by Gr-1-positive cells infected with the MCMV m131/m129-null mutant was modestly different from that for wild-type MCMV-infected lungs. These results are consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provide local amplification.

IMPORTANCE
Cytomegaloviruses (CMVs) chronically and systemically infect most mammals. Human CMV infection is usually asymptomatic but causes lung disease in people with poor immune function. As human infection is hard to analyze, studies with related animal viruses provide important insights. We show that murine CMV has two targets in the lungs: macrophages and surfactant-secreting epithelial cells. Acute virus replication occurred largely in epithelial cells. Macrophages had an important defensive role, as their removal increased the level of infection. These results establish the dual nature of lung infection, with local virus replication occurring in epithelial cells and spread occurring via quiescently infected macrophages. Distinct therapies may be needed to target these contrasting events.
Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection
Authors: Woods Tyson A. , Du Min , Carmody Aaron , Peterson Karin E.
Published: December 2015

Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection. Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY
−/−
mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wild-type mice. Both Ly6C
hi
inflammatory and Ly6C
lo
alternatively activated monocytes were increased in the CNS of NPY
−/−
mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types.
Ex vivo
analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY
−/−
mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease.

IMPORTANCE
Monocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY, can suppress monocyte trafficking to the brain and reduce retrovirus-induced neurological disease.
Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection
Authors: Yun Nadezhda E. , Ronca Shannon , Tamura Atsushi , Koma Takaaki , Seregin Alexey V. , Dineley Kelly T. , Miller Milagros , Cook Rebecca , Shimizu Naoki , Walker Aida G. , Smith Jeanon N. , Fair Joseph N. , Wauquier Nadia , Bockarie Bayon , Khan Sheik Humarr , Makishima Tomoko , Paessler Slobodan
Published: December 2015

Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss.

IMPORTANCE
Sensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.
Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain
Authors: Beatman Erica L. , Massey Aaron , Shives Katherine D. , Burrack Kristina S. , Chamanian Mastooreh , Morrison Thomas E. , Beckham J. David
Published: December 2015

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10
4.5
infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease.

IMPORTANCE
Neuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alpha-synuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS.
Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral
trans
-Infection of CD4
+
T Cells
Authors: Jiang Ai-Ping , Jiang Jin-Feng , Wei Ji-Fu , Guo Ming-Gao , Qin Yan , Guo Qian-Qian , Ma Li , Liu Bao-Chi , Wang Xiaolei , Veazey Ronald S. , Ding Yong-Bing , Wang Jian-Hua
Published: December 2015

The gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4
+
T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viral
trans
-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.

IMPORTANCE
In this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1
trans
-infection of CD4
+
T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.
Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies
Authors: Jiang Bingfu , Himmelsbach Kiyoshi , Ren Huimei , Boller Klaus , Hildt Eberhard
Published: December 2015

In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by α-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles.

IMPORTANCE
This study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.
MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells
Authors: Opp Silvana , Vieira Daniel A. S. A. , Schulte Bianca , Chanda Sumit K. , Diaz-Griffero Felipe
Published: December 2015

MxB restricts HIV-1 infection by directly interacting with the HIV-1 core, which is made of viral capsid; however, the contribution of MxB to the HIV-1 restriction observed in alpha interferon (IFN-α)-treated human cells is unknown. To understand this contribution, we used HIV-1 bearing the G208R capsid mutant (HIV-1-G208R), which overcomes the restriction imposed by cells expressing MxB. Here we showed that the reason why MxB does not block HIV-1-G208R is that MxB does not interact with HIV-1 cores bearing the mutation G208R. To understand whether MxB contributes to the HIV-1 restriction imposed by IFN-α-treated human cells, we challenged IFN-α-treated cells with HIV-G208R and found that MxB does not contribute to the restriction imposed by IFN-α-treated cells. To more directly test the contribution of MxB, we challenged IFN-α-treated human cells that are knocked out for the expression of MxB with HIV-1. These experiments suggested that MxB does not contribute to the HIV-1 restriction observed in IFN-α-treated human cells.

