Relationship Between B-Vitamin Biomarkers and Dietary Intake with Apolipoprotein E є4 in Alzheimer's Disease.
The potential for B-vitamins to reduce plasma homocysteine (Hcy) and reduce the risk of Alzheimer's disease (AD) has been described previously. However, the role of Apolipoprotein E є4 (APOE4) in this relationship has not been adequately addressed. This case-control study explored APOE4 genotype in an Australian sample of 63 healthy individuals (female = 38; age = 76.9 ± 4.7 y) and 63 individuals with AD (female = 35, age = 77.1 ± 5.3 y). Findings revealed 55 of 126 participants expressed the APOE4 genotype with 37 of 126 having both AD and the APOE4 genotype. Analysis revealed an increased likelihood of AD when Hcy levels are >11.0 µmol/L (p = 0.012), cysteine levels were <255 µmol/L (p = 0.033) and serum folate was <22.0 nmol/L (p = 0.003; in males only). In females, dietary intake of total folate <336 µg/day (p=0.001), natural folate <270 µg/day (p = 0.011), and vitamin B2 < 1.12 mg/day (p = 0.028) was associated with an increased AD risk. These results support Hcy, Cys, and SF as useful biomarkers for AD, irrespective of APOE4 genotype and as such should be considered as part of screening and managing risk of AD.


Neural correlates of abstract verb processing.
The present study investigated the neural correlates of the processing of abstract (low imageability) verbs. An extensive body of literature has investigated concrete versus abstract nouns but little is known about how abstract verbs are processed. Spanish abstract verbs including emotion verbs (e.g., amar, "to love"; molestar, "to annoy") were compared to concrete verbs (e.g., llevar, "to carry"; arrastrar, "to drag"). Results indicated that abstract verbs elicited stronger activity in regions previously associated with semantic retrieval such as inferior frontal, anterior temporal, and posterior temporal regions, and that concrete and abstract activation networks (compared to that of pseudoverbs) were partially distinct, with concrete verbs eliciting more posterior activity in these regions. In contrast to previous studies investigating nouns, verbs strongly engage both left and right inferior frontal gyri, suggesting, as previously found, that right prefrontal cortex aids difficult semantic retrieval. Together with previous evidence demonstrating nonverbal conceptual roles for the active regions as well as experiential content for abstract word meanings, our results suggest that abstract verbs impose greater demands on semantic retrieval or property integration, and are less consistent with the view that abstract words recruit left-lateralized regions because they activate verbal codes or context, as claimed by proponents of the dual-code theory. Moreover, our results are consistent with distributed accounts of semantic memory because distributed networks may coexist with varying retrieval demands.


Simultaneous and controlled release of two different bioactive small molecules from nature inspired single material.
Extended and controlled release of more than a single bioactive molecule, simultaneously, from the same biocompatible matrix is challenging to achieve. However, this is important for combating various severe challenges (drug resistance, improved efficacy, etc.) related to drug delivery. In the recent past, the meta-stable trapped air (in the lotus leaf inspired artificial interfaces), which attributed to the extreme water repellency in biomimicked heirarchical (consisted of micro/nano features) interfaces, was unprecedentedly exploited for addressing multiple relevant aspects related to drug delivery (e.g., multiple drug release, tunable drug release, dose control through post-loading of drug molecules, etc.). A biocompatible polymeric material that is (a) synthesized using a one-step covalent and featured gelation of a single polymer and (b) capable of tailoring with a wide range of water wettabilities, was exploited for post loading both hydrophilic and hydrophobic small molecules from a wide variety (less polar, more polar, nonpolar) of organic solvents. Such small molecules loaded polymeric materials continued to display durable nature-inspired bulk wettability and provided simultaneous co-release of two different bioactive drug molecules (i.e., doxorubicin (DOX, anticancer drug) and tetracycline (TC, antibacterial drug)), over 6 months. Moreover, the release extent (from hours to months) of these small molecules was successfully tuned by controlling the water wettability of the single porous polymeric material. The released drug molecules remained bioactive and capable of inhibiting the proliferation of cancer cells (MG-63 (human osteosarcoma) and MDA-MB-231 (human breast adenocarcinoma)) and microorganisms (S. aureus and E. coli). These results provide a facile basis for developing a more potent and multifunctional drug release system for prospective biomedical applications.


Terpenoid-Induced Feeding Deterrence and Antennal Response of Honey Bees.
Multiple interacting stressors negatively affect the survival and productivity of managed honey bee colonies. Pesticides remain a primary concern for beekeepers, as even sublethal exposures can reduce bee immunocompetence, impair navigation, and reduce social communication. Pollinator protection focuses on pesticide application guidelines; however, a more active protection strategy is needed. One possible approach is the use of feeding deterrents that can be delivered as an additive during pesticide application. The goal of this study was to validate a laboratory assay designed to rapidly screen compounds for behavioral changes related to feeding or feeding deterrence. The results of this investigation demonstrated that the synthetic Nasonov pheromone and its terpenoid constituents citral, nerol, and geraniol could alter feeding behavior in a laboratory assay. Additionally, electroantennogram assays revealed that these terpenoids elicited some response in the antennae; however, only a synthetic Nasonov pheromone, citral, and geraniol elicited responses that differed significantly from control and vehicle detections.


"Like filling a lottery ticket with quite high stakes": a qualitative study exploring mothers' needs and perceptions of state-provided financial support for a child with a long-term illness in Finland.
A child's long-term illness or disability is always a serious matter that impacts the whole family. Costs related to an illness can substantially affect a family's financial situation. To date, there is little research on how parents experience available support for financial assistance. Surveys in Finland have found that families of children with long-term illnesses and disabilities could experience financial struggle and perceive the state provided financial support system as too complex. This article aimed to explore how caregivers of children with long-term illnesses perceived their financial situation, need for financial support and experienced its provision by the state in the Helsinki greater region. Convenience sampling was used. Participants were contacted through peer-support groups on Facebook. Eleven mothers of children with varying long-term illnesses and disabilities residing in the Helsinki greater region were interviewed using in-depth interviews. Recordings of the interviews were transcribed and analysed using framework analysis. An analytical framework was built to label the dataset, which was then charted. Lastly, themes were formed through descriptive analysis. The main findings showed how the burden of caring for a child with a long-term illness or disability causes fatigue, which affects a family's financial situation holistically. This affected both employment and financial management, but also receiving information about and applying for the state provided allowances. Mental resources were further depleted by seeking information and applying for allowances. This contributed to a vicious cycle between parental fatigue and financial struggle. Participants found the allocation of funds inequitable across the country. Finally, participants thought the allowance was insufficient in compensating for time spent caring for their child's illness and did not consider their mental strain. Even in a welfare state such as Finland, caregivers of children with long-term illnesses are at risk of poverty and struggle with the organization of state provided financial support. Policies should be designed to ensure equity across the country and consider how the parental fatigue should be addressed. The study has implications for achieving sustainable development goals on wellbeing and reducing poverty.


Occupational therapy goal achievement for persons with postacute cerebrovascular accident in an on-campus student clinic.
A retrospective study was conducted to determine to what extent persons with postacute cerebrovascular accident (CVA) made progress toward rehabilitation goals during occupational therapy treatment and whether age and time since CVA onset affected the rate of goal achievement. Data were collected from the admission and discharge records of persons with CVA who had received occupational therapy at a university clinic, who were at least 8 months post CVA, and who had not received therapy in the community for at least 6 months. The treatment was provided by occupational therapy students under supervision and had a mean length of 12 1-hr sessions over one semester. A sample size of 85 was obtained from 13 years of clinic records. All patients in the sample except one made progress toward at least one of their selected rehabilitation goals. The group mean score for goal progress indicated that as a whole, the patients made significant gains. In addition, independent t tests showed no significant differences in mean scores between younger and older patients, between longer and shorter times since onset, between men and women, or between right and left CVA. There was no significant linear association between mean score and the number of treatments received. Patients with CVA showed progress toward rehabilitation goals during postacute treatment. Patients with recent CVA onset or of younger age did not achieve goals at a significantly higher rate than those with less recent onset or of greater age.


A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury.
Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30 % of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the "miserable minority," the cognitive and physical symptoms do not resolve following the first 3 months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both posttraumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using objective radiological measures. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI.


