bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease‐associated ubiquitin C‐terminal hydrolase L1 and alters its structure and function
Authors: Contu Viorica Raluca , Kotake Yaichiro , Toyama Takashi , Okuda Katsuhiro , Miyara Masatsugu , Sakamoto Shuichiro , Samizo Shigeyoshi , Sanoh Seigo , Kumagai Yoshito , Ohta Shigeru
Published: May 2014

Parkinson's disease (PD) is a common neurodegenerative disease, but its pathogenesis remains elusive. A mutation in ubiquitin C‐terminal hydrolase L1 (UCH‐L1) is responsible for a form of genetic PD which strongly resembles the idiopathic PD. We previously showed that 1‐(3′,4′‐dihydroxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (3′,4′DHBnTIQ) is an endogenous parkinsonism‐inducing dopamine derivative. Here, we investigated the interaction between 3′,4′DHBnTIQ and UCH‐L1 and its possible role in the pathogenesis of idiopathic PD. Our results indicate that 3′,4′DHBnTIQ binds to UCH‐L1 specifically at Cys152 in vitro. In addition, 3′,4′DHBnTIQ treatment increased the amount of UCH‐L1 in the insoluble fraction of SH‐SY5Y cells and inhibited its hydrolase activity to 60%, reducing the level of ubiquitin in the soluble fraction of SH‐SY5Y cells. Catechol‐modified UCH‐L1 as well as insoluble UCH‐L1 were detected in the midbrain of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐treated PD model mice. Structurally as well as functionally altered UCH‐L1 have been detected in the brains of patients with idiopathic PD. We suggest that conjugation of UCH‐L1 by neurotoxic endogenous compounds such as 3′,4′DHBnTIQ might play a key role in onset and progression of idiopathic PD.

image

We investigated the interaction between ubiquitin C‐terminal hydrolase L1 (UCH‐L1) and the brain endogenous parkinsonism inducer 1‐(3′,4′‐dihydroxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (3′,4′DHBnTIQ). Our results indicate that 3′,4′DHBnTIQ binds to UCH‐L1 specifically at cysteine 152 and induces its aggregation. 3′,4′DHBnTIQ also inhibits the hydrolase activity of UCH‐L1. Catechol‐modified as well as insoluble UCH‐L1 were detected in the midbrains of MPTP‐treated Parkinson's disease (PD) model mice. Conjugation of UCH‐L1 by neurotoxic endogenous compounds like 3′,4′DHBnTIQ might play a key role in onset and progression of PD.
THE IMPACT OF MIGRATION ON REGIONAL WAGE INEQUALITY: A SEMIPARAMETRIC APPROACH
Authors: Dickey Heather
Published: May 2014

According to economic theory, regional migration is a primary mechanism through which regional wage convergence is predicted to occur. However, this does not necessarily imply that regional migration has an equalizing effect on regional inequality. Despite considerable literatures on regional migration and regional wage inequality, little attention has focused on the relationship between the two. This paper investigates one of the primary mechanisms through which migration affects individual region's wage distributions. It adopts a semiparametric procedure to examine how the regional wage distributions in Great Britain have changed as a result of migration using British Household Panel Survey data for 1991–2007.
Fire frequency, agricultural history and the multivariate control of pine savanna understorey plant diversity
Authors: Veldman Joseph W. , Brudvig Lars A. , Damschen Ellen I. , Orrock John L. , Mattingly W. Brett , Walker Joan L.
Published: May 2014

Question

Human‐altered disturbance regimes and agricultural land uses are broadly associated with reduced plant species diversity in terrestrial ecosystems. In this study, we seek to understand how fire frequency and agricultural land‐use history influence savanna understorey plant diversity through complex relationships (i.e. indirect effects) among multiple biophysical variables.

Location

Fort Bragg, NC, US, Savannah River Site, SC, US and Fort Stewart, GA, US.

Methods

We use structural equation modelling (SEM) to evaluate the relationships among six groups of predictor variables and their influence on local‐scale species richness in pine savannas at 256 sites from three locations in the southeastern USA. In the model, fire frequency and agricultural history are hypothesized to control richness through a combination of direct effects, and indirect effects mediated by resource availability, tree abundance, understorey plant abundance and the O horizon (litter and duff depth).

Results

Frequent fires promote richness by limiting tree abundance, which increases understorey abundance and reduces the O horizon. Frequent fires also limit the O horizon independent of tree abundance. Of the total positive effect of fire on richness, 70% is attributable to reductions in the O horizon and 30% to reduced tree abundance. Agricultural history has a negative effect on richness through a positive correlation with tree abundance, which decreases understorey abundance and increases the O horizon. Agricultural history has a modest negative effect on richness by reducing resource availability as well as a strong direct negative effect (38% of the total effect) that is unrelated to other modelled variables.