IMPORTANCE
MxB is a restriction factor that blocks HIV-1 infection in human cells. Although it has been postulated that MxB is the factor that blocks HIV-1 infection in IFN-α-treated cells, this is a hard concept to grasp due to the great number of genes that are induced by IFN-α in cells from the immune system. The work presented here elegantly demonstrates that MxB has minimal or no contribution to the ability of IFN-α-treated human cells to block HIV-1 infection. Furthermore, this work suggests the presence of novel restriction factors in IFN-α-treated human cells that block HIV-1 infection.
Verum versus Sham Manual Acupuncture for Migraine: A Systematic Review of Randomised Controlled Trials
Authors: Yang Yan , Que Qinghui , Ye Xiaode , Zheng Guo hua
Published: December 2015

Background

Manual acupuncture (MA) is commonly used as a treatment for migraine in China. However, its specific clinical effects have been challenged on the basis that some of its effects may relate to psychological or ‘placebo’ mechanisms.

Objective

To identify the effectiveness of verum MA compared with sham acupuncture for the treatment of migraine.

Methods

Eight electronic databases were searched for randomised controlled trials (RCTs) evaluating the effect of verum versus sham MA on migraine. The quality of included trials was assessed using the ‘risk of bias’ tool provided by the Cochrane Handbook for Systematic Review of Intervention. RevMan 5.2 software was used for data analysis.

Results

Ten trials with 997 participants were included. Most trials had high methodological quality and were at low risk of bias. Meta-analysis showed superior effects of verum MA over sham acupuncture on the total effective rate, reflected by a reduction in the ‘not effective’ rate (relative risk (RR) 0.24, 95% CI 0.15 to 0.38; p<0.0001, four trials) and a reduced recurrence rate (RR 0.47, 95% CI 0.28 to 0.81; p=0.006, two trials), but no significant differences in headache intensity, frequency or duration, accompanying symptoms and use of medication. No severe adverse events related to acupuncture occurred during treatment with either verum or sham MA.

Conclusions

Current clinical evidence suggests that verum acupuncture is superior to sham acupuncture in migraine, reflected by a higher total effective rate and decreased recurrence rate. Nevertheless, further large-scale RCTs with a rigorous design are required to confirm these findings in view of the relative paucity of eligible RCTs and small sample sizes of those included.
Recognition, assessment and management of hypoglycaemia in childhood
Authors: Ghosh Arunabha , Banerjee Indraneel , Morris Andrew A M
Published: December 2015

Hypoglycaemia is frequent in children and prompt management is required to prevent brain injury. In this article we will consider hypoglycaemia in children after the neonatal period. The most common causes are diabetes mellitus and idiopathic ketotic hypoglycaemia (IKH) but a number of endocrine disorders and inborn errors of metabolism (IEMs) need to be excluded. Elucidation of the diagnosis relies primarily on investigations during a hypoglycaemic episode but may also involve biochemical tests between episodes, dynamic endocrine tests and molecular genetics. Specific treatment such as cortisol replacement and pancreatic surgery may be required for endocrine causes of hypoglycaemia, such as adrenal insufficiency and congenital hyperinsulinism. In contrast, in IKH and most IEMs, hypoglycaemia is prevented by limiting the duration of fasting and maintaining a high glucose intake during illnesses.
Preterm birth and behavioural outcomes at 8 years of age: a nationwide survey in Japan
Authors: Higa Diez Midory , Yorifuji Takashi , Kado Yoko , Sanada Satoshi , Doi Hiroyuki
Published: December 2015

Objective

To analyse the effect of different preterm birth categories on behavioural outcomes.

Design

Prospective cohort design.

Settings

The Japanese Longitudinal Survey of Babies in the 21st Century was used for the study.

