bluuebunny/crossref_metadata_2025 huggingface dataset:
MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study
Authors: Martin-Broto Javier , Gutierrez Antonio M. , Ramos Rafael F. , Lopez-Guerrero José A. , Ferrari Stefano , Stacchiotti Silvia , Picci Piero , Calabuig Silvia , Collini Paola , Gambarotti Marco , Bague Silvia , Dei Tos Angelo P. , Palassini Elena , Luna Pablo , Cruz Josefina , Cubedo Ricardo , Martinez-Trufero Javier , Poveda Andres , Casali Paolo G. , Fernandez-Serra Antonio , Lopez-Pousa Antonio , Gronchi Alessandro
Published: October 2013

Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS. Mol Cancer Ther; 13(1); 249–59. ©2013 AACR.
Classical Transient Receptor Potential 1 and 6 Contribute to Hypoxic Pulmonary Hypertension Through Differential Regulation of Pulmonary Vascular Functions
Authors: Xia Yang , Yang Xiao-Ru , Fu Zhenzhen , Paudel Omkar , Abramowitz Joel , Birnbaumer Lutz , Sham James S.K.
Published: October 2013

Hypoxic pulmonary hypertension is characterized by increased vascular tone, altered vasoreactivity, and vascular remodeling, which are associated with alterations in Ca
2+
homeostasis in pulmonary arterial smooth muscle cells. We have previously shown that classical transient receptor potential 1 and 6 (TRPC1 and TRPC6) are upregulated in pulmonary arteries (PAs) of chronic hypoxic rats, but it is unclear whether these channels are essential for the development of pulmonary hypertension. Here we found that pulmonary hypertension was suppressed in TRPC1 and TRPC6 knockout (
Trpc1
−/−
and
Trpc6
−/−
) mice compared with wild-type after exposure to 10% O
2
for 1 and 3 weeks. Muscularization of pulmonary microvessels was inhibited, but rarefaction was unaltered in hypoxic
Trpc1
−/−
and
Trpc6
−/−
mice. Small PAs of normoxic wild-type mice exhibited vasomotor tone, which was significantly enhanced by chronic hypoxia. Similar vasomotor tone was found in normoxic
Trpc1
−/−
PAs, but the hypoxia-induced enhancement was blunted. In contrast, there was minimal vascular tone in normoxic
Trpc6
−/−
PAs, but the hypoxia-enhanced tone was preserved. Chronic hypoxia caused significant increase in serotonin-induced vasoconstriction; the augmented vasoreactivity was attenuated in
Trpc1
−/−
and eliminated in
Trpc6
−/−
PAs. Moreover, the effects of 3-week hypoxia on pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of microvessels were further suppressed in TRPC1-TRPC6 double-knockout mice. Our results, therefore, provide clear evidence that TRPC1 and TRPC6 participate differentially in various pathophysiological processes, and that the presence of TRPC1 and TRPC6 is essential for the full development of hypoxic pulmonary hypertension in the mouse model.
Disease Location Is Associated With Survival in Patients With Peripheral Arterial Disease
Authors: Chen Qian , Smith Carin Y. , Bailey Kent R. , Wennberg Paul W. , Kullo Iftikhar J.
Published: October 2013

Background

We investigated whether disease location influences survival in patients with peripheral arterial disease.

Methods and Results

Patients (n=12 731; mean age, 67.5±12.7 years; 57.4% male) who underwent outpatient noninvasive lower extremity arterial evaluation were followed up for 5.9±3.1 years for all‐cause mortality. Peripheral arterial disease (n=8930) was defined as a resting or postexercise ankle‐brachial index (
ABI
) ≤0.90, and normal
ABI
(n=3 801) was defined as a resting and postexercise
ABI
of 1.00 to 1.30. Presence or absence of disease at the proximal location or distal location was determined on the basis of
D
oppler signals in leg arteries; 42% had no
PD
or
DD
, 45% had proximal (14% postexercise
PD
only), 30% had distal disease, 17% had both proximal and distal disease, 28% had proximal only and 14% had distal only. We performed multivariable logistic regression to identify factors associated with disease location, and
C
ox proportional hazard regression to assess the respective effects of proximal or distal disease on survival. Older age, male sex, diabetes, heart failure, and critical limb ischemia were associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and critical limb ischemia were associated with proximal disease. Over a mean follow‐up of 5.9±3.1 years, 3039 patients (23.9%) died. After adjustment for potential confounders, the hazard ratios (
HR
s) of death associated with
PD
only and
DD
only were 1.3 (1.3 to 1.4) and 1.5 (1.4 to 1.6), respectively. After additional adjustment for resting
ABI
, there was no significant association between proximal disease and death, whereas the association of distal disease with death remained significant (
HR
, 1.2; 95%
CI
, 1.1 to 1.3).

