Assessing the vulnerability of traditional maize seed systems in Mexico to climate change.
Climate change is predicted to have major impacts on small-scale farmers in Mexico whose livelihoods depend on rain-fed maize. We examined the capacity of traditional maize seed systems to provide these farmers with appropriate genetic material under predicted agro-ecological conditions associated with climate change. We studied the structure and spatial scope of seed systems of 20 communities in four transects across an altitudinal gradient from 10-2,980 m above sea level in five states of eastern Mexico. Results indicate that 90% of all of the seed lots are obtained within 10 km of a community and 87% within an altitudinal range of ±50 m but with variation across four agro-climate environments: wet lowland, dry lowland, wet upper midlatitude, and highlands. Climate models suggest a drying and warming trend for the entire study area during the main maize season, leading to substantial shifts in the spatial distribution patterns of agro-climate environments. For all communities except those in the highlands, predicted future maize environments already are represented within the 10-km radial zones, indicating that in the future farmers will have easy access to adapted planting material. Farmers in the highlands are the most vulnerable and probably will need to acquire seed from outside their traditional geographical ranges. This change in seed sources probably will entail important information costs and the development of new seed and associated social networks, including improved linkages between traditional and formal seed systems and more effective and efficient seed-supply chains. The study has implications for analogous areas elsewhere in Mexico and around the world.


Does Personality Moderate the Effects of Mindfulness Training for Medical and Psychology Students?
The majority of mindfulness research to date has reported only on the group-level effects of interventions. Therefore, there is a need to better understand who is most likely to benefit from mindfulness interventions. This study reports on moderation analyses from a two-centre randomised controlled trial of mindfulness-based stress reduction (MBSR) among 288 medical and psychology students. The study investigated whether baseline personality factors (neuroticism, conscientiousness and extroversion) and baseline mindfulness moderated effects on mental distress, study stress and subjective well-being measured after the intervention. An increased effect of the intervention on mental distress and subjective well-being was found in students with higher scores on neuroticism. Students with higher scores on conscientiousness showed an increased effect of mindfulness training on study stress. The training protected students against an increase in mental distress and study stress and a decrease in subjective well-being that was seen in the control group. Baseline mindfulness and extroversion did not moderate the effects of the intervention on the outcomes. The majority of the 288 medical and psychology students in the study sample were female. Female participants scored significantly higher on neuroticism and conscientiousness, and they may therefore be an important target group for mindfulness interventions among students.


Newborn screening for fragile X syndrome.
Fragile X syndrome (FXS), caused by a trinucleotide expansion (>200 CGG repeats) in the fragile X mental retardation gene (FMR1), is currently not included in newborn screening (NBS) panels in the United States as it does not meet the standards for recommendation. Although in the past few years FXS has met many of the criteria for population screening and studies have shown that NBS for FXS is feasible, the idea is still controversial and the debate is open. The recent advances in genomic testing as well as groundbreaking advances in targeted treatment for FXS have been challenging the dogma and principle of the national NBS program: screen only if you can intervene. Arguments in favor of NBS include benefits of early intervention and follow-up for the identified baby, which would justify NBS even in the absence of medical benefit to the child. In addition, the extended family members may benefit from genetic and reproductive counseling, informed decision making before a subsequent pregnancy, and access to treatment and services. However, communicating the results and the potential consequences to families is a challenge and could lead to a heavy psychosocial burden. A controversial issue is the identification of premutation carriers (55-200 CGG repeats), because it not only can lead to information on the reproductive possibility of having a child with FXS but also leads to information about personal health risks associated with the premutation. Yet, knowledge of carrier status could stimulate and encourage lifestyle changes and preventive measures likely to reduce the risk of medical problems reported in premutation carriers. If NBS for FXS is developed, it must be carried out with clear awareness of the potential impact on the lives of the children, and it should be done after counseling and parents' informed consent. Importantly, the infrastructure to support testing, counseling, treatment, and follow-up will have to be made available to the families.


A key region in the human parietal cortex for processing proprioceptive hand feedback during reaching movements.
Seemingly effortless, we adjust our movements to continuously changing environments. After initiation of a goal-directed movement, the motor command is under constant control of sensory feedback loops. The main sensory signals contributing to movement control are vision and proprioception. Recent neuroimaging studies have focused mainly on identifying the parts of the posterior parietal cortex (PPC) that contribute to visually guided movements. We used event-related TMS and force perturbations of the reaching hand to test whether the same sub-regions of the left PPC contribute to the processing of proprioceptive-only and of multi-sensory information about hand position when reaching for a visual target. TMS over two distinct stimulation sites elicited differential effects: TMS applied over the posterior part of the medial intraparietal sulcus (mIPS) compromised reaching accuracy when proprioception was the only sensory information available for correcting the reaching error. When visual feedback of the hand was available, TMS over the anterior intraparietal sulcus (aIPS) prolonged reaching time. Our results show for the first time the causal involvement of the posterior mIPS in processing proprioceptive feedback for online reaching control, and demonstrate that distinct cortical areas process proprioceptive-only and multi-sensory information for fast feedback corrections.


American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines.
The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.


Physical interventions to interrupt or reduce the spread of respiratory viruses.
Viral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a world-wide threat. Antiviral drugs and vaccinations may be insufficient to prevent catastrophe. To systematically review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2); MEDLINE (1966 to May 2009); OLDMEDLINE (1950 to 1965); EMBASE (1990 to May 2009); and CINAHL (1982 to May 2009). We scanned 2958 titles, excluded 2790 and retrieved the full papers of 168 trials, to include 59 papers of 60 studies. We included any physical interventions (isolation, quarantine, social distancing, barriers, personal protection and hygiene) to prevent transmission of respiratory viruses. We included the following study designs: randomised controlled trials (RCTs), cohorts, case controls, cross-over, before-after, and time series studies. We used a standardised form to assess trial eligibility. RCTs were assessed by: randomisation method; allocation generation; concealment; blinding; and follow up. Non-RCTs were assessed for the presence of potential confounders, and classified into low, medium, and high risks of bias. The risk of bias for the four RCTs, and most cluster RCTs, was high. The observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis.The highest quality cluster RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Additional benefit from reduced transmission from children to other household members is broadly supported in results of other study designs, where the potential for confounding is greater. Six case-control studies suggested that implementing barriers to transmission, isolation, and hygienic measures are effective at containing respiratory virus epidemics. We found limited evidence that N95 respirators were superior to simple surgical masks, but were more expensive, uncomfortable, and caused skin irritation. The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease respiratory disease remains uncertain. Global measures, such as screening at entry ports, were not properly evaluated. There was limited evidence that social distancing was effective especially if related to the risk of exposure. Many simple and probably low-cost interventions would be useful for reducing the transmission of epidemic respiratory viruses. Routine long-term implementation of some of the measures assessed might be difficult without the threat of a looming epidemic.


Nursing students' perception of the quality of clinical learning: a mixed methods inquiry.
As part of the Nursing Degree Course, the "internship" period represents a strategic lever to systemize the fundamental combination of theoretical study and nursing practice. However, only a few studies have examined in depth students' perception of this experience. The aim of the study was to assess the quality of the places in which the University of Parma's Nursing students did their internships based on their experience. Through a quantitative and qualitative study, students who had completed at least one clinical internship (n.200) were asked to fill out a self-report questionnaire on the quality of learning using the CLEQUEI scale (1) and answer a few social and demographical questions. In addition to the questionnaire, 24 narrative interviews (semi-structured) were conducted; these interviews deepened the significance of the assigned internship experience. Throughout all the clinical contexts that were analyzed, the dimension of the perceived quality of the internship averaged a value ≥ 44 (the minimum cut-off indicating the presence of necessary elements to promote the processes of quality clinical learning). The perceived quality dimension particularly stands out in the Pediatric Area, in which it amounted to a mean value of 66 (close to the maximum cut-off value of > 66). This result indicates the opportunity to further develop the processes used in students' quality clinical learning. The latter describe the internship as a moment of both personal and professional growth of fundamental importance in one's own training process. Overall, the University of Parma's Nursing students have a good perception of the quality of clinical learning. The significance of assigned internship presents some elements which are a relevant part of the new paradigm. However, there are still some aspects which need improvement, such as the necessity to reevaluate certain parts of the teaching organization of the professionalizing activities and of the clinical internships throughout the duration of the three-year course.


Shoulder complaints more likely in volleyball players with a thickened bursa or supraspinatus tendon neovessels.
Shoulder problems are common in volleyball and greatly impede both training and player performance. Subacromial bursa (SAB) thickening and tendon neovascularity have shown relevance in other populations, but their relationship with the development of shoulder complaints has not been investigated in volleyball players or overhead-throwing athletes. The study aim was to examine the role of SAB thickness, neovascularization of the supraspinatus tendon, shoulder strength, range of motion (ROM), player position, and age in the development of shoulder complaints in professional volleyball players. Players underwent preseason baseline testing (n = 86) and reported shoulder complaints during the subsequent 12-week period. Generalized estimating equations were used to model for probabilities of complaints after adjusting for player position, SAB side-to-side difference, neovessel presence, shoulder external rotation (ER) ROM, and age. Outside hitters and opposites were 12.2-fold more likely to develop complaints, and greater shoulder ER ROM increased risk by 8% for each additional degree. A side-to-side difference in SAB thickness ≥0.3 mm in the dominant compared with the non-dominant arm was associated with a 10.2-fold increased risk. Those with neovessels were 6.5 times more likely to develop complaints. Players without neovessels and with normal SAB thickness were very unlikely to develop complaints. This stark contrast to players with neovessels or increased SAB thickness, where nearly half of the players developed complaints, is of interest. Players with current complaints at baseline presented with greater IR:ER strength ratios; however, neither strength nor IR ROM at baseline was associated with an increased risk of developing complaints.


Involvement of novel human immunodeficiency virus type 1 reverse transcriptase mutations in the regulation of resistance to nucleoside inhibitors.
We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naïve patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L+L210W+T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N+K70R+K219Q+T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs.


Kerr-lens-mediated dynamics of two nonlinearly coupled mode-locked laser oscillators.
The dynamics of two nonlinearly coupled femtosecond oscillators are investigated for the case where two distinct nonlinear mechanisms are balanced to determine the temporal relationship and properties of the pulses in the two oscillators. In the time domain the shared bleaching of a common absorber creates an attractive mechanism for the pulses, while interactive Kerr lens deflections create a repulsive mechanism. The interplay of these two mechanisms causes a variety of dynamical behaviors, including pulse synchronization, pulse duration switching, and a latching type of amplitude bistability.


A Public Program to Evaluate Commercial Soybean Cultivars for Pathogen and Pest Resistance.
The soybean crop is one of the most important crops worldwide, as the seeds are used for both protein meal and vegetable oil. Soybean acreage covers an estimated 6% of the arable land in the world, and since the 1970s, soybean has had the highest percent increase of hectares in production compared to any other major crop. As demand for soybean continues to rise, the production area and worldwide trade are likely to increase. Biotic constraints, such as pathogens, pests, and weeds, can be detrimental to soybean production, causing significant negative impacts to yield. To successfully reduce losses caused by pathogens and pests, various practices such as cultural and seed sanitation techniques, pesticide applications, and deployment of resistance are used. For many years, public institutions have conducted regional yield trials on both private and public sector soybean cultivars. In Illinois, the University of Illinois Variety Testing Program created a public database for growers. Prompted in part by disease reports on cultivars entered into the Variety Testing Program, the Illinois Soybean Association began providing funds in 1998 to obtain additional information from regional trials to benefit growers in the state. The researchers in the Soybean Variety Testing Program conduct replicated field trials and evaluate these plots for agronomic characteristics such as height, lodging, maturity, and yield. In addition to standard yield trial data, protein and oil content are analyzed.


Self-medication in nursing mothers and its influence on the duration of breastfeeding.
To investigate the practice of self-medication by nursing mothers, the main drugs used and the influence on the duration of breastfeeding. A longitudinal cohort study involving 246 women seen at the maternity unit of Hospital Manoel Gonçalves in Itaúna, state of Minas Gerais, Brazil. A monthly follow-up of mothers and newborns was performed for the first 12 months postpartum or until weaning. The effect of the practice of self-medication on the duration of breastfeeding was evaluated by multivariate analysis using Cox's regression model with time-dependent variables. Self-medication was practiced by 52.4% of the nursing mothers. The most used pharmacological classes were: analgesics/antipyretics (54.5%), non-steroidal anti-inflammatories (15%), spasmolytics (6.2%), laxatives (3.5%), benzodiazepines (3%), nasal decongestants (1.4%), and antibiotics (0.9%). The most used drugs were dipyrone (31.5%) and paracetamol (17.9%). The practice of self-medication was associated with a higher probability of the use of drugs posing the risk of adverse effects for the infant or for lactation (p = 0.000). However, the practice of self-medication was not associated with weaning (p = 0.135). The high rates of self-medication among nursing mothers and the use of drugs posing risks of undesirable effects for the infant and for lactation reveal the need for better education on the risks of self-medication by nursing mothers. However, self-medication was not proven to be a risk factor for weaning.


A science that knows no country: Pandemic preparedness, global risk, sovereign science.
This paper examines political norms and relationships associated with governance of pandemic risk. Through a pair of linked controversies over scientific access to H5N1 flu virus and genomic data, it examining the duties, obligations, and allocations of authority articulated around the imperative for globally free-flowing information and around the corollary imperative for a science that is set free to produce such information. It argues that scientific regimes are laying claim to a kind of sovereignty, particularly in moments where scientific experts call into question the legitimacy of claims grounded in national sovereignty, by positioning the norms of scientific practice, including a commitment to unfettered access to scientific information and to the authority of science to declare what needs to be known, as essential to global governance. Scientific authority occupies a constitutional position insofar as it figures centrally in the repertoire of imaginaries that shape how a global community is imagined: what binds that community together and what shared political commitments, norms, and subjection to delegated authority are seen as necessary for it to be rightly governed.


Predicting acute contact toxicity of pesticides in honeybees (Apis mellifera) through a k-nearest neighbor model.
Ecological risk assessment of plant protection products (PPPs) requires an understanding of both the toxicity and the extent of exposure to assess risks for a range of taxa of ecological importance including target and non-target species. Non-target species such as honey bees (Apis mellifera), solitary bees and bumble bees are of utmost importance because of their vital ecological services as pollinators of wild plants and crops. To improve risk assessment of PPPs in bee species, computational models predicting the acute and chronic toxicity of a range of PPPs and contaminants can play a major role in providing structural and physico-chemical properties for the prioritisation of compounds of concern and future risk assessments. Over the last three decades, scientific advisory bodies and the research community have developed toxicological databases and quantitative structure-activity relationship (QSAR) models that are proving invaluable to predict toxicity using historical data and reduce animal testing. This paper describes the development and validation of a k-Nearest Neighbor (k-NN) model using in-house software for the prediction of acute contact toxicity of pesticides on honey bees. Acute contact toxicity data were collected from different sources for 256 pesticides, which were divided into training and test sets. The k-NN models were validated with good prediction, with an accuracy of 70% for all compounds and of 65% for highly toxic compounds, suggesting that they might reliably predict the toxicity of structurally diverse pesticides and could be used to screen and prioritise new pesticides.


Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions.
Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective. The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes.


High-throughput knockout screen in fission yeast.
We have designed the most efficient strategy to knock out genes in fission yeast Schizosaccharomyces pombe on a large scale. Our technique is based on knockout constructs that contain regions homologous to the target gene cloned into vectors carrying dominant drug-resistance markers. Most of the steps are carried out in a 96-well format, allowing simultaneous deletion of 96 genes in one batch. Based on our knockout technique, we designed a strategy for cloning knockout constructs for all predicted fission yeast genes, which is available in a form of a searchable database http://mendel.imp.ac.at/Pombe_deletion/. We validated this technique in a screen where we identified novel genes required for chromosome segregation during meiosis. Here, we present our protocol with detailed instructions. Using this protocol, one person can knock out 96 S. pombe genes in 8 days.


Asthma discordance in twins is linked to epigenetic modifications of T cells.
T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.


Beta-lactamase: an ideal reporter system for monitoring gene expression in live eukaryotic cells.
To gain insightful information about the mechanisms through which genes are activated and repressed requires gene reporter systems that are sensitive, robust, and cost-effective. Although numerous reporter gene technologies are commercially available, none are as sophisticated and user-friendly as beta-lactamase (BLA) when it comes to studying gene expression in live cells. This article presents an overview of the BLA technology and describes how it can be exploited for studying rare events such as homologous recombination in somatic cells and be used to deliver any DNA sequence of choice anywhere within the genome.


A qualitative analysis of the benefits of strength training for young people with cerebral palsy.
This qualitative study investigated the positive and negative outcomes of a home-based strength-training programme for young people with cerebral palsy (CP). Eleven young people with spastic diplegic CP (seven females, four males; mean age 12 years 9 months, SD 2 years 10 months; range 8 to 18 years) and their parents were interviewed. Gross Motor Function Classification System scores ranged from I (walks without limitations) to III (walks with assistive device), with a mode of III. The strength-training programme, which was conducted in the participants' homes three times per week for 6 weeks (total of 18 prescribed sessions), comprised three exercises targeting the major support muscles of the lower limbs. Exercises were bilateral half squats, heel raises, and step-ups. The training load was increased by adding free weights to a backpack so that 8 to 10 repetitions of each exercise could be performed. Using thematic coding, three categories of outcome emerged: body function and structure, activity, and participation, which were influenced by environmental and personal contextual factors. The programme generated overwhelmingly positive outcomes with only minor negative responses about some equipment and the need for parental involvement. Benefits included perceptions that strength, flexibility, posture, walking, and the ability to negotiate steps had improved. In addition, participants reported psychological benefits such as a feeling of increased well-being and improved participation in school and leisure activities. The contextual factors highlighted the fact that sufficient clinician resources must be allocated to solve individual exercise and equipment problems. As well as providing further evidence that strength training can be beneficial, this study provides useful indicators to guide future quantitative studies of outcomes that are meaningful for people with CP.


In vivo therapy of a murine B cell tumor (BCL1) using antibody-ricin A chain immunotoxins.
Prolonged remissions were induced in mice bearing advanced BCL1 tumors by the combined approach of nonspecific cytoreductive therapy and administration of a tumor-reactive immunotoxin. Thus, the vast majority of the tumor cells (approximately 95%) were first killed by nonspecific cytoreductive therapy using total lymphoid irradiation (TLI) and splenectomy. The residual tumor cells were then eliminated by intravenous administration of an anti-delta immunotoxin. In three of four experiments, all animals treated in the above fashion appeared tumor free 12-16 wk later. In one experiment, blood cells from the mice in remission were transferred to normal BALB/c recipients, and the latter animals have not developed detectable tumor for the 6 mo of observation. Because 1-10 adoptively transferred BCL1 cells will cause tumor in normal BALB/c mice by 12 wk, the inability to transfer tumor to recipients might indicate that the donor animals were tumor free. In the remainder of the animals treated with the tumor-reactive immunotoxin there was a substantial remission in all animals, but the disease eventually reappeared. In contrast, all mice treated with the control immunotoxin or antibody alone relapsed significantly earlier (3-4 wk after splenectomy).


FGF21 is dispensable for hypothermia induced by fasting in mice.
Fibroblast growth factor 21 (FGF21) is a key metabolic regulator that is induced by peroxisome proliferator-activated receptor alpha (PPARalpha) activation in response to fasting. We recently reported that bezafibrate, a pan-agonist of PPARs, decreases body temperature late at night through hypothalamic neuropeptide Y (NPY) activation and others have shown that mice overexpressing FGF21 are prone to torpor. We examined whether FGF21 is essential for fasting-induced hypothermia using FGF21 knockout (KO) mice. Acute fasting decreased body temperature late at night accompanied by the induction of hepatic FGF21 and hypothalamic NPY expression in wild-type mice. A deficiency of FGF21 affected neither fasting-induced hypothermia nor hypothalamic NPY induction. Fasting enhanced locomotor activity in both genotypes. On the other hand, a deficiency of FGF21 significantly attenuated chronic hypothermia and hypoactivity induced by a ketogenic diet (KD). Our findings suggest that FGF21 is not essential for the hypothermia that is associated with the early stages of fasting, although it might be involved in the adaptive response of body temperature to chronic starvation.


Whole-Body Biodistribution and Dosimetry of the Dopamine Transporter Radioligand 18F-FE-PE2I in Human Subjects.
18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane (18F-FE-PE2I) was recently developed and has shown adequate affinity and high selectivity for the dopamine transporter (DAT). Previous studies have shown promising results for 18F-FE-PE2I as a suitable radioligand for DAT imaging. In this study, we investigated the whole-body biodistribution and dosimetry of 18F-FE-PE2I in healthy volunteers to support its utility as a suitable PET imaging agent for the DAT. Methods: Five healthy volunteers were given a mean activity of 2.5 MBq/kg, and 3 PET scans, head to thigh, were performed immediately after injection followed by 4 whole-body PET/CT scans between 0.5 and 6 h after injection. Blood samples were drawn in connection with the whole-body scans, and all urine was collected until 6 h after injection. Volumes of interest were delineated around 17 organs on all images, and the areas under the time-activity curves were calculated to obtain the total number of decays in the organs. The absorbed doses to organs and the effective dose were calculated using the software IDAC. Results: The highest activity concentration was observed in the liver (0.9%-1.2% injected activity/100 g) up to 30 min after injection. At later time points, the highest concentration was seen in the gallbladder (1.1%-0.1% injected activity/100 g). The activity excreted with urine ranged between 23% and 34%, with a mean of 28%. The urinary bladder received the highest absorbed dose (119 μGy/MBq), followed by the liver (46 μGy/MBq). The effective dose was 23 μSv/MBq (range, 19-28 μSv/MBq), resulting in an effective dose of 4.6 mSv for an administered activity of 200 MBq. Conclusion: The effective dose is within the same order of magnitude as other commonly used PET imaging agents as well as DAT agents. The reasonable effective dose, together with the previously reported favorable characteristics for DAT imaging and quantification, indicates that 18F-FE-PE2I is a suitable radioligand for DAT imaging.


Understanding Drivers of Resistance Toward Implementation of Web-Based Self-Management Tools in Routine Cancer Care Among Oncology Nurses: Cross-Sectional Survey Study.
Supporting patients to engage in (Web-based) self-management tools is increasingly gaining importance, but the engagement of health care professionals is lagging behind. This can partly be explained by resistance among health care professionals. The aim of this study was to investigate drivers of resistance among oncology nurses toward Web-based self-management tools in cancer care. Drawing from previous research, combining clinical and marketing perspectives, and several variables and instruments, we developed the Resistance to Innovation model (RTI-model). The RTI-model distinguishes between passive and active resistance, which can be enhanced or reduced by functional drivers (incompatibility, complexity, lack of value, and risk) and psychological drivers (role ambiguity, social pressure from the institute, peers, and patients). Both types of drivers can be moderated by staff-, organization-, patient-, and environment-related factors. We executed a survey covering all components of the RTI-model on a cross-sectional sample of nurses working in oncology in the Netherlands. Structural equation modeling was used to test the full model, using a hierarchical approach. In total, 2500 nurses were approached, out of which 285 (11.40%) nurses responded. The goodness of fit statistic of the uncorrected base model of the RTI-model (n=239) was acceptable (χ21=9.2; Comparative Fit Index=0.95; Tucker Lewis index=0.21; Root Mean Square Error of Approximation=0.19; Standardized Root Mean Square=0.016). In line with the RTI-model, we found that both passive and active resistance among oncology nurses toward (Web-based) self-management tools were driven by both functional and psychological drivers. Passive resistance toward Web-based self-management tools was enhanced by complexity, lack of value, and role ambiguity, and it was reduced by institutional social pressure. Active resistance was enhanced by complexity, lack of value, and social pressure from peers, and it was reduced by social pressure from the institute and patients. In contrast to what we expected, incompatibility with current routines was not a significant driver of either passive or active resistance. This study further showed that these drivers of resistance were moderated by expertise (P=.03), managerial support (P=.004), and influence from external stakeholders (government; P=.04). Both passive and active resistance in oncology nurses toward Web-based self-management tools for patients with cancer are driven by functional and psychological drivers, which may be more or less strong, depending on expertise, managerial support, and governmental influence.


Molecular ecological analysis of porcine ileal microbiota responses to antimicrobial growth promoters.
Cultivation-independent microbial molecular ecology approaches were used to examine the effects of antibiotic growth promoters on the pig ileal microbiota. Five-week-old barrows were fitted with a simple T-cannula at the distal ileum. Three diets meeting or exceeding the minimum nutrient requirements were fed for 5 wk and supplemented as follows: 1) negative control (no antibiotic; n = 5), 2) continuous tylosin administration (n = 5), and 3) an antibiotic rotation sequence (wk 1, chlorotetracycline sulfathiazole penicillin; wk 2, bacitracin and roxarsone; wk 3, lincomycin; wk 4, carbadox; wk 5, virginiamycin; n = 5). Ileal luminal contents were collected for DNA isolation at the end of each of the 5 wk of the testing period. The V3 region of 16S rDNA was amplified by PCR and analyzed via denaturing gradient gel electrophoresis (DGGE) and quantitative polymerase chain reaction (qPCR). Resulting PCR-DGGE band numbers (bacterial species) were counted, and the banding patterns analyzed by calculating Sorenson's pairwise similarity coefficients (C(S)), an index measuring bacterial species in common among samples. Band numbers and total bacterial DNA concentrations decreased (P < 0.05) temporally in antibiotic-treated pigs compared with controls. Comparisons between treatments yielded low intertreatment C(S) indices, indicating treatment-dependent alterations in banding patterns, whereas intratreatment comparisons revealed increased homogeneity in antibiotic-treated vs. control pigs. Sequence analysis of treatment-specific bands identified three Lactobacillus, one Streptococcus, and one Bacillus species that were diminished with antibiotic rotation treatment, whereas tylosin selected for the presence of L. gasseri. Lactobacillus-specific qPCR was performed and analyzed as a percentage of total bacteria to further evaluate the effects of antibiotic administration on this genus. Total bacteria were decreased (P < 0.05) by tylosin and rotation treatments, whereas the percentage of lactobacilli increased (P < 0.05) by d 14 and through d 28 in tylosin-treated pigs. The decrease in total bacteria by antibiotics may reduce host-related intestinal or immune responses, which would divert energy that could otherwise be used for growth. Conversely, the ability of tylosin to improve animal growth may relate to its apparent selection for lactobacilli, commensals known to competitively exclude potentially pathogenic species from colonizing the intestine.


Modification of the aminopyridine unit of 2'-deoxyaminopyridinyl-pseudocytidine allowing triplex formation at CG interruptions in homopurine sequences.
The antigene strategy based on site-specific recognition of duplex DNA by triplex DNA formation has been exploited in a wide range of biological activities. However, specific triplex formation is mostly restricted to homo-purine strands within the target duplex DNA, due to the destabilizing effect of CG and TA inversion sites where there is an absence of natural nucleotides that can recognize the CG and TA base pairs. Hence, the design of artificial nucleosides, which can selectively recognize these inversion sites with high affinity, should be of great significance. Recently, we determined that 2-amino-3-methylpyridinyl pseudo-dC (3MeAP-ΨdC) possessed significant affinity and selectivity toward a CG inversion site and showed effective inhibition of gene expression. We now describe the design and synthesis of new modified aminopyridine derivatives by focusing on small chemical modification of the aminopyridine unit to tune and enhance the selectivity and affinity toward CG inversion sites. Remarkably, we have newly found that 2-amino-4-methoxypyridinyl pseudo-dC (4OMeAP-ΨdC) could selectively recognize the CG base pair in all four adjacent base pairs and form a stable triplex structure against the promoter sequence of the human gene including multiple CG inversion sites.


Quantitative analysis of breast echotexture patterns in automated breast ultrasound images.
Breast tissue composition is considered to be associated with breast cancer risk. This study aimed to develop a computer-aided classification (CAC) system to automatically classify echotexture patterns as heterogeneous or homogeneous using automated breast ultrasound (ABUS) images. A CAC system was proposed that can recognize breast echotexture patterns in ABUS images. For each case, the echotexture pattern was assessed by two expert radiologists and classified as heterogeneous or homogeneous. After neutrosophic image transformation and fuzzy c-mean clusterings, the lower and upper boundaries of the fibroglandular tissues were defined. Then, the number of hypoechoic regions and histogram features were extracted from the fibroglandular tissues, and the support vector machine model with the leave-one-out cross-validation method was utilized as the classifier. The authors' database included a total of 208 ABUS images of the breasts of 104 females. The accuracies of the proposed system for the classification of heterogeneous and homogeneous echotexture patterns were 93.48% (43/46) and 92.59% (150/162), respectively, with an overall Az (area under the receiver operating characteristic curve) of 0.9786. The agreement between the radiologists and the proposed system was almost perfect, with a kappa value of 0.814. The use of ABUS and the proposed method can provide quantitative information on the echotexture patterns of the breast and can be used to evaluate whether breast echotexture patterns are associated with breast cancer risk in the future.


Association of Angiotensin Modulators With the Course of Idiopathic Pulmonary Fibrosis.
Angiotensin peptides have been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Angiotensin modulators are used to treat arterial hypertension, a frequent comorbidity of IPF. This post hoc analysis evaluated associations of antihypertensive treatments with disease-related outcomes in IPF. All patients randomized to placebo (n = 624) in the CAPACITY and ASCEND studies were categorized by antihypertensive treatment at baseline. Outcomes of disease progression (first occurrence of ≥ 10% absolute decline in % predicted FVC, ≥ 50-m decline in 6-min walk distance, or death) and all-cause mortality were assessed over 52 weeks. At baseline, 111 and 121 patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), respectively; 392 were receiving neither. In multivariable analyses adjusted for differences in baseline characteristics compared with the non-ACEi/ARB group, ACEi treatment (hazard ratio [HR], 0.6 [95% CI, 0.4-0.9]; P = .026), but not ARB (HR, 0.9 [95% CI, 0.6-1.2]; P = .413), was associated with slower disease progression. Furthermore, the increase in all-cause mortality associated with cardiovascular disease was not observed in the ACEi group (HR, 1.1 [95% CI, 0.5-2.9]; P = .782), which presented a similar percentage of IPF-related mortality as the non-ACEi/ARB group (3.6% vs 3.6%). In contrast, patients in the ARB group had greater risk of all-cause mortality (HR, 2.5 [95% CI, 1.2-5.2]). These observations were validated in a pooled analysis that included patients from the INSPIRE trial. Prospective clinical trials are needed to evaluate whether angiotensin modulators may be beneficial to clinical outcomes in IPF. ClinicalTrials.gov; Nos.: NCT01366209, NCT00287716, NCT00287729, NCT00075998; URL: www.clinicaltrials.gov).


Changes in air quality and tropospheric composition due to depletion of stratospheric ozone and interactions with climate.
Air pollution will be directly influenced by future changes in emissions of pollutants, climate, and stratospheric ozone, and will have significant consequences for human health and the environment. UV radiation is one of the controlling factors for the formation of photochemical smog, which includes tropospheric ozone (O(3)) and aerosols; it also initiates the production of hydroxyl radicals (˙OH), which control the amount of many climate- and ozone-relevant gases (e.g., methane and HCFCs) in the atmosphere. Numerical models predict that future changes in UV radiation and climate will modify the trends and geographic distribution of ˙OH, thus affecting the formation of photochemical smog in many urban and regional areas. Concentrations of ˙OH are predicted to decrease globally by an average of 20% by 2100, with local concentrations varying by as much as a factor of two above and below current values. However, significant differences between modelled and measured values in a limited number of case studies show that chemistry of hydroxyl radicals in the atmosphere is not fully understood. Photochemically produced tropospheric ozone is projected to increase. If emissions of anthropogenic air pollutants from combustion of fossil fuels, burning of biomass, and agricultural activities continue to increase, concentrations of tropospheric O(3) will tend to increase over the next 20-40 years in certain regions of low and middle latitudes because of interactions of emissions, chemical processes, and climate change. Climate-driven increases in temperature and humidity will also increase production of tropospheric O(3) in polluted regions, but reduce it in more pristine regions. Higher temperatures tend to increase emissions of nitrogen oxides (NO(x)) from some soils and release of biogenic volatile organic compounds (VOCs) from vegetation, leading to greater background concentrations of ozone in the troposphere. The net effects of future changes in UV radiation, meteorological conditions, and anthropogenic emissions may be large, thus posing challenges for prediction and management of air quality. Aerosols composed of organic substances have a major role in both climate and air quality, and contribute a large uncertainty to the energy budget of the atmosphere. These aerosols are mostly formed via the UV-initiated oxidation of VOCs from anthropogenic and biogenic sources, although the details of the chemistry are still poorly understood and current models under-predict their abundance. A better understanding of their formation, chemical composition, and optical properties is required to assess their significance for air quality and to better quantify their direct and indirect radiative forcing of climate. Emissions of compounds containing fluorine will continue to have effects on the chemistry of the atmosphere and on climate change. The HCFCs and HFCs used as substitutes for ozone-depleting CFCs can break down into trifluoroacetic acid (TFA), which will accumulate in oceans, salt lakes, and playas. Based on historical use and projections of future uses, including new products entering the market, such as the fluoro-olefins, increased loadings of TFA in these environmental sinks will be small. Even when added to existing amounts from natural sources, risks to humans or the environment from the historical use of CFCs or continued use of their replacements is judged to be negligible.


How many eggs are needed to produce an assisted reproductive technology baby: is more always better?
To evaluate the association between the number of mature (metaphase II [MII]) oocytes per assisted reproductive technology (ART) cycle and the likelihood of live birth. Retrospective study. Academic infertility practice. Seven hundred thirty-seven infertile women undergoing their initial fresh embryo, nondonor IVF or intracytoplasmic sperm injection cycle at Montefiore's Institute for Reproductive Medicine and Health between January 2002 and December 2008. None. Live birth. Two hundred twenty-four cycles resulted in a live birth (30.4%). Live birth cycles had significantly more MII oocytes obtained per cycle as compared with their unsuccessful counterparts (11.0 ± 5.9 vs. 9.7 ± 6.2, respectively). Multivariate logistic regression was done to determine the minimum number of MII oocytes per cycle as a predictor of live birth after adjustment for age and historical maximum FSH values. Cycles that included the average number of MII in this cohort were used as a reference group. For cycles with five or fewer MII oocytes obtained, there was a statistically significant decrease in the likelihood of a live birth as compared with the reference group (odds ratio 0.61, 95% confidence interval 0.38-0.99). However, cycles with six or fewer obtained MII oocytes were not less likely to result in a live birth when compared with the reference group (odds ratio 0.69, 95% confidence interval 0.45-1.08). In our cohort, there was an advantage to obtaining six or more MII oocytes during the fresh oocyte retrieval compared with five or fewer oocytes. There was not an advantage, however, to obtaining 10 or more or 15 or more oocytes as compared with obtaining 6-9 oocytes. The strategy of aiming for a greater number of oocytes in an ART cycle should be revisited.


Utilization of preoperative endoscopic ultrasound for pancreatic adenocarcinoma.
Endoscopic ultrasound (EUS) is used for pancreatic adenocarcinoma staging and obtaining a tissue diagnosis. The objective was to determine patterns of preoperative EUS and the impact on downstream treatment. The Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database was used to identify patients with pancreatic adenocarcinoma. The staging period was the first staging procedure within 6 months of surgery until surgery. Logistic regression was used to determine factors associated with preoperative EUS. The main outcome was EUS in the staging period, with secondary outcomes including number of staging tests and time to surgery. 2782 patients were included, 56% were treated at an academic hospital (n = 1563). 1204 patients underwent EUS (43.3%). The factors most associated with receipt of EUS were: earlier year of diagnosis, SEER area, and a NCI or academic hospital (all p < 0.0001). EUS was associated with a longer time to surgery (17.8 days; p < 0.0001), and a higher number of staging tests (40 tests/100 patients; p < 0.0001). Factors most associated with receipt of EUS are geographic, temporal, and institutional, rather than clinical/disease factors. EUS is associated with a longer time to surgery and more preoperative testing, and additional study is needed to determine if EUS is overused.


[High effectiveness of the method with cefpirome in detection of extended-spectrum beta-lactamases in different species of gram-negative bacilli].
Gram-negative bacilli were examined for ESBL production by using four methods: double-disc synergy diffusion test (DDST), and three tests of combined discs with cefpodoxime, ceftazidime and cefotaxime alone and the same cephalosporins with clavulanic acid. Strains determined as ESBL-negative with all these tests were examined by using fifth method with cefpirome. 47,5% from 178 negative in other methods strains, appeared ESBL-positive in this test. The examined strains belonged to 16 different species. Most of them were Enterobacter cloaceae, Serratia marcescens, Pseudomonas aeruginosa and Acinetobacter baumanii. It seems that the combined discs method with cefpirome may be usefull for phenotypic detection of ESBL producing bacteria also in the case of strains where ESBL production is camouflaged with derepressed chromosomal AmpC beta-lactamases.


Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis.
It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≥6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216-0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336-1.017, p = 0.0575). Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.


Legacy of land use history determines reprogramming of plant physiology by soil microbiome.
Microorganisms associated with roots are thought to be part of the so-called extended plant phenotypes with roles in the acquisition of nutrients, production of growth hormones, and defense against diseases. Since the crops selectively enrich most rhizosphere microbes out of the bulk soil, we hypothesized that changes in the composition of bulk soil communities caused by agricultural management affect the extended plant phenotype. In the current study, we performed shotgun metagenome sequencing of the rhizosphere microbiome of the peanut (Arachis hypogaea) and metatranscriptome analysis of the roots of peanut plants grown in the soil with different management histories, peanut monocropping and crop rotation. We found that the past planting record had a significant effect on the assembly of the microbial community in the peanut rhizosphere, indicating a soil memory effect. Monocropping resulted in a reduction of the rhizosphere microbial diversity, an enrichment of several rare species, and a reduced representation of traits related to plant performance, such as nutrients metabolism and phytohormone biosynthesis. Furthermore, peanut plants in monocropped soil exhibited a significant reduction in growth coinciding with a down-regulation of genes related to hormone production, mainly auxin and cytokinin, and up-regulation of genes related to the abscisic acid, salicylic acid, jasmonic acid, and ethylene pathways. These findings suggest that land use history affects crop rhizosphere microbiomes and plant physiology.


An empirical research on relationships between subjective judgement, technology acceptance tendency and knowledge transfer.
The purpose of this study was to explore the relationships among employees' usage intention pertaining to mobile information devices, focusing on subjective judgement, technology acceptance tendency, information sharing behavior and information transfer. A research model was established to verify several hypotheses. The research model based on integrated concepts of knowledge management and technology acceptance modeling. Participants were employees of enterprises in Taiwan, selected by combining snowball and convenience sampling. Data obtained from 779 e-surveys. Multiple-regression analysis was employed for hypothesis verification. The results indicate that perceived ease-of-use of mobile devices was affected by computer self-efficacy and computer playfulness directly; meanwhile, perceived ease-of-use directly affects perceived usefulness. In addition, perceived ease-of-use and perceived usefulness can predict information-sharing behavior in a positive manner, and impact knowledge transfer as well. Based on the research findings, it suggested that enterprises should utilize mobile information devices to create more contact with customers and enrich their service network. In addition, it is recommended that managers use mobile devices to transmit key information to their staff and that they use these devices for problem-solving and decision-making. Further, the staff's skills pertaining to the operation of mobile information devices and to fully implement their features are reinforced in order to inspire the users' knowledge transfer. Enhancing the playfulness of the interface is also important. In general, it is useful to promote knowledge transfer behavior within an organization by motivating members to share information and ideas via mobile information devices. In addition, a well-designed interface can facilitate employees' use of these devices.


Left ventricular assist device-induced reverse remodeling: it's not just about myocardial recovery.
The abnormal structure, function and molecular makeup of dilated cardiomyopathic hearts can be partially normalized in patients supported by a left ventricular assist device (LVAD), a process called reverse remodeling. This leads to recovery of function in many patients, though the rate of full recovery is low and in many cases is temporary, leading to the concept of heart failure remission, rather than recovery. Areas covered: We summarize data indicative of ventricular reverse remodeling, recovery and remission during LVAD support. These terms were used in searches performed in Pubmed. Duplication of topics covered in depth in prior review articles were avoided. Expert commentary: Although most patients undergoing mechanical circulatory support (MCS) show a significant degree of reverse remodeling, very few exhibit sufficiently improved function to justify device explantation, and many from whom LVADs have been explanted have relapsed back to the original heart failure phenotype. Future research has the potential to clarify the ideal combination of pharmacological, cell, gene, and mechanical therapies that would maximize recovery of function which has the potential to improve exercise tolerance of patients while on support, and to achieve a higher degree of myocardial recovery that is more likely to persist after device removal.


X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with alpha-difluoromethylornithine.
Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate (PLP) dependent homodimeric enzyme. It is a recognized drug target against African sleeping sickness, caused by Trypanosoma brucei. One of the currently used drugs, alpha-difluoromethylornithine (DFMO), is a suicide inhibitor of ODC. The structure of the T. brucei ODC (TbODC) mutant K69A bound to DFMO has been determined by X-ray crystallography to 2.0 A resolution. The protein crystallizes in the space group P2(1) (a = 66.8 A, b = 154.5 A, c = 77.1 A, beta = 90.58 degrees ), with two dimers per asymmetric unit. The initial phasing was done by molecular replacement with the mouse ODC structure. The structure of wild-type uncomplexed TbODC was also determined to 2.9 A resolution by molecular replacement using the TbODC DFMO-bound structure as the search model. The N-terminal domain of ODC is a beta/alpha-barrel, and the C-terminal domain of ODC is a modified Greek key beta-barrel. In comparison to structurally related alanine racemase, the two domains are rotated 27 degrees relative to each other. In addition, two of the beta-strands in the C-terminal domain have exchanged positions in order to maintain the location of essential active site residues in the context of the domain rotation. In ODC, the contacts in the dimer interface are formed primarily by the C-terminal domains, which interact through six aromatic rings that form stacking interactions across the domain boundary. The PLP binding site is formed by the C-termini of beta-strands and loops in the beta/alpha-barrel. In the native structure Lys69 forms a Schiff base with PLP. In both structures, the phosphate of PLP is bound between the seventh and eighth strands forming interactions with Arg277 and a Gly loop (residues 235-237). The pyridine nitrogen of PLP interacts with Glu274. DFMO forms a Schiff base with PLP and is covalently attached to Cys360. It is bound at the dimer interface and the delta-carbon amino group of DFMO is positioned between Asp361 of one subunit and Asp332 of the other. In comparison to the wild-type uncomplexed structure, Cys-360 has rotated 145 degrees toward the active site in the DFMO-bound structure. No domain, subunit rotations, or other significant structural changes are observed upon ligand binding. The structure offers insight into the enzyme mechanism by providing details of the enzyme/inhibitor binding site and allows for a detailed comparison between the enzymes from the host and parasite which will aid in selective inhibitor design.


Characteristics and the fate of intraluminal thrombus of the intracranial and extracranial cerebral arteries in acute ischemic stroke patients.
The characteristics and fate of intraluminal thrombus (IT), which may incidentally be detected in acute stroke patients, are not well known and the optimal treatment strategy for IT remains controversial. We have identified patients with IT in either the extracranial or intracranial artery and followed up on their clinical courses and imaging findings. We categorized it based on its morphology and investigated clinical outcomes and fate of IT in those patients. Among 495 patients with acute ischemic stroke, 9 (1.9%, 8 men, age range of 61-84 years) were identified with IT. Patients with IT could be categorized into three groups: a filling defect (4) during digital subtraction angiography (DSA), a stenosis-mimic lesion on DSA (3), and a mobile mass on carotid duplex (2). All patients had follow-up vascular imaging studies. Complete or partial resolution of IT was seen in 8 patients. Four patients developed transient or minor ischemic symptoms, which were potentially related to IT. Stenosis-mimic lesions and IT adjacent to atherosclerotic plaques appeared to be associated with unstable clinical courses. IT can be categorized according to its morphological features. The outcome may depend on the morphology and location of the IT.


Addressing the Mental Health Needs of Latino Children in Immigrant Families.
Latino children in the United States, whether immigrants themselves or children in immigrant families, are at high risk for mental health disorders stemming from poverty, exposure to trauma, assimilation stressors, and discrimination. The timely identification and treatment of mental health disorders in Latino children are compromised by limited healthcare access and quality as well as the lack of routine mental health screening in pediatric primary care. Here we review Spanish-language validity and implementation studies of Bright Futures previsit mental health screening tools and models of care. We identify strengths and weaknesses in the literature and suggest tools for use in mental health care assessment, management, and treatment for Latino children in pediatric primary care. Pediatricians can improve care of Latino children through awareness of risk factors for mental health disorders, integration of evidence-based screening tools, and advocacy for culturally tailored mental health resources.


Oscillatory Correlates of Control over Working Memory Gating and Updating: An EEG Study Using the Reference-back Paradigm.
Optimal working memory (WM) functioning depends on a control mechanism that balances between maintenance and updating by closing or opening the gate to WM, respectively. Here, we examined the neural oscillation correlates of WM updating and of the control processes involved in gating. The reference-back paradigm was employed to manipulate gate opening, gate closing, and updating independently and examine how the control functions involved in these processes are mapped to oscillatory EEG activity. The results established that different oscillatory patterns were associated with the control process related to gate opening than in gate closing. During the time of gate closing, a relative increase in theta power was observed over midfrontal electrodes. This theta response is a known EEG signature of cognitive control that is proposed here to reflect reactive conflict resolution, achieved by closing the gate when facing irrelevant information. On the other hand, proactive gate opening in preparation for relevant information was associated with an increase in relative delta power over parietal-occipital electrodes. Finally, WM updating was associated with relative increase in delta power over midfrontal electrodes, suggesting a functional role of delta oscillations in WM updating.


How long do centenarians survive? Life expectancy and maximum lifespan.
The purpose of this study was to explore the pattern of mortality above the age of 100 years. In particular, we aimed to examine whether Scandinavian data support the theory that mortality reaches a plateau at particularly old ages. Whether the maximum length of life increases with time was also investigated. The analyses were based on individual level data on all Swedish and Danish centenarians born from 1870 to 1901; in total 3006 men and 10 963 women were included. Birth cohort-specific probabilities of dying were calculated. Exact ages were used for calculations of maximum length of life. Whether maximum age changed over time was analysed taking into account increases in cohort size. The results confirm that there has not been any improvement in mortality amongst centenarians in the past 30 years and that the current rise in life expectancy is driven by reductions in mortality below the age of 100 years. The death risks seem to reach a plateau of around 50% at the age 103 years for men and 107 years for women. Despite the rising life expectancy, the maximum age does not appear to increase, in particular after accounting for the increasing number of individuals of advanced age. Mortality amongst centenarians is not changing despite improvements at younger ages. An extension of the maximum lifespan and a sizeable extension of life expectancy both require reductions in mortality above the age of 100 years.


Priming of Hypothalamic Ghrelin Signaling and Microglia Activation Exacerbate Feeding in Rats' Offspring Following Maternal Overnutrition.
Maternal overnutrition during pregnancy leads to metabolic alterations, including obesity, hyperphagia, and inflammation in the offspring. Nutritional priming of central inflammation and its role in ghrelin sensitivity during fed and fasted states have not been analyzed. The current study aims to identify the effect of maternal programming on microglia activation and ghrelin-induced activation of hypothalamic neurons leading to food intake response. We employed a nutritional programming model exposing female Wistar rats to a cafeteria diet (CAF) from pre-pregnancy to weaning. Food intake in male offspring was determined daily after fasting and subcutaneous injection of ghrelin. Hypothalamic ghrelin sensitivity and microglia activation was evaluated using immunodetection for Iba-1 and c-Fos markers, and Western blot for TBK1 signaling. Release of TNF-alpha, IL-6, and IL-1β after stimulation with palmitic, oleic, linoleic acid, or C6 ceramide in primary microglia culture were quantified using ELISA. We found that programmed offspring by CAF diet exhibits overfeeding after fasting and peripheral ghrelin administration, which correlates with an increase in the hypothalamic Iba-1 microglia marker and c-Fos cell activation. Additionally, in contrast to oleic, linoleic, or C6 ceramide stimulation in primary microglia culture, stimulation with palmitic acid for 24 h promotes TNF-alpha, IL-6, and IL-1β release and TBK1 activation. Notably, intracerebroventricular (i.c.v.) palmitic acid or LPS inoculation for five days promotes daily increase in food intake and food consumption after ghrelin administration. Finally, we found that i.c.v. palmitic acid substantially activates hypothalamic Iba-1 microglia marker and c-Fos. Together, our results suggest that maternal nutritional programing primes ghrelin sensitivity and microglia activation, which potentially might mirror hypothalamic administration of the saturated palmitic acid.


Extraordinary Stability of IrO2(110) Ultrathin Films Supported on TiO2(110) under Cathodic Polarization.
Down to a cathodic potentials of -1.20 V versus the reversible hydrogen electrode, the structure of IrO2(110) electrodes supported by TiO2(110) is found to be stable by in situ synchrotron-based X-ray diffraction. Such high cathodic potentials should lead to reduction to metallic Ir (Pourbaix diagram). From the IrO2 lattice parameters, determined during cathodic polarization in a H2SO4 electrolyte solution (pH 0.4), it is estimated that the unit cell volume increases by 1% due likely to proton incorporation, which is supported by the lack of significant swelling of the IrO2(110) film derived from X-ray reflectivity experiments. Ex situ X-ray photoelectron spectroscopy suggests that protons are incorporated into the IrO2(110) lattice below -1.0 V, although Ir remains exclusively in the IV+ oxidation state down to -1.20 V. Obviously, further hydrogenation of the lattice oxygen of IrO2(110) toward water is suppressed for kinetic reasons and hints at a rate-determining chemical step that cannot be controlled by the electrode potential.


Full bandwidth dynamic coarse integral holographic displays with large field of view using a large resonant scanner and a galvanometer scanner.
An efficient method to implement the coarse integral holographic (CIH) concept for dynamic CIH displays is to scan the information generated from a spatial light modulator (SLM) of a low space bandwidth product (SBP) but high bandwidth to form the hologram array for the integral optics. Previously, just over half of the SLMs bandwidth was utilized due to the fact that the galvanometer scanner in use could not tile all the holograms that the SLM is capable to produce, resulting in the loss of nearly half of the field of view (FOV). Here, we propose a full bandwidth dynamic CIH display using a large resonant scanner in conjunction with a hybrid raster scanner, which can utilize the full bandwidth of the spatial light modulator and double the horizontal FOV. Experimental results confirm that with the SLM and scanners as used, the FOV can reach 48° when the SLM reaches its full bandwidth. This approach can be used for future scalable and tileable CIH display systems.


Coherent population trapping in diamond N-V centers at zero magnetic field.
Coherent population trapping at zero magnetic field was observed for nitrogen-vacancy centers in diamond under optical excitation. This was measured as a reduction in photoluminescence when the detuning between two excitation lasers matched the 2.88 GHz crystal-field splitting of the color center ground states. This behavior is highly sensitive to strain, which modifies the excited states, and was unexpected following recent experiments demonstrating optical readout of single nitrogen-vacancy electron spins based on cycling transitions. These results demonstrate for the first time that three-level Lambda configurations suitable for proposed quantum information applications can be realized simultaneously for all four orientations of nitrogen-vacancy centers at zero magnetic field.


Further development of an Australian-based measure of social capital in a US sample.
Social capital is an increasingly popular construct in research examining social and behavioral determinants of health and well-being. Yet, comparing the results of social capital research is inhibited by inconsistencies in labeling, different definitions and subsequent disagreement on level of analysis, and limited evaluation of the psychometric properties of measures of social capital. This study examined the psychometric properties of the Social Capital Questionnaire (Journal of Applied Behavioral Science 36(1) (2000) 23). In the current study, the original Australian-based instrument was modified for telephone administration with a US sample. Exploratory factor analysis revealed a similar factor structure to that found during initial survey development. These findings lend support to the notion of social capital as a meaningful construct and suggest the Onyx and Bullen instrument deserves further attention as a practical tool for health researchers and community agencies interested in social capital.


Clinical predictive circulating peptides in rectal cancer patients treated with neoadjuvant chemoradiotherapy.
Preoperative chemoradiotherapy is worldwide accepted as a standard treatment for locally advanced rectal cancer. Current standard of treatment includes administration of ionizing radiation for 45-50.4 Gy in 25-28 fractions associated with 5-fluorouracil administration during radiation therapy. Unfortunately, 40% of patients have a poor or absent response and novel predictive biomarkers are demanding. For the first time, we apply a novel peptidomic methodology and analysis in rectal cancer patients treated with preoperative chemoradiotherapy. Circulating peptides (Molecular Weight <3 kDa) have been harvested from patients' plasma (n = 33) using nanoporous silica chip and analyzed by Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometer. Peptides fingerprint has been compared between responders and non-responders. Random Forest classification selected three peptides at m/z 1082.552, 1098.537, and 1104.538 that were able to correctly discriminate between responders (n = 16) and non-responders (n = 17) before therapy (T0) providing an overall accuracy of 86% and an area under the receiver operating characteristic (ROC) curve of 0.92. In conclusion, the nanoporous silica chip coupled to mass spectrometry method was found to be a realistic method for plasma-based peptide analysis and we provide the first list of predictive circulating biomarker peptides in rectal cancer patients underwent preoperative chemoradiotherapy.


Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure.
Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.


Improving self-care of patients with chronic disease using online personal health record.
Effective management of chronic diseases such as prostate cancer is important. Research suggests a tendency to use self-care treatment options such as over-the-counter (OTC) complementary medications among prostate cancer patients. The current trend in patient-driven recording of health data in an online Personal Health Record (PHR) presents an opportunity to develop new data-driven approaches for improving prostate cancer patient care. However, the ability of current online solutions to share patients' data for better decision support is limited. An informatics approach may improve online sharing of self-care interventions among these patients. It can also provide better evidence to support decisions made during their self-managed care. To identify requirements for an online system and describe a new case-based reasoning (CBR) method for improving self-care of advanced prostate cancer patients in an online PHR environment. A non-identifying online survey was conducted to understand self-care patterns among prostate cancer patients and to identify requirements for an online information system. The pilot study was carried out between August 2010 and December 2010. A case-base of 52 patients was developed. The data analysis showed self-care patterns among the prostate cancer patients. Selenium (55%) was the common complementary supplement used by the patients. Paracetamol (about 45%) was the commonly used OTC by the patients. The results of this study specified requirements for an online case-based reasoning information system. The outcomes of this study are being incorporated in design of the proposed Artificial Intelligence (Al) driven patient journey browser system. A basic version of the proposed system is currently being considered for implementation.


Cost Effectiveness of Neonatal Resuscitation at 22 Weeks of Gestation.
To evaluate the cost effectiveness of three different approaches to the care of neonates born at 22 weeks of gestation: universal resuscitation, selective resuscitation, or no resuscitation. We constructed a decision-analytic model using TreeAge to compare the outcomes of death and survival with and without neurodevelopmental impairment in a theoretical cohort of 5,176 neonates (an estimate of the annual number of deliveries that occur in the 22nd week of gestation in the United States). We took a societal perspective using a lifetime horizon, and all costs were expressed in 2017 U.S. dollars. Effectiveness was based on combined maternal and neonatal quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio was determined (cost/QALY) for each additional survivor. The willingness to pay threshold was set at $100,000/QALY. All model inputs were derived from the literature. Deterministic and probabilistic sensitivity analyses were performed to interrogate model assumptions. Universal resuscitation would result in 373 survivors, 123 of whom would have severe disability. Selective resuscitation would produce 78 survivors with 26 affected by severe impairments. No resuscitation would result in only eight survivors and three neonates with severe sequelae. Selective resuscitation was eliminated by extended dominance because this strategy had a higher incremental cost-effectiveness ratio than universal resuscitation, which was a more effective intervention. The incremental cost-effectiveness ratio of universal resuscitation compared with no resuscitation was not cost effective at $106,691/QALY. Monte Carlo simulations demonstrated that universal resuscitation is more effective but also more expensive compared with no resuscitation, with only 35% of simulations below the willingness to pay threshold. In our model, neither selective nor universal resuscitation of 22-week neonates is a cost-effective strategy compared with no resuscitation.


Excited state proton transfer dynamics of Topotecan inside biomimicking nanocavity.
The excited state proton transfer (ESPT) dynamics of a potentially important anticancer drug, Topotecan (TPT), has been explored in aqueous reverse micelle (RM) using steady-state and time-resolved fluorescence measurements. Both the time-resolved emission spectrum and time-resolved area normalized emission spectrum infer the generation of excited state zwitterionic form of TPT from the excited state cationic form of TPT, as a result of ESPT process from the -OH group of TPT to the nearby water molecule. The ESPT dynamics were found to be severely retarded inside the nanocavities of RMs, yielding time constants of 250 ps to 1.0 ns, which is significantly slower than the dynamics obtained in bulk water (32 ps). The observed slow ESPT dynamics in RM compared to bulk water is mainly attributed to the sluggish hydrogen-bonded network dynamics of water molecules inside the nanocavity of RM and the screening of the sodium ions present at the interface.


Tunable, biodegradable gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging.
Gold nanoparticles (AuNP) have been proposed for many applications in medicine. Although large AuNP (>5.5 nm) are desirable for their longer blood circulation and accumulation in diseased tissues, small AuNP (<5.5 nm) are required for excretion via the kidneys. We present a novel platform where small, excretable AuNP are encapsulated into biodegradable poly di(carboxylatophenoxy)phosphazene (PCPP) nanospheres. These larger nanoparticles (Au-PCPP) can perform their function as contrast agents, then subsequently break down into harmless byproducts and release the AuNP for swift excretion. Homogeneous Au-PCPP were synthesized using a microfluidic device. The size of the Au-PCPP can be controlled by the amount of polyethylene glycol-polylysine (PEG-PLL) block co-polymer in the formulation. Synthesis of Au-PCPP nanoparticles and encapsulation of AuNP in PCPP were evaluated using transmission electron microscopy and their biocompatibility and biodegradability confirmed in vitro. The Au-PCPP nanoparticles were found to produce strong computed tomography contrast. The UV-Vis absorption peak of Au-PCPP can be tuned into the near infrared region via inclusion of varying amounts of AuNP and controlling the nanoparticle size. In vitro and in vivo experiments demonstrated the potential of Au-PCPP as contrast agents for photoacoustic imaging. Therefore, Au-PCPP nanoparticles have high potency as contrast agents for two imaging modalities, as well as being biocompatible and biodegradable, and thus represent a platform with potential for translation into the clinic.


Anomalous protein kinetics on low-fouling surfaces.
In this work, protein-surface interactions were probed in terms of adsorption and desorption of a model protein, bovine serum albumin, on a low-fouling surface with single-molecule localization microscopy. Single-molecule experiments enable precise determination of both adsorption and desorption rates. Strikingly the experimental data show anomalous desorption kinetics, evident as a surface dwell time that exhibits a power-law distribution, i.e. a heavy-tailed rather than the expected exponential distribution. As a direct consequence of this heavy-tailed distribution, the average desorption rate depends upon the time scale of the experiment and the protein surface concentration does not reach equilibrium. Further analysis reveals that the observed anomalous desorption emerges due to the reversible formation of a small fraction of soluble protein multimers (small oligomers), such that each one desorbs from the surface with a different rate. The overall kinetics can be described by a series of elementary reactions, yielding simple scaling relations that predict experimental observations. This work reveals a mechanistic origin for anomalous desorption kinetics that can be employed to interpret observations where low-protein fouling surfaces eventually foul when in long-term contact with protein solutions. The work also provides new insights that can be used to define design principles for non-fouling surfaces and to predict their performance.


Anti-aging potential of tree nuts with a focus on the phytochemical composition, molecular mechanisms and thermal stability of major bioactive compounds.
Tree nuts, complete functional foods, contain macro- and micronutrients of high biological value. These bioactive compounds have a synergistic effect in preventing and delaying many age-related pathologies (e.g. cardiovascular diseases, stroke, type 2 diabetes mellitus, certain types of cancer, and several neurodegenerative diseases). Tree nuts are low in carbohydrates, but they abound in healthy fatty acids, in optimal proportion for a good plasma lipid profile, and are a good source of proteins, rich in proteinogenic amino acids. They contain significant amounts of vitamin E, minerals, polyphenols, and phytosterols. Polyphenols, which are powerful phytochemicals, act as direct and indirect antioxidants, reduce the inflammatory response, improve proteostasis and mitochondrial biogenesis, modulate many cell signaling pathways, have a major role in cytoprotection, are Nrf2/ARE activators, down-regulate the NFκB system, promote anticancer potential, and prevent cell senescence. Some of them have senolytic effects, interfere in specific cell signaling pathways modulated by caloric restriction, and protect against UV radiation and photoaging. Moreover, tree nuts are good prebiotics and improve gut microbiota. The stability of polyphenolic compounds and their antioxidant activity can be influenced by cooking techniques, temperature of storage, and post-harvest processing methods. The consumption of tree nuts has been scientifically proven to improve lifespan and healthspan and should be a part of a healthy diet in the elderly.


Electronic dispersion compensation in a 50 Gb/s optically unamplified direct-detection receiver enabled by vestigial-sideband orthogonal frequency division multiplexing.
We present a novel method for dispersion compensation based on vestigial-sideband transmission of an orthogonal frequency division multiplexed signal through standard signal-mode fiber with a direct-detection receiver. This technique requires simpler optical components and can withstand greater link attenuation and splitting ratios than similar methods previously studied, making the method ideal for optically unamplified receivers, such as those in passive optical networks. We present simulations as well as experimental measurements to demonstrate its practicality.


Functional similarities and differences of AMPA and kainate receptors expressed by cultured rat sensory neurons.
Dorsal root ganglion neurons express functional AMPA and kainate receptors near their central terminals. Activation of these receptors causes a decrease in glutamate release during action potential evoked synaptic transmission. Due to differences in kinetic properties and expression patterns of these two families of glutamate receptors in subpopulations of sensory neurons, AMPA and kainate receptors are expected to function differently. We used embryonic dorsal root ganglion (DRG) neurons maintained in culture to compare functional properties of kainate and AMPA receptors. Most DRG neurons in culture expressed kainate receptors and about half also expressed AMPA receptors. Most AMPA and kainate receptor-expressing DRG neurons were sensitive to capsaicin, suggesting involvement of these glutamate receptors in nociception. When activated by kainate, AMPA receptors were capable of driving a sustained train of action potentials while kainate receptors tended to activate action potential firing more transiently. Glutamate elicited more action potentials and a larger steady-state depolarization in neurons expressing both AMPA and kainate receptors than in neurons expressing only kainate receptors. Adding to their more potent activation properties, AMPA receptors recovered from desensitization much more quickly than kainate receptors. Activation of presynaptic receptors by low concentrations of kainate, but not ATPA, caused a tetrodotoxin-sensitive increase in the frequency of spontaneous EPSCs recorded in dorsal horn neurons. By recording synaptic pairs of DRG and dorsal horn neurons, we found that activation of presynaptic kainate and AMPA receptors decreased evoked glutamate release from terminals of DRG neurons in culture. Our data suggest that the endogenous ligand, glutamate, will cause a different physiological impact when activating these two types of non-NMDA glutamate receptors at central or peripheral nerve endings of sensory neurons.


A role for transglutaminase in glucose-stimulated insulin release from the pancreatic beta-cell.
Preincubation of rat islets of Langerhans with the potent inhibitors of islet transglutaminase activity, monodansylcadaverine (30-100 microM) and N-(5-aminopentyl)-2-naphthalenesulphonamide (100-200 microM), led to significant inhibition of glucose-stimulated insulin release from islets. In contrast, the respective N'-dimethylated derivatives of these two compounds, which did not inhibit islet transglutaminase activity, were much less effective as inhibitors of glucose-stimulated insulin release. None of the compounds inhibited rat spleen protein kinase C activity at concentrations which gave rise to inhibition of glucose-stimulated insulin release. When tested for their effects on calmodulin-stimulated bovine heart phosphodiesterase activity, of the compounds that inhibited insulin release, only monodansylcadaverine did not act as an effective antagonist of calmodulin at concentrations (up to 50 microM) that gave rise to significant inhibition of glucose-stimulated insulin release. Furthermore, at 50 microM, monodansylcadaverine did not inhibit methylation of islet lipids. The inhibition of glucose-stimulated insulin release by monodansylcadaverine is therefore likely to be attributable to its interference with islet transglutaminase activity. The sensitivity of islet transglutaminase to activation by Ca2+ was investigated by using a modified assay incorporating dephosphorylated NN'-dimethylcasein as a substrate protein. The Km for Ca2+ obtained (approx. 3 microM) was an order of magnitude lower than previously reported for the islet enzyme [Bungay, Potter & Griffin (1984) Biochem. J. 219, 819-827]. Mg2+ (2 mM) was found to have little effect on the sensitivity of the enzyme to Ca2+. Investigation of the endogenous substrate proteins of islet transglutaminase by using the Ca2+-dependent incorporation of [14C]methylamine into proteins of islet homogenates demonstrated that most of the incorporated radiolabel was present in cross-linked polymeric aggregates which did not traverse 3% (w/v) acrylamide gels. The radiolabelled polymeric aggregates were present in 71 000 g-sedimented material of homogenates, and their formation was transglutaminase-mediated. These findings provide new evidence for the involvement of islet transglutaminase in the membrane-mediated events necessary for glucose-stimulated insulin release.


College Students' Health Behavior Clusters: Differences by Sex.
The study purpose was to identify clusters of weight-related behaviors by sex in a college student populations. We conducted secondary data analysis from online surveys and physical assessments collected in Project Young Adults Eating and Active for Health (YEAH) with a convenience sample of students on 13 college campuses in the United States. We performed 2-step cluster analysis by sex to identify subgroups with homogeneous characteristics and behaviors. We used 8 derivation variables: healthy eating; eating restraints; external cues; stress; fruit/vegetable intake; calories from fat; calories from sugar-sweetened beverages; and physical activity. Contribution of derivation variables to clusters was analyzed with a MANOVA test. Data from 1594 students were included. Cluster analysis revealed 2-clusters labeled "Healthful Behavior" and "At-risk" for males and females with an additional "Laid Back" cluster for males. "At-risk" clusters had the highest BMI, waist circumference, elevated health risk, and stress and least healthy dietary intake and physical activity. The "Laid Back" cluster had normal weights and the lowest restrained eating, external cues sensitivity, and stress. Identified differences in characteristics and attitudes towards weight-related behaviors between males and females can be used to tailor weight management programs.


Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer.
Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.