Subjects

Neonates born in 2001 in Japan (n=34 163) and followed up at the age of 8 years. Post-term births were excluded and the sample was divided into four groups according to gestational age: <34 weeks, 34–36 weeks, 37–38 weeks and 39–41 weeks.

Outcome measures

Seven behavioural outcomes were examined: three attention problems and four delinquent/aggressive behaviours.

Results

Logistic regression was used to estimate adjusted ORs and 95% CIs for each outcome. Positive associations were found between preterm birth (<37 weeks) and adverse behavioural outcomes compared with full-term birth (39–41 weeks). For attention problems, the OR for ‘inability to wait his/her turn’ was increased by 1.72 (95% CI 1.22 to 2.43) for gestational age <34 weeks and by 1.28 (95% CI 1.03 to 1.59) for 34–36 weeks’ gestation. For delinquent/aggressive behaviour, the OR for the outcome ‘destroying books/toys’ was increased by 1.46 (95% CI 1.07 to 1.99) for gestational age <34 weeks, while the outcome ‘disturbance in public’ was increased by 1.20 (95% CI 1.04 to 1.38) for 34–36 weeks’ gestation.

Conclusions

Children who are born <34 weeks, but also between 34 and 36 weeks, are at increased risk of behavioural problems related to attention and delinquent/aggressive behaviour when 8 years old.
Exercise improves quality of life in patients with cancer: a systematic review and meta-analysis of randomised controlled trials
Authors: Gerritsen Jasper K W , Vincent Arnaud J P E
Published: December 2015

Purpose

Exercise may be associated with increased health-related quality of life (QoL) in patients with cancer, but it is not prescribed as standard care during or after cancer treatment. We systematically reviewed the methodological quality of, and summarised the evidence from, randomised controlled trials (RCTs). A meta-analysis was performed to examine the effectiveness of exercise in improving the QoL in patients with cancer, during and after medical treatment.

Methods

RCTs that met the PICO (Patient Intervention Control Outcome) format were included in this study. 16 RCTs were identified through a search of Embase, Medline (OvidSP) and the Cochrane Library. These trials were reviewed for substantive results and the methodological quality was assessed using the Delphi criteria list.

Results

Exercise interventions differed widely in content, frequency, duration and intensity. Based on the meta-analysis, exercise improved QoL significantly in patients with cancer as compared to usual care (mean difference 5.55, 95% CI (3.19 to 7.90), p<0.001). Other outcomes closely related to QoL, such as fatigue and physical functioning, also improved.

Conclusions

Exercise has a direct positive impact on QoL in patients with cancer, during and following medical intervention. Exercise is a clinically relevant treatment and should be an adjunct to disease therapy in oncology.
Epidemiology of National Collegiate Athletic Association men's and women's tennis injuries, 2009/2010–2014/2015
Authors: Lynall Robert C , Kerr Zachary Y , Djoko Aristarque , Pluim Babette M , Hainline Brian , Dompier Thomas P
Published: December 2015

Background

This study describes the epidemiology of men's and women's tennis injuries reported by the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) during the 2009/2010–2014/2015 academic years.

Methods

Injuries and athlete-exposure (AE) data originated from 19 varsity men's programmes (38 team-seasons); women's tennis data originated from 25 varsity programmes (52 team-seasons). Injury rates, injury rate ratios (IRRs) and injury proportions ratios (IPRs) were reported with 95% CIs.

Results

The ISP captured 181 and 227 injuries for men's and women's tennis, respectively, for injury rates of 4.89 and 4.88/1000 AE for men and women, respectively. There were 32.2% and 63.9% reductions in men's and women's tennis practice injury rates between 2009/2010–2011/2012 and 2012/2013–2014/2015, but no reductions in competition injury rates. Competition injury rates were higher than practice injury rates in men's (IRR=2.32; 95% CI 1.72 to 3.13) and women's tennis (IRR=1.77; 95% CI 1.35 to 2.33). Most injuries in men's and women's tennis occurred to the lower extremities (47.0% and 52.4%, respectively), compared with the trunk (16.6% and 17.6%, respectively) and upper extremities (23.8 and 23.8, respectively).