Conclusions

Through a multivariate framework and large‐scale data set, this study unites and tests our understanding of the factors that control plant species diversity in a fire‐dependent ecosystem. We show that the effects of fire frequency and agricultural history on richness are largely mediated through other ecosystem attributes, including vegetation structure (i.e. tree and understorey abundance), resource availability and the O horizon. Persistent, negative effects of agricultural history demonstrate the slow rates of savanna plant community recovery on post‐agricultural land and highlight the conservation value of frequently burned savanna remnants.
The Woody Allen Puzzle: How ‘Authentic Alienation’ Complicates Autonomy
Authors: Killmister Suzy
Published: May 2014

Theories of autonomy commonly make reference to some form of endorsement: an action is autonomous insofar as the agent has a second‐order desire towards the motivating desire, or takes it to be a reason for action, or is not alienated from it. In this paper I argue that all such theories have difficulty accounting for certain kinds of agents, what I call ‘Woody Allen cases’. In order to make sense of such cases, I suggest, it is necessary to disambiguate two distinct forms of endorsement, both of which contribute to autonomy.
Efficacy of Withania somnifera chemotypes NMITLI – 101R, 118R and Withaferin A against experimental visceral leishmaniasis
Authors: Tripathi C. D. P. , Gupta R. , Kushawaha P. K. , Mandal C. , Misra Bhattacharya S. , Dube A.
Published: May 2014

The immunoprophylactic and therapeutic potentials of root extracts of Withania somnifera chemotypes (NMITLI‐118, NMITLI‐101) and pure withanolide–withaferin A was investigated against Leishmania donovani infection in hamsters. The naive animals, fed orally with immunostimulatory doses of chemotypes 101R, 118R (10 and 3 mg/kg) and withaferin A (9 and 3 mg/kg) for five consecutive days and challenged with Leishmania parasites on day 6, were euthanized on days 30 and 45 p.c. for the assessment of parasite clearance, real‐time analysis of mRNAs of Th1/Th2 cytokines (IFN‐γ, IL‐12, TNF‐α, iNOS/IL‐4, IL‐10 and TGF‐β), NO production, reactive oxygen species (ROS) generation, lymphocyte transformation test and antibody responses. By day 45 p.c., there was a significant increase in the mRNA expression of iNOS, IFN‐γ, IL‐12 and TNF‐α but decrease in IL‐4, IL‐10 and TGF‐β, an enhanced Leishmania‐specific LTT response as well as ROS, NO and antileishmanial IgG2 levels in 101R‐treated hamsters followed by 118R‐ and withaferin A‐treated ones, respectively. When these chemotypes were given to L. donovani‐infected hamsters at different doses, there was moderate therapeutic efficacy of chemotype 101R (~50%) at 30 mg/kg × 5 followed by the other two. The results established that the 101R is the most potential chemotype and can be evaluated for combination therapy along with available antileishmanials.
Effects of simulated acid rain on germination, seedling growth and oxidative metabolism of recalcitrant‐seeded Trichilia dregeana grown in its natural seed bank
Authors: Ramlall Chandika , Varghese Boby , Ramdhani Syd , Pammenter Norman W. , Bhatt Arvind , Berjak Patricia , Sershen
Published: May 2014

Increased air pollution in a number of developing African countries, together with the reports of vegetation damage typically associated with acid precipitation in commercial forests in South Africa, has raised concerns over the potential impacts of acid rain on natural vegetation in these countries. Recalcitrant (i.e. desiccation sensitive) seeds of many indigenous African species, e.g. must germinate shortly after shedding and hence, may not be able to avoid exposure to acid rain in polluted areas. This study investigated the effects of simulated acid rain (rainwater with pH adjusted to pH 3.0 and 4.5 with 70:30, H2SO4:HNO3) on germination, seedling growth and oxidative metabolism in a recalcitrant‐seeded African tree species Trichilia dregeana Sond., growing in its natural seed bank. The results suggest that acid rain did not compromise T. dregeana seed germination and seedling establishment significantly, relative to the control (non‐acidified rainwater). However, pH 3.0 treated seedlings exhibited signs of stress typically associated with acid rain: leaf tip necrosis, abnormal bilobed leaf tips, leaf necrotic spots and chlorosis, reduced leaf chlorophyll concentration, increased stomatal density and indications of oxidative stress. This may explain why total and root biomass of pH 3.0 treated seedlings were significantly lower than the control. Acid rain also induced changes in the species composition and relative abundance of the different life forms emerging from T. dregeana's natural seed bank and in this way could indirectly impact on T. dregeana seedling establishment success.
Cannabis smoking and respiratory health: Consideration of the literature
Authors: Gates Peter , Jaffe Adam , Copeland Jan
Published: May 2014

The respiratory health effects from tobacco smoking are well described. Cannabis smoke contains a similar profile of carcinogenic chemicals as tobacco smoke but is inhaled more deeply. Although cannabis smoke is known to contain similar harmful and carcinogenic substances to tobacco smoke, relatively little is understood regarding the respiratory health effects from cannabis smoking. There is a need to integrate research on cannabis and respiratory health effects so that gaps in the literature can be identified and the more consistent findings can be consolidated with the purpose of educating smokers and health service providers. This review focuses on several aspects of respiratory health and cannabis use (as well as concurrent cannabis and tobacco use) and provides an update to (i) the pathophysiology; (ii) general respiratory health including symptoms of chronic bronchitis; and (iii) lung cancer.
The Determinants of Salience of Energy Issues
Authors: Lowry William R. , Joslyn Mark
Published: May 2014

