bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality (1950–1999) and cancer incidence (1969–1999) of workers in the Port Hope cohort study exposed to a unique combination of radium, uranium and γ-ray doses
Authors: Zablotska Lydia B , Lane Rachel S D , Frost Stanley E
Published: March 2013

Objectives

Uranium processing workers are exposed to uranium and radium compounds from the ore dust and to γ-ray radiation, but less to radon decay products (RDP), typical of the uranium miners. We examined the risks of these exposures in a cohort of workers from Port Hope radium and uranium refinery and processing plant.

Design

A retrospective cohort study with carefully documented exposures, which allowed separation of those with primary exposures to radium and uranium.

Settings

Port Hope, Ontario, Canada, uranium processors with no mining experience.

Participants

3000 male and female workers first employed (1932–1980) and followed for mortality (1950–1999) and cancer incidence (1969–1999).

Outcome measures

Cohort mortality and incidence were compared with the general Canadian population. Poisson regression was used to evaluate the association between cumulative RDP exposures and γ-ray doses and causes of death and cancers potentially related to radium and uranium processing.

Results

Overall, workers had lower mortality and cancer incidence compared with the general Canadian population. In analyses restricted to men (n=2645), the person-year weighted mean cumulative RDP exposure was 15.9 working level months (WLM) and the mean cumulative whole-body γ-ray dose was 134.4 millisieverts. We observed small, non-statistically significant increases in radiation risks of mortality and incidence of lung cancer due to RDP exposures (excess relative risks/100 WLM=0.21, 95% CI <−0.45 to 1.59 and 0.77, 95% CI <−0.19 to 3.39, respectively), with similar risks for those exposed to radium and uranium. All other causes of death and cancer incidence were not significantly associated with RDP exposures or γ-ray doses or a combination of both.

Conclusions

In one of the largest cohort studies of workers exposed to radium, uranium and γ-ray doses, no significant radiation-associated risks were observed for any cancer site or cause of death. Continued follow-up and pooling with other cohorts of workers exposed to by-products of radium and uranium processing could provide valuable insight into occupational risks and suspected differences in risk with uranium miners.
Protocol for an experimental study design to evaluate computer-enabled intervention to prevent and manage metabolic syndrome
Authors: Joshi Ashish , Mehta Shruti , Talati Kandarp , Grover Ashoo
Published: March 2013

Introduction

The rising prevalence of overweight and obesity has a direct correlation with increasing prevalence of hypertension, dyslipidaemia, type 2 diabetes, metabolic syndrome (MetS) and cardiovascular diseases. Most of the previous studies have been cross-sectional in nature and have looked at the prevalence of metabolic syndrome. Despite the clinical and public health importance of this phenomenon, not enough work has been carried out so far to study and remedy this situation. The objectives of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account user sociodemographics, health behaviour, prior disease state and knowledge attitudes and practices.

Objective

The objective of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account users’ sociodemographics, health behaviour, prior disease state and knowledge, attitudes and behaviour.

Methods and analysis

A randomised two-group repeated-measures clinical trial design will be used, on 750 subjects from urban, rural and slum areas, in an Indian setting. The study participants will be randomly assigned to either the intervention (computer-based MetS Program, CBMP) or control (printed educational material, PEM) group. Both the groups will undergo screening, learning and evaluation assessments at the time of the visit and at follow-up visits 30, 60 and 90 days after the first visit.

Outcomes

The outcomes expected in the intervention group include improvement in Mets-related knowledge, adherence to self-care practices, better quality of life and increased satisfaction with medical care.

Ethics and dissemination

The study has been approved by the Institutional Review Board of Asian Institute of Public Health (IRB#621). The proposed study will also help us assess the usefulness and challenges of technology to disseminate health education among diverse users. Findings will be disseminated through peer-reviewed publications and national and international conference presentations to various stakeholders and local community health leaders. The ClinicalTrials.gov Identifier isNCT01713465.
Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson's disease: a cross-sectional and 3-year longitudinal cohort study
Authors: Kikuchi Akio , Baba Toru , Hasegawa Takafumi , Kobayashi Michiko , Sugeno Naoto , Konno Masatoshi , Miura Emiko , Hosokai Yoshiyuki , Ishioka Toshiyuki , Nishio Yoshiyuki , Hirayama Kazumi , Suzuki Kyoko , Aoki Masashi , Takahashi Shoki , Fukuda Hiroshi , Itoyama Yasuto , Mori Etsuro , Takeda Atsushi
Published: March 2013

Objective

Dysphagia is one of the cardinal symptoms of Parkinson’s disease (PD). It is closely related to the quality of life and longevity of PD patients. The aim of the study is to clarify the pathophysiological mechanisms responsible for dysphagia in PD.

Design

A cross-sectional and longitudinal comparative study.

Setting

Tohoku University Hospital.

Participants

Eight patients with dysphagia, 15 patients without dysphagia and 10 normal control subjects.

Main outcome measures

The time needed for swallowing initiation and changes in brain glucose metabolism at baseline and after a 3-year follow-up period.