Three-year change in the wellbeing of orphaned and separated children in institutional and family-based care settings in five low- and middle-income countries.
With more than 2 million children living in group homes, or "institutions", worldwide, the extent to which institution-based caregiving negatively affects development and wellbeing is a central question for international policymakers. A two-stage random sampling methodology identified community representative samples of 1,357 institution-dwelling orphaned and separated children (OSC) and 1,480 family-dwelling OSC aged 6-12 from 5 low and middle income countries. Data were collected from children and their primary caregivers. Survey-analytic techniques and linear mixed effects models describe child wellbeing collected at baseline and at 36 months, including physical and emotional health, growth, cognitive development and memory, and the variation in outcomes between children, care settings, and study sites. At 36-month follow-up, institution-dwelling OSC had statistically significantly higher height-for-age Z-scores and better caregiver-reported physical health; family-dwelling OSC had fewer caregiver-reported emotional difficulties. There were no statistically significant differences between the two groups on other measures. At both baseline and follow-up, the magnitude of the differences between the institution- and family-dwelling groups was small. Relatively little variation in outcomes was attributable to differences between sites (11-27% of total variation) or care settings within sites (8-14%), with most variation attributable to differences between children within settings (60-75%). The percent of variation in outcomes attributable to the care setting type, institution- versus family-based care, ranged from 0-4% at baseline, 0-3% at 36-month follow-up, and 0-4% for changes between baseline and 36 months. These findings contradict the hypothesis that group home placement universally adversely affects child wellbeing. Without substantial improvements in and support for family settings, the removal of institutions, broadly defined, would not significantly improve child wellbeing and could worsen outcomes of children who are moved from a setting where they are doing relatively well to a more deprived setting.


Strengthening Indonesia's Field Epidemiology Training Programme to address International Health Regulations requirements.
According to the International Health Regulations (IHR), countries need to strengthen core capacity for disease surveillance and response systems. Many countries are establishing or enhancing their field epidemiology training programmes (FETPs) to meet human resource needs but face challenges in sustainability and training quality. Indonesia is facing these challenges, which include limited resources for field training and limited coordination in a newly decentralized health system. A national FETP workplan was developed based on an evaluation of the existing programme and projected human resource needs. A Ministry of Health Secretariat linking universities, national and international partners was established to oversee revision and implementation of the FETP. The FETP is integrated into the curriculum of Indonesian universities and field training is conducted in district and provincial health offices under the coordination of the universities and the FETP Secretariat. The FETP was included in the Ministry of Health workforce development strategy through governmental decree. Curricula have been enhanced and field placements strengthened to provide trainees with better learning experiences. To improve sustainability of the FETP, links were established with the Indonesian Epidemiologists' Association, local governments and donors to cultivate future FETP champions and maintain funding. Courses, competitions and discussion forums were established for field supervisors and alumni. These changes have increased the geographic distribution of students, intersectoral and international participation and the quality of student performance. The main lesson learnt is that linkages with universities, ministries and international agencies such as the World Health Organization are critical for building a sustainable high-quality programme. The most critical factors were development of trusting relationships and clear definitions of the responsibilities of each stakeholder.


Low Prevalence of Aeromonas hydrophilain Infectious Diarrhea Samples of Pediatric Patients in Arak, Iran.
Aeromonashydrophila (A. hydrophila) is an aquatic bacterium that can cause a spectrum of infectious diseases, including both gastrointestinal and extraintestinal infections. Due to the high rate of diarrheal infections in pediatric patients in central Iran, this study was designed to determine the frequency of A. hydrophila in diarrhea samples from children in this region. In this descriptive cross-sectional study, diarrheal stool specimens were collected from 200 children admitted between February and October of 2015 to educational and medical centers affiliated with the Arak University of Medical Sciences. The samples were analyzed both phenotypically by culture and genotypically by the polymerase chain reaction (PCR). A. hydrophila was isolated from two of the 200 samples tested (1%). The presence of bacterial genetic markers further confirmed the diagnosis. Based on this study, A. hydrophilais not highly prevalent in children with diarrhea in Arak; however clinical diagnostic laboratory personnel should be aware of the possible presence of A.hydrophila in children with diarrhea as it can cause dangerous health problems in both them and young adolescents.


Mutagen sensitivity and environmental exposures as contributing causes of chromosome 3p losses in head and neck cancers.
The interaction between environmental exposures and host susceptibility may lead to specific mutational events within head and neck squamous cell carcinoma (HNSCC). Furthermore, this interplay may determine not only the probability of cancer development but also the biologic characteristics of the tumor once it occurs. To better understand the relationship of mutagen sensitivity and tobacco and/or alcohol consumption on HNSCC carcinogenesis, we examined loss of heterozygosity on chromosome 3p in 58 HNSCCs using 10 microsatellite markers. Mutagen sensitivity was determined in vitro by quantitating bleomycin-induced chromatid breaks utilizing peripheral blood lympocytes from respective patients. Forty-six of the 58 invasive cancers showed allelic loss at one or more loci. Consistent with previous investigations, three discrete regions of deletions were identified: 3p13-14.2, 3p21.1-21. 2, and 3p25.1-26.1. The frequency and types of deletions were dependent upon tobacco and alcohol exposures. The distal region of 3p but not the remaining two regions was most frequently influenced by tobacco exposure. In contrast, heavy alcohol use when combined with tobacco use was associated with whole-arm loss of 3p rather than identifiable site-specific damage. Furthermore, this combined influence of alcohol and tobacco exposures on whole-arm loss was most apparent in those patients who expressed mutagen-sensitivity; the odds ratio of whole-arm loss increasing from 2.67 (95% CI 0. 21-33.49) in those individuals who were mutagen resistant to 13.5 (95% CI 1.3-136.0; P = 0.02 by Fisher's exact test) in those who were mutagen sensitive. An assessment of clinical parameters in this population demonstrated that patients with whole-arm loss were more likely to present with cervical lymph node metastases and advanced stage disease than patients with partial losses. Results indicate that various environmental exposures as well as the expression of mutagen sensitivity will influence the types of chromosome 3p allelic losses in head and neck cancers as well as the behavior of disease once it develops.


Availability and quality of cause-of-death data for estimating the global burden of injuries.
To assess the availability and quality of global death registration data used for estimating injury mortality. The completeness and coverage of recent national death registration data from the World Health Organization mortality database were assessed. The quality of data on a specific cause of injury death was judged high if fewer than 20% of deaths were attributed to any of several partially specified causes of injury, such as "unspecified unintentional injury". Recent death registration data were available for 83 countries, comprising 28% of the global population. They included most high-income countries, most countries in Latin America and several in central Asia and the Caribbean. Categories commonly used for partially specified external causes of injury resulting in death included "undetermined intent," "unspecified mechanism of unintentional injury," "unspecified road injury" and "unspecified mechanism of homicide". Only 20 countries had high-quality data. Nevertheless, because the partially specified categories do contain some information about injury mechanisms, reliable estimates of deaths due to specific external causes of injury, such as road injury, suicide and homicide, could be derived for many more countries. Only 20 countries had high-quality death registration data that could be used for estimating injury mortality because injury deaths were frequently classified using imprecise partially specified categories. Analytical methods that can derive national estimates of injury mortality from alternative data sources are needed for countries without reliable death registration systems.


The mechanisms of drug release from solid dispersions in water-soluble polymers.
Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. However, despite the publication of numerous original papers and reviews on the subject, the mechanisms underpinning the observed improvements in dissolution rate are not yet understood. In this review the current consensus with regard to the solid-state structure and dissolution properties of solid dispersions is critically assessed. In particular the theories of carrier- and drug-controlled dissolution are highlighted. A model is proposed whereby the release behaviour from the dispersions may be understood in terms of the dissolution or otherwise of the drug into the concentrated aqueous polymer layer adjacent to the solid surface, including a derivation of an expression to describe the release of intact particles from the dispersions. The implications of a deeper understanding of the dissolution mechanisms are discussed, with particular emphasis on optimising the choice of carrier and manufacturing method and the prediction of stability problems.


Racial differences in influenza vaccination among older Americans 1996-2000: longitudinal analysis of the Health and Retirement Study (HRS) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey.
Influenza is a common and serious public health problem among the elderly. The influenza vaccine is safe and effective. The purpose of the study was to determine whether frequencies of receipt vary by race, age group, gender, and time (progress from 1995/1996 to 2000), and whether any racial differences remain in age groups covered by Medicare. Subjects were selected from the Health and Retirement Study (HRS) (12,652 Americans 50-61 years of age (1992-2000)) and the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey (8,124 community-dwelling seniors aged 70+ years (1993-2000)). Using multivariate logistic regression, adjusting for potential confounders, we estimated the relationship between race, age group, gender, time and the main outcome measure, receipt of influenza vaccination in the last 2 years. There has been a clear increase in the unadjusted rates of receipt of influenza vaccination for all groups from 1995/1996 to 2000. However, the proportions immunized are 10-20% higher among White than among Black elderly, with no obvious narrowing of the racial gap from 1995/1996 to 2000. There is an increase in rates from age 50 to age 65. After age 70, the rate appears to plateau. In multivariate analyses, the racial difference remains after adjusting for a series of socioeconomic, health, and health care related variables. (HRS: OR = 0.63 (0.55-0.72), AHEAD: OR = 0.55 (0.44-0.66)) There is much work left if the Healthy People 2010 goal of 90% of the elderly immunized against influenza annually is to be achieved. Close coordination between public health programs and clinical prevention efforts in primary care is necessary, but to be truly effective, these services must be culturally appropriate.