Conclusions

In patients with peripheral arterial disease, proximal and distal disease locations were associated with distinctive risk factor and comorbidity profiles. Distal disease was associated with worse survival even after adjustment for risk factors, comorbidities, and resting
ABI
.
A new skink (Scincidae: Saproscincus) from rocky rainforest habitat on Cape Melville, north-east Australia
Authors: HOSKIN CONRAD J.
Published: October 2013

Saproscincus skinks are restricted to wet forest habitats of eastern Australia. Eleven species have previously been described, with most having small distributions in disjunct areas of subtropical and tropical rainforest. The localized distributions and specific habitat requirements of Saproscincus have made them a key group for understanding the biogeographic history of Australia’s rainforests. Here I describe a new species of Saproscincus from the Melville Range on Cape Melville, north-east Australia. The Melville Range is composed of boulder-fields and areas of rainforest in the uplands, and is highly isolated from other areas of elevated rainforest. All individuals of the new species were found on a moist ridgeline, active on boulders under a rainforest canopy or on boulder-field immediately adjacent to rainforest. Saproscincus saltus sp. nov. is highly distinct in morphology and colour pattern. Of particular interest are its long limbs and digits compared to congeners, which in conjunction with the observed ecology, suggest a long history of association with rock. The discovery of S. saltus sp. nov. extends the distribution of the genus over 100 km north from the nearest congeners in the Wet Tropics region. This species brings the number of vertebrates known to be endemic to the Melville Range to six, which is remarkable for such a small area.
Does Morality Condition the Deterrent Effect of Perceived Certainty Among Incarcerated Felons?
Authors: Piquero Alex R. , Bouffard Jeffrey A. , Piquero Nicole Leeper , Craig Jessica M.
Published: October 2013

Deterrence researchers have long considered the extent to which perceived certainty and severity inhibit offending. More recently, scholars have encouraged more specific investigations about the conditions under which sanction threats may deter offending. This study contributes to and extends this line of research by exploring whether morality conditions this relationship among a large sample of incarcerated felons. Results show that while certainty and morality are independently associated with a lower likelihood of offending, perceived certainty relates to offending only among those persons with high—but not low—moral beliefs.
First, There Was A Country; Then There Wasn’t: Reflections on Achebe’s New Book
Authors: Jeyifo Biodun
Published: October 2013

Chinua Achebe is one of the greatest realist writers in world literature in perhaps the last one and half centuries. But the Achebe that appears in There Was a Country is to me entirely a new one. The challenge is how to characterize this other Achebe that is standing beside the old, urbane and subtle writer in this new book.
Complete video-assisted thoracoscopic surgery for lung cancer in 400 patients
Authors: Srisomboon Chaisit , Koizumi Kiyoshi , Haraguchi Shuji , Mikami Iwao , Iijima Yoshihito , Shimizu Kazuo
Published: October 2013

Background

We report the results of complete video-assisted thoracoscopic surgery for treatment of primary non-small cell lung cancer, which was performed completely through the monitor in 400 consecutive patients.

Patients and methods

Between September 25, 2002 and August 25, 2011, a retrospective database of 400 consecutive patients who underwent complete video-assisted thoracoscopic surgery for treatment of primary non-small cell lung cancer was reviewed. Demographic, histopathologic, preoperative, perioperative, postoperative, and outcome variables were assessed using standard descriptive statistics and Kaplan-Meier survival analyses.

Results

Operating time was 258.13 ± 62.53 min, volume of blood loss was 253.21 ± 206.66 mL, duration of drainage was 3.6 ± 3.2 days, volume of drainage was 708.1 ± 522.8 mL, the postoperative respiratory complication rate was 14.8%, the reoperation rate was 1.3%, and operative mortality was 1.0%. The 5-year postsurgical survival rates for pathologic stages I, II, and III were 93.9%, 62.0%, and 61.6%, respectively; the 3-year postsurgical survival rate for pathologic stage IV was 40.0%

Conclusions

Complete video-assisted thoracoscopic surgery for treatment of primary non-small cell lung cancer is associated with safety and acceptable postoperative complication rates, operative mortality rates, and survival rates.
Identification of Multiple Theoretical Linkages for High Performance Work System
Authors: Marathe Gaurav , Pathak Kasturee Govind
Published: October 2013

Multiple theoretical linkages are developed for High Performance Work System (HPWS). This model explores the HR system, its links with performance and performance outcomes based on the direction given by Guest ( 1997 ). This article attempts to provide three pathways for effect of HPWS on performance—first through direct effect on employee’s skill and ability, second through system effect produced by creation of organizational climate through internal fit, and lastly, interaction effect produced by strategic context through external fit. Further performance of organization is considered as employee level outcomes, organizational level outcomes and financial level outcomes.
Exploring the Mediating Effect of Organizational Trust Between Organizational Justice Dimensions and Affective Commitment
Authors: Mukherjee Kamal , Bhattacharya Ranan
Published: October 2013