Conclusions

Injury rates in NCAA men's and women's tennis were similar overall. Practice injury rates in men's and women's tennis have declined, although competition rates have not changed. These findings may help inform injury prevention programmes in the future.
Lumacaftor-ivacaftor (Orkambi) for cystic fibrosis: behind the ‘breakthrough’
Authors: Mayer Martin
Published: December 2015

Lumacaftor-ivacaftor (Orkambi) was recently approved by the Food and Drug Administration (FDA) in the USA to treat patients at least 12 years old who have cystic fibrosis due to two copies of theF508del(Phe508del) mutation in thecystic fibrosis transmembrane conductance regulator(CFTR) gene. Lumacaftor-ivacaftor has been designated a ‘breakthrough’ and is slated to cost $259 000 per year per patient, but close scrutiny of the data behind this new medication reveals modest improvements in outcomes that are not exclusively benefited by lumacaftor-ivacaftor, and the $259 000 cost is questionable and problematic. Providers considering this therapy should have a candid and easily-understandable discussion with their patients about what the data show for lumacaftor-ivacaftor so their patients can make an informed decision about taking it. This article aims to help this process.
The National Violent Death Reporting System: overview and future directions
Authors: Blair Janet M , Fowler Katherine A , Jack Shane P D , Crosby Alexander E
Published: December 2015

Objective

To describe the National Violent Death Reporting System (NVDRS). This is a surveillance system for monitoring the occurrence of homicides, suicides, unintentional firearm deaths, deaths of undetermined intent, and deaths from legal intervention (excluding legal executions) in the US.

Design

This report provides information about the history, scope, data variables, processes, utility, limitations, and future directions of the NVDRS.

Results

The NVDRS currently operates in 32 states, with the goal of future expansion to all 50 states, the District of Columbia, and US territories. The system uses existing primary data sources (death certificates, coroner/medical examiner reports, and law enforcement reports), and links them together to provide a comprehensive picture of the circumstances surrounding violent deaths.

Conclusions

This report provides an overview of the NVDRS including a description of the system, discussion of its expanded capability, the use of new technologies as the system has evolved, how the data are being used for violence prevention efforts, and future directions.
Infective endocarditis in intravenous drug users: a review article
Authors: Colville Thomas , Sharma Vishal , Albouaini Khaled
Published: December 2015

Approximately 10% of infective endocarditis (IE) involves the right side of the heart with the majority of these cases occurring in intravenous drug users. Patients are less likely to present with classical IE signs of a new murmur and peripheral stigmata, are more frequently immunocompromised and often have significant social difficulties. These factors result in both diagnostic and therapeutic challenges in this patient group that are not often seen in other patient populations with IE.
Hybrid compact star in the presence of strong magnetic field
Authors: Mohanta K. , Panda N. R. , Sahu P. K.
Published: December 2015

Compact neutron stars (NSs) can consist of either hadronic matter or strange quark matter or exotic color superconducting matter. If the stars have a quark core and are surrounded by hadronic matter, they are called hybrid stars (HSs). The HS is a mixture of the hadron and exotic quark phases. Observational results suggest that magnetars are certain NSs having huge surface magnetic field. We calculate equation of states (EOSs) of hadronic and quark matter at high densities in the presence of strong magnetic field and then study the quark–hadron phase having mixed phase in between giving rise to hybrid star. The intermediate mixed phase is constructed based on the Glendenning conjecture. The magnetic field significantly affects the EOS of the matter if the field strength is above [Formula: see text]G. We also calculate HS structure parameters such as the maximum mass, radius, moment of inertia, fundamental period and surface redshift and compare them specially the maximum mass with the recent observation of pulsars PSR 1903+0327 and PSR J1614-2230. The observation restricts a severe constraint on the EOS of matter at extreme conditions.
Septal flash and septal rebound stretch have different underlying mechanisms
Authors: Walmsley John , Huntjens Peter R. , Prinzen Frits W. , Delhaas Tammo , Lumens Joost
Published: December 2015