The necessity and reliability of intraoperative parathyroid hormone (PTH) testing in patients with mild hyperparathyroidism and PTH levels in the normal range.
Intraoperative parathyroid hormone (IoPTH) testing is useful in the management of hyperparathyroidism. The successful removal of hypersecreting parathyroids is indicated by a decrease in PTH levels >50% within 15 min. A subset of patients with mild hyperparathyroidism will actually have starting PTH levels in the normal range. We sought to determine if IoPTH testing is necessary in these patients and if the 50% rule delineating surgical cure is reliable. A retrospective review was performed on all patients who underwent parathyroidectomy for hyperparathyroidism at a single institution from 3/2001 to 8/2008. Of the 1,001 patients, 142 (14%) had mild hyperparathyroidism and normal baseline PTH levels (<65 pg/ml). Their mean PTH was 59 ± 1 pg/ml. During surgery, 105 (74%) had a >50% decline in PTH levels after resection of hyperfunctioning parathyroid glands, and their operations were terminated. In contrast, 37 (26%) patients did not have a >50% decline in PTH levels leading to further surgical exploration. In these 37 patients, the PTH levels fell by >50% after the removal of the additional glands in 25 patients (17.6%) and dropped after 20 min in 7 patients (4.9%). In 5 patients (3.5%) the IoPTH did not drop. Of the 142 total patients, 91 had single adenomas and 51 patients had multi-gland disease. All patients (100%) were cured (normal serum calcium after 6 months). Intraoperative PTH testing plays an important role in the operative management in 14% of patients with mild hyperparathyroidism. Importantly, a 50% decline in IoPTH level within 15 min of parathyroidectomy is 96.5% reliable in predicting cure in these patients with PTH starting in the normal range.


Assessment of the Effect of Recruitment Maneuver on Lung Aeration Through Imaging Analysis in Invasively Ventilated Patients: A Systematic Review.
Background: Recruitment maneuvers (RMs) have heterogeneous effects on lung aeration and have adverse side effects. We aimed to identify morphological, anatomical, and functional imaging characteristics that might be used to predict the RMs on lung aeration in invasively ventilated patients. Methods: We performed a systemic review. Studies included invasively ventilated patients who received an RM and in whom re-aeration was examined with chest computed tomography (CT), electrical impedance tomography (EIT), and lung ultrasound (LUS) were included. Results: Twenty studies were identified. Different types of RMs were applied. The amount of re-aerated lung tissue after an RM was highly variable between patients in all studies, irrespective of the used imaging technique and the type of patients (ARDS or non-ARDS). Imaging findings suggesting a non-focal morphology (i.e., radiologic findings consistent with attenuations with diffuse or patchy loss of aeration) were associated with higher likelihood of recruitment and lower chance of overdistention than a focal morphology (i.e., radiological findings suggestive of lobar or segmental loss of aeration). This was independent of the used imaging technique but only observed in patients with ARDS. In patients without ARDS, the results were inconclusive. Conclusions: ARDS patients with imaging findings suggestive of non-focal morphology show most re-aeration of previously consolidated lung tissue after RMs. The role of imaging techniques in predicting the effect of RMs on re-aeration in patients without ARDS remains uncertain.


Off-chip beam steering with a one-dimensional optical phased array on silicon-on-insulator.
Optical phased arrays are versatile components enabling rapid and precise beam steering. An integrated approach is followed in which a 1D optical phased array is fabricated on silicon-on-insulator. The optical phased array consists of 16 parallel grating couplers spaced 2 mum apart. Steering in one direction is done thermo-optically by means of a titanium electrode on top of the structure using the phased array principle, while steering in the other direction is accomplished by wavelength tuning. At a wavelength of 1550 nm, continuous thermo-optical steering of 2.3 degrees and wavelength steering of 14.1 degrees is reported.


A virtual source model for Monte Carlo simulation of helical tomotherapy.
The purpose of this study was to present a Monte Carlo (MC) simulation method based on a virtual source, jaw, and MLC model to calculate dose in patient for helical tomotherapy without the need of calculating phase-space files (PSFs). Current studies on the tomotherapy MC simulation adopt a full MC model, which includes extensive modeling of radiation source, primary and secondary jaws, and multileaf collimator (MLC). In the full MC model, PSFs need to be created at different scoring planes to facilitate the patient dose calculations. In the present work, the virtual source model (VSM) we established was based on the gold standard beam data of a tomotherapy unit, which can be exported from the treatment planning station (TPS). The TPS-generated sinograms were extracted from the archived patient XML (eXtensible Markup Language) files. The fluence map for the MC sampling was created by incorporating the percentage leaf open time (LOT) with leaf filter, jaw penumbra, and leaf latency contained from sinogram files. The VSM was validated for various geometry setups and clinical situations involving heterogeneous media and delivery quality assurance (DQA) cases. An agreement of < 1% was obtained between the measured and simulated results for percent depth doses (PDDs) and open beam profiles for all three jaw settings in the VSM commissioning. The accuracy of the VSM leaf filter model was verified in comparing the measured and simulated results for a Picket Fence pattern. An agreement of < 2% was achieved between the presented VSM and a published full MC model for heterogeneous phantoms. For complex clinical head and neck (HN) cases, the VSM-based MC simulation of DQA plans agreed with the film measurement with 98% of planar dose pixels passing on the 2%/2 mm gamma criteria. For patient treatment plans, results showed comparable dose-volume histograms (DVHs) for planning target volumes (PTVs) and organs at risk (OARs). Deviations observed in this study were consistent with literature. The VSM-based MC simulation approach can be feasibly built from the gold standard beam model of a tomotherapy unit. The accuracy of the VSM was validated against measurements in homogeneous media, as well as published full MC model in heterogeneous media.


A systematic review on Asian's farmers' adaptation practices towards climate change.
Climate change in Asia is affecting farmers' daily routines. Much of the focus surrounding climate change has targeted the economic and environmental repercussions on farming. Few systematic reviews have been carried out on the social impacts of climate change among farmers in Asia. The present article set out to analyse the existing literature on Asian farmers' adaptation practices towards the impacts of climate change. Guided by the PRISMA Statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) review method, a systematic review of the Scopus and Web of Science databases identified 38 related studies. Further review of these articles resulted in six main themes - crop management, irrigation and water management, farm management, financial management, physical infrastructure management and social activities. These six themes further produced a total of 35 sub-themes. Several recommendations are highlighted related to conducting more qualitative studies, to have specific and a standard systematic review method for guide research synthesis in context of climate change adaptation and to practice complimentary searching techniques such as citation tracking, reference searching, snowballing and contacting experts.


Aging, the Medical Subspecialties, and Career Development: Where We Were, Where We Are Going.
Historically, the medical subspecialties have not focused on the needs of older adults. This has changed with the implementation of initiatives to integrate geriatrics and aging research into the medical and surgical subspecialties and with the establishment of a home for internal medicine specialists within the annual American Geriatrics Society (AGS) meeting. With the support of AGS, other professional societies, philanthropies, and federal agencies, efforts to integrate geriatrics into the medical and surgical subspecialties have focused largely on training the next generation of physicians and researchers. They have engaged several subspecialties, which have followed parallel paths in integrating geriatrics and aging research. As a result of these combined efforts, there has been enormous progress in the integration of geriatrics and aging research into the medical and surgical subspecialties, and topics once considered to be geriatric concerns are becoming mainstream in medicine, but this integration remains a work in progress and will need to adapt to changes associated with healthcare reform.