Studies show that salience of an issue influences the behavior of political elites, policy responses, and the attitudes of the public. Yet while the effects of salience are given considerable attention, less is known about the factors that produce salience. Specifically, what are the determinants of an issue's salience? We examine salience of energy issues in theUnitedStates over the past six decades and make two contributions. First, we provide systematic explanations of issue salience. Second, contrary to popular conceptions that energy salience is driven entirely by gasoline prices, or some scholarly analyses that salience depends on crises, we argue that other factors increase salience. Specifically, we find that political actors and activities increase energy salience, even after controlling for higher gas prices and shocks. This is an important finding; political dynamics enhance salience. Meaningful political action, therefore, driven by enhanced salience, is not entirely dependent on market forces or unplanned events.
Retailer Supply Chain and Market Access: Evidence From French Agri‐food Firms Certified with Private Standards
Authors: Latouche Karine , Chevassus‐Lozza Emmanuelle
Published: May 2014

This paper explores an original data set identifying French agri‐food firms certified with two European private standards: the International Food Standard and/or the British Retail Consortium standard (BRC). Certified firms complying with such requirements are able to supply some European retailers with products sold under their retailers' own private label. Our analysis revealed that certified firms were among the biggest and most productive firms in the sample. Then, based on recent developments in international economics, we propose a modification of Chaney's model and estimations to test for the hypothesis that entering retailer networks reduces export costs faced by certified firms to access European union (EU) markets. After controlling for size and productivity effects, model estimations show that French firms who adopt BRC and enter the corresponding network benefit from better access through a significant decrease in their entry costs to certain EU markets.
South–South Labor Internationalism: SIGTUR and the Challenges to the Status Quo
Authors: Dobrusin Bruno
Published: May 2014

Labor internationalism and solidarity has been dominated historically by the European trade union movement. The 2008 economic crisis and the rise of emerging economies have led to a gradual reorientation of labor relations, increasing the capacity of a group of southern trade unions to influence transnational labor solidarity. This article reviews the increasing connectivity between southern trade unions, with a focus on the Southern Initiative on Globalisation and Trade Union Rights (SIGTUR), which groups confederations from the Global South, with leading unions from Brazil, Argentina, Korea, South Africa, and Australia, among others. The leading argument is that despite shortcomings, SIGTUR has the potential to revitalize labor internationalism through extending the network into articulated global actions that challenge dominant neoliberal globalization.
Working for Global Justice in the New Labor Movement
Authors: Zweig Michael
Published: May 2014

The AFL‐CIO's new domestic organizing strategy, engaging working people in their communities, provides a context to re‐evaluate and redirect labor's foreign policy as well. For nearly twenty years many unions, and the Federation, have undertaken genuine international solidarity efforts well beyond tactical cross‐border organizing. Domestic and international work must be closely linked in a single global economy. Redefining labor's foreign policy must be integral to the reorientation of the labor movement as a whole. The context, history, and institutional capacity for this purpose are at hand.
A functional coupling between extrasynaptic NMDA receptors and A‐type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity
Authors: Naskar Krishna , Stern Javier E.
Published: May 2014

Key points

In hypothalamic magnocellular neurosecretory cells, activation of glutamate NMDA receptors leads to inhibition of the transient voltage‐gated A‐type K+ current (IA), in a Ca2+‐ and protein kinase C‐dependent manner.

The negative NMDAR–IA functional coupling involves activation of extrasynaptic (e)NMDARs. The eNMDAR–IA coupling is engaged by endogenous extracellular glutamate, whose levels are controlled by astrocyte glutamate GLT1 transporters.

The eNMDAR–IA coupling is enhanced during dehydration, a condition in which astrocyte GLT1 efficiency is blunted.

The eNMDAR–IA coupling results in increased neuronal excitability and firing activity in magnocellular neurosecretory neurons.

Taken together these studies support the concept that the eNMDAR–IA coupling is a powerful mechanism by which glutamate increases magnocellular neurosecretory excitability and firing activity.

Neuronal activity is controlled by a fine‐tuned balance between intrinsic properties and extrinsic synaptic inputs. Moreover, neighbouring astrocytes are now recognized to influence a wide spectrum of neuronal functions. Yet, how these three key factors act in concert to modulate and fine‐tune neuronal output is not well understood. Here, we show that in rat hypothalamic magnocellular neurosecretory cells (MNCs), glutamate NMDA receptors (NMDARs) are negatively coupled to the transient, voltage‐gated A‐type K+ current (IA). We found that activation of NMDARs by extracellular glutamate levels influenced by astrocyte glutamate transporters resulted in a significant inhibition of IA. The NMDAR–IA functional coupling resulted from activation of extrasynaptic NMDARs, was calcium‐ and protein kinase C‐dependent, and involved enhanced steady‐state, voltage‐dependent inactivation of IA. The NMDAR–IA coupling diminished the latency to the first evoked spike in response to membrane depolarization and increased the total number of evoked action potentials, thus strengthening the neuronal input/output function. Finally, we found a blunted NMDA‐mediated inhibition of IA in dehydrated rats. Together, our findings support a novel signalling mechanism that involves a functional coupling between extrasynaptic NMDARs and A‐type K+ channels, which is influenced by local astrocytes. We show this signalling complex to play an important role in modulating hypothalamic neuronal excitability, which may contribute to adaptive responses during a sustained osmotic challenge such as dehydration.
Genome Sequence of Serratia plymuthica V4
Authors: Cleto S. , Van der Auwera G. , Almeida C. , Vieira M. J. , Vlamakis H. , Kolter R.
Published: May 2014