Results

The time needed for swallowing initiation was significantly longer in the patients with dysphagia compared with the patients without dysphagia at baseline and after the 3-year follow-up period (p<0.05). The patients with dysphagia exhibited hypometabolism in the supplementary motor area (SMA) and the anterior cingulate cortex (ACC) compared with the 10 normal control subjects at baseline (uncorrected p<0.001). After the 3-year follow-up period, the number of brain areas showing hypometabolism increased, involving not only the SMA and the ACC but also the bilateral medial frontal lobes, middle cingulate cortex, thalamus and right superior, middle, inferior and orbital frontal gyri (uncorrected p<0.001). In contrast, the patients without dysphagia showed virtually no regional hypometabolism at baseline (uncorrected p<0.001) and only a small degree of hypometabolism in the SMA and ACC after the 3-year follow-up period (uncorrected p<0.001).

Conclusions

These results suggest that dysphagia in PD patients is mainly related to a difficulty in swallowing initiation that is based on a combination of poor movement planning due to SMA dysfunction and impaired cognitive processing due to ACC dysfunction.
The incidence and impact of recurrent workplace injury and disease: a cohort study of WorkSafe Victoria, Australia compensation claims
Authors: Ruseckaite Rasa , Collie Alex
Published: March 2013

Objective

To determine the incidence and impact of recurrent workplace injury and disease over the period 1995–2008.

Design

Population-based cohort study using data from the state workers’ compensation system database.

Setting

State of Victoria, Australia.

Participants

A total of 448 868 workers with an accepted workers’ compensation claim between 1 January 1995 and 31 December 2008 were included into this study. Of them, 135 349 had at least one subsequent claim accepted for a recurrent injury or disease during this period.

Main outcome measures

Incidence of initial and recurrent injury and disease claims and time lost from work for initial and recurrent injury and disease.

Results

Over the study period, 448 868 workers lodged 972 281 claims for discrete occurrences of work-related injury or disease. 53.4% of these claims were for recurrent injury or disease. On average, the rates of initial claims dropped by 5.6%, 95% CI (−5.8% to −5.7%) per annum, while the rates of recurrent injuries decreased by 4.1%, 95% CI (−4.2% to −0.4%). In total, workplace injury and disease resulted in 188 978 years of loss in full-time work, with 104 556 of them being for the recurrent injury.

Conclusions

Recurrent work-related injury and disease is associated with a substantial social and economic impact. There is an opportunity to reduce the social, health and economic burden of workplace injury by enacting secondary prevention programmes targeted at workers who have incurred an initial occupational injury or disease.
Poststroke fatigue and depression are related to mortality in young adults: a cohort study
Authors: Naess Halvor , Nyland Harald
Published: March 2013

Objectives

To investigate the relationship between poststroke fatigue and depression and subsequent mortality in young ischaemic stroke patients in a population-based study.

Design

A prospective cohort study.

Setting

All surviving young ischaemic stroke patients living in Hordaland County.

Participants

Young ischaemic stroke patients aged 15–50 years at the time of the stroke were invited to a follow-up on an average 6 years after the index stroke. Psychosocial factors and risk factors were registered. Fatigue was self-assessed by the Fatigue Severity Scale (FSS). Depression was measured by Montgomery-Åsberg Depression Rating Scale (MADRS).

Intervention

No intervention was performed.

Primary and secondary outcome measure

Mortality on follow-up.

Results

In total, 190 patients were included. The mean age on follow-up was 48 years and subsequent follow-up period was 12 years. Cox regression analysis showed that mortality was associated with FSS score (p=0.005) after adjusting for age (p=0.06) and sex (p=0.19). Cox regression analysis showed that mortality was associated with MADRS score (p=0.006) after adjusting for age (p=0.10) and sex (p=0.11).

Conclusions

Both fatigue and depression are associated with long-term mortality in young adults with ischaemic stroke. Depression may be linked to higher mortality because of psychosocial factors and unhealthy lifestyles whereas the link between fatigue and mortality is broader including connection to diabetes mellitus, myocardial infarction and psychosocial factors.
A cluster-randomised, parallel group, controlled intervention study of genetic prostate cancer risk assessment and use of PSA tests in general practice—the ProCaRis study: study protocol
Authors: Kirkegaard Pia , Vedsted Peter , Edwards Adrian , Fenger-Grøn Morten , Bro Flemming
Published: March 2013

Introduction

Unsystematic screening for prostate cancer (PCa) is common, causing a high number of false-positive results. Valid instruments for assessment of individual risk of PCa have been called for. A DNA-based genetic test has been tested retrospectively. The clinical use of this test needs further investigation. The primary objective is to evaluate the impact on the use of prostate-specific antigen (PSA) tests of introducing genetic PCa risk assessment in general practice. The secondary objectives are to evaluate PCa-related patient experiences, and to explore sociocultural aspects of genetic risk assessment in patients at high PCa risk.