Early Extubation: A Proposed New Metric.
Shorter intubation periods after cardiac surgery are associated with decreased morbidity and mortality. Although the Society of Thoracic Surgeons uses a 6-hour benchmark for early extubation, the time threshold above which complications increase is unknown. Using an institutional Society of Thoracic Surgeons database, we identified 3007 adult patients who underwent 1 of 7 index cardiac operations from 2010-2014. Patients were stratified by the duration of time to extubation after surgery-0-6, 6-9, 9-12, and 12-18 hours. Aggregate outcomes were compared among time-to-extubation cohorts. Primary outcomes included operative mortality and a composite of major postoperative complications; secondary outcomes included prolonged postoperative hospital length of stay (PLOS) (> 14 days) and reintubation. Multivariable logistic regression analysis was used to control for case mix. In results, extubation percentages in each time cohort were hours 0-6-36.4%, 6-9-25.6%, 9-12-12.5%, and 12-18-10.5%. Patients extubated in hours 12-18 vs < 12 experienced a significantly higher risk of operative mortality (odds ratio = 2.7, 95% CI: 1.0-7.5, P = 0.05) and the composite complication outcome (odds ratio = 3.6, 95% CI: 2.2-6.1, P < 0.01); however, insignificant differences were observed in those extubated in hours 6-9 vs 0-6 nor in hours 9-12 vs 0-9. An identical trend was observed for our secondary outcomes of PLOS and reintubation. In conclusion, our results indicate that the risks of operative mortality, major morbidity, and PLOS do not significantly increase until the time interval to extubation exceeds 12 hours. Cardiac surgery programs should be evaluated on their ability to extubate patients within this time interval.


Influence of Two Major Toxoplasma Gondii Virulence Factors (ROP16 and ROP18) on the Immune Response of Peripheral Blood Mononuclear Cells to Human Toxoplasmosis Infection.
Toxoplasma gondii ROP16 and ROP18 proteins have been identified as important virulence factors for this parasite. Here, we describe the effect of ROP16 and ROP18 proteins on peripheral blood mononuclear cells (PBMCs) from individuals with different clinical status of infection. We evaluated IFN-γ, IL-10, and IL-1β levels in supernatants from PBMCs cultures infected with tachyzoites of the T. gondii wild-type RH strain or with knock-out mutants of the rop16 and rop18 encoding genes (RHΔrop16 and RHΔrop18). Cytokine secretion was compared between PBMCs obtained from seronegative individuals (n = 10), with those with chronic asymptomatic (n = 8), or ocular infection (n = 12). We also evaluated if polymorphisms in the genes encoding for IFN-γ, IL-10, IL-1β, Toll-like receptor 9 (TLR9), and purinoreceptor P2RX7 influenced the production of the encoded proteins after ex vivo stimulation. In individuals with chronic asymptomatic infection, only a moderate effect on IL-10 levels was observed when PBMCs were infected with RHΔrop16, whereas a significant difference in the levels of inflammatory cytokines IFN-γ and IL-1β was observed in seronegative individuals, but this was also dependent on the host's cytokine gene polymorphisms. Infection with ROP16-deficient parasites had a significant effect on IFN-γ production in previously non-infected individuals, suggesting that ROP16 which is considered as a virulence factor plays a role during the primary infection in humans, but not in the secondary immune response.


Early life recorded in archean pillow lavas.
Pillow lava rims from the Mesoarchean Barberton Greenstone Belt in South Africa contain micrometer-scale mineralized tubes that provide evidence of submarine microbial activity during the early history of Earth. The tubes formed during microbial etching of glass along fractures, as seen in pillow lavas from recent oceanic crust. The margins of the tubes contain organic carbon, and many of the pillow rims exhibit isotopically light bulk-rock carbonate delta13C values, supporting their biogenic origin. Overlapping metamorphic and magmatic dates from the pillow lavas suggest that microbial life colonized these subaqueous volcanic rocks soon after their eruption almost 3.5 billion years ago.


A flexible graphical model for multi-modal parcellation of the cortex.
Advances in neuroimaging have provided a tremendous amount of in-vivo information on the brain's organisation. Its anatomy and cortical organisation can be investigated from the point of view of several imaging modalities, many of which have been studied for mapping functionally specialised cortical areas. There is strong evidence that a single modality is not sufficient to fully identify the brain's cortical organisation. Combining multiple modalities in the same parcellation task has the potential to provide more accurate and robust subdivisions of the cortex. Nonetheless, existing brain parcellation methods are typically developed and tested on single modalities using a specific type of information. In this paper, we propose Graph-based Multi-modal Parcellation (GraMPa), an iterative framework designed to handle the large variety of available input modalities to tackle the multi-modal parcellation task. At each iteration, we compute a set of parcellations from different modalities and fuse them based on their local reliabilities. The fused parcellation is used to initialise the next iteration, forcing the parcellations to converge towards a set of mutually informed modality specific parcellations, where correspondences are established. We explore two different multi-modal configurations for group-wise parcellation using resting-state fMRI, diffusion MRI tractography, myelin maps and task fMRI. Quantitative and qualitative results on the Human Connectome Project database show that integrating multi-modal information yields a stronger agreement with well established atlases and more robust connectivity networks that provide a better representation of the population.


Provider-Level and Hospital-Level Factors and Process Measures of Quality Care Delivered in Pediatric Emergency Departments.
Differences in the quality of emergency department (ED) care are often attributed to nonclinical factors such as variations in the structure, systems, and processes of care. Few studies have examined these associations among children. We aimed to determine whether process measures of quality of care delivered to patients receiving care in children's hospital EDs were associated with physician-level or hospital-level factors. We included children (<18 years old) who presented to any of the 12 EDs participating in the Pediatric Emergency Care Applied Research Network (PECARN) between January 2011 and December 2011. We measured quality of care from medical record reviews using a previously validated implicit review instrument with a summary score ranging from 5 to 35, and examined associations between process measures of quality and physician- and hospital-level factors using a mixed-effects linear regression model adjusted for patient case-mix, with hospital site as a random effect. Among the 620 ED encounters reviewed, we did not find process measures of quality to be associated with any physician-level factors such as physician sex, years since medical school graduation, or physician training. We found, however, that process measures of quality were positively associated with delivery at freestanding children's hospitals (1.96 points higher in quality compared to nonfreestanding status, 95% confidence interval: 0.49, 3.43) and negatively associated with higher annual ED patient volume (-0.03 points per thousand patients, 95% confidence interval: -0.05, -0.01). Process measures of quality of care delivered to children were higher among patients treated at freestanding children's hospitals but lower among patients treated at higher volume EDs.


Pseudorandom phase masks for superresolution imaging from subpixel shifting.
We present a method for overcoming the pixel-limited resolution of digital imagers. Our method combines optical point-spread function engineering with subpixel image shifting. We place an optimized pseudorandom phase mask in the aperture stop of a conventional imager and demonstrate the improved performance that can be achieved by combining multiple subpixel shifted images. Simulation results show that the pseudorandom phase-enhanced lens (PRPEL) imager achieves as much as 50% resolution improvement over a conventional multiframe imager. The PRPEL imager also enhances reconstruction root-mean-squared error by as much as 20%. We present experimental results that validate the predicted PRPEL imager performance.


Does Dopamine Replacement Medication Affect Postural Sequence Learning in Parkinson's Disease?
Deficits in sequence-specific learning (SSL) may be a product of Parkinson's disease (PD) but this deficit could also be related to dopamine replacement. The purpose of this study was to determine whether dopamine replacement affected acquisition and retention of a standing Continuous Tracking Task in individuals with PD. SSL (difference between random/repeated Root Mean Square Error across trials) was calculated over 2 days of practice and 1 day of retention for 4 groups; 10 healthy young (HY), 10 healthy elders, 10 individuals with PD on, 9 individuals with PD off their usual dosage of dopamine replacement. Improvements in acquisition were observed for all groups; however, only the HY demonstrated retention. Therefore, age appeared to have the largest effect on SSL with no significant effect of medication. Additional research is needed to understand the influence of factors such as practice amount, task difficulty, and dopamine replacement status on SSL deficits during postural tasks.


Selection of forward osmosis draw solutes for subsequent integration with anaerobic treatment to facilitate resource recovery from wastewater.
Forward osmosis (FO) can be used to extract clean water and pre-concentrate municipal wastewater to make it amenable to anaerobic treatment. A protocol was developed to assess the suitability of FO draw solutes for pre-concentrating wastewater for potential integration with anaerobic treatment to facilitate resource recovery from wastewater. Draw solutes were evaluated in terms of their ability to induce osmotic pressure, water flux, and reverse solute flux. The compatibility of each draw solute with subsequent anaerobic treatment was assessed by biomethane potential analysis. The effect of each draw solute (at concentrations corresponding to the reverse solute flux at ten-fold pre-concentration of wastewater) on methane production was also evaluated. The results show that ionic organic draw solutes (e.g., sodium acetate) were most suitable for FO application and subsequent anaerobic treatment. On the other hand, the reverse solute flux of inorganic draw solutions could inhibit methane production from FO pre-concentrated wastewater.