Abnormal left-right motion of the interventricular septum in early systole, known as septal flash (SF), is frequently observed in patients with left bundle branch block (LBBB). Transseptal pressure gradient and early active septal contraction have been proposed as explanations for SF. Similarities in timing (early systole) and location (septum) suggest that SF may be related to septal systolic rebound stretch (SRSsept). We aimed to clarify the mechanisms generating SF and SRSsept. The CircAdapt computer model was used to isolate the effects of timing of activation of the left ventricular free wall (LVFW), right ventricular free wall (RVFW), and septum on SF and SRSsept. LVFW and septal activation times were varied by ±80 ms relative to RVFW activation time. M-mode-derived wall motions and septal strains were computed and used to quantify SF and SRSsept, respectively. SF depended on early activation of the RVFW relative to the LVFW. SF and SRSsept occurred in LBBB-like simulations and against a rising transseptal pressure gradient. When the septum was activated before both LVFW and RVFW, no SF occurred despite the presence of SRSsept. Computer simulations therefore indicate that SF and SRSsept have different underlying mechanisms, even though both can occur in LBBB. The mechanism of leftward motion during SF is early RVFW contraction pulling on and straightening the septum when unopposed by the LVFW. SRSsept is caused by late LVFW contraction following early contraction of the septum. Changes in transseptal pressure gradient are not the main cause of SF in LBBB.
The pathogenesis and treatment of cardiac atrophy in cancer cachexia
Authors: Murphy Kate T.
Published: December 2015

Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia.
Aquaporin 11 variant associates with kidney disease in type 2 diabetic patients
Authors: Choma David P. , Vanacore Roberto , Naylor Helen , Zimmerman Ian A. , Pavlichenko Andrei , Pavlichenko Artyom , Foye Liberty , Carbone David P. , Harris Raymond C. , Dikov Mikhail M. , Tchekneva Elena E.
Published: December 2015

Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic individuals who were identified in the Synthetic Derivative Database with DNA samples in the BioVU DNA repository at Vanderbilt University (Nashville, TN). A χ2-test and multivariable logistic regression analysis with adjustments for age, sex, baseline serum creatinine, and underlying comorbid disease covariates showed a significant association between rs2276415 and the prevalence of any event of acute kidney injury and chronic kidney disease (CKD) in diabetic patients but not in patients without diabetes. This result was replicated in the second independent study. Diabetic CKD patients over 55 yrs old with the minor AQP11 allele had a significantly faster progression of estimated glomerular filtration rate decline than patients with the wild-type genotype. Three-dimensional structural analysis suggested a functional impairment of AQP11 with rs2276415, which could place diabetic patients at a higher risk for kidney disease. These studies identified rs2276415 as a candidate genetic factor predisposing patients with type 2 diabetes to CKD.
Protection of nitro-fatty acid against kidney diseases
Authors: Wang Weidong , Li Chunling , Yang Tianxin
Published: December 2015

Nitrated derivatives of unsaturated fatty acids are endogenously formed under oxidative and nitrative stress condition and are defined as electrophilic fatty acids containing a nitro group to a carbon-carbon double bond. Among the most studied nitro derivatives of unsaturated fatty acids are nitro-oleic acid (OA-NO2) and nitro-linoleic acid (LNO2). These products exhibit novel protective actions in a variety of rodent disease models. Diverse signaling events are responsible for effects of nitrated fatty acid, including activating peroxisome proliferator-activated receptor-dependent gene expression, suppressing NF-κB-induced inflammation, inhibiting oxidative stress, and increasing both endothelial nitric oxide synthase- and Nrf2-dependent gene regulation. Nitrated fatty acids have been emerging not only as a unique class of signaling molecules produced endogenously and but also as multipotent modulators of cell signaling pathways in cardiovascular and renal diseases. In this review, we discuss biochemical properties of nitrated fatty acid and its signaling pathways in the modulation of cellular events. A major focus is to review recent knowledge of nitrated fatty acid on the treatment of kidney diseases and its therapeutic potential for inflammation and metabolic disorders, with special emphasis on acute kidney injury and diabetic kidney disease.
S1P3receptor influences key physiological properties of fast-twitch extensor digitorum longus muscle
Authors: Germinario Elena , Bondì Michela , Cencetti Francesca , Donati Chiara , Nocella Marta , Colombini Barbara , Betto Romeo , Bruni Paola , Bagni Maria Angela , Danieli-Betto Daniela
Published: December 2015