Serratia
spp. are gammaproteobacteria and members of the family
Enterobacteriaceae
. Here, we announce the genome sequence of
Serratia plymuthica
strain V4, which produces the siderophore serratiochelin and antimicrobial compounds.
Complete Genome of the Attenuated Sparfloxacin-Resistant Streptococcus agalactiae Strain 138spar
Authors: Pridgeon Julia W. , Zhang Dunhua , Zhang Lee
Published: May 2014

Through the selection of resistance to sparfloxacin, an attenuated
Streptococcus agalactiae
strain, 138spar, was obtained from its virulent parent strain,
S. agalactiae
138P. The full genome of
S. agalactiae
138spar is 1,838,126 bp. This genome will allow comparative genomics to identify genes associated with virulence, antibiotic resistance, or other characteristics.
Complete Genome Sequence of Bordetella bronchiseptica S798, an Isolate from a Pig with Atrophic Rhinitis
Authors: Okada Keisuke , Ogura Yoshitoshi , Hayashi Tetsuya , Abe Akio , Kuwae Asaomi , Horiguchi Yasuhiko , Abe Hiroyuki
Published: May 2014

Bordetella bronchiseptica
colonizes the respiratory tracts of a wide variety of mammals and causes a range of diseases, from lethal pneumonia to asymptomatic chronic infection. We report the complete genome sequence of
Bordetella bronchiseptica
strain S798, isolated from a pig with atrophic rhinitis in Japan.
Complete Genome Sequences of Noncoding Regions of Korean Equine H3N8 Influenza Virus
Authors: Na Woonsung , Hong Minki , Yeom Minju , Kim Sanghyun , Kim Jeong-Ki , Song Daesub
Published: May 2014

We analyzed the complete genome sequence containing the 3′ and 5′ noncoding regions (NCRs) of the Korean H3N8 equine influenza virus (EIV), which will provide a better understanding of the pathogenesis, transmission, and evolution of EIV.
Abdominal pain as initial presentation of lung cancer
Authors: Eisa Naseem , Alhafez Bishr , Alraiyes Abdul Hamid , Alraies M Chadi
Published: May 2014

Isolated spleen metastasis (ISM) in general is very rare with a reported incidence of 2.3–7.1% for all solid cancers. Lung cancers rarely metastasise to the spleen. It is very atypical for ISM to be the initial presentation of lung cancer as well. In our case, a 55-year-old woman presented with a 3-week history of left-sided abdominal fullness and dull pain. Workup was remarkable for splenic mass that turns out to be adenocarcinoma with unknown primary tumour. Biopsy of the mass with immunohistochemistry and whole body position emission tomography scan was able to identify lung cancer as the primary tumour. The patient underwent splenectomy, wedge resection of the lung mass along with short-course of chemotherapy. She never had any recurrences since then.
Thorn-induced pseudotumour of the fibula
Authors: Challawar Nikhil Subhash , Sud Vikas , Shah Hitesh
Published: May 2014

Foreign body granulomas are common in the hand and foot. Diagnosis of the same is often delayed or missed, especially in unusual locations and in the paediatric age group. Radiographs usually reveal an osteolytic lesion with absence of periosteal reaction and non-metallic foreign bodies are not visualised in plain radiographs. An ultrasound and MRI can delineate the foreign body. Clinical and radiological presentation mimics that of a tumour and hence is rightly called pseudotumour. We present a case of thorn-induced pseudotumour of the fibula in a 5-year-old boy.
Comparative efficacy and safety of treatments for localised prostate cancer: an application of network meta-analysis
Authors: Xiong Tengbin , Turner Rebecca M , Wei Yinghui , Neal David E , Lyratzopoulos Georgios , Higgins Julian P T
Published: May 2014

Context

There is ongoing uncertainty about the optimal management of patients with localised prostate cancer.

Objective

To evaluate the comparative efficacy and safety of different treatments for patients with localised prostate cancer.

Design

Systematic review with Bayesian network meta-analysis to estimate comparative ORs, and a score (0–100%) that, for a given outcome, reflects average rank order of superiority of each treatment compared against all others, using the Surface Under the Cumulative RAnking curve (SUCRA) statistic.

Data sources

Electronic searches of MEDLINE without language restriction.

Study selection

Randomised trials comparing the efficacy and safety of different primary treatments (48 papers from 21 randomised trials included 7350 men).

Data extraction

2 reviewers independently extracted data and assessed risk of bias.