Methods and analysis

The study is a cluster-randomised, controlled intervention study with practice as the unit of randomisation. We expect 140 practices to accept participation and include a total of 1244 patients in 4 months. Patients requesting a PSA test in the intervention group practices will be offered a genetic PCa risk assessment. Patients requesting a PSA test in the control group practices will be handled according to current guidelines. Data will be collected from registers, patient questionnaires and interviews. Quantitative data will be analysed according to intention-to-treat principles. Baseline characteristics will be compared between groups. Longitudinal analyses will include time in risk, and multivariable analysis will be conducted to evaluate the influence of general practitioner and patient-specific variables on future PSA testing. Interview data will be transcribed verbatim and analysed from a social-constructivist perspective.

Ethics and dissemination

Consent will be obtained from patients who can withdraw from the study at any time. The study provides data to the ongoing conceptual and ethical discussions about genetic risk assessment and classification of low-risk and high-risk individuals. The intervention model might be applicable to other screening areas regarding risk of cancer with identified genetic components, for example, colon cancer. The study is registered at the ClinicalTrials.gov (Identifier:NCT01739062).
Use of record-linkage to handle non-response and improve alcohol consumption estimates in health survey data: a study protocol
Authors: Gray Linsay , McCartney Gerry , White Ian R , Katikireddi Srinivasa Vittal , Rutherford Lisa , Gorman Emma , Leyland Alastair H
Published: March 2013

Introduction

Reliable estimates of health-related behaviours, such as levels of alcohol consumption in the population, are required to formulate and evaluate policies. National surveys provide such data; validity depends on generalisability, but this is threatened by declining response levels. Attempts to address bias arising from non-response are typically limited to survey weights based on sociodemographic characteristics, which do not capture differential health and related behaviours within categories. This project aims to explore and address non-response bias in health surveys with a focus on alcohol consumption.

Methods and analysis

The Scottish Health Surveys (SHeS) aim to provide estimates representative of the Scottish population living in private households. Survey data of consenting participants (92% of the achieved sample) have been record-linked to routine hospital admission (Scottish Morbidity Records (SMR)) and mortality (from National Records of Scotland (NRS)) data for surveys conducted in 1995, 1998, 2003, 2008, 2009 and 2010 (total adult sample size around 40 000), with maximum follow-up of 16 years. Also available are census information and SMR/NRS data for the general population. Comparisons of alcohol-related mortality and hospital admission rates in the linked SHeS-SMR/NRS with those in the general population will be made. Survey data will be augmented by quantification of differences to refine alcohol consumption estimates through the application of multiple imputation or inverse probability weighting. The resulting corrected estimates of population alcohol consumption will enable superior policy evaluation. An advanced weighting procedure will be developed for wider use.

Ethics and dissemination

Ethics approval for SHeS has been given by the National Health Service (NHS) Multi-Centre Research Ethics Committee and use of linked data has been approved by the Privacy Advisory Committee to the Board of NHS National Services Scotland and Registrar General. Funding has been granted by the MRC. The outputs will include four or five public health and statistical methodological international journal and conference papers.

Primary subject heading

Public health.

Secondary subject heading

Addiction: health policy; mental health.
High-reliability emergency response teams in the hospital: improving quality and safety using in situ simulation training
Authors: Wheeler Derek S , Geis Gary , Mack Elizabeth H , LeMaster Tom , Patterson Mary D
Published: March 2013

Introduction

In situ simulation training is a team-based training technique conducted on actual patient care units using equipment and resources from that unit, and involving actual members of the healthcare team. We describe our experience with in situ simulation training in a major children's medical centre.

Materials and methods

In situ simulations were conducted using standardised scenarios approximately twice per month on inpatient hospital units on a rotating basis. Simulations were scheduled so that each unit participated in at least two in situ simulations per year. Simulations were conducted on a revolving schedule alternating on the day and night shifts and were unannounced. Scenarios were preselected to maximise the educational experience, and frequently involved clinical deterioration to cardiopulmonary arrest.

Results

We performed 64 of the scheduled 112 (57%) in situ simulations on all shifts and all units over 21 months. We identified 134 latent safety threats and knowledge gaps during these in situ simulations, which we categorised as medication, equipment, and/or resource/system threats. Identification of these errors resulted in modification of systems to reduce the risk of error. In situ simulations also provided a method to reinforce teamwork behaviours, such as the use of assertive statements, role clarity, performance of frequent updating, development of a shared mental model, performance of independent double checks of high-risk medicines, and overcoming authority gradients between team members. Participants stated that the training programme was effective and did not disrupt patient care.

Conclusions

In situ simulations can identify latent safety threats, identify knowledge gaps, and reinforce teamwork behaviours when used as part of an organisation-wide safety programme.
Vitamin D: a negative acute phase reactant
Authors: Waldron Jenna Louise , Ashby Helen L , Cornes Michael P , Bechervaise Julia , Razavi Cyrus , Thomas Osmond L , Chugh Sanjiv , Deshpande Shreeram , Ford Clare , Gama Rousseau
Published: March 2013

Objective

We evaluated the effect of the systemic inflammatory response (SIR), as provoked by elective orthopaedic surgery, on serum vitamin D [25-(OH)D].