To examine the role of sphingosine 1-phosphate (S1P) receptor 3 (S1P3) in modulating muscle properties, we utilized transgenic mice depleted of the receptor. Morphological analyses of extensor digitorum longus (EDL) muscle did not show evident differences between wild-type and S1P3-null mice. The body weight of 3-mo-old S1P3-null mice and the mean cross-sectional area of transgenic EDL muscle fibers were similar to those of wild-type. S1P3deficiency enhanced the expression level of S1P1and S1P2receptors mRNA in S1P3-null EDL muscle. The contractile properties of S1P3-null EDL diverge from those of wild-type, largely more fatigable and less able to recover. The absence of S1P3appears responsible for a lower availability of calcium during fatigue. S1P supplementation, expected to stimulate residual S1P receptors and signaling, reduced fatigue development of S1P3-null muscle. Moreover, in the absence of S1P3, denervated EDL atrophies less than wild-type. The analysis of atrophy-related proteins in S1P3-null EDL evidences high levels of the endogenous regulator of mitochondria biogenesis peroxisome proliferative-activated receptor-γ coactivator 1α (PGC-1α); preserving mitochondria could protect the muscle from disuse atrophy. In conclusion, the absence of S1P3makes the muscle more sensitive to fatigue and slows down atrophy development after denervation, indicating that S1P3is involved in the modulation of key physiological properties of the fast-twitch EDL muscle.
Oxidative fuel selection and shivering thermogenesis during a 12- and 24-h cold-survival simulation
Authors: Haman François , Mantha Olivier L. , Cheung Stephen S. , DuCharme Michel B. , Taber Michael , Blondin Denis P. , McGarr Gregory W. , Hartley Geoffrey L. , Hynes Zach , Basset Fabien A.
Published: December 2015

Because the majority of cold exposure studies are constrained to short-term durations of several hours, the long-term metabolic demands of cold exposure, such as during survival situations, remain largely unknown. The present study provides the first estimates of thermogenic rate, oxidative fuel selection, and muscle recruitment during a 24-h cold-survival simulation. Using combined indirect calorimetry and electrophysiological and isotopic methods, changes in muscle glycogen, total carbohydrate, lipid, protein oxidation, muscle recruitment, and whole body thermogenic rate were determined in underfed and noncold-acclimatized men during a simulated accidental exposure to 7.5°C for 12 to 24 h. In noncold-acclimatized healthy men, cold exposure induced a decrease of ∼0.8°C in core temperature and a decrease of ∼6.1°C in mean skin temperature (range, 5.4-6.9°C). Results showed that total heat production increased by approximately 1.3- to 1.5-fold in the cold and remained constant throughout cold exposure. Interestingly, this constant rise in Ḣprod and shivering intensity was accompanied by a large modification in fuel selection that occurred between 6 and 12 h; total carbohydrate oxidation decreased by 2.4-fold, and lipid oxidation doubled progressively from baseline to 24 h. Clearly, such changes in fuel selection dramatically reduces the utilization of limited muscle glycogen reserves, thus extending the predicted time to muscle glycogen depletion to as much as 15 days rather than the previous estimates of approximately 30–40 h. Further research is needed to determine whether this would also be the case under different nutritional and/or colder conditions.
Immediate postarousal sleep dynamics: an important determinant of sleep stability in obstructive sleep apnea
Authors: Younes Magdy , Hanly Patrick J.
Published: December 2015