Results

Comparative efficacy and safety evidence was available for prostatectomy, external beam radiotherapy (different types and regimens), observational management and cryotherapy, but not high-intensity focused ultrasound. There was no evidence of superiority for any of the compared treatments in respect of all-cause mortality after 5 years. Cryotherapy was associated with less gastrointestinal and genitourinary toxicity than radiotherapy (SUCRA: 99% and 77% for gastrointestinal and genitourinary toxicity, respectively).

Conclusions

The limited available evidence suggests that different treatments may be optimal for different efficacy and safety outcomes. These findings highlight the importance of informed patient choice and shared decision-making about treatment modality and acceptable trade-offs between different outcomes. More trial evidence is required to reduce uncertainty. Network meta-analysis may be useful to optimise the power of evidence synthesis studies once data from new randomised controlled studies in this field are published in the future.
Non-cancer morbidity among Estonian Chernobyl cleanup workers: a register-based cohort study
Authors: Rahu Kaja , Bromet Evelyn J , Hakulinen Timo , Auvinen Anssi , Uusküla Anneli , Rahu Mati
Published: May 2014

Objective

To examine non-cancer morbidity in the Estonian Chernobyl cleanup workers cohort compared with the population sample with special attention to radiation-related diseases and mental health disorders.

Design

Register-based cohort study.

Setting

Estonia.

Participants

An exposed cohort of 3680 men (cleanup workers) and an unexposed cohort of 7631 men (population sample) were followed from 2004 to 2012 through the Population Registry and Health Insurance Fund database.

Methods

Morbidity in the exposed cohort compared with the unexposed controls was estimated in terms of rate ratio (RR) with 95% CIs using Poisson regression models.

Results

Elevated morbidity in the exposed cohort was found for diseases of the nervous system, digestive system, musculoskeletal system, ischaemic heart disease and for external causes. The most salient excess risk was observed for thyroid diseases (RR=1.69; 95% CI 1.38 to 2.07), intentional self-harm (RR=1.47; 95% CI 1.04 to 2.09) and selected alcohol-related diagnoses (RR=1.25; 95% CI 1.12 to 1.39). No increase in morbidity for stress reactions, depression, headaches or sleep disorders was detected.

Conclusions

No obvious excess morbidity consistent with biological effects of radiation was seen in the exposed cohort, with the possible exception of benign thyroid diseases. Increased alcohol-induced morbidity may reflect alcohol abuse, and could underlie some of the higher morbidity rates. Mental disorders in the exposed cohort were probably under-reported. The future challenge will be to study mental and physical comorbidities in the Chernobyl cleanup workers cohort.
Quality improvement in emergency obstetric referrals: qualitative study of provider perspectives in Assin North district, Ghana
Authors: Afari Henrietta , Hirschhorn Lisa R , Michaelis Annie , Barker Pierre , Sodzi-Tettey Sodzi
Published: May 2014

Objective

To describe healthcare worker (HCW)-identified system-based bottlenecks and the value of local engagement in designing strategies to improve referral processes related to emergency obstetric care in rural Ghana.

Design

Qualitative study using semistructured interviews of participants to obtain provider narratives.

Setting

Referral systems in obstetrics in Assin North Municipal Assembly, a rural district in Ghana. This included one district hospital, six health centres and four local health posts. This work was embedded in an ongoing quality improvement project in the district addressing barriers to existing referral protocols to lessen delays.

Participants

18 HCWs (8 midwives, 4 community health officers, 3 medical assistants, 2 emergency room nurses, 1 doctor) at different facility levels within the district.

Results

We identified important gaps in referral processes in Assin North, with the most commonly noted including recognising danger signs, alerting receiving units, accompanying critically ill patients, documenting referral cases and giving and obtaining feedback on referred cases. Main root causes identified by providers were in four domains: (1) transportation, (2) communication, (3) clinical skills and management and (4) standards of care and monitoring, and suggested interventions that target these barriers. Mapping these challenges allowed for better understanding of next steps for developing comprehensive, evidence-based solutions to identified referral gaps within the district.

Conclusions

Providers are an important source of information on local referral delays and in the development of approaches to improvement responsive to these gaps. Better engagement of HCWs can help to identify and evaluate high-impact holistic interventions to address faulty referral systems which result in poor maternal outcomes in resource-poor settings. These perspectives need to be integrated with patient and community perspectives.
Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis
Authors: Riku Yuichi , Atsuta Naoki , Yoshida Mari , Tatsumi Shinsui , Iwasaki Yasushi , Mimuro Maya , Watanabe Hirohisa , Ito Mizuki , Senda Jo , Nakamura Ryoichi , Koike Haruki , Sobue Gen
Published: May 2014

Objective

Progressive muscular atrophy (PMA) is a clinical diagnosis characterised by progressive lower motor neuron (LMN) symptoms/signs with sporadic adult onset. It is unclear whether PMA is simply a clinical phenotype of amyotrophic lateral sclerosis (ALS) in which upper motor neuron (UMN) signs are undetectable. To elucidate the clinicopathological features of patients with clinically diagnosed PMA, we studied consecutive autopsied cases.