The Design of ZnO Nanorod Arrays Coated with MnOx for High Electrochemical Stability of a Pseudocapacitor Electrode.
Tremendous efforts have been made on the development of unique electrochemical capacitors or pseudocapacitors due to the overgrowing electrical energy demand. Here, the authors report a new and simple strategy for fabricating hybrid MnOx-coated ZnO nanorod arrays. First, the vertically aligned ZnO nanorods were prepared by chemical bath deposition (CBD) as a template providing a large surface area for active material deposition. The manganese oxide was subsequently coated onto the surface of the ZnO nanorods to form a hybrid MnOx-coated ZnO nanostructure by anodic deposition in a manganese acetate (MnA)-containing aqueous solution. The hybrid structure of MnOx-coated ZnO nanorod arrays exhibits a large surface area and high conductivity, essential for enhancing the faradaic processes across the interface and improving redox reactions at active MnOx sites. A certain concentration of the deposition solution was selected for the MnOx coating, which was studied as a function of deposition time. Cyclic voltammetry (CV) curves showed that the specific capacitance (SC) of the MnOx-coated ZnO nanostructure was 222 F/g for the deposition times at 10 s when the concentration of MnA solution was 0.25 M. The unique hybrid nanostructures also exhibit excellent cycling stability with >97.5% capacitance retention after 1200 CV cycles. The proposed simple and cost-effective method of fabricating hybrid nanostructures may pave the way for mass production of future intelligent and efficient electrochemical energy storage devices.


Identification of the vaccinia virus gene encoding an 18-kilodalton subunit of RNA polymerase and demonstration of a 5' poly(A) leader on its early transcript.
The DNA-dependent RNA polymerase of vaccinia virus contains 8 to 10 virus-encoded polypeptides. We have mapped the gene encoding an 18-kilodalton RNA polymerase subunit to D7R, the seventh open reading frame of the HindIII D genomic subfragment. Localization of this gene was achieved by using antibody to the purified RNA polymerase for immunoprecipitation of the in vitro translation products of in vivo-synthesized early mRNA selected by hybridization to cloned DNA fragments. The identification was confirmed by translation of D7R transcripts made in vitro with bacteriophage T7 RNA polymerase. The phenotypes of two previously isolated conditionally lethal temperature-sensitive mutants that map to D7R (J. Seto, L. M. Celenza, R. C. Condit, and E. G. Niles, Virology 160:110-119, 1987) are consistent with an essential role of this subunit in late transcription. This polymerase gene, designated rpo18, predicts a polypeptide of 161 amino acids with a molecular mass of 17,892. The rpo18 gene is transcribed early in infection, even though the 5'-TAAATG-3' motif, which is conserved among many genes of the late class, is present near the RNA start site. Characterization of the 5' end of the early transcript by several different methods, including cDNA cloning, revealed a poly(A) leader with up to 14 adenylate residues, whereas only 3 are present in the corresponding location of the DNA template. Similar but somewhat longer poly(A) leaders have previously been observed in mRNAs of late genes. We noted a TAAATG motif near the initiation site of several other early genes, including the viral DNA polymerase, and carried out additional experiments to demonstrate that their early transcripts also have 5' poly(A) leaders. Thus, formation of the poly(A) leader is not exclusively a late function but apparently depends on sequences around the transcription initiation site.


Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus.
Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves--could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.


Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial.
Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial. To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes. The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007. Cardiac death or nonfatal myocardial infarction (MI). The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44-1.88; P = .73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9-20.1; P = .001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45-1.1; P = .14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups. In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. clinicaltrials.gov Identifier: NCT00769275.


Evaluation of a digital method to assess evening meal intake in a free-living adult population.
In recent years new applications of technologies, including digital images, to capture dietary behaviour in real time have been explored. To validate a digital method for estimating evening meal intake in a free-living adult population, and to examine the feasibility of the method for recording evening meal intake over a prolonged period of time. The digital method was compared against weighed records of 19 participants' usual evening meals for five consecutive days. Two trained image analysts independently estimated the weight of individual foods within the meals into major food categories, and the nutrient content was calculated. A second study included interviews with 28 participants recording their evening meals on weekdays for three consecutive weeks to get their perspective on the feasibility of the method. High correlation coefficients between the digital method and weighed records were found for all measured food categories and nutrients. Comparable means and acceptable limits of agreement (mean difference +/- 2 SD) were found with regard to macronutrient distribution (e.g. fat content -5 to 6 E%), energy density (-75 to 91 kJ/100 g), and energy-adjusted foods (e.g. fruit and vegetable content -241 to 236 g/10 MJ). The majority of the participants expressed satisfaction with the method and were willing to record their evening meals for 1 month or more using the digital method. The digital method is valid and feasible for evening meal estimation in real-time where a prolonged recording period of participants' meals is needed.


Centrode patterns in the lumbar spine. Baseline studies in normal subjects.
Segmental spinal instability is a known cause of back pain, but no method of accurately quantifying instability exists. The movement of complex joints with rotational and translational components (such as the lumbar motion segment) is tracked by a pathway of instantaneous centers of rotation, or a centrode. Instability, ie, excessive and/or erratic movement, is reflected by increased centrode length in cadaver studies. This study describes an in vivo method that precisely determines the centrode pattern and reports the results for 21 normal male volunteers who were studied at the L4-5 and L5-S1 levels. Each volunteer underwent lateral radiographs of the lumbar spine. High speed films were used and six positions, from full extension to full flexion, were recorded. Acetate tracings and contour matching techniques recorded the relative positions of the vertebral bodies on each film. Multiple tracings of each radiograph, combined with a digitizer and computer, were used to improve precision in the calculated centrode patterns. Centrode lengths measured 43.7 mm and 55.9 mm, respectively, for the L4-5 and L5-S1 levels. This study demonstrates that precise centrode pattern analysis for sagittal plane motion of the lumbar spine is possible in vivo. Studies are under way to determine whether this technique will be useful as a clinical test in diagnosing early segmental instability of the lumbar spine in patients with low-back pain.


A simple method to cure established tumors by inflammatory killing of normal cells.
We describe a simple technology used to cure an established metastatic disease. Intradermal injection of plasmid DNA encoding a transcriptionally targeted cytotoxic gene, along with hsp70, not only promoted tissue-specific, inflammatory killing of normal melanocytes, but also induced a CD8(+) T-cell-dependent, antigen-specific response in mice that eradicated systemically established B16 tumors. This CD8(+) T cell response was subsequently suppressed in vivo within a few days. The data demonstrate that deliberate destruction of normal tissue can be exploited to generate immunity against a malignant disease originating from that tissue. This approach obviates the need to identify tumor antigens and does not require complex isolation of tumor cells or their derivatives. In addition, it provides a model system for studying the mechanisms underlying the etiology and control of autoimmune diseases. Finally, despite targeting normal tissue, therapy could be separated from development of overt autoimmune symptoms, suggesting that the strategy may be valuable against tumors derived from both non-essential and essential tissue types.


Genetic ablation of neural crest cell diversification.
The neural crest generates multiple cell types during embryogenesis but the mechanisms regulating neural crest cell diversification are incompletely understood. Previous studies using mutant zebrafish indicated that foxd3 and tfap2a function early and differentially in the development of neural crest sublineages. Here, we show that the simultaneous loss of foxd3 and tfap2a function in zebrafish foxd3(zdf10);tfap2a(low) double mutant embryos globally prevents the specification of developmentally distinct neural crest sublineages. By contrast, neural crest induction occurs independently of foxd3 and tfap2a function. We show that the failure of neural crest cell diversification in double mutants is accompanied by the absence of neural crest sox10 and sox9a/b gene expression, and that forced expression of sox10 and sox9a/b differentially rescues neural crest sublineage specification and derivative differentiation. These results demonstrate the functional necessity for foxd3 and tfap2a for neural crest sublineage specification and that this requirement is mediated by the synergistic regulation of the expression of SoxE family genes. Our results identify a genetic regulatory pathway functionally discrete from the process of neural crest induction that is required for the initiation of neural crest cell diversification during embryonic development.