Arousability from sleep is increasingly recognized as an important determinant of the clinical spectrum of sleep disordered breathing (SDB). Patients with SDB display a wide range of arousability. The reason for these differences is not known. We hypothesized that differences in the speed with which sleep deepens following arousals/awakenings (postarousal sleep dynamics) is a major determinant of these differences in arousability in patients with SDB. We analyzed 40 preexisting clinical polysomnography records from patients with a range of SDB severity (apnea-hypopnea index 5-135/h). Sleep depth was determined every 3 s using the odds ratio product (ORP) method, a continuous index of sleep depth (0 = deep sleep, 2.5 = full wakefulness) that correlates strongly ( r = 0.98) with arousability (Younes M, Ostrowski M, Soiferman M, Younes H, Younes M, Raneri J, and Hanly P. Sleep 38: 641–654, 2015). Time course of ORP was determined from end of arousal until the next arousal. All arousals were analyzed (142 ± 65/polysomnogram). ORP increased from 0.58 ± 0.32 during sleep to 1.67 ± 0.35 during arousals. ORP immediately (first 9 s) following arousals/awakenings (ORP-9) ranged from 0.21(very deep sleep) to 1.71 (highly arousable state) in different patients. In patients with high ORP-9, sleep deepened slowly (over minutes) beyond 9 s but only if no arousals/awakenings recurred. ORP-9 correlated strongly with average non-rapid eye movement sleep depth ( r = 0.87, P < 2E-13), the arousal/awakening index ( r = 0.68, P < 5E-6), and with the apnea-hypopnea index ( r = 0.60, P < 0.001). ORP-9 was consistent within each patient and did not change on continuous positive airway pressure despite marked improvement in sleep architecture. We conclude that postarousal sleep dynamics are highly variable among patients with sleep-disordered breathing and largely determine average sleep depth and continuity.
Adaptation of multijoint coordination during standing balance in healthy young and healthy old individuals
Authors: Engelhart D. , Pasma J. H. , Schouten A. C. , Aarts R. G. K. M. , Meskers C. G. M. , Maier A. B. , van der Kooij H.
Published: December 2015

Standing balance requires multijoint coordination between the ankles and hips. We investigated how humans adapt their multijoint coordination to adjust to various conditions and whether the adaptation differed between healthy young participants and healthy elderly. Balance was disturbed by push/pull rods, applying two continuous and independent force disturbances at the level of the hip and between the shoulder blades. In addition, external force fields were applied, represented by an external stiffness at the hip, either stabilizing or destabilizing the participants' balance. Multivariate closed-loop system-identification techniques were used to describe the neuromuscular control mechanisms by quantifying the corrective joint torques as a response to body sway, represented by frequency response functions (FRFs). Model fits on the FRFs resulted in an estimation of time delays, intrinsic stiffness, reflexive stiffness, and reflexive damping of both the ankle and hip joint. The elderly generated similar corrective joint torques but had reduced body sway compared with the young participants, corresponding to the increased FRF magnitude with age. When a stabilizing or destabilizing external force field was applied at the hip, both young and elderly participants adapted their multijoint coordination by lowering or respectively increasing their neuromuscular control actions around the ankles, expressed in a change of FRF magnitude. However, the elderly adapted less compared with the young participants. Model fits on the FRFs showed that elderly had higher intrinsic and reflexive stiffness of the ankle, together with higher time delays of the hip. Furthermore, the elderly adapted their reflexive stiffness around the ankle joint less compared with young participants. These results imply that elderly were stiffer and were less able to adapt to external force fields.
Brain stem as a target site for the metabolic side effects of olanzapine
Authors: Anwar Imran J. , Miyata Kayoko , Zsombok Andrea
Published: December 2015