Methods

Serum 25-(OH)D, serum vitamin D binding protein (VDBP) and urinary VDBP were measured in 30 patients before and 48-hours after knee or hip arthroplasty. C-reactive protein (CRP) was measured to assess the SIR.

Results

The mean (SD) CRP increased following surgery [5.0 (5.5) vs 116.0 (81.2) mg/L; P<0.0001] as did urine VDBP/Creatinine ratio [8 (9) vs 20 (25) pg/mmol; p=0.0004]. Serum 25-(OH)D [56.2 (30.3) vs 46.0 (27.6) nmol/L; p = 0.0006] and serum VDBP [334 (43) vs 298 (37) mg/L]; P<0.0001] decreased.

Conclusions

Serum 25-(OH)D is a negative acute phase reactant, which has implications for acute and chronic inflammatory diseases. Serum 25-(OH)D is an unreliable biomarker of vitamin D status after acute inflammatory insult. Hypovitaminosis D may be the consequence rather than cause of chronic inflammatory diseases.
Classifying unknowns: the idiopathic problem
Authors: Beaney Thomas
Published: March 2013

The term,idiopathic, emerged as a key concept in the classification of disease in the 18th century and has become ingrained in our terminology in defining diseases and their aetiologies throughout all fields of medicine. Despite, or perhaps because of this, little has been written about the meaning ormeaningsof the word itself. Although most medical professionals will be able to offer a definition ofidiopathic, different definitions of the word are in use and are often confused or used without an appreciation of the range of meanings. This article aims to clarify these different meanings with reference to historic and current uses. The change from the earliernosologicaldefinition of ‘primary’ to the most widely accepted current definition, ‘of unknown cause’, occurred in the late 19th century, reflecting changing perspectives of disease causation. Far from being an innocent translation of ‘unknown’,idiopathiccreates problems for future terminology and adds little to medical understanding. In masking the unknown, the termidiopathicmaintains a paternalistic patient–practitioner relationship, and so should be avoided in modern medical terminology.
A study examining rates of medical staff recognition of pressure ulceration in hospital inpatients
Authors: Blackman Jonathan , Walsgrove Joe , Gunawardena Indunil
Published: March 2013

Background

The incidence of pressure ulceration among UK hospital inpatients has been estimated at 10.2–10.3%. These patients are at increased risk of developing osteomyelitis and subsequent sepsis. This study sought to test whether medical staff recognition rates of hospital inpatients with pressure ulceration were low and to consider underlying causes and potential solutions.

Methods

Interviews were conducted with nursing staff on multiple wards in July 2012 to obtain a definitive list of patients with pressure ulcers, with their corresponding location and grade. Junior members of medical teams with responsibility for the same group of patients were independently interviewed and asked to identify all patients who they knew to have pressure ulcers. The number correctly identified by the medical teams was compared with the total number of known pressure ulcers to produce a recognition rate. Patients with clinical evidence of sepsis were highlighted.

Results

Twenty-seven patients on five wards were identified by nursing staff as having pressure ulceration areas. Nine patients were stated to have multiple pressure ulceration areas, giving a total of 38 pressure ulcers. Medical teams correctly identified eight of 27 (29.6%) of these patients. The correct site and grade was identified in four of 38 (10.5%) and two of 38 (5.3%) cases, respectively. Of these patients 14/27 (51.8%) had evidence of infection. In this subgroup five of 14 (35.7%) were correctly identified as having pressure ulceration areas.

Conclusions

The lack of medical awareness could lead to delayed recognition of deep-seated infection or osteomyelitis. Reasons for this are likely to be multifactorial and require a combination of cultural change, improved education and improved information sharing.
ADAPTIVE AND PREDICTIVE CONTROL OF A SIMULATED ROBOT ARM
Authors: TOLU SILVIA , VANEGAS MAURICIO , GARRIDO JESÚS A. , LUQUE NICETO R. , ROS EDUARDO
Published: March 2013

In this work, a basic cerebellar neural layer and a machine learning engine are embedded in a recurrent loop which avoids dealing with the motor error or distal error problem. The presented approach learns the motor control based on available sensor error estimates (position, velocity, and acceleration) without explicitly knowing the motor errors. The paper focuses on how to decompose the input into different components in order to facilitate the learning process using an automatic incremental learning model (locally weighted projection regression (LWPR) algorithm). LWPR incrementally learns the forward model of the robot arm and provides the cerebellar module with optimal pre-processed signals. We present a recurrent adaptive control architecture in which an adaptive feedback (AF) controller guarantees a precise, compliant, and stable control during the manipulation of objects. Therefore, this approach efficiently integrates a bio-inspired module (cerebellar circuitry) with a machine learning component (LWPR). The cerebellar-LWPR synergy makes the robot adaptable to changing conditions. We evaluate how this scheme scales for robot-arms of a high number of degrees of freedom (DOFs) using a simulated model of a robot arm of the new generation of light weight robots (LWRs).
ON AN EXPERIMENTAL TEST OF PREQUANTUM THEORY OF CLASSICAL RANDOM FIELDS: AN ESTIMATE FROM ABOVE OF THE COEFFICIENT OF SECOND-ORDER COHERENCE
Authors: KHRENNIKOV ANDREI , NILSSON BÖRJE , NORDEBO SVEN
Published: March 2013