Extant research has established that perceptions of justice in the organizational arena lead to desirable employee attitudes and behaviours. However, there seems to be a paucity of research exploring how social exchange variables act as mechanisms linking justice perceptions with their output. The present research is therefore a small step towards bridging this gap by examining the role of a social exchange variable, Organizational Trust (Trust), as mediating the relationship between each of the three Organizational Justice dimensions: Distributive (DJ), Procedural (PJ) and Interactional Justice (IJ), and an organizational level outcome (Affective Organizational Commitment - OC). The study finds that PJ and IJ does not have any significant relationship with Trust and only the relation between DJ and OC is fully mediated by Trust. Further, there is no interaction effect of the three justice dimensions upon Trust.

The study concludes with a discussion regarding the findings, the limitations under which it has been conducted, and its implications for management practice.
A Study of Work Exhaustion in Frontline Bank Employees
Authors: Khanna Meenakshi , Maini Vandana
Published: October 2013

Today’s business environment, characterized by rapid change, knowledge explosion, technological advancement and intense competition, has given birth to a serious psychological menace in terms of work exhaustion. This article analyzes the antecedents of work exhaustion among employees working in banks. It is based on the structured survey through a questionnaire with frontline bank employees working in Ludhiana. A comparative study of bank employees working in public and private sector banks has also been made with respect to various organizational variables influencing work exhaustion. The results indicate that the strain arising from managing a professional career and family responsibilities results in a lot of stress for the bank employees. The findings have significant implications for the employers in terms of retaining a consistent workforce by revising its work schedules and introducing family-friendly policies to accommodate the personal roles and responsibilities of bank employees.
The Hierarchy of Ethical Consumption Behavior
Authors: Wooliscroft Ben , Ganglmair-Wooliscroft Alexandra , Noone Abigayle
Published: October 2013

Consumers need to move to more sustainable/ethical behavior. Previous research has explored changing consumption with most studies concentrating on specific aspects of sustainable/ethical consumption. This study uses a full range of citizen defined ethical choices. Applying Rasch modeling to consumers' reports of ethically motivated consumption choices, a hierarchy of ethical choices is created. This hierarchy of ethical consumption choices allows the application of stages of change theory to progress consumers up the hierarchy of ethical choices, with implications for public policy, pressure groups and consumers.
Exploiting multipath fading with a mobile robot
Authors: Lindhé Magnus , Johansson Karl Henrik
Published: October 2013

In indoor or urban applications, a moving robot with wireless communications will experience multipath fading. This causes rapid signal strength variations due to interfering reflections of the radio signal. By making short stops at positions with high signal-to-noise ratio (SNR), the robot can trade trajectory tracking accuracy for increased link quality. This represents a type of opportunistic communication-aware motion planning. We propose two novel strategies for improving the link capacity or throughput when either the robot has full knowledge of how the SNR varies along the trajectory, or when only the SNR distribution is known or can be estimated. In the latter case, this leads to an optimal stopping problem over a finite horizon. Both cases are analyzed for independent as well as correlated SNR samples, and a bounded maximum trajectory tracking error. We derive the resulting SNR distributions for the proposed strategies and use them to show how the expected capacity and throughput vary with the allowed tracking error. The results are confirmed by simulations and experiments. Experiments in six different locations validate the communication model and show that the proposed motion planning is robust to non-static fading and can yield throughput improvements of more than 100%.
Cutting Words
Authors: Calogero Rachel M. , Pina Afroditi , Sutton Robbie M.
Published: October 2013

We examined whether subtle exposure to sexually objectifying cues increases women’s intentions to have cosmetic surgery. Undergraduate women ( N = 116) were randomly assigned to a condition in which they unscrambled sentences containing words associated with sexual objectification, non-self-objectifying physicality, or neutral content. Following a manipulation check of these primes, participants reported their body shame and intentions to have cosmetic surgery in the future. Results revealed that priming a state of self-objectification, compared to the two non-self-objectifying conditions, increased both body shame and intentions to have cosmetic surgery. In a mediational model, the link between self-objectification and intentions to have cosmetic surgery was partially mediated by body shame. Controlling for other key intrapersonal and social motives linked to interest in cosmetic surgery did not alter these patterns. These findings highlight the potential for the consumption of cosmetic surgery to stand as another harmful micro-level consequence of self-objectification that may be perpetuated via subtle exposure to sexually objectifying words, even in the absence of visual depictions or more explicit encounters of sexual objectification.
My Beliefs of My Peers’ Beliefs
Authors: Hertzog Jodie L. , Rowley Rochelle Lynn
Published: October 2013