Olanzapine, an atypical antipsychotic, is widely prescribed for the treatment of schizophrenia and bipolar disorder despite causing undesirable metabolic side effects. A variety of mechanisms and brain sites have been proposed as contributors to the side effects; however, the role of the dorsal motor nucleus of the vagus nerve (DMV), which plays a crucial role in the regulation of subdiaphragmatic organs and thus governs energy and glucose homeostasis, is largely unknown. Identifying the effect of olanzapine on the excitability of DMV neurons in both sexes is thus crucial to understanding possible underlying mechanisms. Whole cell patch-clamp electrophysiological recordings were conducted in stomach- and liver-related DMV neurons identified with retrograde viral tracers and in random DMV neurons. The effect of olanzapine on the neuronal excitability of DMV neurons both in male and female mice was established. Our data demonstrate that olanzapine hyperpolarizes the DMV neurons in both sexes and this effect is reversible. The hyperpolarization is associated with decreased firing rate and input resistance. Olanzapine also decreases the excitability of a subset of stomach- and liver-related DMV neurons. Our study demonstrates that olanzapine has a powerful effect on DMV neurons in both sexes, indicating its ability to reduce vagal output to the subdiaphragmatic organs, which likely contributes to the metabolic side effects observed in both humans and experimental models. These findings suggest that the metabolic side effects of olanzapine may partially originate in the DMV.
New evidence of corticospinal network modulation induced by motor imagery
Authors: Grosprêtre Sidney , Lebon Florent , Papaxanthis Charalambos , Martin Alain
Published: December 2015

Motor imagery (MI) is the mental simulation of movement, without the corresponding muscle contraction. Whereas the activation of cortical motor areas during MI is established, the involvement of spinal structures is still under debate. We used original and complementary techniques to probe the influence of MI on spinal structures. Amplitude of motor-evoked potentials (MEPs), cervico-medullary-evoked potentials (CMEPs), and Hoffmann (H)-reflexes of the flexor carpi radialis (FCR) muscle and of the triceps surae muscles was measured in young, healthy subjects at rest and during MI. Participants were asked to imagine maximal voluntary contraction of the wrist and ankle, while the targeted limb was fixed (static condition). We confirmed previous studies with an increase of FCR MEPs during MI compared with rest. Interestingly, CMEPs, but not H-reflexes, also increased during MI, revealing a possible activation of subcortical structures. Then, to investigate the effect of MI on the spinal network, we used two techniques: 1) passive lengthening of the targeted muscle via an isokinetic dynamometer and 2) conditioning of H-reflexes with stimulation of the antagonistic nerve. Both techniques activate spinal inhibitory presynaptic circuitry, reducing the H-reflex amplitude at rest. In contrast, no reduction of H-reflex amplitude was observed during MI. These findings suggest that MI has modulatory effects on the spinal neuronal network. Specifically, the activation of low-threshold spinal structures during specific conditions (lengthening and H-reflex conditioning) highlights the possible generation of subliminal cortical output during MI.
A Novel Approach to Evaluate the Time-Variant System Reliability of Deteriorating Concrete Bridges
Authors: Tian Hao , Chen Yuanli , Li Fangyuan
Published: December 2015

Bridge time-variant system reliability is a useful measure to evaluate the lifetime performance of deteriorating bridge structures under uncertainty and is an influential performance indicator in bridge maintenance management programs. This paper proposes a computational methodology based on the Monte Carlo simulations for evaluating the time-variant system reliability of concrete bridges under environmental attacks. Methods related to the reduction of concrete sections and the variation of the load effects acting on the components are investigated using a finite element-based computational program, CBDAS (Concrete Bridge Durability Analysis System), to perform the assessment of lifetime structural performance. With regard to system reliability, a practical technique for searching the structural failure mode is also presented and a program, SRMCS (System Reliability by Monte Carlo Simulations), based on the Monte Carlo simulations is written to calculate and evaluate the structural system reliability of deteriorating concrete bridges. Finally, three numerical examples are presented to display the CBDAS and SRMCS functions.