We show that quantum probabilities for photon detection can be reproduced by a model in which classical random fields interact with detectors of the threshold type. This approach is applied to the old problem of distinguishing classical and quantum light sources with the aid of the coefficient of second-order coherence g(2)(0) (the problem of "existence of photon"). In our classical random field model, we obtain an estimate of this coefficient implying that it becomes strictly less than one for sufficiently small value of parameter [Formula: see text], where [Formula: see text] is the average energy of pulses (photons) emitted by a source and [Formula: see text] is the detection threshold. This prediction can in principle be tested experimentally. Thus in the presented model experimental technicalities (such as e.g. the detection thresholds) are lifted to the level of the fundamental entities of theory.
LARGE-NC UNIVERSALITY IN QCD AND QCD-LIKE THEORIES
Authors: HANADA MASANORI , MATSUO YOSHINORI , YAMAMOTO NAOKI
Published: March 2013

A direct application of the lattice Monte Carlo method to QCD with a finite baryon chemical potential is difficult due to the sign problem. We introduce a novel approach to avoid the sign problem, which is inspired by the string theory.
D3/D5 SYSTEM AND HOLOGRAPHIC INTERFACE CFT
Authors: NAGASAKI KOICHI , YAMAGUCHI SATOSHI
Published: March 2013

We consider two [Formula: see text] supersymmetric gauge theories connected by an interface and the gravity dual of this system. This interface is expressed by a fuzzy funnel solution of Nahmfs equation in the gauge theory side. The gravity dual is a probe D5-brane in AdS5 × S5. The potential energy between this interface and a test particle is calculated in both the gauge theory side and the gravity side by the expectation value of a Wilson loop. In the gauge theory it is evaluated by just substituting the classical solution to the Wilson loop. On the other hand it is done by the on-shell action of the fundamental string stretched between the AdS boundary and the D5-brane in the gravity. We show the gauge theory result and the gravity one agree with each other.
RELATIVISTIC VISCOELASTIC FLUID MECHANICS
Authors: FUKUMA MASAFUMI , SAKATANI YUHO
Published: March 2013

We explain the relativistic theory of viscoelasticity which we have recently constructed on the basis of Onsager's linear nonequilibrium thermodynamics. This theory universally reduces to the standard relativistic Navier-Stokes fluid mechanics in the long time limit. Since effects of elasticity are taken into account, the dynamics at short time scales is modified from that given by the Navier-Stokes equations, so that acausal problems intrinsic to relativistic Navier-Stokes fluids are significantly remedied. We then present conformal higher-order viscoelastic fluid mechanics with strain allowed to take arbitrarily large values. We particularly show that a conformal second-order fluid with all possible parameters in the constitutive equations can be obtained without breaking the hypothesis of local thermodynamic equilibrium, if the conformal fluid is defined as the long time limit of a conformal second-order viscoelastic system.
Multiplexed Sensing and Imaging with Colloidal Nano- and Microparticles
Authors: Carregal-Romero Susana , Caballero-Díaz Encarnación , Beqa Lule , Abdelmonem Abuelmagd M. , Ochs Markus , Hühn Dominik , Suau Bartolome Simonet , Valcarcel Miguel , Parak Wolfgang J.
Published: March 2013

Sensing and imaging with fluorescent, plasmonic, and magnetic colloidal nano- and microparticles have improved during the past decade. In this review, we describe the concepts and applications of how these techniques can be used in the multiplexed mode, that is, sensing of several analytes in parallel or imaging of several labels in parallel.
Microgenomics: Genome-Scale, Cell-Specific Monitoring of Multiple Gene Regulation Tiers
Authors: Bailey-Serres J.
Published: March 2013

The expression of nuclear protein-coding genes is controlled by dynamic mechanisms ranging from DNA methylation, chromatin modification, and gene transcription to mRNA maturation, turnover, and translation and the posttranslational control of protein function. A genome-scale assessment of the spatiotemporal regulation of gene expression is essential for a comprehensive understanding of gene regulatory networks. However, there are major obstacles to the precise evaluation of gene regulation in multicellular plant organs; these include the monitoring of regulatory processes at levels other than steady-state transcript abundance, resolution of gene regulation in individual cells or cell types, and effective assessment of transient gene activity manifested during development or in response to external cues. This review surveys the advantages and applications of microgenomics technologies that enable panoramic quantitation of cell-type-specific expression in plants, focusing on the importance of querying gene activity at multiple steps in the continuum, from histone modification to selective translation.
Plants, Diet, and Health
Authors: Martin Cathie , Zhang Yang , Tonelli Chiara , Petroni Katia
Published: March 2013