Dating violence in adolescent relationships is a growing social problem in the United States. A majority of adolescents have dated by the time they finish high school and these experiences have an impact on their relationship trajectories as adults. Although more and more prevention efforts are aimed at reducing teen dating violence and/or teaching adolescents about healthy relationships, very few of these efforts investigate discrepancies in descriptive and injunctive norms associated with adolescent dating. This pilot study adds to the existing literature by investigating the dating norms of early and mid-adolescents to aid in tailoring prevention efforts among this population. One hundred eighty-seven middle and high school student leaders from public schools in the Midwest completed an annual relationship survey. Findings suggest that participants did not support unhealthy relationship norms overall. However, two patterns of discrepancies emerged: one between participant attitudes (descriptive norms) and their perceptions of peer attitudes (injunctive norms), and another between perceptions participants hold about their male versus female peers’ beliefs. Results imply the development of pluralistic ignorance occurs during adolescence and that perceptions of peer norms are in line with the principles of hegemonic masculinity. Implications for possible prevention initiatives and future research directions are noted.
International Relations
Authors: Crooks Andrew , Masad David , Croitoru Arie , Cotnoir Amy , Stefanidis Anthony , Radzikowski Jacek
Published: October 2013

The international community can be viewed as a set of networks manifested through various transnational activities. The availability of longitudinal data sets such as international arms trades and United Nations General Assembly (UNGA) allows for the study of state-driven interactions over time. In parallel to this top-down approach, the recent emergence of social media is fostering a bottom-up and citizen-driven avenue for international relations (IRs). The comparison of these two network types offers a new lens to study the alignment between states and their people. This article presents a network-driven approach to analyze communities as they are established through different forms of bottom-up (e.g., Twitter) and top-down (e.g., UNGA voting records and international arms trade records) IRs. By constructing and comparing different network communities, we were able to evaluate the similarities between state-driven and citizen-driven networks. In order to validate our approach we identified communities in UNGA voting records during and after the Cold War. Our approach showed that the similarity between UNGA communities during and after the Cold War was 0.55 and 0.81, respectively (in a 0–1 scale). To explore the state- versus citizen-driven interactions, we focused on the recent events in Syria within Twitter over a sample period of 1 month. The analysis of these data show a clear misalignment (0.25) between citizen-formed international networks and the ones established by the Syrian government (e.g., through its UNGA voting patterns).
Learning From Each Other
Authors: Hague Gill
Published: October 2013

Designed to act possibly as an anchor for other contributions, this article responds to the preceding article on the Special Cell for Women and Children in Mumbai, and offers a broad, brush-stroke overview of a selection of criminal justice-focused activist responses to violence against women in India, the United Kingdom, and other countries. It reflects on the work of the Special Cell in the context of other women’s support projects in police stations across the world, including Domestic Violence Matters, London, UK; the Family Consultant Service, London, Canada; and the women’s police stations in Brazil. The article goes on to discuss the different activist responses in India and the United Kingdom, and both the contradictions around, and recent developments in, the activist provision of shelters worldwide.
A retrospective analysis of urethral rupture in 63 cats
Authors: Addison Elena S , Halfacree Zoe , Moore Alasdair Hotston , Demetriou Jackie , Parsons Kevin , Tivers Michael
Published: October 2013

The aim of this study was to investigate the short- and long-term morbidity and mortality associated with urethral rupture in cats. Medical records were reviewed from four veterinary hospitals. Diagnosis was made from retrograde urethrography or direct visualisation during surgery. Location of rupture was categorised as pre-, intra- or post-pelvic. Follow-up data were collected from referring veterinarians. Sixty-three cats were included in the study of which, males predominated (88.9%). Trauma was the most common cause (n = 35; 55.6%) with the remainder due to iatrogenic injury. Forty-eight cats (88.9%) were treated surgically and six (11.1%) managed conservatively. Significant differences between cats suffering traumatic versus iatrogenic injury included the presence of musculoskeletal injuries ( P <0.001); the location of rupture ( P <0.001); the degree of rupture ( P <0.001); definitive management ( P <0.001) and short-term complications ( P = 0.026). Short-term complications were significantly associated with the following: musculoskeletal injuries ( P = 0.012); uroabdomen/uroretroperitoneum ( P = 0.004); azotaemia ( P = 0.021); postoperative urinary diversion ( P = 0.036) and >1 surgery performed ( P = 0.006). Forty-seven cats (74.6%) survived to discharge. Prognostic factors associated with survival to discharge included the presence of musculoskeletal injuries ( P = 0.017); cause of rupture ( P = 0.017); location of rupture ( P = 0.039) and definitive management ( P = 0.020). Twenty-four cats (57.1%) suffered short-term complications and 10 (27.0%) suffered long-term complications. Of those cats surviving to discharge 30 (71.4%) had a good outcome. Median follow-up was 16 months. Outcome was significantly associated with cause of rupture ( P = 0.04); short-term complications ( P = 0.03) and long-term complications ( P <0.001). In conclusion, a significantly greater proportion of cats with iatrogenic injuries survived to discharge and had a good outcome compared with those that suffered trauma.
A randomized clinical trial of oral versus intravenous methylprednisolone for relapse of MS
Authors: Ramo-Tello C , Grau-López L , Tintoré M , Rovira A , Ramió i Torrenta L , Brieva L , Cano A , Carmona O , Saiz A , Torres F , Giner P , Nos C , Massuet A , Montalbán X , Martínez-Cáceres E , Costa J
Published: October 2013