Design

Retrospective, observational.

Setting

Autopsied patients.

Participants

We compared clinicopathological profiles of clinically diagnosed PMA and ALS using 107 consecutive autopsied patients. For clinical analysis, 14 and 103 patients were included in clinical PMA and ALS groups, respectively. For neuropathological evaluation, 13 patients with clinical PMA and 29 patients with clinical ALS were included.

Primary outcome measures

Clinical features, UMN and LMN degeneration, axonal density in the corticospinal tract (CST) and immunohistochemical profiles.

Results

Clinically, no significant difference between the prognosis of clinical PMA and ALS groups was shown. Neuropathologically, 84.6% of patients with clinical PMA displayed UMN and LMN degeneration. In the remaining 15.4% of patients with clinical PMA, neuropathological parameters that we defined as UMN degeneration were all negative or in the normal range. In contrast, all patients with clinical ALS displayed a combination of UMN and LMN system degeneration. CST axon densities were diverse in the clinical PMA group, ranging from low values to the normal range, but consistently lower in the clinical ALS group. Immunohistochemically, 85% of patients with clinical PMA displayed 43-kDa TAR DNA-binding protein (TDP-43) pathology, while 15% displayed fused-in-sarcoma (FUS)-positive basophilic inclusion bodies. All of the patients with clinical ALS displayed TDP-43 pathology.

Conclusions

PMA has three neuropathological background patterns. A combination of UMN and LMN degeneration with TDP-43 pathology, consistent with ALS, is the major pathological profile. The remaining patterns have LMN degeneration with TDP-43 pathology without UMN degeneration, or a combination of UMN and LMN degeneration with FUS-positive basophilic inclusion body disease.
Alcoholic Chlorhexidine or Alcoholic Iodine Skin Antisepsis (ACAISA): protocol for cluster randomised controlled trial of surgical skin preparation for the prevention of superficial wound complications in prosthetic hip and knee replacement surgery
Authors: Peel T N , Cheng A C , Buising K L , Dowsey M M , Choong P F M
Published: May 2014

Introduction

Wound complications following arthroplasty are associated with significant impact on the patient and healthcare system. Skin cleansing prior to surgical incision is a simple and effective method to prevent wound complications however, the question of which agent is superior for surgical skin antisepsis is unresolved.

Methods and analysis

This cluster randomised controlled trial aims to compare the incidence of superficial wound complications in patients undergoing elective prosthetic hip or knee replacement surgery receiving surgical skin antisepsis with either: 0.5% chlorhexidine gluconate (CHG) in 70% alcohol or 10% povidone in 70% alcohol. The trial will be conducted at an Australian tertiary, university affiliated hospital over a 3-year period involving 750 participants. Participants will be drawn from the surgical waiting list. Consent for this study will be ‘opt-out’ consent. On a given day, all eligible participants will have skin preparation either with 0.5% chlorhexidine in 70% alcohol or 10% povidone iodine in 70% alcohol. The primary outcome is superficial wound complications (comprised of superficial incisional surgical site infections (SSI) and/or prolonged wound ooze) in the first 30 days following prosthetic joint replacement surgery. Secondary outcomes will include the incidence of wound complications according to the joint replaced, assessment of the causative agents of SSI and cost-effectiveness analysis. The primary analysis is an intention-to-treat analysis including all participants who undergo randomisation and will be performed at the individual level taking into account the clustering effect.

Ethics and dissemination

The study design and protocol was reviewed and approved by the St Vincent's Hospital Human Research Ethics Committee (HREC-A 016/14 10/3/2014). Study findings will be disseminated in the printed media, and learned forums. A written lay summary will be available to study participants on request.

Trial registration number

The trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614000177651.
Preference for a single or shared room in a UK inpatient hospice: patient, family and staff perspectives
Authors: Williams Clare , Gardiner Clare
Published: May 2014

Objective

This study investigated the preferences of patients, family and staff for single or shared rooms in a UK hospice.

Method

Semistructured interviews were conducted with patients, informal carers and staff at a hospice, focusing on room type preference.

Results

14 current and former hospice inpatients, 15 patients attending the hospice day centre, 23 carers of current and former inpatients and 10 hospice staff were interviewed. Patients most often stated a preference for a shared room, especially if they had experience of being in this room type at the hospice. The main reason for this preference was the company of others. Patients preferring single rooms cited the benefits of increased privacy, reduced noise and private facilities. Other patients said their room preference would depend on how ill they were. Carers valued the social contact and increased staff presence in shared rooms, but felt that single rooms were easier for visitors and more appropriate when patients reached the end of life. Staff found it easier to observe patients in a shared room, and to maintain privacy and confidentiality in a single room.

Conclusions

The study concludes that single and shared rooms should be available in a hospice. Innovative planning can enable the social benefits of shared rooms to be maintained without compromising patients’ privacy and dignity.
EUROPEAN OPTIONS SENSITIVITY WITH RESPECT TO THE CORRELATION FOR MULTIDIMENSIONAL HESTON MODELS
Authors: ABBAS-TURKI LOKMAN A. , LAMBERTON DAMIEN
Published: May 2014

We study the sensitivity of European option prices with respect to correlation parameters in the multi-asset Heston model. The differentiability of the price function with respect to the correlation is proved by using the regularity of the flow of the Cox–Ingersoll–Ross model. In the bidimensional case and when the Feller condition is satisfied, we establish an asymptotic approximation for the derivative of the price with respect to the correlation for short maturities. This approximation is used to discuss monotony issues for exchange and spread option prices. Monotony properties are also obtained for some values of "the volatility of the volatility parameter" and of the correlation between stock prices and their volatilities. We conclude with a large number of simulations that confirm the theoretical results.
CREDIT-EQUITY MODELING UNDER A LATENT LÉVY FIRM PROCESS
Authors: KIJIMA MASAAKI , SIU CHI CHUNG
Published: May 2014

Recent empirical studies have demonstrated the informative nature of the equity returns in explaining the variation of the underlying firm's credit default swap (CDS) spreads. Motivated by these findings, we propose a unified credit-equity model by extending the latent structural model in Kijima et al. (2009). As in the original latent model, we treat the actual status of the firm to be unobservable and one can extract information from the marker process that is observable to the investors. Default occurs when the actual firm value drops below a default threshold for the first time. Different from the model in Kijima et al. (2009), however, we define the marker process to be the firm's equity process. Choosing firm's equity process to be a marker process subsequently relaxes the restrictions imposed in Kijima et al. (2009), enabling us to price firm-related securities.

Additionally, we enrich the original latent structural model with jump and regime-switching dynamics. The purpose of the extensions is to capture more realistic credit spreads and implied volatility skews under different economic environments. The proposed model maintains analytical tractability even under such complex dynamics, for the prices of CDSs and equity options admit semi-closed-form solutions. In sum, our model can evaluate corporate securities and their derivatives in a unified framework.
Nonlinear consistent valuation of CCP cleared or CSA bilateral trades with initial margins under credit, funding and wrong-way risks
Authors: Brigo Damiano , Pallavicini Andrea
Published: May 2014

The introduction of Central Clearing Counterparties (CCPs) in most derivative transactions will dramatically change the landscape of derivatives pricing, hedging and risk management, and, according to the TABB Group, will lead to an overall liquidity impact of about USD 2 trillions. In this paper, we develop for the first time a comprehensive approach for pricing under CCP clearing, including variation and initial margins, gap credit risk and collateralization, showing concrete examples for interest rate swaps. This framework stems from our 2011 framework on credit, collateral and funding costs in Pallavicini et al. (Pallavicini, A., D. Perini and D. Brigo, 2011, Funding Valuation Adjustment: FVA consistent with CVA, DVA, WWR, Collateral, Netting and Re-hypothecation, arxiv.org, ssrn.com). Mathematically, the inclusion of asymmetric borrowing and lending rates in the hedge of a claim, and a replacement closeout at default, lead to nonlinearities showing up in claim dependent pricing measures, aggregation dependent prices, nonlinear Partial Differential Equations (PDEs) and Backward Stochastic Differential Equations (BSDEs). This still holds in presence of CCPs and CSA. We introduce a modeling approach that allows us to enforce rigorous separation of the interconnected nonlinear risks into different valuation adjustments where the key pricing nonlinearities are confined to a funding costs component that is analyzed through numerical schemes for BSDEs. We present a numerical case study for Interest Rate Swaps that highlights the relative size of the different valuation adjustments and the quantitative role of initial and variation margins, of liquidity bases, of credit risk, of the margin period of risk and of wrong-way risk correlations.
Marginally excessive iron loading transiently blocks mucosal iron uptake in iron-deficient rats
Authors: Shinoda Shoko , Yoshizawa Shiho , Nozaki Eriko , Tadai Kouki , Arita Anna
Published: May 2014

Regular “mucosal block” is characterized by decreased uptake of a normal iron load 3–72 h after the administration of excess iron (generally 10 mg) to iron-deficient animals. We found that short-acting mucosal block could be induced by much lower iron concentration and much shorter induction time than previously reported, without affecting levels of gene expression. A rapid endocytic mechanism was reported to decrease intestinal iron absorption after a high iron load, but the activating iron load and the time to decreased absorption were undetermined. We assessed the effects of 30–2,000 μg iron load on iron uptake in the duodenal loop of iron-deficient and iron-sufficient rats under anesthesia. One hour later, mucosal cellular iron uptake in iron-deficient rats administered 30 μg iron was 76.1%, decreasing 25% to 50.7% in rats administered 2,000 μg iron. In contrast, iron uptake by iron-sufficient rats was 63% (range 60.3–65.5%) regardless of iron load. Duodenal mucosal iron concentration was significantly lower in iron-deficient than in iron-sufficient rats. Iron levels in portal blood were consistently higher in iron-deficient rats regardless of iron load, in contrast to the decreased iron uptake on the luminal side. Iron loading blocked mucosal uptake of marginally excess iron (1,000 μg), with a greater effect at 15 min than at 30 min. The rapid induction of short-acting mucosal block only in iron-deficient rats suggests DMT1 internalization.
Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium
Authors: Koay Luan C. , Rigby Rachael J. , Wright Karen L.
Published: May 2014