Chronic disease is a major social challenge of the twenty-first century. In this review, we examine the evidence for discordance between modern diets and those on which humankind evolved as the cause of the increasing incidence of chronic diseases, and the evidence supporting consumption of plant foods as a way to reduce the risk of chronic disease. We also examine the evidence for avoiding certain components of plant-based foods that are enriched in Western diets, and review the mechanisms by which different phytonutrients are thought to reduce the risk of chronic disease. This body of evidence strongly suggests that consuming more fruits and vegetables could contribute both to medical nutrition therapies, as part of a package of treatments for conditions like type 2 diabetes, heart disease, cancer, and obesity, and to the prevention of these diseases. Plant science should be directed toward improving the quality of plant-based foods by building on our improved understanding of the complex relationships between plants, our diet, and our health.
Flap Endonuclease 1
Authors: Balakrishnan Lata , Bambara Robert A.
Published: March 2013

First discovered as a structure-specific endonuclease that evolved to cut at the base of single-stranded flaps, flap endonuclease (FEN1) is now recognized as a central component of cellular DNA metabolism. Substrate specificity allows FEN1 to process intermediates of Okazaki fragment maturation, long-patch base excision repair, telomere maintenance, and stalled replication fork rescue. For Okazaki fragments, the RNA primer is displaced into a 5′ flap and then cleaved off. FEN1 binds to the flap base and then threads the 5′ end of the flap through its helical arch and active site to create a configuration for cleavage. The threading requirement prevents this active nuclease from cutting the single-stranded template between Okazaki fragments. FEN1 efficiency and specificity are critical to the maintenance of genome fidelity. Overall, recent advances in our knowledge of FEN1 suggest that it was an ancient protein that has been fine-tuned over eons to coordinate many essential DNA transactions.
Considering Protonation as a Posttranslational Modification Regulating Protein Structure and Function
Authors: Schönichen André , Webb Bradley A. , Jacobson Matthew P. , Barber Diane L.
Published: March 2013

Posttranslational modification is an evolutionarily conserved mechanism for regulating protein activity, binding affinity, and stability. Compared with established posttranslational modifications such as phosphorylation or ubiquitination, posttranslational modification by protons within physiological pH ranges is a less recognized mechanism for regulating protein function. By changing the charge of amino acid side chains, posttranslational modification by protons can drive dynamic changes in protein conformation and function. Addition and removal of a proton is rapid and reversible and, in contrast to most other posttranslational modifications, does not require an enzyme. Signaling specificity is achieved by only a minority of sites in proteins titrating within the physiological pH range. Here, we examine the structural mechanisms and functional consequences of proton posttranslational modification of pH-sensing proteins regulating different cellular processes.
Molecular Traffic Jams on DNA
Authors: Finkelstein Ilya J. , Greene Eric C.
Published: March 2013

All aspects of DNA metabolism—including transcription, replication, and repair—involve motor enzymes that move along genomic DNA. These processes must all take place on chromosomes that are occupied by a large number of other proteins. However, very little is known regarding how nucleic acid motor proteins move along the crowded DNA substrates that are likely to exist in physiological settings. This review summarizes recent progress in understanding how DNA-binding motor proteins respond to the presence of other proteins that lie in their paths. We highlight recent single-molecule biophysical experiments aimed at addressing this question, with an emphasis placed on analyzing the single-molecule, ensemble biochemical, and in vivo data from a mechanistic perspective.
Influences of Membrane Mimetic Environments on Membrane Protein Structures
Authors: Zhou Huan-Xiang , Cross Timothy A.
Published: March 2013

The number of membrane protein structures in the Protein Data Bank is becoming significant and growing. Here, the transmembrane domain structures of the helical membrane proteins are evaluated to assess the influences of the membrane mimetic environments. Toward this goal, many of the biophysical properties of membranes are discussed and contrasted with those of the membrane mimetics commonly used for structure determination. Although the mimetic environments can perturb the protein structures to an extent that potentially gives rise to misinterpretation of functional mechanisms, there are also many structures that have a native-like appearance. From this assessment, an initial set of guidelines is proposed for distinguishing native-like from nonnative-like membrane protein structures. With experimental techniques for validation and computational methods for refinement and quality assessment and enhancement, there are good prospects for achieving native-like structures for these very important proteins.
Molecular Mechanisms of Drug Action: An Emerging View
Authors: Sonner James M. , Cantor Robert S.
Published: March 2013

Volatile anesthetics serve as useful probes of a conserved biological process that is essential to the proper functioning of the central nervous system. A kinetic and thermodynamic analysis of their unusual pharmacological and physiological characteristics has led to a general, predictive theory in which small molecules that adsorb to membranes modulate ion channel function by altering physical properties of membrane bilayers. A kinetic model that is both parsimonious and falsifiable has been developed to test this mechanism. This theory leads to predictions about the structure, function, origin, and evolution of synapses, the etiology of several diseases and disease symptoms affecting the brain, and the mechanism of action of several drugs that are used therapeutically. Neuronal membranes may offer an appealing drug target, given the large number of compounds that adsorb to interfaces and hence membranes.
Structural Insights into the Evolution of the Adaptive Immune System
Authors: Deng Lu , Luo Ming , Velikovsky Alejandro , Mariuzza Roy A.
Published: March 2013