Background:

Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain.

Objective:

The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse.

Methods:

Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks’ post-treatment initiation. Secondary outcomes were safety and tolerability.

Results:

The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0–1) vs 0 (0–0.5), p = 0.630), volume of Gd+ lesions (0 (0–88.0) vs 0 (0–32.9) mm3, p = 0.735), or new or enlarged T2 lesions (0 (0–194) vs 0 (0–123), p = 0.769). MP was well tolerated, and no serious adverse events were reported.

Conclusions:

This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe.

Trial registration:

clinicaltrials.gov identifier: NCT00753792
A study of atmosphere perception of dynamic coloured light
Authors: Wang HH , Luo M Ronnier , Liu P , Yang Y , Zheng Z , Liu X
Published: October 2013

A psychophysical experiment has been carried out to investigate the impact of dynamic lighting parameters on atmosphere perception. The experiment was conducted in a purpose-built LED lighting lab, where the lighting could be spatially and dynamically changed and colorimetric specifications controlled. The aim of this study was to investigate the impacts of speed, saturation and brightness of dynamic lighting on the perceived atmosphere, preference and suitability for certain spaces. Twenty native Chinese observers participated in the experiment, each assessing the environment under dynamic lighting conditions using 21 atmosphere terms. The results show significant gender differences on some scales such as safe, spatial, chilly, formal, preference and office-like. Factor analysis showed that the 21 scales can be grouped into three categories: tenseness, coziness and liveliness, and that a living room-like atmosphere evaluation is consistent with coziness. Dynamic lighting does have a significant influence on atmosphere perception. A more saturated LED light would lead to less tense, more cosy, more safe and more lively atmosphere perceptions. By increasing the speed, a more tense and less cosy atmosphere can be generated. Medium speed offers the most lively and preferred atmosphere. Brighter lighting will generate a less tense environment. More saturated colour and a slower speed will produce a more living room-like environment, but it seems that such dynamic lighting is not suitable for an office-like environment.
Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence
Authors: Nunez Yury O , Truitt Jay M , Gorini Giorgio , Ponomareva Olga N , Blednov Yuri A , Harris R Adron , Mayfield R Dayne
Published: October 2013

Background

Although the study of gene regulation via the action of specific microRNAs (miRNAs) has experienced a boom in recent years, the analysis of genome-wide interaction networks among miRNAs and respective targeted mRNAs has lagged behind. MicroRNAs simultaneously target many transcripts and fine-tune the expression of genes through cooperative/combinatorial targeting. Therefore, they have a large regulatory potential that could widely impact development and progression of diseases, as well as contribute unpredicted collateral effects due to their natural, pathophysiological, or treatment-induced modulation. We support the viewpoint that whole mirnome-transcriptome interaction analysis is required to better understand the mechanisms and potential consequences of miRNA regulation and/or deregulation in relevant biological models. In this study, we tested the hypotheses that ethanol consumption induces changes in miRNA-mRNA interaction networks in the mouse frontal cortex and that some of the changes observed in the mouse are equivalent to changes in similar brain regions from human alcoholics.

Results

miRNA-mRNA interaction networks responding to ethanol insult were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA). Important pathways (coexpressed modular networks detected by WGCNA) and hub genes central to the neuronal response to ethanol are highlighted, as well as key miRNAs that regulate these processes and therefore represent potential therapeutic targets for treating alcohol addiction. Importantly, we discovered a conserved signature of changing miRNAs between ethanol-treated mice and human alcoholics, which provides a valuable tool for future biomarker/diagnostic studies in humans. We report positively correlated miRNA-mRNA expression networks that suggest an adaptive, targeted miRNA response due to binge ethanol drinking.