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered.
Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis
Authors: Powell Anne E. , Vlacich Gregory , Zhao Zhen-Yang , McKinley Eliot T. , Washington M. Kay , Manning H. Charles , Coffey Robert J.
Published: May 2014

Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli ( APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1+) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1+ cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.
Ibuprofen treatment blunts early translational signaling responses in human skeletal muscle following resistance exercise
Authors: Markworth James F. , Vella Luke D. , Figueiredo Vandre C. , Cameron-Smith David
Published: May 2014

Cyclooxygenase-1 and -2 pathway-derived prostaglandins (PGs) have been implicated in adaptive muscle responses to exercise, but the role of PGs in contraction-induced muscle signaling has not been determined. We investigated the effect of inhibition of cyclooxygenase-1 and -2 activities with the nonsteroidal anti-inflammatory drug ibuprofen on human muscle signaling responses to resistance exercise. Subjects orally ingested 1,200 mg ibuprofen (or placebo control) in three 400-mg doses administered ∼30 min before and ∼6 h and ∼12 h following a bout of unaccustomed resistance exercise (80% one repetition maximum). Muscle biopsies were obtained at rest (preexercise), immediately postexercise (0 h), 3 h postexercise, and at 24 h of recovery. In the placebo (PLA) group, phosphorylation of ERK1/2 (Thr202/Tyr204), ribosomal protein S6 kinase (RSK, Ser380), mitogen-activated kinase 1 (Mnk1, Thr197/202), and p70S6 kinase (p70S6K, Thr421/Ser424) increased at both 0 and 3 h postexercise, with delayed elevation of phospho (p)-p70S6K (Thr389) and p-rpS6 (Ser235/S36 and Ser240/244) at 3 h postexercise. Only p-ERK1/2 (Thr202/Tyr204) remained significantly elevated in the 24-h postexercise biopsy. Ibuprofen treatment prevented sustained elevation of MEK-ERK signaling at 3 h (p-ERK1/2, p-RSK, p-Mnk1, p-p70S6K Thr421/Ser424) and 24 h (p-ERK1/2) postexercise, and this was associated with suppressed phosphorylation of ribosomal protein S6 (Ser235/236 and Ser240/244). Early contraction-induced p-Akt (Ser473) and p-p70S6K (Thr389) were not influenced by ibuprofen, but p-p70S6K (Thr389) remained elevated 24 h postexercise only in those receiving ibuprofen treatment. Early muscle signaling responses to resistance exercise are, in part, ibuprofen sensitive, suggesting that PGs are important signaling molecules during early postexercise recovery.
A Rare Polymorphic Variant of NBS1 Reduces DNA Repair Activity and Elevates Chromosomal Instability
Authors: Yamamoto Yuki , Miyamoto Mamiko , Tatsuda Daisuke , Kubo Michiaki , Nakagama Hitoshi , Nakamura Yusuke , Satoh Hitoshi , Matsuda Koichi , Watanabe Toshiki , Ohta Tsutomu
Published: May 2014

Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia. This polymorphic variant is located in the N-terminal region that interacts with other DNA repair factors. In earlier work, we had identified a remarkable number of structural chromosomal aberrations in a patient with pediatric aplastic anemia with a homozygous polymorphic variant of NBS1-I171V; however, it was unclear whether this variant affected DSB repair activity or chromosomal instability. In this report, we demonstrate that NBS1-I171V reduces DSB repair activity through a loss of association with the DNA repair factor MDC1. Furthermore, we found that heterozygosity in this polymorphic variant was associated with breast cancer risk. Finally, we showed that this variant exerted a dominant-negative effect on wild-type NBS1, attenuating DSB repair efficiency and elevating chromosomal instability. Our findings offer evidence that the failure of DNA repair leading to chromosomal instability has a causal impact on the risk of breast cancer development. Cancer Res; 74(14); 3707–15. ©2014 AACR.
Ernest Henry Starling (1866-1927) on the Formation and Reabsorption of Lymph
Authors: Fine Leon G.
Published: May 2014

Ernest Henry Starling laid the groundwork for our modern understanding of how the interstitial fluid, which he referred to as ‘lymph', is regulated. Together with his colleague, William Bayliss, he provided the crucial insight into how fluid is driven out of the capillary to form interstitial fluid. That was to measure (estimate) the capillary pressure in different parts of the circulation and to relate changes in these pressures to altered lymph formation. In addressing how interstitial fluid re-enters the circulation, he was able to show that this occurs not only via the lymphatics, but also by re-entering the capillaries, mediated by the oncotic pressure of the plasma proteins. Starling's discoveries put to rest all notions that the processes of filtration and reabsorption of fluid are mediated by the ‘vital activity' of cells. They could be explained entirely on the basis of physic-chemical forces. Based upon his insights from animal experiments, he was able to explain the genesis of edema (dropsy) in a number of disease states, including venous obstruction, cardiac disease and inflammatory conditions.