The adaptive immune system, which is based on highly diverse antigen receptors that are generated by somatic recombination, arose approximately 500 Mya at the dawn of vertebrate evolution. In jawed vertebrates, adaptive immunity is mediated by antibodies and T cell receptors (TCRs), which are composed of immunoglobulin (Ig) domains containing hypervariable loops that bind antigen. In striking contrast, the adaptive immune receptors of jawless vertebrates, termed variable lymphocyte receptors (VLRs), are constructed from leucine-rich repeat (LRR) modules. Structural studies of VLRs have shown that these LRR-based receptors bind antigens though their concave surface, in addition to a unique hypervariable loop in the C-terminal LRR capping module. These studies have revealed a remarkable example of convergent evolution in which jawless vertebrates adopted the LRR scaffold to recognize as broad a spectrum of antigens as the Ig-based antibodies and TCRs of jawed vertebrates, with altogether comparable affinity and specificity.
Ethical, Legal, Social, and Policy Implications of Behavioral Genetics
Authors: Berryessa Colleen M. , Cho Mildred K.
Published: March 2013

The field of behavioral genetics has engendered a host of moral and social concerns virtually since its inception. The policy implications of a genetic basis for behaviors are widespread and extend beyond the clinic to the socially important realms of education, criminal justice, childbearing, and child rearing. The development of new techniques and analytic approaches, including whole-genome sequencing, noninvasive prenatal genetic testing, and optogenetics, has clearly changed the study of behavioral genetics. However, the social context of biomedical research has also changed profoundly over the past few decades, and in ways that are especially relevant to behavioral genetics. The ever-widening scope of behavioral genetics raises ethical, legal, social, and policy issues in the potential new applications to criminal justice, education, the military, and reproduction. These issues are especially critical to address because of their potentially disproportionate effects on vulnerable populations such as children, the unborn, and the incarcerated.
Phase-Field Model for Microstructure Evolution at the Mesoscopic Scale
Authors: Steinbach Ingo
Published: March 2013

This review presents a phase-field model that is generally applicable to homogeneous and heterogeneous systems at the mesoscopic scale. Reviewed first are general aspects about first- and second-order phase transitions that need to be considered to understand the theoretical background of a phase field. The mesoscopic model equations are defined by a coarse-graining procedure from a microscopic model in the continuum limit on the atomic scale. Special emphasis is given to the question of how to separate the interface and bulk contributions to the generalized thermodynamic functional, which forms the basis of all phase-field models. Numerical aspects of the discretization are discussed at the lower scale of applicability. The model is applied to spinodal decomposition and ripening in Ag-Cu with realistic thermodynamic and kinetic data from a database.
Regime Change Cascades: What We Have Learned from the 1848 Revolutions to the 2011 Arab Uprisings
Authors: Hale Henry E.
Published: March 2013

Works on the 1848 revolutions, 1989 collapse of European communism, 1998–2005 postcommunist color revolutions, and 2011 Arab uprisings frequently cross-reference each other, implying what is called here the concept of a “regime change cascade.” Research on these “Big Four” events shows that cascading can occur in protest calling for regime change as well as revolution in the name of regime change, but these rarely lead to actual regime change. Regime change cascades can occur through demonstration effects and active mediation, although common external causes and contemporaneous domestic triggers can cause events outwardly resembling them. Regime change cascades tend to occur where (a) there exists a common frame of political reference, (b) unpopular leaderships are becoming lame ducks; (c) elites lack other focal points for coordinated defection, and (d) structural conditions supporting a new regime type are in place. Cascading to hybrid regimes or autocracy may be more likely than cascading to democracy.
Reconsidering Judicial Preferences
Authors: Epstein Lee , Knight Jack
Published: March 2013

Among political scientists, not only is it uncontroversial to say that judges seek to etch their political values into law; it would be near heresy to suggest otherwise. And yet this article does just that because research conducted by scholars (mostly outside of political science) has demonstrated that the policy goal is not the only motivation; it may not even be dominant for many judges. The evidence is now so strong that it poses a serious challenge to the extremely (un)realist(ic) conception of judicial behavior that has dominated the study of law and legal institutions for generations. In addition to reviewing this evidence, we offer a more realistic conception of judicial motivations and suggest how different approaches to the study of courts can contribute to this new avenue of research.
Cardiac optogenetics
Authors: Entcheva Emilia
Published: March 2013

Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins (light-gated ion channels and pumps). These can achieve fast and specific excitatory or inhibitory response, offering distinct advantages over traditional pharmacological or electrical means of perturbation. Since the first demonstrations of utility in mammalian cells (neurons) in 2005, optogenetics has spurred immense research activity and has inspired numerous applications for dissection of neural circuitry and understanding of brain function in health and disease, applications ranging from in vitro to work in behaving animals. Only recently (since 2010), the field has extended to cardiac applications with less than a dozen publications to date. In consideration of the early phase of work on cardiac optogenetics and the impact of the technique in understanding another excitable tissue, the brain, this review is largely a perspective of possibilities in the heart. It covers the basic principles of operation of light-sensitive ion channels and pumps, the available tools and ongoing efforts in optimizing them, overview of neuroscience use, as well as cardiac-specific questions of implementation and ideas for best use of this emerging technology in the heart.
Gene expression profiles reveal molecular mechanisms involved in the progression and resolution of bleomycin-induced lung fibrosis
Authors: Cabrera Sandra , Selman Moises , Lonzano-Bolaños Alfredo , Konishi Kazuhisa , Richards Thomas J. , Kaminski Naftali , Pardo Annie
Published: March 2013

Lung fibrosis is the final result of a large number of disorders and is usually considered an irreversible process. However, some evidence suggests that fibrosis could eventually be reversible. In this study we aimed to document the time-related reversibility of bleomycin-induced lung fibrosis and to examine the gene expression profile associated with its initial progression and subsequent resolution. C57BL/6 mice were instilled with a single dose of bleomycin and euthanized at 1, 4, 8, 12, and 16 wk. Control animals received an equal volume of saline. Lung fibrosis was examined by morphology and hydroxyproline content and the transcriptional signature by gene microarray analysis. Our results showed that bleomycin-injured mice developed prominent inflammation at 1 wk, followed by fibrosis that peaked at 2 mo. Then fibrosis resolved until lungs displayed almost normal architecture at 4 mo. Genomewide transcriptional profiling revealed 533 significantly changed genes. Self-organizing maps analysis of these genes identified four clusters based on the temporal pattern of gene expression. Clusters 1 and 2 contained genes upregulated during the inflammatory and fibrotic response and were enriched for extracellular matrix-related genes including several collagens, matrix metalloproteinases, and TIMP-1. Cluster 3 identified upregulated genes during the fibrotic response, and cluster 4 contained genes decreased during inflammation and fibrosis that increased during resolution. Most enriched pathways included genes involved in cell cycle and in regulation of transcription. Our findings corroborate the reversibility of bleomycin-induced lung fibrosis and reveal transcriptional signatures that characterize the progression and resolution.
Household air pollution: a call for studies into biomarkers of exposure and predictors of respiratory disease
Authors: Rylance Jamie , Gordon Stephen B. , Naeher Luke P. , Patel Archana , Balmes John R. , Adetona Olorunfemi , Rogalsky Derek K. , Martin William J.
Published: March 2013

Household air pollution (HAP) from indoor burning of biomass or coal is a leading global cause of morbidity and mortality, mostly due to its association with acute respiratory infection in children and chronic respiratory and cardiovascular diseases in adults. Interventions that have significantly reduced exposure to HAP improve health outcomes and may reduce mortality. However, we lack robust, specific, and field-ready biomarkers to identify populations at greatest risk and to monitor the effectiveness of interventions. New scientific approaches are urgently needed to develop biomarkers of human exposure that accurately reflect exposure or effect. In this Perspective, we describe the global need for such biomarkers, the aims of biomarker development, and the state of development of tests that have the potential for rapid transition from laboratory bench to field use.
Gastric Parietal Cell Antibodies, Helicobacter Pylori Infection, and Chronic Atrophic Gastritis: Evidence from a Large Population-based Study in Germany
Authors: Zhang Yan , Weck Melanie N. , Schöttker Ben , Rothenbacher Dietrich , Brenner Hermann
Published: March 2013

Background: Striking similarities between autoimmune gastritis and Helicobacter Pylori (H. pylori)-associated gastritis have suggested a potential link between these two pathologic conditions in the progression of chronic atrophic gastritis (CAG); however, evidence has remained conflicting.

Methods: Serum pepsinogen I and II, and antibodies against H. pylori in general, the cytotoxin-associated gene A protein (CagA) and parietal cells were measured by ELISA in 9,684 subjects aged 50 to 74 years. Antigastric parietal cell antibody (APCA) prevalence was examined in the overall population and according to sex, age, and H. pylori serostatus. The association between APCA prevalence and CAG was assessed by logistic regression, overall and according to H. pylori status, controlling for potential confounding factors.

Results: Overall APCA prevalence was 19.5%. APCA prevalence was strongly associated with CAG, and the association was increasing with increasing severity of CAG. Furthermore, the association between APCA and CAG was even stronger among H. pylori-negative subjects [odds ratio (OR) = 11.3; 95% confidence interval (CI): 7.5–17.1)] than among H. pylori-positive subjects (OR = 2.6; 95% CI: 2.1–3.3).

Conclusions: APCA may play a role on the development of gastric atrophy, irrespective of H. pylori infection.

Impact: Assessment of APCA might be a useful complement to established markers (such as pepsinogens and H. pylori antibodies) in screening for CAG. Cancer Epidemiol Biomarkers Prev; 22(5); 821–6. ©2013 AACR.