Conclusions

This study provides new evidence for the role of miRNA regulation in brain homeostasis and sheds new light on current understanding of the development of alcohol dependence. To our knowledge this is the first report that activated expression of miRNAs correlates with activated expression of mRNAs rather than with mRNA downregulation in anin vivomodel. We speculate that early activation of miRNAs designed to limit the effects of alcohol-induced genes may be an essential adaptive response during disease progression.
Salmonella Typhimurium TTSS-2 deficient mig-14 mutant shows attenuation in immunocompromised mice and offers protection against wild-type Salmonella Typhimurium infection
Authors: Pati Niladri Bhusan , Vishwakarma Vikalp , Selvaraj Sathish kumar , Dash Sabyasachi , Saha Bhaskar , Singh Neera , Suar Mrutyunjay
Published: October 2013

Background

Development of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Several mutants of S. Typhimurium have been proposed as an effective live attenuated vaccine strain. Unfortunately, many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. However, it remained unclear, whether the existing live attenuated S. Typhimurium strains can further be attenuated with improved safety and immune efficacy or not.

Results

We deleted a specific non-SPI (Salmonella Pathogenicity Island) encoded virulence factor mig-14 (an antimicrobial peptide resistant protein) in ssaV deficient S. Typhimurium strain. The ssaV is an important SPI-II gene involved in Salmonella replication in macrophages and its mutant strain is considered as a potential live attenuated strain. However, fatal systemic infection was previously reported in immunocompromised mice like Nos2
−/− and Il-10
−/− when infected with ssaV deficient S. Typhimurium. Here we reported that attenuation of S. Typhimurium ssaV mutant in immunocompromised mice can further be improved by introducing additional deletion of gene mig-14. The ssaV, mig-14 double mutant was as efficient as ssaV mutant, with respect to host colonization and eliciting Salmonella-specific mucosal sIgA and serum IgG response in wild-type C57BL/6 mice. Interestingly, this double mutant did not show any systemic infection in immunocompromised mice.

Conclusions

This study suggests that ssaV, mig-14 double mutant strain can be effectively used as a potential vaccine candidate even in immunocompromised mice. Such attenuated vaccine strain could possibly used for expression of heterologous antigens and thus for development of a polyvalent vaccine strain.
Fine mapping and identification of a candidate gene for a major locus controlling maturity date in peach
Authors: Pirona Raul , Eduardo Iban , Pacheco Igor , Da Silva Linge Cassia , Miculan Mara , Verde Ignazio , Tartarini Stefano , Dondini Luca , Pea Giorgio , Bassi Daniele , Rossini Laura
Published: October 2013

Background

Maturity date (MD) is a crucial factor for marketing of fresh fruit, especially those with limited shelf-life such as peach (Prunus persica L. Batsch): selection of several cultivars with differing MD would be advantageous to cover and extend the marketing season. Aims of this work were the fine mapping and identification of candidate genes for the major maturity date locus previously identified on peach linkage group 4. To improve genetic resolution of the target locus two F2 populations derived from the crosses Contender x Ambra (CxA, 306 individuals) and PI91459 (NJ Weeping) x Bounty (WxBy, 103 individuals) were genotyped with the Sequenom and 9K Illumina Peach Chip SNP platforms, respectively.

Results

Recombinant individuals from the WxBy F2 population allowed the localisation of maturity date locus to a 220 kb region of the peach genome. Among the 25 annotated genes within this interval, functional classification identified ppa007577m and ppa008301m as the most likely candidates, both encoding transcription factors of the NAC (NAM/ATAF1, 2/CUC2) family. Re-sequencing of the four parents and comparison with the reference genome sequence uncovered a deletion of 232 bp in the upstream region of ppa007577m that is homozygous in NJ Weeping and heterozygous in Ambra, Bounty and the WxBy F1 parent. However, this variation did not segregate in the CxA F2 population being the CxA F1 parent homozygous for the reference allele. The second gene was thus examined as a candidate for maturity date. Re-sequencing of ppa008301m, showed an in-frame insertion of 9 bp in the last exon that co-segregated with the maturity date locus in both CxA and WxBy F2 populations.

Conclusions

Using two different segregating populations, the map position of the maturity date locus was refined from 3.56 Mb to 220 kb. A sequence variant in the NAC gene ppa008301m was shown to co-segregate with the maturity date locus, suggesting this gene as a candidate controlling ripening time in peach. If confirmed on other genetic materials, this variant may be used for marker-assisted breeding of new cultivars with differing maturity date.
Progression from new methicillin-resistant Staphylococcus aureus colonisation to infection: an observational study in a hospital cohort
Authors: Balm Michelle ND , Lover Andrew A , Salmon Sharon , Tambyah Paul A , Fisher Dale A
Published: October 2013

Background

Patients newly colonised with methicillin-resistant Staphylococcus aureus (MRSA) are at higher risk of clinical MRSA infection. At present, there are limited data on the duration or magnitude of this risk in a hospital population with a known time of MRSA acquisition.