Problems in the coupling of eye and hand in the sequential movements of children with Developmental Coordination Disorder.
Shifting gaze and attention ahead of the hand is a natural component in the performance of skilled manual actions. Very few studies have examined the precise co-ordination between the eye and hand in children with Developmental Coordination Disorder (DCD). This study directly assessed the maturity of eye-hand co-ordination in children with DCD. A double-step pointing task was used to investigate the coupling of the eye and hand in 7-year-old children with and without DCD. Sequential targets were presented on a computer screen, and eye and hand movements were recorded simultaneously. There were no differences between typically developing (TD) and DCD groups when completing fast single-target tasks. There were very few differences in the completion of the first movement in the double-step tasks, but differences did occur during the second sequential movement. One factor appeared to be the propensity for the DCD children to delay their hand movement until some period after the eye had landed on the target. This resulted in a marked increase in eye-hand lead during the second movement, disrupting the close coupling and leading to a slower and less accurate hand movement among children with DCD. In contrast to skilled adults, both groups of children preferred to foveate the target prior to initiating a hand movement if time allowed. The TD children, however, were more able to reduce this foveation period and shift towards a feedforward mode of control for hand movements. The children with DCD persevered with a look-then-move strategy, which led to an increase in error. For the group of DCD children in this study, there was no evidence of a problem in speed or accuracy of simple movements, but there was a difficulty in concatenating the sequential shifts of gaze and hand required for the completion of everyday tasks or typical assessment items.


Characterization of novel reverse transcriptase and other RNA-associated catalytic activities by human DNA polymerase gamma: importance in mitochondrial DNA replication.
During mitochondrial DNA (mtDNA) replication, DNA/RNA heteroduplex intermediates are formed. To understand how and why ribonucleotides are involved in mtDNA replication, we have studied the novel RNA-associated activities of human mitochondrial DNA polymerase (Pol gamma), including reverse transcription, RNA-directed 3' --> 5' DNA excision, RNA-primed DNA synthesis, and ribonucleotide incorporation. Remarkably, Pol gamma catalyzes reverse transcription with a slightly higher efficiency than HIV-1 reverse transcriptase, suggesting that the activity may be physiologically significant, and furthermore, proofreading activity with an RNA template was also observed. RNA-primed DNA synthesis activity is required for initiation of mtDNA replication, and we have found that Pol gamma holoenzyme is capable of performing this reaction at a physiologically relevant rate and that the accessory subunit plays an essential role in the initiation steps. Single ribonucleotides have been found scattered in the mtDNA genome, although their role and significance are not yet defined. Our finding that Pol gamma also incorporates ribonucleotide triphosphates into a DNA primer offers a plausible enzymatic pathway for the origin of the RNA-containing mtDNA genome.


Excessive testicular progesterone secretion in aged male Fischer 344 rats: a potential cause of age-related gonadotropin suppression and confounding variable in aging studies.
Previous studies have inconsistently reported elevated sex steroid levels in aging male F344 rats, which frequently develop testicular Leydig cell tumors. The aims of this study were to characterize circulating steroid levels and to determine the in vivo source and functional significance of altered steroid secretion in these animals. Progesterone (P) and to a lesser extent estradiol (E2) levels were increased, while gonadotropins and testosterone (T) were decreased, in intact 24-mo-old compared to 12-mo-old rats. P levels were inversely correlated with gonadotropins and T. All old rats demonstrated Leydig cell hyperplasia or tumors. After orchidectomy, P levels were markedly decreased. Gonadotropin levels were similar in orchidectomized 24-mo compared to 3-mo-old rats. We conclude that the testis is the source of excessive P and E2 secretion in vivo in old F344 rats. Increased P (or E2) negative feedback may contribute to the suppression of gonadotropins and reproductive function in aging male F344 rats. Finally, excessive P secretion may be a confounding pathological variable in aging studies using this rat model.


Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide.
Fenretinide or N-(4-hydroxyphenyl)retinamide is a vitamin A analogue synthesized in the United States in the late 1960s. This retinoid shows a preferential accumulation in breast instead of liver, is effective in the inhibition of chemically induced mammary carcinoma in rats, and has proved to be less toxic than many other vitamin A analogues. The Milan Cancer Institute has put a particular effort in this molecule in both the experimental and clinical fields. We have demonstrated, in animals and humans, that fenretinide induces a rapid reduction of retinol plasma concentration, that its blood levels remain constant during administration for as long as 5 years, and that the drug is able to accumulate in the human breast. To date, 2969 stage I breast cancer patients have been randomized to evaluate the efficacy of this retinoid to prevent contralateral new primaries, 709 subjects have been accrued in a prevention trial of basal cell carcinoma of the head and neck, and 153 patients entered a study the preliminary results of which already show the capability of fenretinide to prevent recurrences and new localizations of oral leukoplakia. Further studies on fenretinide will be aimed at evaluating its preventive efficacy in superficial bladder and prostate cancers and at exploring possible synergism with tamoxifen and interferons in breast cancer and skin cancer, respectively.


EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma.
Glioblastoma multiforme (GBM) is the most lethal of brain tumors and is highly resistant to ionizing radiation (IR) and chemotherapy. Here, we report on a molecular mechanism by which a key glioma-specific mutation, epidermal growth factor receptor variant III (EGFRvIII), confers radiation resistance. Using Ink4a/Arf-deficient primary mouse astrocytes, primary astrocytes immortalized by p53/Rb suppression, as well as human U87 glioma cells, we show that EGFRvIII expression enhances clonogenic survival following IR. This enhanced radioresistance is due to accelerated repair of DNA double-strand breaks (DSB), the most lethal lesion inflicted by IR. The EGFR inhibitor gefitinib (Iressa) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 attenuate the rate of DSB repair. Importantly, expression of constitutively active, myristylated Akt-1 accelerates repair, implicating the PI3K/Akt-1 pathway in radioresistance. Most notably, EGFRvIII-expressing U87 glioma cells show elevated activation of a key DSB repair enzyme, DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Enhanced radioresistance is abrogated by the DNA-PKcs-specific inhibitor NU7026, and EGFRvIII fails to confer radioresistance in DNA-PKcs-deficient cells. In vivo, orthotopic U87-EGFRvIII-derived tumors display faster rates of DSB repair following whole-brain radiotherapy compared with U87-derived tumors. Consequently, EGFRvIII-expressing tumors are radioresistant and continue to grow following whole-brain radiotherapy with little effect on overall survival. These in vitro and in vivo data support our hypothesis that EGFRvIII expression promotes DNA-PKcs activation and DSB repair, perhaps as a consequence of hyperactivated PI3K/Akt-1 signaling. Taken together, our results raise the possibility that EGFR and/or DNA-PKcs inhibition concurrent with radiation may be an effective therapeutic strategy for radiosensitizing high-grade gliomas.


High rate of infection after aseptic revision of failed metal-on-metal total hip arthroplasty.
Evidence suggests some metal-on-metal (MOM) THAs have higher rates of failure and subsequent revision than other bearing surfaces. However, there are few studies demonstrating how these patients fare after revision. We asked: (1) What is the short-term survivorship of revision THA in patients whose index THAs employed MOM bearings? (2) What are the causes of failure of revision THA in these patients (ie, what are the indications for repeat revision)? (3) What are the most common complications after revisions of MOM THAs? We identified 37 patients (24 women, 13 men; mean age, 55 years; 37 hips) revised for aseptic failure of primary stemmed MOM THAs. Reasons for revision included pain with loose components (n = 19), adverse reaction to metal debris (n = 8), periprosthetic fracture (n = 4), impingement (n = 3), dislocation (n = 2), and pain of unknown origin (n = 1). Minimum followup was 24 months (mean, 33 months; range, 24-81 months) postrevision, but 11 were not seen in the last 2 years as our routine followup is at 2 and 5 years. Clinical histories were reviewed for reasons for failure of the MOM THAs and complications associated with revision surgery. Survivorship free from further revision for any cause was 95% at 24 months and 92% at latest followup (24-81 months). There were three repeat revisions, all for periprosthetic infection, and all were treated with two-stage reimplantation. No other complications were observed. We observed a higher-than-expected rate of infection after revision of MOM THAs. The infection rate was higher in this report than in an earlier series looking at revision THAs for other indications at our institution. As revision of MOM THA becomes more common, it will be important to continue monitoring postrevision outcomes and providing treatment strategies to mitigate complications for these patients.


Speaking Out and Being Heard Residents' Committees in Quebec's Residential Long-Term Care Centre.
Residents' councils in Quebec's residential and long-term care centres have the mandate to promote the improvement of living conditions for residents, to assess their level of satisfaction, and to defend their rights. Based on two studies on the autonomy of councils, we examined how committees can express themselves on topics other than those the management is already aware of, to reveal various previously unknown aspects of the services, and to voice unexpressed concerns. We are especially interested in what makes management receptive, or not, to what the committee members say. The councils' ability to express them selves is, in fact, inseparable from its capacity to listen to the management teams, and we seek to determine the conditions required to perform this dual capacity.