Methods

A retrospective cohort study of 909 adult patients known to have newly identified MRSA colonisation during admission to National University Hospital, Singapore between 1 July 2007 and 30 June 2011 was undertaken. Patients were excluded if they had history of previous MRSA colonisation or infection, or if they had been a hospital inpatient in the preceding 12 months. Data were collected on the development of MRSA infection requiring hospitalisation up to 30 June 2012.

Results

Of 840 patients newly colonised with MRSA as identified on active surveillance and not clinical specimens, 546 were men (65.0%) and the median age was 65 years (range 18–103 years). Median follow up was 24 months (range 0 –64 months, 85.1% followed >6 months). Clinical infection occurred in 121 patients (14.4%) with median time to infection of 22 days (95% CI 14–31). Overall 71.9% (87/121) of infected patients developed infection within 60 days of the date MRSA colonisation was detected. However, 17/121 patients (14.0%) developed clinical infection more than six months after documented MRSA acquisition. The most common sites of clinical infection were skin and soft tissue (49/121, 40.5%, 95% CI 31.7-49.8), respiratory tract (37/121, 30.6%, 95% CI 22.5-39.6) and bone and joint infections (14/121, 11.6%, 95% CI 6.5-18.7). Thirteen patients (13/121, 10.7%, 95% CI 5.8-17.7) had bacteraemias, of which six (5.0% 95% CI 1.8-10.5) were primary and seven (5.7%, 95% CI 2.3-11.6) were secondary to infection at other sites. Crude mortality at 30 days and six months was higher in patients with MRSA infection than colonisation alone (aOR 5.49, 95% CI 2.75-10.95, p<0.001 and aOR 2.94, 95% CI 1.78-4.85, p<0.001 respectively).

Conclusion

Risk of clinical infection is highest soon after MRSA acquisition. Prevention of MRSA acquisition in hospital will have significant impact on morbidity and mortality for patients.
Burden of peripheral arterial disease in Europe and the United States: a patient survey
Authors: Marrett Elizabeth , DiBonaventura Marco daCosta , Zhang Qiaoyi
Published: October 2013

Background

The aim of the current study was to quantify the burden of peripheral arterial disease (PAD) with respect to health-related quality of life, work productivity and activity impairment, and healthcare resource utilization.

Methods

Data were obtained from the 2010 EU National Health and Wellness Survey (NHWS), which included participants from France, Germany, Italy, Spain, and the UK (5EU, N = 57,805) as well as the 2010 US NHWS (N = 75,000). The NHWS is an annual, cross-sectional, self-administered Internet survey which employs a stratified random sampling frame to match the age and gender characteristics of the NHWS sample with known population statistics. Participants who self-reported a diagnosis of PAD were compared with participants who did not self-report a diagnosis of PAD on health-related quality of life (mental and physical component summary scores and health utilities from the Short Form-12v2), work productivity and activity impairment (Work Productivity and Activity Impairment questionnaire), and healthcare resource use in terms of the number of physician visits, emergency room visits, and hospitalizations in the past six months through regression modeling adjusting for demographics and health characteristics.

Results

A total of 743 (1.29%) and 777 (1.04%) participants self-reported a diagnosis of PAD in the 5EU and US, respectively. After adjusting for demographics and health characteristics, patients with PAD reported worse health-related quality of life, as measured by health utilities (5EU: 0.66 vs. 0.70; US: 0.66 vs. 0.72; all p < .05), greater overall work impairment percentage (5EU: 38.27% vs. 27.48%; US: 23.89% vs. 14.26%) and greater healthcare resource use compared to participants without PAD (all p < .05).

Conclusions

These results suggest a significant burden for patients with PAD in both the 5 EU countries and the US with respect to both quality of life and economic outcomes. Improved management of these patients may have profound effects from both patient and societal perspectives.
Quantitative real-time PCR detection of Zika virus and evaluation with field-caught Mosquitoes
Authors: Faye Oumar , Faye Ousmane , Diallo Diawo , Diallo Mawlouth , Weidmann Manfred , Sall Amadou Alpha
Published: October 2013

A bstract

Background

Zika virus (ZIKV), a mosquito borne flavivirus is a pathogen affecting humans in Asia and Africa. ZIKV infection diagnosis relies on serology–which is challenging due to cross-reactions with other flaviviruses and/or absence or low titer of IgM and IgG antibodies at early phase of infection- virus isolation, which is labor intensive, time consuming and requires appropriate containment. Therefore, real-time RT-PCR (rRT-PCR) is an appealing option as a rapid, sensitive and specific method for detection of ZIKV in the early stage of infection. So far, only one rRT-PCR assay has been described in the context of the outbreak in Micronesia in 2007. In this study, we described a one step rRT-PCR for ZIKV which can detect a wider genetic diversity of ZIKV isolates from Asia and Africa.