Parental Motivational Perseverance Predicts Adolescents' Depressive Symptoms: An Intergenerational Analysis with Actor-Partner Interdependence Model.
Adolescents' depressive symptoms are affected by a number of factors including life stress, gender, socio-economic status, and parental depression symptoms. However, little is known about whether adolescent depressive symptoms are also affected by parental motivational characteristics. The current study explores the relationship between parental motivational perseverance (i.e., parents' persistency in the face of setbacks and difficulties) and children's depressive symptoms during the adolescence, given the critical role of perseverance in psychological well-being. The predictive utility of two motivational characteristics relevant to perseverance: parents' growth mindset (i.e., one's belief about the malleability of human competence) and grit (i.e., perseverance for long term goals) were examined. Four hundred pairs of Japanese parents (82% mothers) and their adolescent children (50% females; average age at the time of the first assessment = 14.05 years; SD = 0.84) independently completed surveys measuring their growth mindset, grit, and depressive symptoms at two time points (approximately one year apart; attrition rate = 25%). The Actor-Partner Independence Model, a statistical model that accounts for inter-dependence between dyads (e.g., parents and children), was used to examine how parental motivational perseverance predicts the long-term change in their offspring's depressive symptoms. The results showed that parental grit led to the decrease in adolescents' depressive symptoms through the changes in adolescents' grit. On the other hand, parental growth mindset directly predicted the adolescents' depressive symptoms, and this was not mediated by the adolescents' growth mindset. These findings underscore the importance of parental motivational characteristics in regards to adolescents' depressive symptoms.


Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow.
Hematopoietic stem cells (HSCs) are defined in mice by three activities: they must rescue lethally irradiated mice (radioprotection), they must self-renew, and they must restore all blood cell lineages permanently. We initially demonstrated that HSCs were contained in a rare (approximately 0.05%) subset of bone marrow cells with the following surface marker profile: Thy-1.1lo Lin- Sca-1+. These cells were capable of long-term, multi-lineage reconstitution and radioprotection of lethally irradiated mice with an enrichment that mirrors their representation in bone marrow, namely, 1,000-2,000-fold. However, the experiments reported did not exclude the possibility that stem cell activity may also reside in populations that are Thy-1.1-, Sca-1-, or Lin+. In this article stem cell activity was determined by measuring: (a) radioprotection provided by sorted cells; (b) long-term, multi-lineage reconstitution of these surviving mice; and (c) long-term, multi-lineage reconstitution by donor cells when radioprotection is provided by coinjection of congenic host bone marrow cells. Here we demonstrate that HSC activity was detected in Thy-1.1+, Sca-1+, and Lin- fractions, but not Thy-1.1-, Sca-1-, or Lin+ bone marrow cells. We conclude that Thy-1.1lo Lin- Sca-1+ cells comprise the only adult C57BL/Ka-Thy-1.1 mouse bone marrow subset that contains pluripotent HSCs.


[Impact on hospital days of care due to unnecessary emergency admissions].
Unnecessary admissions of acute cases have major impacts on hospital efficiency and organization. This study is aimed to identify percentage of unnecessary admissions from a hospital emergency department and the reasons why, as well as to quantify the unnecessary hospital days of care generated by these admissions. It has been analyzed the appropriateness of 622 admissions made in 2002, selected at random, all of the hospital stays generated by the inappropriate admissions and a representative sample of the appropriate admissions of a second-level hospital in Asturias. The review tool was the Appropriateness Evaluation Protocol. A descriptive analysis, a bivariate analysis and a multivariate logic regression analysis were made. A total of 63 admissions (10.1%) were judged inappropriate. The main cause of inappropriateness were admissions for performing diagnostic tests and/or treatments, which could be carried out on an outpatient basis. These unnecessary admissions generated 78.2% of unnecessary stays, and the appropriate admissions generated 24.8% of unnecessary stays. Referrals to hospital emergency rooms from physicians outside of the hospital proper heightened the risk of unnecessary admissions (OR:4.50, 95% CI: 1.59-12.76), daytime admissions (OR: 13.97, 95% CI: 1.86-104.76) or evening admissions (OR: 7.70, 95% CI: 1.01-58.72), admissions to cardiology wards (OR: 3.93, 95% CI: 1.22-12.70) and neurology wards (OR: 5.86, 95% CI: 1.88-18.30), the experience of prior admissions having lowered the risk of unnecessary admission (OR: 0.34, 95% CI: 0.18-0.65). Unnecessary admissions generate three times more inappropriate stays than the necessary admissions. Hospital organization-related problems are the main cause of inappropriate admissions.


Epicutaneous immunotherapy for the treatment of peanut allergy in children and young adults.
Peanut allergy is common, life-threatening, and without therapeutic options. We evaluated peanut epicutaneous immunotherapy (EPIT) by using Viaskin Peanut for peanut allergy treatment. We sought to evaluate the clinical, safety, and immunologic effects of EPIT for the treatment of peanut allergy. In this multicenter, double-blind, randomized, placebo-controlled study, 74 participants with peanut allergy (ages 4-25 years) were treated with placebo (n = 25), Viaskin Peanut 100 μg (VP100; n = 24) or Viaskin Peanut 250 μg (VP250; n = 25; DBV Technologies, Montrouge, France). The primary outcome was treatment success after 52 weeks, which was defined as passing a 5044-mg protein oral food challenge or achieving a 10-fold or greater increase in successfully consumed dose from baseline to week 52. Adverse reactions and mechanistic changes were assessed. At week 52, treatment success was achieved in 3 (12%) placebo-treated participants, 11 (46%) VP100 participants, and 12 (48%) VP250 participants (P = .005 and P = .003, respectively, compared with placebo; VP100 vs VP250, P = .48). Median change in successfully consumed doses were 0, 43, and 130 mg of protein in the placebo, VP100, and VP250 groups, respectively (placebo vs VP100, P = .014; placebo vs VP250, P = .003). Treatment success was higher among younger children (P = .03; age, 4-11 vs >11 years). Overall, 14.4% of placebo doses and 79.8% of VP100 and VP250 doses resulted in reactions, predominantly local patch-site and mild reactions (P = .003). Increases in peanut-specific IgG4 levels and IgG4/IgE ratios were observed in peanut EPIT-treated participants, along with trends toward reduced basophil activation and peanut-specific TH2 cytokines. Peanut EPIT administration was safe and associated with a modest treatment response after 52 weeks, with the highest responses among younger children. This, when coupled with a high adherence and retention rate and significant changes in immune pathways, supports further investigation of this novel therapy.


The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases.
Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.


Epidemiology of therapy-related myeloid neoplasms after treatment for pediatric acute lymphoblastic leukemia in the nordic countries.
Of 1614 Nordic children with ALL that were treated according to the NOPHO ALL92 protocol, 20 developed an SMN (cumulative risk at 12 years: 1.6%). Sixteen of the twenty SMNs were acute myeloid leukemias or myelodysplasias, and 9 of these had either monosomy 7 (n=7) or 7q deletions (n=2). In Cox multivariate analysis longer duration of oral MTX/6MP maintenance therapy (p=0.02; being longest for standard risk patients) and presence of high-hyperdiploidy (p=0.07) were related to an increased risk of SMN. In 524 patients we determined the erythrocyte activity of thiopurine methyltransferase (TPMT), which methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. The TPMT activity was significantly lower in those that did compared to those that did not develop an SMN (Median: 12.1 vs 18.1 IU/ml; p=0.02). Among 427 TPMT wild type patients, those who developed SMN received higher 6MP doses than the remaining (69.7 vs 60.4 mg/m(2), p=0.03), which may reflect increased levels of methylated metabolites that inhibit purine de novo synthesis and thus enhance incorporation of 6-thioguanine nucleotides into DNA. In conclusion, the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMN.


Antioxidant and cytoprotective effects of N-acetylcysteine against subchronic oral glyphosate-based herbicide-induced oxidative stress in rats.
It is claimed that oxidative stress has a prominent role in the mechanism of toxic effects formed by glyphosate-based herbicide (GBH) in living systems. A strong thiol compound, N-acetylcysteine (NAC), has antioxidative and cytoprotective properties. The objective in this subchronic toxicity study was to identify the prophylactic effect of NAC over histopathological changes and oxidative stress induced by GBH in blood, renal, liver, cardiac, and brain tissues. A sum of 28 male Wistar rats were divided into four equal groups, each containing 7 rats. During the study, group I (control group) was supplied with normal rodent bait and tap water ad libitum. The applied agents were 160 mg/kg NAC to group II, 375 mg/kg as equivalent to 1/10 of lethal dose 50% (LD50) of GBH to group III, and 160 mg/kg of NAC and 375 mg/kg of GBH together once per day as oral gavage to group IV for 8 weeks. While GBH decreased the levels of GSH in blood, liver, kidney, and brain tissues, it considerably increased malondialdehyde levels. On the contrary, these parameters happened to improve in the group supplied with NAC. Besides, it was seen that NAC was observed to improve the histopathologic changes in rat tissues induced by GBH. It was concluded that NAC protects oxidative stress and tissue damage induced by GBH in blood and tissue and this prophylactic effect could be attributed to its antioxidant and free radical sweeper character.


The effects of muscle vibration on anticipatory postural adjustments.
The current study investigated the influence of changes in sensory information related to postural stability on anticipatory postural adjustments (APAs) in standing subjects. Subjects performed fast arm movements and a load release task while standing on a stable force platform or on an unstable board. We manipulated sensory information through vibration of the Achilles tendons and additional finger touch (contact forces under 1 N). Changes in the background activity of leg, trunk, and arm muscles and displacements of the center of pressure (COP) were quantified within time intervals typical for APAs. In the arm movement task, leg and trunk muscles showed a significant drop in the APAs with finger touch, while the vibration and standing on the unstable board each led to an increase in the APA magnitude. In the load release task, ventral muscles decreased their APA activity with touch, while dorsal muscles showed increased inhibition during APAs. During vibration, dorsal and ventral muscles showed increased excitation and inhibition during APAs, respectively. An additional analysis of APAs at a joint level, has shown that in both tasks, an index related to the co-activation of agonist-antagonist muscle pairs (C-index) was modulated with touch, vibration, and stability particularly in leg muscles. Small changes in the other index related to reciprocal activation (R-index) were found only in trunk muscles. Light touch and vibration induced opposing changes in the C-index, suggesting their opposite effects on the stabilization of a reference point or vertical. We conclude that the central nervous system deploys patterns of adjustments in which increased co-contraction of distal muscles and reciprocal adjustments in trunk muscles are modified to ensure equilibrium under postural instability.


Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.
We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation.


Effect of methylene blue on the genomic response to reperfusion injury induced by cardiac arrest and cardiopulmonary resuscitation in porcine brain.
Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest.


Meta-Analysis of Multiple Sclerosis Microarray Data Reveals Dysregulation in RNA Splicing Regulatory Genes.
Abnormalities in RNA metabolism and alternative splicing (AS) are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS) and altered AS, including functional studies showing that an imbalance in alternatively-spliced isoforms may contribute to disease etiology. Here, we tested whether the altered expression of AS-related genes represents a MS-specific signature. A comprehensive comparative analysis of gene expression profiles of publicly-available microarray datasets (190 MS cases, 182 controls), followed by gene-ontology enrichment analysis, highlighted a significant enrichment for differentially-expressed genes involved in RNA metabolism/AS. In detail, a total of 17 genes were found to be differentially expressed in MS in multiple datasets, with CELF1 being dysregulated in five out of seven studies. We confirmed CELF1 downregulation in MS (p=0.0015) by real-time RT-PCRs on RNA extracted from blood cells of 30 cases and 30 controls. As a proof of concept, we experimentally verified the unbalance in alternatively-spliced isoforms in MS of the NFAT5 gene, a putative CELF1 target. In conclusion, for the first time we provide evidence of a consistent dysregulation of splicing-related genes in MS and we discuss its possible implications in modulating specific AS events in MS susceptibility genes.


Does logging and forest conversion to oil palm agriculture alter functional diversity in a biodiversity hotspot?
Forests in Southeast Asia are rapidly being logged and converted to oil palm. These changes in land-use are known to affect species diversity but consequences for the functional diversity of species assemblages are poorly understood. Environmental filtering of species with similar traits could lead to disproportionate reductions in trait diversity in degraded habitats. Here, we focus on dung beetles, which play a key role in ecosystem processes such as nutrient recycling and seed dispersal. We use morphological and behavioural traits to calculate a variety of functional diversity measures across a gradient of disturbance from primary forest through intensively logged forest to oil palm. Logging caused significant shifts in community composition but had very little effect on functional diversity, even after a repeated timber harvest. These data provide evidence for functional redundancy of dung beetles within primary forest and emphasize the high value of logged forests as refugia for biodiversity. In contrast, conversion of forest to oil palm greatly reduced taxonomic and functional diversity, with a marked decrease in the abundance of nocturnal foragers, a higher proportion of species with small body sizes and the complete loss of telecoprid species (dung-rollers), all indicating a decrease in the functional capacity of dung beetles within plantations. These changes also highlight the vulnerability of community functioning within logged forests in the event of further environmental degradation.


Organic farming in the corn belt.
A small minority of farmers in the Midwest produces crops on a commercial scale without using modern fertilizers and pesticides. On the basis of a 5-year study, it appears that these farmers have more in common with the majority of farmers in the region than with certain stereotypes of organic farmers. Their farming practices (other than chemical use), the size and labor requirements of their farms, and the production and profitability they achieve differ from those of conventional farmers by considerably less than might be expected on the basis of the fundamental importance of chemicals in modern agricultural production. Compared to conventional methods, organic methods consume less fossil energy and cause less soil erosion, but have mixed effects on soil nutrient status and grain protein content.


β-Arrestin1 Reduces Oxidative Stress via Nrf2 Activation in the Rostral Ventrolateral Medulla in Hypertension.
Oxidative stress in the rostral ventrolateral medulla (RVLM), a key region for blood pressure (BP) regulation, has been demonstrated to be responsible for the overactivity of the sympathetic nervous system in hypertension and heart failure. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is a key transcription factor that maintains redox homeostasis by governing a broad array of antioxidant genes in response to oxidative stress. β-Arrestin1 is a multifunctional scaffold protein with the ability to interact with diverse signaling molecules independent of G protein-coupled receptors (GPCRs), and its overexpression in the RVLM could reduce BP and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHR). The goal of this study was to investigate whether Nrf2-mediated antioxidative stress is involved in the antihypertensive effect of β-arrestin1 in the RVLM. It was found that the activation level of Nrf2 in the RVLM of SHR was significantly reduced, compared with normotensive Wistar-Kyoko (WKY) rats. Overexpression of β-arrestin1 in the RVLM significantly decreased ROS production and facilitated the Nrf2 activation in the RVLM of SHR, accompanied by upregulating the expression of HO-1 and NQO-1. However, Nrf2 knockdown attenuated the antioxidant effect of β-arrestin1 overexpression in the RVLM by downregulating HO-1 and NQO-1 expression levels. In conclusion, the current results suggested that the antihypertensive effect of β-arrestin1 overexpression in the RVLM is mediated by decreased ROS production, which is associated with Nrf2 activation.


Effect of Heart Structure on Ventricular Fibrillation in the Rabbit: A Simulation Study.
Ventricular fibrillation (VF) is a lethal condition that affects millions worldwide. The mechanism underlying VF is unstable reentrant electrical waves rotating around lines called filaments. These complex spatio-temporal patterns can be studied using both experimental and numerical methods. Computer simulations provide unique insights including high resolution dynamics throughout the heart and systematic control of quantities such as fiber orientation and cellular kinetics that are not feasible experimentally. Here we study filament dynamics using two bi-ventricular 3-D high-resolution rabbit heart geometries, one with detailed fine structure and another without fine structure. We studied filament dynamics using anisotropic and isotropic conductivities, and with four cellular action potential models with different recovery kinetics. Spiral wave dynamics observed in isotropic two-dimensional sheets were not predictive of the behavior in the whole heart. In 2-D the four cell models exhibited stable reentry, meandering spiral waves, and spiral-wave breakup. In the whole heart with fine structure, all simulation results exhibited complex dynamics reminiscent of fibrillation observed experimentally. In the whole heart without fine structure, anisotropy acted to destabilize filament dynamics although the number of filaments was reduced compared to the heart with structure. In addition, in isotropic hearts without structure the two cell models that exhibited meandering spiral waves in 2-D, stabilized into figure-of-eight surface patterns. We also studied the sensitivity of filament dynamics to computer system configuration and initial conditions. After large simulation times, different macroscopic results sometimes occurred across different system configurations, likely due to a lack of bitwise reproducibility. The study conclusions were insensitive to initial condition perturbations, however, the exact number of filaments over time and their trends were altered by these changes. In summary, we present the following new results. First, we provide a new cell model that resembles the surface patterns of VF in the rabbit heart both qualitatively and quantitatively. Second, filament dynamics in the whole heart cannot be predicted from spiral wave dynamics in 2-D and we identified anisotropy as one destabilizing factor. Third, the exact dynamics of filaments are sensitive to a variety of factors, so we suggest caution in their interpretation and their quantitative analyses.