Results

The NS5 protein coding regions of African ZIKV isolates were sequenced and aligned with representative flaviviruses sequences from GenBank to design primers and probe from conserved regions. The analytical sensitivity of the assay was evaluated to be 32 genome-equivalents and 0.05 plaque forming unit (pfu). The assay was shown to detect 37 ZIKV isolates covering a wide geographic in Africa and Asia over 36 years but none of the 31 other flaviviruses tested showing high analytical specificity. The rRT-PCR could be performed in less than 3 hours. This method was used successfully to detect ZIKV strains from field-caught mosquitoes.

Conclusion

We have developed a rapid, sensitive and specific rRT – PCR for detection of ZIKV. This assay is a useful tool for detection of ZIKV infection in regions where a number of other clinically indistinguishable arboviruses like dengue or chikungunya co-circulate. Further studies are needed to validate this assay in clinical positive samples collected during acute ZIKV infection.
Poor knowledge of methotrexate associated with older age and limited English-language proficiency in a diverse rheumatoid arthritis cohort
Authors: Barton Jennifer L , Schmajuk Gabriela , Trupin Laura , Graf Jonathan , Imboden John , Yelin Edward H , Schillinger Dean
Published: October 2013

Introduction

Our objective was to determine rheumatoid arthritis (RA) patients’ understanding of methotrexate and assess whether knowledge varies by age, education, English language proficiency, or other disease-related factors.

Methods

Adults with RA (n = 135) who were enrollees of an observational cohort completed a structured telephone interview in their preferred language between August 2007 and July 2009. All subjects who reported taking methotrexate were asked 11 questions about the medication in addition to demographics, education level, and language proficiency. Primary outcome was a total score below the 50th percentile (considered inadequate methotrexate knowledge). Bivariable and multivariable logistic regressions were performed. Covariates included demographics, language proficiency, education, and disease characteristics.

Results

Of 135 subjects, 83% were female, with a mean age of 55 ± 14 years. The majority spoke English (64%), followed by 22% Spanish and 14% Cantonese or Mandarin. Limited English language proficiency (LEP) was reported in 42%. Mean methotrexate knowledge score was 5.4 ± 2.6 (range, 0 to 10); 73 (54%) had a score lower than 5 (of 10). Age older than 55, less than high school education, LEP, better function, and biologic use were independently associated with poor knowledge.

Conclusions

In a diverse RA cohort, overall methotrexate knowledge was poor. Older age and limited proficiency in English were significant correlates of poor knowledge. Identification of language barriers and improved clinician-patient communication around methotrexate dosing and side effects may lead to improved safety and enhanced benefits of this commonly used RA medication.
Safety, Efficacy, and Biomarkers of Nivolumab With Vaccine in Ipilimumab-Refractory or -Naive Melanoma
Authors: Weber Jeffrey S. , Kudchadkar Ragini Reiney , Yu Bin , Gallenstein Donna , Horak Christine E. , Inzunza H. David , Zhao Xiuhua , Martinez Alberto J. , Wang Wenshi , Gibney Geoffrey , Kroeger Jodi , Eysmans Cabell , Sarnaik Amod A. , Chen Y. Ann
Published: October 2013

Purpose

Nivolumab, a human immunoglobulin G4–blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.

Patients and Methods

In this phase I study, 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy (cohorts 1 to 3, 34 patients) or experienced progression after prior ipilimumab (cohorts 4 to 6, 56 patients) received nivolumab at 1, 3, or 10 mg/kg every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine.

Results

Nivolumab with vaccine was well tolerated and safe at all doses. The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25%. Median duration of response was not reached at a median of 8.1 months of follow-up. High pretreatment NY-ESO-1 and MART-1–specific CD8+ T cells were associated with progression of disease. At week 12, increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression. PD-L1 tumor staining was associated with responses to nivolumab, but negative staining did not rule out a response. Patients who experienced progression after nivolumab could respond to ipilimumab.

Conclusion

In patients with ipilimumab-refractory or -naive melanoma, nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks. Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab.
Prediagnostic Body Mass Index and Pancreatic Cancer Survival
Authors: Yuan Chen , Bao Ying , Wu Chen , Kraft Peter , Ogino Shuji , Ng Kimmie , Qian Zhi Rong , Rubinson Douglas A. , Stampfer Meir J. , Giovannucci Edward L. , Wolpin Brian M.
Published: October 2013

Purpose

Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival.

Patients and Methods

We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis.

Results

The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI ≥ 35 kg/m2 with those with BMI < 25 kg/m2 (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend < .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI ≥ 35 kg/m2 with BMI < 25 kg/m2. Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02).

Conclusion

Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts.