Caffeine induces CYP1A2 expression in rat hepatocytes but not in human hepatocytes.
Caffeine is the active constituent in coffee. Continual consumption of caffeine can lead to an attenuated response also known as tolerance. Results from rat studies have shown that caffeine is an inducer of CYP1A2, the enzyme responsible for caffeine's metabolism. This suggests that CYP1A2 induction by caffeine may be in part responsible for caffeine tolerance. However, whether caffeine induces CYP1A2 expression in humans remains unknown. Our results from luciferase assays performed in HepG2 cells showed that caffeine is not an activator of the aromatic hydrocarbon receptor (AhR), a major transcription factor involved in upregulation of CYP1A2. Furthermore, caffeine did not induce CYP1A2 expression in primary human hepatocytes at a concentration attained by ordinary coffee drinking. On the other hand, caffeine enhanced CYP1A2 expression by 9-fold in rat hepatocytes. Our results suggest that caffeine from ordinary coffee drinking does not induce CYP1A2 expression in humans and that factors other than CYP1A2 induction by caffeine likely contribute to development of caffeine tolerance in humans.


Receptors for insulin-like growth factor II in the rat uterus: characterization and variation throughout the estrus cycle.
This study was undertaken to identify uterine insulin-like growth factor II receptors and examine the regulation of these receptor levels throughout the estrus cycle. We have demonstrated IGF-II receptors in crude uterine membranes by binding and cross-linking experiments. IGF-II binding to the rat uterine membranes displayed time and temperature dependence and maximum binding was achieved by 2 h at 22 degrees C. Uterine IGF-II binding sites were specific for binding IGF-II peptide and demonstrated negligible binding affinity for IGF-I and no affinity for insulin. The specific anti-IGF-II receptor antibody, R-II-PAB1, blocked the specific [125I]IGF-II binding to uterine membranes in a dose-dependent manner. The characteristics of uterine IGF-II receptor are similar to those reported for other tissues, with a single class of high-affinity binding sites with an apparent dissociation constant of 1.2 +/- 0.5 nmol/l and Beta max of 2.65 +/- 0.41 pmol/mg protein. Affinity cross-linking experiments indicated that the specific binding of [125I]IGF-II in the uterus is associated with a single band of protein with a mol wt of 250 kD. In mature cycling rats, the proestrus uterus had the lowest level of [125I]IGF-II binding per mg membrane protein, without changes in receptor affinity. However, because of greater yield of protein from proestrus uteri, the total [125I]IGF-II binding capacity of the uterus was similar to the other stages of the estrus cycle. These studies demonstrate the presence of authentic IGF-II receptors in the rat uterus and illustrate variations in the concentration of these receptors in the uterus throughout the estrus cycle.


Trends in quality during medical home transformation.
PURPOSE We describe changes over time in performance on measures of technical quality and patient experience as a group of primary care clinics transformed themselves into level III patient-centered medical homes. METHODS A group of 21 Minnesota primary care clinics achieving level III recognition as medical homes by the National Committee for Quality Assurance has been tracking a variety of quality and patient satisfaction measures for years. We analyzed trends in these measures and compared them with those of other medical groups in the community to estimate what we might expect as other primary care sites gear up to achieve medical home status. RESULTS The clinics in this group achieved a 1% to 3% increase per year in patient satisfaction and a 2% to 7% increase per year in performance on quality measures for diabetes, coronary artery disease, preventive services, and generic medication use. When compared with the average for other medical groups in the region, the rates of increase were greater for satisfaction, but similar for the quality measures. CONCLUSIONS Achieving medical home recognition was associated with improvements in quality and patient satisfaction for these clinics, but the rate of improvement is slow and does not always exceed levels in the surrounding community in Minnesota (which are also improving). Expectations for large and rapid change are probably unrealistic.


Risks and benefits of reducing target volume margins in breast tangent radiotherapy.
This study investigates the potential benefits of planning target volume (PTV) margin reduction for whole breast radiotherapy in relation to dose received by organs at risk (OARs), as well as reductions in radiation-induced secondary cancer risk. Such benefits were compared to the increased radiation-induced secondary cancer risk attributed from increased ionizing radiation imaging doses. Ten retrospective patients' computed tomography datasets were considered. Three computerized treatment plans with varied PTV margins (0, 5 and 10 mm) were created for each patient complying with the Radiation Therapy Oncology Group (RTOG) 1005 protocol requirements. The BEIR VII lifetime attributable risk (LAR) model was used to estimate secondary cancer risk to OARs. The LAR was assessed for all treatment plans considering (a) doses from PTV margin variation and (b) doses from two (daily and weekly) kilovoltage cone beam computed tomography (kV CBCT) imaging protocols during the course of treatment. We found PTV margins from largest to smallest resulted in a mean OAR relative dose reduction of 31% (heart), 28% (lung) and 23% (contralateral breast) and the risk of radiation-induced secondary cancer by a relative 23% (contralateral breast) and 22% (contralateral lung). Daily image-guidance using kV CBCT increased the risk of radiation induced secondary cancer to the contralateral breast and contralateral lung by a relative 1.6-1.9% and 1.9-2.5% respectively. Despite the additional dose from kV CBCT for the two considered imaging protocols, smaller PTV margins would still result in an overall reduction in secondary cancer risk.


Metronidazole or Rifaximin for Treatment of Clostridium difficile in Pediatric Patients with Inflammatory Bowel Disease: A Randomized Clinical Trial.
Interestingly, Clostridium difficile infection (CDI) worsens the course of inflammatory bowel disease (IBD); however, there is a paucity of data regarding the treatment of CDI in this group of patients. This was a prospective, single-blind trial. Children with flare of IBD and CDI were randomly assigned to receive metronidazole or rifaximin orally for 14 days. CDI was diagnosed based on a positive well-type enzyme immunoassay (EIA) toxins A/B stool test for C. difficile toxins A and/or B. The cure rate was defined as the percentage of patients with a negative EIA stool test for C. difficile toxins A/B measured 4 weeks after the end of treatment. Recurrence was defined as a repeat CDI within 2 to 8 weeks. In total, we included 31 patients with IBD including 12 patients with Crohn's disease and 19 with ulcerative colitis. Of them, 17 received metronidazole and 14 received rifaximin. There were no statistically significant differences between the 2 study groups including age, type of treatment, and disease activity. There was no statistically significant difference in the cure rate between patients treated with metronidazole and rifaximin (70.6% versus 78.6%, respectively, P = 0.5). We found no difference in recurrence rate between the 2 study treatment types (17% versus 0%, respectively, P = 0.3). We did not find an association between immunosuppressive therapy and CDI cure rate or CDI recurrence rate. Metronidazole and rifaximin were similarly effective treatments for CDI in pediatric patients with IBD.


Monoclonal antibodies to Paragonimus heterotremus and their potential for diagnosis of paragonimiasis.
Monoclonal antibodies (MAbs) specific to the lung fluke (Paragonimus heterotremus) were produced against the soluble metabolic products (excretory-secretory antigen). Three hybrids secreting MAbs specific for P. heterotremus antigens were identified by an indirect enzyme-linked immunosorbent assay (ELISA) against a panel of homologous and 24 heterologous parasite antigens and Mycobacterium tuberculosis. Of the three specific clones, clone 10F2, which was IgG1 producing and which gave immune complex bands with 31.5-kD and 22-kD polypeptides by gel electrophoresis and immunoblotting, was selected for further characterization and evaluation of its possible diagnostic potential. The result obtained from an indirect immunofluorescent antibody test suggested that MAb 10F2 reacted with mucosa and contents of the worm's intestine. The antibody could be readily used to prepare an affinity-purified antigen for use in an indirect ELISA that was highly sensitive and specific for the detection of circulating antibody in sera of paragonimiasis patients.


Evidence for human fronto-central gamma activity during long-term memory encoding of word sequences.
Although human gamma activity (30-80 Hz) associated with visual processing is often reported, it is not clear to what extend gamma activity can be reliably detected non-invasively from frontal areas during complex cognitive tasks such as long term memory (LTM) formation. We conducted a memory experiment composed of 35 blocks each having three parts: LTM encoding, working memory (WM) maintenance and LTM retrieval. In the LTM encoding and WM maintenance parts, participants had to respectively encode or maintain the order of three sequentially presented words. During LTM retrieval subjects had to reproduce these sequences. Using magnetoencephalography (MEG) we identified significant differences in the gamma and beta activity. Robust gamma activity (55-65 Hz) in left BA6 (supplementary motor area (SMA)/pre-SMA) was stronger during LTM rehearsal than during WM maintenance. The gamma activity was sustained throughout the 3.4 s rehearsal period during which a fixation cross was presented. Importantly, the difference in gamma band activity correlated with memory performance over subjects. Further we observed a weak gamma power difference in left BA6 during the first half of the LTM rehearsal interval larger for successfully than unsuccessfully reproduced word triplets. In the beta band, we found a power decrease in left anterior regions during LTM rehearsal compared to WM maintenance. Also this suppression of beta power correlated with memory performance over subjects. Our findings show that an extended network of brain areas, characterized by oscillatory activity in different frequency bands, supports the encoding of word sequences in LTM. Gamma band activity in BA6 possibly reflects memory processes associated with language and timing, and suppression of beta activity at left frontal sensors is likely to reflect the release of inhibition directly associated with the engagement of language functions.


An aposymbiotic primary coral polyp counteracts acidification by active pH regulation.
Corals build their skeletons using extracellular calcifying fluid located in the tissue-skeleton interface. However, the mechanism by which corals control the transport of calcium and other ions from seawater and the mechanism of constant alkalization of calcifying fluid are largely unknown. To address these questions, we performed direct pH imaging at calcification sites (subcalicoblastic medium, SCM) to visualize active pH upregulation in live aposymbiotic primary coral polyps treated with HCl-acidified seawater. Active alkalization was observed in all individuals using vital staining method while the movement of HPTS and Alexa Fluor to SCM suggests that certain ions such as H+ could diffuse via a paracellular pathway to SCM. Among them, we discovered acid-induced oscillations in the pH of SCM (pHSCM), observed in 24% of polyps examined. In addition, we discovered acid-induced pH up-regulation waves in 21% of polyps examined, which propagated among SCMs after exposure to acidified seawater. Our results showed that corals can regulate pHSCM more dynamically than was previously believed. These observations will have important implications for determining how corals regulate pHSCM during calcification. We propose that corals can sense ambient seawater pH via their innate pH-sensitive systems and regulate pHSCM using several unknown pH-regulating ion transporters that coordinate with multicellular signaling occurring in coral tissue.


The Concept of Travel Medicine and the Actual Situation of Travel-Related Illnesses.
Travel medicine defines all diseases and medical situations that are related to travel. Travel medicine comprises infectious diseases, traumas, altitude sickness, sun burns, embolisms, jet lag, and many more travel-related situations. With the increasing possibility and ease of travel, the number of people who have travelled internationally has exceeded 1.13 billion in 2014, and the revenues of international travel have exceeded 1.25 trillion dollars. With every passing day, international travels are shifting toward the developing countries and to more exotic regions of the world, and travelers tend to be more adventurous and daring, thereby increasing risky behaviors during travels. Traveling plays an important role in transmitting infections such as Zika virus infection, Ebola, avian flu, severe acute respiratory syndrome, Chikungunya, and dengue fever and is the principal reason for the epidemics of these types of infections on a global scale. With this background, we suggest that travel medicine is an important but "neglected" medical discipline as the discipline of Parasitology itself like most parasitic diseases.


Consent models in Canadian critical care randomized controlled trials: a scoping review.
Our primary objective was to describe consent models used in Canadian-led adult and pediatric intensive care unit (ICU/PICU) randomized controlled trials (RCTs). Our secondary objectives were to determine the consent rate of ICU/PICU RCTs that did and did not use an alternate consent model to describe consent procedures. Using scoping review methodology, we searched MEDLINE, Embase, and CENTRAL databases (from 1998 to June 2019) for trials published in English or French. We included Canadian-led RCTs that reported on the effects of an intervention on ICU/PICU patients or their families. Two independent reviewers assessed eligibility, abstracted data, and achieved consensus. We identified 48 RCTs of 17,558 patients. Included RCTs had ethics approval to use prior informed consent (43/48; 90%), deferred consent (13/48; 27%), waived consent (5/48; 10%), and verbal consent (1/48; 2%) models. Fifteen RCTs (15/48; 31%) had ethics approval to use more than one consent model. Twice as many trials used alternate consent between 2010 and 2019 (13/19) than between 2000 and 2009 (6/19). The consent rate for RCTs using only prior informed consent ranged from 54 to 91% (ICU) and 43 to 94% (PICU) and from 78 to 100% (ICU) and 74 to 87% (PICU) in trials using an alternate/hybrid consent model. Alternate consent models were used in the minority of Canadian-led ICU/PICU RCTs but have been used more frequently over the last decade. This suggests that Canadian ethics boards and research communities are becoming more accepting of alternate consent models in ICU/PICU trials.


Family psychosocial characteristics influencing criminal behaviour and mortality--possible mediating factors: a longitudinal study of male and female subjects in the Stockholm Birth Cohort.
Family psychosocial characteristics in childhood have been associated with children's development into criminal behaviour and mortality. This study explored these possible relationships and examined alcohol and/or drug use and mental problems as possible mediating factors, highlighting gender-specific patterns. Data from Swedish subjects born in 1953 (n = 14,294) from the Stockholm Birth Cohort study were examined. Several indicators of adverse family factors and individual problems were included in the present study. The information was derived from various data sources, covering different periods. Gender-specific associations with incidence of criminality (1966-1980) and mortality (1981-2009) were analysed using logistic regression. Furthermore, the population attributable fraction (PAF) was calculated for all variables in the fully adjusted models which were positively related to the outcome. Overall incidence of criminality and mortality was (m/f 32.3/6.6) and (m/f 6.1/3.5), respectively. The results showed that all aspects of family psychosocial and individual problems studied were associated with criminality for both genders. Among males, individual problems seemed to partly mediate these relations, but the associations remained statistically significant. Interestingly, the PAF analysis revealed a reduction in criminality of 17.5% when individual problems with alcohol and/or drug use were considered. Among females, a significant impact of alcohol and/or drug use on the association between family psychosocial characteristics and subsequent criminality was obtained. Inclusion of father's occupational class only somewhat reduced the estimates for the genders. Concerning male mortality, father's alcohol abuse was significantly related to an increased risk. When individual criminality was accounted for, the association was substantially reduced but remained statistically significant. Among females, when adjusting for family psychosocial factors, only the association between parents' mental problems and females' mortality was significant. None of the individual problem variables managed to explain this association. Family psychosocial characteristics were associated with both subsequent criminal behaviour and mortality. These connections were partly explained by individual risk factors, especially by alcohol and/or drug use. The practical implications of the findings point to the importance of addressing the individual's alcohol and/or drug use in reducing criminal behaviour, which would also lower the mortality rates.


Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs.
Adenosine deaminases that act on RNA bind double-stranded and structured RNAs and convert adenosines to inosines by hydrolytic deamination. Inosines are recognized as guanosines, and, hence, RNA editing alters the sequence information but also structure of RNAs. Editing by ADARs is widespread and essential for normal life and development. Precursors of miRNAs are abundantly edited by ADARs, but neither the abundance nor the consequences of miRNA editing has been firmly established. Using transgenic mouse embryos that are deficient in the two enzymatically active editing enzymes ADAR and ADARB1, we compare relative frequencies but also sequence composition of miRNAs in these genetically modified backgrounds to wild-type mice by "next-generation sequencing." Deficiency of ADARB1 leads to a reproducible change in abundance of specific miRNAs and their predicted targets. Changes in miRNA abundance seem unrelated to editing events. Additional deletion of ADAR has surprisingly little impact on the mature miRNA repertoire, indicating that miRNA expression is primarily dependent on ADARB1. A-to-G transitions reflecting A-to-I editing events can be detected at few sites and at low frequency during the early embryonic stage investigated. Again, most editing events are ADARB1-dependent with only few editing sites being specifically edited by ADAR. Besides known editing events in miRNAs, a few novel, previously unknown editing events were identified. Some editing events are located to the seed region of miRNAs, opening the possibility that editing leads to their retargeting.


An integrated residency in internal and preventive medicine.
The importance of preventive and population-based principles in clinical practice is widely acknowledged. The challenge of imparting these principles in either undergraduate or postgraduate medical education has, however, not been fully met. The necessary skills are provided comprehensively by preventive medicine residency programs, but at the expense of clinical training. Sequential residencies in primary care and preventive medicine, the currently available means of obtaining thorough preparation in both clinical and population-based principles, represent an inefficient, generally unappealing, and non-integrated approach. In response to these concerns, and in an effort to make preventive medicine training appeal to a wider audience, the authors developed and implemented a residency program fully integrating internal and preventive medicine. The program meets, and generally exceeds, the requirements of both specialty boards over a four-year period. The program provides extensive training in clinical, preventive, and public health skills, along with case management and cost-effective care, conferring the MPH degree and leading to dual board eligibility. The model is ideally wed to the demands of the modern health care environment in the United States, is extremely attractive to applicants, and may warrant replication both to train academic and administrative leaders and to raise the standards of preventive and public health practice in primary care.


Modified and conventional ultrafiltration during pediatric cardiac surgery: clinical outcomes compared.
This prospective study compared clinical outcomes after heart surgery between three groups of infants with congenital heart disease. One group received dilutional conventional ultrafiltration (group D), another received modified ultrafiltration (group M), and a third group received both dilutional conventional and modified ultrafiltration (group B). We hypothesized that group B patients would have the best clinical outcome. Children younger than 1 year undergoing heart surgery for biventricular repair by the same surgeon were randomly allocated to one of the three study groups. Patient management was standardized, and intensive care staff were blinded to group allocation. Primary outcome measure was duration of postoperative mechanical ventilation. Other outcome measures recorded included total blood products transfused, duration of chest tube in situ, chest tube output, and stays in intensive care and in the hospital. Sixty infants completed study protocol. Mean age and weight were as follows: group D (n = 19), 61 days, 4.3 kg; group M (n = 20), 64 days, 4.5 kg; and group B (n = 21), 86 days, 4.4 kg. Preoperative and intraoperative characteristics were similar between groups. Ultrafiltrate volumes obtained were 196 +/- 93 mL/kg in group D, 105 +/- 33 mL/kg in group M, and 261 +/- 113 mL/kg in group B. There were no significant differences between groups for any outcome variable. Technical difficulties prevented completion of modified ultrafiltration in 2 of 41 infants. There was no clinical advantage in combining conventional and modified ultrafiltration. Because clinical outcomes were similar across groups, relative risks of the ultrafiltration strategies may influence choice.


High-speed MALDI MS/MS imaging mass spectrometry using continuous raster sampling.
A matrix-assisted laser desorption/ionization time of flight/time of flight tandem mass spectrometer (MALDI TOF/TOF) has been used for high-speed precursor/fragment ion transition image acquisition. High-throughput analysis is facilitated by an Nd:YLF solid state laser capable of pulse repetition rates up to 5 kHz, a high digitizer acquisition rate (up to 50 pixels/s), and continuous laser raster sampling. MS/MS experiments are enabled through the use of a precision timed ion selector, second source acceleration, and a dedicated collision cell. Continuous raster sampling is shown here to facilitate rapid MS/MS ion image acquisition from thin tissue sections for the drug rifampicin and for a common kidney lipid, SM4s(d18:1/24:1). The ability to confirm the structural identity of an analyte as part of the MS/MS imaging experiment is an essential part of the analysis. Additionally, the increase in sensitivity and specificity afforded by an MS/MS approach is highly advantageous, especially when interrogating complex chemical environments such as those in biological tissues. Herein, we report continuous laser raster sampling TOF/TOF imaging methodologies which demonstrate 8 to 14-fold increases in throughput compared with existing MS/MS instrumentation, an important advantage when imaging large areas on tissues.


The Effect of Intensity on the Speech Evoked Auditory Late Latency Response in Normal Hearing Individuals.
Among the stimulus factors, the influence of presentation level is less studied in normal-hearing individuals when using speech stimuli withvarious presentation levels for the auditory late latency response (ALLR). Hence, the present study aimed to explore the Latency-Intensity (L-I) function, i.e., how the latency and amplitude change as a function of intensity using speech stimuli. Speech-evoked ALLR was obtained from 15 normal-hearing individuals. The syllable/ta/ was used to record ALLR with an intensity of 30, 50, 70, and 90 dBSPL. Electroencephalography (EEG) from five channels was recorded and analyzed offline. The overall results revealed that there is an influence of intensity on P1 and N1 latencies in a nonlinear fashion. The latency change is consistent at lower intensities than at moderate and high intensities. The amplitude changes did not reach significance, though a decrease with a reduction in intensity was obvious. There is a significant effect of intensity on the latency and amplitude of ALLR in speech stimulus. However, this effect may vary for different speech stimuli.


Aminoguanidine reverses the loss of functional hyperemia in a rat model of diabetic retinopathy.
Flickering light dilates retinal arterioles and increases retinal blood flow, a response termed functional hyperemia. This response is diminished in diabetic patients even before the appearance of overt clinical retinopathy. The loss of functional hyperemia could deprive retinal neurons of oxygen and nutrients, possibly exacerbating the development of diabetic retinopathy. We have tested whether inhibiting inducible nitric oxide synthase (iNOS) reverses the loss of functional hyperemia in diabetic rat retinas in vivo. Changes in retinal arteriole diameter were measured following diffuse flickering light stimulation in control rats, streptozotocin-induced type 1 diabetic rats and diabetic rats treated with aminoguanidine (AG; an iNOS inhibitor), either acutely via IV injection or chronically in drinking water. Flickering light-evoked large arteriole dilations (10.8 ± 1.1%) in control rats. This response was diminished by 61% in diabetic animals (4.2 ± 0.3%). Both acute and chronic treatment with AG restored flicker-induced arteriole dilations in diabetic rats (8.8 ± 0.9 and 9.5 ± 1.3%, respectively). The amplitude of the corneal electroretinogram b-wave was similar in control and diabetic animals. These findings demonstrate that inhibiting iNOS with AG is effective in preventing the loss of, and restoring, normal functional hyperemia in the diabetic rat retina. Previous work has demonstrated the efficacy of iNOS inhibitors in slowing the progression of diabetic retinopathy. This effect could be due, in part, to a restoration of functional hyperemia.


PReventing early unplanned hOspital readmission aFter critical ILlnEss (PROFILE): protocol and analysis framework for a mixed methods study.
Survivors of critical illness experience multidimensional disabilities that reduce quality of life, and 25-30% require unplanned hospital readmission within 3 months following index hospitalisation. We aim to understand factors associated with unplanned readmission; develop a risk model to identify intensive care unit (ICU) survivors at highest readmission risk; understand the modifiable and non-modifiable readmission drivers; and develop a risk assessment tool for identifying patients and areas for early intervention. We will use mixed methods with concurrent data collection. Quantitative data will comprise linked healthcare records for adult Scottish residents requiring ICU admission (1 January 2000-31 December 2013) who survived to hospital discharge. The outcome will be unplanned emergency readmission within 90 days of index hospital discharge. Exposures will include pre-ICU demographic data, comorbidities and health status, and critical illness variables representing illness severity. Regression analyses will be used to identify factors associated with increased readmission risk, and to develop and validate a risk prediction model. Qualitative data will comprise recorded/transcribed interviews with up to 60 patients and carers recently experiencing unplanned readmissions in three health board regions. A deductive and inductive thematic analysis will be used to identify factors contributing to readmissions and how they may interact. Through iterative triangulation of quantitative and qualitative data, we will develop a construct/taxonomy that captures reasons and drivers for unplanned readmission. We will validate and further refine this in focus groups with patients/carers who experienced readmissions in six Scottish health board regions, and in consultation with an independent expert group. A tool will be developed to screen for ICU survivors at risk of readmission and inform anticipatory interventions. Data linkage has approval but does not require ethical approval. The qualitative study has ethical approval. Dissemination with key healthcare stakeholders and policymakers is planned. UKCRN18023.


My Village Is Dying? Integrating Methods from the Inside Out.
The purpose of this paper is to confront the notion of "decline" at the village level by illustrating a more immersive approach to sociological and demographic research within rural and remote communities. The research uses case studies of three villages in Australia, Canada, and Sweden, all of which have been labeled as "declining villages," typified by population loss, an aging population, high rates of youth outmigration, and loss of businesses and services. This paper argues that focusing solely on quantitative indicators of demographic change provides a narrow view of rural village trajectories and ignores subtle processes of local adaptation that are hidden from quantitative data sets. Our research integrates quantitative data from the "outside" with qualitative data from the "inside," including visual ethnography, to develop a more balanced perspective on how villages have been changing and what change could mean locally. These objectives are accomplished by revisiting a Dirt Research methodology applicable to a broad range of research into rural and remote villages.


Factors Associated with Parental Compliance with Supine Infant Sleep: An Integrative Review.
Despite educational programs, sudden infant death syndrome (SIDS) rates remain unacceptably high, especially among low-income and African-American populations. The purpose of this review is to examine reasons for parental noncompliance with supine sleep recommendations. A database search in Cochrane Database of Systematic Reviews, PubMed, EBSCOhost, and CINAHL was conducted using keywords SIDS, prevention and control, parental compliance, nursing, supine position, Back to Sleep campaign, and Safe to Sleep campaign. Literature was included from 2002 to 2014. Types of studies included randomized control trials, literature reviews, and descriptive studies. Literature from academic journals was also included. Included literature discussed parental knowledge, the Back to Sleep and the Safe to Sleep campaigns, compliance with recommendations from the American Academy of Pediatrics (AAP), and interventions and education. Seventeen studies were included that used data collection methods, including surveys, focus groups, face-to-face interviews, and questionnaires. Major trends identified as being associated with noncompliance included parent knowledge, sources of advice, infant comfort and quality of infant sleep, safety concerns (i.e., choking), race/ethnicity, education level, and income. Noncompliance was highest among single, less-educated, low-income, or African-American parents.


Serum prohepcidin levels in premature newborns with oxygen radical diseases.
This study aimed to investigate the prohepcidin levels in premature newborns with oxygen radical diseases such as bronchopulmonary dysplasia, retinopathy of prematurity and necrotizing enterocolitis and to compare these levels with those of healthy premature newborns. Eighty premature infants (25-34 weeks gestational age) were enrolled. The patient group was composed of 38 premature babies with oxygen radical diseases, and the control group consisted of 42 healthy premature newborns. Complete blood count, serum iron and ferritin concentrations, iron-binding capacity (IBC), transferrin and prohepcidin levels were measured. The mean ferritin and prohepcidin levels were higher in the patient group than in the control group (p = 0.038 and p = 0.022, respectively). No significant correlations were found between serum prohepcidin levels and iron parameters. We believe that this finding will contribute to a greater understanding of the etiopathogenesis of oxygen radical diseases. There is a need for future studies to explore the link between underlying inflammatory mechanisms and hepcidin in oxygen radical diseases.


Using Digital Masks to Enhance the Bandwidth Tolerance and Improve the Performance of On-Chip Reservoir Computing Systems.
Reservoir computing (RC) is a computing scheme related to recurrent neural network theory. As a model for neural activity in the brain, it attracts a lot of attention, especially because of its very simple training method. However, building a functional, on-chip, photonic implementation of RC remains a challenge. Scaling delay lines down from optical fiber scale to chip scale results in RC systems that compute faster, but at the same time requires that the input signals be scaled up in speed, which might be impractical or expensive. In this brief, we show that this problem can be alleviated by a masked RC system in which the amplitude of the input signal is modulated by a binary-valued mask. For a speech recognition task, we demonstrate that the necessary input sample rate can be a factor of 40 smaller than in a conventional RC system. In addition, we also show that linear discriminant analysis and input matrix optimization is a well-performing alternative to linear regression for reservoir training.


Three-dimensional fabrication of engineered bone with human bio-derived bone scaffolds in a rotating wall vessel bioreactor.
Bone tissue engineering has emerged as a promising strategy in the effort to regenerate and repair diseased or damaged bone. The bioreactor, within which engineered bone tissue is cultured, plays a key role in the development of engineered bone graphs. In this work, the potentials of the rotating wall vessel bioreactor (RWVB) and the human bio-derived bone scaffolds (BDBS) for 3D bone culture are evaluated. The osteoblasts isolated from the cranium of neonatal Sprague-Dawley (SD) rat of 3 days old were expanded firstly with microcarrier suspension culture in a RWVB. After the assessment of the biological functions of the expanded cells by histomorphometry, the cells were seeded at 2 x 10(6) and 1 x 10(6) cells/mL, respectively, onto the 3D human BDBS and cultured for 3 weeks in the RWVB. The cells metabolism and nutrient concentration were monitored in the whole culture processes. The structure of the harvested bone tissues was observed with optical microscope and scanning electron microscope (SEM). The biological properties of the engineered bone were detected by alkaline phosphatase (ALP) expression and alizarin red staining to visualize the newly formed bone. Acridine orange/ethidium bromide (AO/EB) double fluorescence staining was used to analyze the cell activity. For a comparative study, cell seeded constructs were also cultured in static conditions. The results indicate that the bone grafts cultured in RWVB with two different seeded cell densities grew well, and the cell number expanded in RWVB was five times as that in T-flask and spinner flask. There were significantly more collagen fibers mineralized nodules and new osteoid tissue formed than those in T-flask and spinner flask. It also demonstrated that with the stress stimulation inside the fluid in the RWVB, the ALP expression could be increased; the formation of mineralized nodules can be accelerated.


Prevalence of Coxiella burnetii in ticks after a large outbreak of Q fever.
Q fever has emerged as an important human and veterinary public health problem in the Netherlands with major outbreaks in three consecutive years. Goat farms are probably the prime source from which Coxiella burnetii have spread throughout the environment, infecting people living in the vicinity. Coxiella burnetii infection not only spilled over from animal husbandry to humans but could also have spread to neighbouring wildlife and pets forming novel reservoirs and consequently posing another and lingering threat to humans, companion animals and livestock. In these cases, transmission routes other than airborne spread of contaminated aerosols may become significant. Therefore, the role of ticks in the transmission of Coxiella burnetii in the current situation was investigated. A total of 1891 questing Ixodes ricinus ticks and 1086 ticks feeding on pets, wildlife and livestock were tested by a recently developed multiplex Q-PCR. All ticks were negative, except for a few ticks feeding on a herd of recently vaccinated sheep. Coxiella-positive ticks were not detected after resampling this particular herd three months later. Based on these data we conclude that the current risk of acquiring Q fever from questing ticks in the Netherlands is negligible. However, for future risk assessments, it might be relevant to sample more ticks in the vicinity of previously C. burnetii infected goat farms and to assess whether C. burnetii can be transmitted transovarially and transstadially in I. ricinus ticks.


Local dynamic mechanical analysis for heterogeneous soft matter using ferrule-top indentation.
There is a strong demand for nanoindentation methods to probe the heterogeneous viscoelastic properties of soft tissues. Important applications include diagnosis of early onset diseases such as arthritis and investigations into cellular mechanoresponse in tissue. Quantification of tissue mechanics at length and time scales relevant to biological processes, however, remains a technical challenge. Here, we present a new nanoindentation approach that is ideally suited to probe the viscoelastic properties of soft, hydrated tissues. We built a ferrule-top probe that uses wavelength modulation in a Fabry-Pérot cavity configuration to detect cantilever deflection and to drive a feedback-controlled piezoelectric actuator. This technique allows us to control the static load applied onto the sample using an all-optical mm-sized probe. We extract the local elastic and viscous moduli of the samples by superposing a small oscillatory load and recording the indentation depth at the frequency of oscillation. By using a set of silicone elastomers with a range of stiffnesses representative of biological tissues, we demonstrate that the technique can accurately determine moduli over a wide range (0.1-100 kPa) and over a frequency range of 0.01-10 Hz. Direct comparison with macroscopic rheology measurements yields excellent quantitative agreement, without any fitting parameters. Finally, we show how this method can provide a spatially-resolved map of large variations in mechanical properties (orders of magnitude) across the surface of soft samples thanks to high sensitivity over large (>μm) cantilever deflections. This approach paves the way to investigations into the local dynamic mechanical properties of biological soft matter.


Derivation of CO2 output from oscillations in arterial pH.
Theory predicts that the rate of rise of the oscillation in arterial CO2 partial pressure (PaCO2) is linearly dependent on CO2 flux from venous blood to alveolar gas. We have measured, in the anesthetized cat, CO2 output (VCO2) and oscillations in arterial pH. The pH signal was differentiated to give the maximum rate of fall of pH on the downstroke of the oscillation (dpH/dt decreases max). Since oscillations in pH are due to oscillations in arterial PCO2, dpH/dt decreases max was considered to be equivalent to the maximum rate of rise of the PCO2 oscillation. VCO2 was increased by ventilating the intestines with CO2 and by the intra-arterial infusion of 2,4-dinitrophenol. VCO2 was decreased by filling the intestines with isotonic tris(hydroxymethyl)methylamine buffer. The maximum range of VCO2 covered was 7.8-51 ml/min, and the mean range was from 13.6 +/- 1.3 to 29.7 +/- 1.6 (SE) ml/min. Although CO2 loading produced a small rise and CO2 unloading a small fall in mean PaCO2, the changes were not statistically significant, so that overall the response was close to isocapnia. Over the limited range of VCO2 studied there was a highly significant linear association between dpH/dt decreases max and VCO2 which supports the contention that the slope of the upstroke of the PaCO2 oscillation is determined by the CO2 flux from mixed venous blood to alveolar gas. As such this slope is a potential chemical signal linking ventilation to CO2 production.


Clonal spread of Escherichia coli resistant to cephalosporins and quinolones in the Nordic broiler production.
The intestinal flora of healthy broilers can contain Escherichia coli resistant to extended spectrum cephalosporins (ESC) and fluoroquinolones (FQ), representing a possible public health problem. We investigated the clonal epidemiology of E. coli with reduced susceptibility to ESC or FQ in broilers in three Nordic countries interconnected by a common source of breeding animals. Isolates (n = 319 and n = 132 non-wild type for ESC and FQ, respectively) from Norwegian, Swedish and Icelandic production originated mainly from the intestinal flora of broilers at the age of 20-35 days. Genetic relationships were investigated by ten loci multilocus variable number tandem repeat analyses (MLVA) and representative isolates of inter-Nordic clusters were subjected to multilocus sequence typing (MLST). Antimicrobial susceptibility data based on minimum inhibitory concentrations was compiled. Approximately one third of the ESC non-wild type isolates, including isolates from all three countries, clustered together. These isolates belonged to sequence type (ST) 38 and contained blaCMY-2. The FQ non-wild type isolates were more genetically diverse, but related isolates occurred in more than one country. MLST typing showed clusters belonging to ST10, ST355, ST349, ST665 and ST93. Our study demonstrated inter-Nordic distribution of E. coli ST38 with blaCMY-2, suggesting clonal proliferation as a contributing factor for spread of ESC resistance in the broiler production. The international trade in breeding material may explain introduction of resistant E. coli. The reason for their success and the success of certain clonal lineages in broiler production not exposed to antimicrobial selection pressure is currently unknown.


Role of Cannabinoid Receptors in Crocin-Induced Hypoalgesia in Neuropathic Pain in Rats.
Neuropathic pain involves injury or alteration of the normal sensory and modulatory nervous systems to produce a set of symptoms that are often difficult to treat. Previous study indicates that crocin has anti-inflammatory properties that may be mediated by the neurotransmitter system. In this study, we determine if there is an interaction between crocin and the cannabinoid system on chronic constriction injury (CCI)-induced neuropathic pain in male rats. In this experimental study, adult male Wistar rats (220-250 g) were used. CCI was induced by setting four loose ligatures around the sciatic nerve. In part 1, after nerve lesion, vehicle, crocin (60 mg/kg) or Win 55-212-2 (0.1 mg/kg) as an agonist and AM 251 (0.1 mg/kg) as an antagonist of cannabinoid receptors were injected intraperitoneally daily in separate groups for 2 weeks. In part 2, two weeks after nerve lesion, vehicle (5 µL), crocin (6 µg/5 µL), Win 55-212-2 (0.1 µg/5 µL), AM 251 (0.1 µg/5 µL) were administered intracerebroventricularly (ICV) in separate groups. Mechanical allodynia and thermal hyperalgesia were measured using Von Frey filaments and plantar test device, respectively, at day 14. Data were analyzed by two-way ANOVA and Sidak's multiple comparisons post-test. Results indicated that centrally administered crocin significantly decreased thermal hyperalgesia and mechanical allodynia. Also, peripheral injection of crocin significantly decreased mechanical allodynia but not thermal hyperalgesia. Central or peripheral administration of Win 55-212-2 or AM 251 modulates the analgesic effect of crocin significantly. Our findings showed that crocin has significant analgesic effects that are probably mediated by an endocannabinoid mechanism.


Altering the fat content affects flavor release in a model yogurt system.
Flavored yogurts differing in fat content were eaten, and the release of flavor volatiles was measured by monitoring the volatile composition of air from the nose in real time by atmospheric pressure ionization mass spectrometry. Low-fat yogurts (0.2%) were found to release volatiles more quickly and at higher intensity but with less persistence than yogurts containing fat at 3.5 and 10% fat. Yogurts with increasing fat content had higher viscosity and lower relative particle size. Lipophilic compounds were more affected by fat for maximum volatile intensity, but not time-to-maximum intensity or persistence. Sensory assessment of the yogurts found significant differences in intensity and speed of onset of flavor, but not overall length of perception.


Inhibition of PDGFR signaling prevents muscular fatty infiltration after rotator cuff tear in mice.
Fatty infiltration in muscle is often observed in patients with sizable rotator cuff tear (RCT) and is thought to be an irreversible event that significantly compromises muscle plasticity and contraction strength. These changes in the mechanical properties of the affected muscle render surgical repair of RCT highly formidable. Therefore, it is important to learn more about the pathology of fatty infiltration to prevent this undesired condition. In the present study, we aimed to generate a mouse model that can reliably recapitulate some of the important characteristics of muscular fatty infiltration after RCT in humans. We found that fatty infiltration can be efficiently induced by a combination of the following procedures: denervation of the suprascapular nerve, transection of the rotator cuff tendon, and resection of the humeral head. Using this model, we found that platelet-derived growth factor receptor-α (PDGFRα)-positive mesenchymal stem cells are induced after this intervention and that inhibition of PDGFR signaling by imatinib treatment can significantly suppress fatty infiltration. Taken together, the present study presents a reliable fatty infiltration mouse model and suggests a key role for PDGFRα-positive mesenchymal stem cells in the process of fatty infiltration after RCT in humans.


Reducing Heart Failure Hospital Readmissions: A Systematic Review of Disease Management Programs.
The recent enactment of the Patient Protection and Affordable Care Act which established the federal Hospital Readmissions Reduction Program (HRRP) has accelerated efforts to develop heart failure (HF) disease management programs (DMPs) that reduce readmissions in patients hospitalized for HF. This systematic review identified randomized controlled trials of HF DMPs which included home care, outpatient clinic interventions, structured telephone support, and non-invasive and invasive telemonitoring. These different types of DMPs have been associated with conflicting results. No specific type of DMP has produced consistent benefit in reducing HF hospitalizations. Although probably effective at reducing readmissions, home visits and outpatient clinic interventions have substantial limitations including cost and accessibility. Telemanagement has the potential to reach a large number of patients at a reasonable cost. Structured telephone support follow-up has been shown to significantly reduce HF readmissions, but does not significantly reduce all-cause mortality or all-cause hospitalization. A meta-analysis of 11 non-invasive telemonitoring studies demonstrated significant reductions in all-cause mortality and HF hospitalizations. Invasive telemonitoring is a potentially effective means of reducing HF hospitalizations, but only one study using pulmonary artery pressure monitoring was able to demonstrate a reduction in HF hospitalizations. Other studies using invasive hemodynamic monitoring have failed to demonstrate changes in rates of readmission or mortality. The efficacy of HF DMPs is associated with inconsistent results. Our review should not be interpreted to indicate that HF DMPs are universally ineffective. Rather, our data suggest that one approach applied to a broad spectrum of different patient types may produce an erratic impact on readmissions and clinical outcomes. HF DMPs should include the flexibility to meet the individualized needs of specific patients.


The politics of unsafe abortion in Burkina Faso: the interface of local norms and global public health practice.
In Burkina Faso, abortion is legally restricted and socially stigmatised, but also frequent. Unsafe abortions represent a significant public health challenge, contributing to the country's very high maternal mortality ratio. Inspired by an internationally disseminated public health framing of unsafe abortion, the country's main policy response has been to provide post-abortion care (PAC) to avert deaths from abortion complications. Drawing on ethnographic research, this article describes how Burkina Faso's PAC policy emerged at the interface of political and moral negotiations between public health professionals, national bureaucrats and international agencies and NGOs. Burkinabè decision-makers and doctors, who are often hostile to induced abortion, have been convinced that PAC is 'life-saving care' which should be delivered for ethical medical reasons. Moreover, by supporting PAC they not only demonstrate compliance with international standards but also, importantly, do not have to contend with any change in abortion legislation, which they oppose. Rights-based international NGOs, in turn, tactically focus on PAC as a 'first step' towards their broader institutional objective to secure safe abortion and abortion rights. Such negotiations between national and international actors result in widespread support for PAC but stifled debate about further legalisation of abortion.


First principle chemical kinetics in zeolites: the methanol-to-olefin process as a case study.
To optimally design next generation catalysts a thorough understanding of the chemical phenomena at the molecular scale is a prerequisite. Apart from qualitative knowledge on the reaction mechanism, it is also essential to be able to predict accurate rate constants. Molecular modeling has become a ubiquitous tool within the field of heterogeneous catalysis. Herein, we review current computational procedures to determine chemical kinetics from first principles, thus by using no experimental input and by modeling the catalyst and reacting species at the molecular level. Therefore, we use the methanol-to-olefin (MTO) process as a case study to illustrate the various theoretical concepts. This process is a showcase example where rational design of the catalyst was for a long time performed on the basis of trial and error, due to insufficient knowledge of the mechanism. For theoreticians the MTO process is particularly challenging as the catalyst has an inherent supramolecular nature, for which not only the Brønsted acidic site is important but also organic species, trapped in the zeolite pores, must be essentially present during active catalyst operation. All these aspects give rise to specific challenges for theoretical modeling. It is shown that present computational techniques have matured to a level where accurate enthalpy barriers and rate constants can be predicted for reactions occurring at a single active site. The comparison with experimental data such as apparent kinetic data for well-defined elementary reactions has become feasible as current computational techniques also allow predicting adsorption enthalpies with reasonable accuracy. Real catalysts are truly heterogeneous in a space- and time-like manner. Future theory developments should focus on extending our view towards phenomena occurring at longer length and time scales and integrating information from various scales towards a unified understanding of the catalyst. Within this respect molecular dynamics methods complemented with additional techniques to simulate rare events are now gradually making their entrance within zeolite catalysis. Recent applications have already given a flavor of the benefit of such techniques to simulate chemical reactions in complex molecular environments.


Variations of physical activity and sedentary behavior between before and after cancer diagnosis: Results from the prospective population-based NutriNet-Santé cohort.
Physical activity (PA) but also reduced sedentary behavior may be associated with better prognosis and lower risk of recurrence in cancer patients. Our aim was to quantify the variations in PA and time spent sedentary between before and after diagnosis, relying on prospective data in French adults. We also investigated sociodemographic and lifestyle factors associated with these variations.Subjects (n = 942) were incident cancer cases diagnosed in the NutriNet-Santé cohort between 2009 and 2015. PA and sedentary behavior were prospectively collected with the 7-day short version of the IPAQ questionnaire every year since subjects' inclusion (i.e., an average of 2 year before diagnosis). All PA and sitting time points before and after diagnosis was compared by mixed model. Factors associated with decrease in PA and increase in sitting time were investigated using logistic regressions.Overall and vigorous PA decreased after diagnosis (P = 0.006, -32.8 ± 36.8 MET-hour/week on average, in those who decreased their overall PA and P = 0.005, -21.1 ± 36.8 MET-hour/week for vigorous PA, respectively), especially in prostate (-39.5 ± 36.3 MET-hour/week) and skin (-35.9 ± 38 MET-hour/week) cancers, in men (-40.8 ± 46.3MET-hour/week), and in those professionally inactive (-34.2 ± 37.1 MET-hour/week) (all P < 0.05). Patients with higher PA level before diagnosis were more likely to decrease their PA (odds ratio [OR]: 4.67 [3.21-6.81], P < 0.0001). Overweight patients more likely to decrease moderate PA (OR: 1.45 [1.11-1.89], P = 0.006) and walking (OR: 1.30 [1.10-1.70], P = 0.04). Sitting time increased (P = 0.02, +2.44 ± 2.43 hour/day on average, in those who increased their sitting time), especially in women (+2.48 ± 2.48 hour/day), older patients (+2.48 ± 2.57 hour/day), and those professionally inactive (2.41 ± 2.40 hour/day) (all P < 0.05). Patients less sedentary before diagnosis were more likely to increase their sitting time (OR: 3.29 [2.45-4.42], P < 0.0001).This large prospective study suggests that cancer diagnosis is a key period for change in PA and sedentary behavior. It provides insights to target the subgroups of patients who are at higher risk of decreasing PA and increasing sedentary behavior after cancer diagnosis.


Multivariate joint frailty model for the analysis of nonlinear tumor kinetics and dynamic predictions of death.
The Response Evaluation Criteria in Solid Tumors are used as standard guidelines for the clinical evaluation of cancer treatments. The assessment is based on the anatomical tumor burden: change in size of target lesions and evolution of nontarget lesions (NTL). Despite unquestionable advantages of this standard tool, Response Evaluation Criteria in Solid Tumors are subject to some limitations such as categorization of continuous tumor size or negligence of its longitudinal trajectory. In particular, it is of interest to capture its nonlinear shape and model it simultaneously with recurrent progressions of NTL and overall survival. We propose a multivariate nonlinear mechanistic joint frailty model for longitudinal data, recurrent events, and a terminal event. In the model, the tumor size trajectory is described using an ordinary differential equation that accounts for the natural growth and treatment-induced decline. We perform a simulation study to validate the method and apply the model to a phase III clinical trial in colorectal cancer. In the results of the analysis, we determine on which component, tumor size, NTL, or death the treatment acts mostly and perform dynamic predictions of death. We compare the model with other models that consider parametric functions or splines for the tumor size trajectory in terms of goodness of fit and predictive accuracy.


Oral rehabilitation with tilted dental implants: a metaanalysis.
To compare the course of patients treated with tilted implants versus those treated conventionally with axial implants, analyzing the success rate and marginal bone loss. A PubMed search was made using the key words "tilted implants ", "angled implants ", "angulated implants ", "inclined implants " and "maxillary atrophy. " A review was made of the articles published between 1999-2010. The inclusion criteria were the use of tilted implants, clinical series involving at least 10 patients, and a minimum follow-up of 12 months after prosthetic loading. The exclusion criteria were isolated clinical cases, studies with missing data, and publications in languages other than English or Spanish. The metaanalysis finally included 13 articles: 7 retrospective studies and 6 prospective studies. On analyzing the success rate in the retrospective studies, two reported a higher success rate with tilted implants; one a higher success rate with axial implants; and two reported similar success rates with both implants. On analyzing the success rate in the prospective studies, two reported a higher success rate with tilted implants; two a higher success rate with axial implants; and two reported similar success rates with both implants. On examining marginal bone loss, three studies reported greater bone loss with axial implants and one with tilted implants. There was no evidence of differences in success rate between tilted and axial implants in either the prospective or retrospective studies subjected to review. The marginal bone loss observed with the tilted and axial implants likewise proved very similar. It thus can be deduced that tilted implants exhibit the same evolutive behavior as axial implants.


Omega-3 Fatty Acid Supplementation Reduces Intervertebral Disc Degeneration.
BACKGROUND Intervertebral disc (IVD) degeneration is a common cause of lower back pain, which carries substantial morbidity and economic cost. Omega-3 fatty acids (n-3 FA) are known to reduce inflammatory processes with a relatively benign side effect profile. This study aimed to investigate the effect of n-3 FA supplementation on IVD degeneration. MATERIAL AND METHODS Two non-contiguous lumbar discs of 12 Sprague Dawley rats were needle-punctured to induce disc degeneration. Post-surgery, rats were randomly assigned to either a daily n-3 FA diet (530 mg/kg/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a 2: 1 ratio, administered in sucrose solution) or control diet (sucrose solution only), which was given for the duration of the study. After 1 month, blood serum arachidonic acid/eicosapentaenoic acid (AA/EPA) ratios were analyzed. After 2 months, micro-MRI (magnetic resonance imaging) analysis and histological staining of disc explants were performed to analyze the IVD. RESULTS A reduction of blood AA/EPA ratios from 40 to 20 was demonstrated after 1 month of daily supplementation with n-3 FA. Micro-MRI analysis showed an injury-induced reduction of IVD hydration, which was attenuated in rats receiving n-3 FA. Histological evaluation demonstrated the destruction of nucleus pulposus tissue in response to needle puncture injury, which was less severe in the n-3 FA diet group. CONCLUSIONS The results of this study suggest that n-3 FA dietary supplementation reduces systemic inflammation by lowering AA/EPA ratios in blood serum and has potential protective effects on the progression of spinal disc degeneration, as demonstrated by reduced needle injury-induced dehydration of intervertebral discs and reduced histological signs of IVD degeneration.


The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells.
Endothelial dysfunction and oxidative stress are matters of concern in patients with chronic renal failure (CRF). Uremic solutes retained in these patients could be involved in these processes. Notably, the protein-bound uremic solute indoxyl sulfate induces endothelial dysfunction in vitro, and has shown pro-oxidant effects. To demonstrate that indoxyl sulfate is a potential mediator of oxidative stress in endothelial cells in vitro. Indoxyl sulfate-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) was studied by measuring reactive oxygen specie (ROS) production by cytofluorimetry, by analyzing the involvement of the pro-oxidative enzymes NAD(P)H oxidase, xanthine oxidase, and NO synthase, and by measuring the levels of the non-enzymatic antioxidant glutathione. We showed that indoxyl sulfate induced a significant production of ROS in HUVEC, with or without human serum albumin. We then investigated the role of pro-oxidative enzymes and measured the levels of the antioxidant glutathione. The NAD(P)H oxidase inhibitors, DPI, and apocynin, inhibited ROS production, whereas inhibitors of xanthine oxidase, NO synthase, and mitochondrial ROS had no effect. Interestingly, indoxyl sulfate strongly decreased the levels of glutathione, one of the most active antioxidant systems of the cell. In addition, the ROS production mediated by indoxyl sulfate was inhibited by the antioxidants vitamin C, vitamin E, and NAC. The uremic solute indoxyl sulfate enhances ROS production, increases NAD(P)H oxidase activity, and decreases glutathione levels in endothelial cells. Thus, indoxyl sulfate induces oxidative stress by modifying the balance between pro- and antioxidant mechanisms in endothelial cells.


Elevated serum IGF-1 levels synergize PTH action on the skeleton only when the tissue IGF-1 axis is intact.
There is growing evidence that insulin-like growth factor 1 (IGF-1) and parathyroid hormone (PTH) have synergistic actions on bone and that part of the anabolic effects of PTH is mediated by local production of IGF-1. In this study we analyzed the skeletal response to PTH in mouse models with manipulated endocrine or autocrine/paracrine IGF-1. We used mice carrying a hepatic IGF-1 transgene (HIT), which results in a threefold increase in serum IGF-1 levels and normal tissue IGF-1 expression, and Igf1 null mice with blunted IGF-1 expression in tissues but threefold increases in serum IGF-1 levels (KO-HIT). Evaluation of skeletal growth showed that elevations in serum IGF-1 in mice with Igf1 gene ablation in all tissues except the liver (KO-HIT) resulted in a restoration of skeletal morphology and mechanical properties by adulthood. Intermittent PTH treatment of adult HIT mice resulted in increases in serum osteocalcin levels, femoral total cross-sectional area, cortical bone area and cortical bone thickness, as well as bone mechanical properties. We found that the skeletal response of HIT mice to PTH was significantly higher than that of control mice, suggesting synergy between IGF-1 and PTH on bone. In sharp contrast, although PTH-treated KO-HIT mice demonstrated an anabolic response in cortical and trabecular bone compartments compared with vehicle-treated KO-HIT mice, their response was identical to that of PTH-treated control mice. We conclude that (1) in the presence of elevated serum IGF-1 levels, PTH can exert an anabolic response in bone even in the total absence of tissue IGF-1, and (2) elevations in serum IGF-1 levels synergize PTH action on bone only if the tissue IGF-1 axis is intact. Thus enhancement of PTH anabolic actions depends on tissue IGF-1.


Interaction of trace metal contaminants on hematological responses: influence of infection with Trypanosoma lewisi.
The influence of trace metal contaminants (lead, cadmium, and mercury) on Sprague-Dawley rats was investigated to determine whether subclinical levels of these metals might have adverse effects on the host's ability to respond to an infective agent.In the present study, a trace metal contaminant-trypanosome system was employed to observe the hematological changes in rats infected with Trypanosoma lewisi. The animal groups were: (1) lead (Pb), (2) cadmium (Cd), (3) mercury (Hg), and (4) controls (animals not exposed to trace metals).Regardless of the trace metals, infected animals showed decreases in total erythrocyte counts and lower hematocrit values. Generally, infected animals also showed increases in total leucocyte counts, decreases in the percentages of lymphocytes and monocytes, increases in percentage of neutrophils, and no changes in percentages of eosinophils and basophils.


Local terahertz microspectroscopy with λ/100 spatial resolution.
We have extended the spectral range of a differential method of infrared microspectroscopy in order to operate in the terahertz spectral region. We show on samples of graphite embedded in a matrix of polymers that the spatial resolution is practically independent of the wavelength and is at least λ/100. This method aims at performing "chemical mapping" of various objects since it is sensitive only to the imaginary part of the index of refraction.


Patients' Conceptualizations of Responsibility for Healthcare: A Typology for Understanding Differing Attributions in the Context of Patient Safety.
This study examines how patients conceptualize "responsibility" for their healthcare and make sense of the complex boundaries between patient and professional roles. Focusing on the specific case of patient safety, narrative methods were used to analyze semistructured interviews with 28 people recently discharged from hospital in England. We present a typology of attribution, which demonstrates that patients' attributions of responsibility to staff and/or to patients are informed by two dimensions of responsibility: basis and contingency. The basis of responsibility is the reason for holding an individual or group responsible. The contingency of responsibility is the extent to which that attribution is contextually situated. The article contributes to knowledge about responsibility in complex organizational environments and offers a set of conceptual tools for exploring patients' understanding of responsibility in such contexts. There are implications for addressing patient engagement in care, within and beyond the field of patient safety.


National and State-Specific Shingles Vaccination Among Adults Aged ≥60 Years.
Shingles (herpes zoster) causes substantial morbidity, especially among older adults. The shingles vaccine has been recommended for people aged ≥60 years since 2006. This study assessed recent shingles vaccination at national and state levels among adults aged ≥60 years. The 2014 Behavioral Risk Factor Surveillance System data were analyzed in 2015 to assess shingles vaccination coverage among adults aged ≥60 years at national and state levels. Multivariable logistic regression and predictive marginal models identified factors independently associated with vaccination. Shingles vaccination coverage among adults aged ≥60 years was 31.8% (95% CI=31.4%, 32.2%). Among states, shingles vaccination coverage ranged from 17.8% (95% CI=15.8%, 20.0%) in Mississippi to 46.6% (95% CI=44.3%, 48.8%) in Vermont, with a median of 33.3%. Coverage was <25% in four states and >40% in nine states. For all states, coverage was significantly higher among non-Hispanic whites compared with non-white races except for Oregon, with coverage differences ranging from -33.2% in the District of Columbia to 0.9% in Oregon and a median of -16.0%. Characteristics independently associated with vaccination were age, race/ethnicity, sex, education, employment status, household income, region, perceived health status, health insurance status, personal healthcare provider, routine checkup status, and whether reporting that cost was a barrier to seeing a doctor. Coverage varied dramatically by state. State-level comparisons may aid in designing tailored intervention programs through sharing of best practices. Strategies are needed to mitigate financial barriers for both provider and patients, improve awareness, and increase provider recommendation of the vaccine.


Hearing Restoration with Cochlear Implantation in Patients Deafened after Blunt Head Trauma.
The objective of the study was to assess the outcomes of cochlear implantation in patients deafened following blunt head trauma. Retrospective case series review of seven patients post-lingually deafened following blunt head trauma and aided with cochlear implants. The following data were analyzed: Cause of injury, computed tomography results, surgical information, intra- and post-implantation complications, audiometric and speech perception assessment, processor mapping, and data from follow-up appointments. The median age of patients at the time of cochlear implantation was 29 years. The median time elapsed between head trauma and cochlear implantation was 5.77 months (minimum 0.8 and maximum 6.73 months). The median post-implantation follow-up time was 11.97 years. No facial nerve stimulation was observed in any case. All patients significantly improved their audiology and speech perception performances within a short time following cochlear implantation and CI performance did not decrease with long-term follow-up in any case. The results of this study showed that cochlear implantation is an effective treatment method for patients deafened following blunt head trauma.


Twenty-stimulus train for rapid acquisition of auditory brainstem responses in humans.
This study addressed the clinical need to obtain frequency-specific auditory brainstem responses (ABRs) more rapidly than is currently possible. ABRs were obtained from 20 subjects using two different methods: a conventional method with tone bursts presented singly and a multiple-stimulus method using a train of 20 tone bursts. For both methods, tone bursts were presented at frequencies 1, 2, 4, and 8 kHz, shaped with a Blackman-Harris window and having intensity levels up to 105 dB peak equivalent sound pressure level (peSPL). The single tone bursts were presented at a 17.2/sec repetition rate. The 20 tone-burst train used the four frequencies at five intensities each and a repetition rate of 3.7/sec (separations between tone bursts of 9-12 msec, with 77 msec off-time between trains). Mean latencies and mean amplitudes for wave V were compared using t-tests for each of 12 conditions (four frequencies, each at the three highest output levels). For latency, only one comparison was significantly different (2 kHz, 77 dB peSPL). Similarly, only one comparison was significant for amplitude (2 kHz, 97 dB peSPL). There was, however, a trend for the tone bursts presented in trains to have longer latencies and reduced amplitudes compared to the respective responses for the single tone-burst condition. These results indicate the presence of some response adaptation when tone bursts are presented in a train. The use of a properly designed stimulus train can result in a significant time savings for obtaining frequency-specific ABRs as compared with single tone-burst presentations.


Structuring Clinical Decision Support Rules for Drug Safety Using Natural Language Processing.
Drug safety is an important aspect in healthcare, resulting in a number of inadvertent events, which may harm the patients. IT based Clinical Decision Support (CDS), integrated in electronic-prescription or Electronic Health Records (EHR) systems, can provide a means for checking prescriptions for errors. This requires expressing prescription guidelines in a way that can be interpreted by IT systems. The paper uses Natural Language Processing (NLP), to interpret drug guidelines by the UK NICE BNF offered in free text. The employed NLP component, MetaMap, identifies the concepts in the instructions and interprets their semantic meaning. The UMLS semantic types that correspond to these concepts are then processed, in order to understand the concepts that are needed to be implemented in software engineering for a CDS engine.


Long-term Adhesion Study of Self-etching Systems to Plasma-treated Dentin.
To determine the influence of atmospheric pressure plasma (APP) treatment on the microtensile dentin bond strength of two self-etching adhesive systems after one year of water storage as well as observe the contact angle changes of dentin treated with plasma and the micromorphology of resin/dentin interfaces using SEM. For contact angle measurements, 6 human molars were sectioned to remove the occlusal enamel surface, embedded in PMMA resin, and ground to expose a flat dentin surface. Teeth were divided into two groups: 1) argon APP treatment for 30 s, and 2) blown air (control). For the microtensile test, 28 human third molars were used and prepared similarly to contact angle measurements. Teeth were randomly divided into 4 groups (n = 7) according to two self-etching adhesives and APP treatment (with/without). After making the composite resin buildup, teeth were sectioned perpendicular to the bonded interface to obtain beam specimens. The specimens were tested after 24 h and one year of water storage until failure. Bond strength data were analyzed by three-way ANOVA and Tukey's post-hoc test (α = 0.05%). Three beam specimens per group that were not used in the bond strength test were prepared for interfacial SEM analysis. APP application decreased the contact angle, but increased the bond strength only for one adhesive tested. SEM evaluation found signs of degradation within interfacial structures following 1-year aging in water. APP increased the dentin surface energy, but the effects of APP and 1-year water storage on dentin bond strength were product dependent. APP increased the dentin surface energy. It also increased the bond strength for Scotchbond Universal, but storage for one year negated the positive effect of APP treatment.


Formulation development and comparative in vitro study of metoprolol tartrate (IR) tablets.
The objective of the present work was to develop Immediate Release (IR) tablets of Metoprolol Tartrate (MT) and to compare trial formulations to a reference product. Six formulations (F1-F6) were designed using central composite method and compared to a reference brand (A). Two marketed products (brands B and C) were also evaluated. F1-F6 were prepared with Avicel PH101 (filler), Crospovidone (disintegrant) and Magnesium Stearate (lubricant) by direct compression. Pharmacopoeial and non-pharmacopoeial methods were used to assess their quality. Furthermore, drug profiles were characterized using model dependent and independent (f(2)) approaches. Brands B and C and F5 and F6 did not qualify the tests for content uniformity. Moreover, brand B did not meet weight variation criteria and brand C did not satisfy requirements for single point dissolution test. Of the trial formulations, F2 failed the test for uniformity in thickness while F4 did not disintegrate within time limit. Only F1 and F3 met all quality parameters and were subjected to accelerated stability testing without significant alterations in their physicochemical characteristics. Based on AIC and r(2)(adjusted) values obtained by applying various kinetic models, drug release was determined to most closely follow Hixson-Crowell cube root law. F1 was determined to be the optimized formulation.


Role of Bacillus subtilis DNA Glycosylase MutM in Counteracting Oxidatively Induced DNA Damage and in Stationary-Phase-Associated Mutagenesis.
Reactive oxygen species (ROS) promote the synthesis of the DNA lesion 8-oxo-G, whose mutagenic effects are counteracted in distinct organisms by the DNA glycosylase MutM. We report here that in Bacillus subtilis, mutM is expressed during the exponential and stationary phases of growth. In agreement with this expression pattern, results of a Western blot analysis confirmed the presence of MutM in both stages of growth. In comparison with cells of a wild-type strain, cells of B. subtilis lacking MutM increased their spontaneous mutation frequency to Rif(r) and were more sensitive to the ROS promoter agents hydrogen peroxide and 1,1'-dimethyl-4,4'-bipyridinium dichloride (Paraquat). However, despite MutM's proven participation in preventing ROS-induced-DNA damage, the expression of mutM was not induced by hydrogen peroxide, mitomycin C, or NaCl, suggesting that transcription of this gene is not under the control of the RecA, PerR, or σ(B) regulons. Finally, the role of MutM in stationary-phase-associated mutagenesis (SPM) was investigated in the strain B. subtilis YB955 (hisC952 metB5 leuC427). Results revealed that under limiting growth conditions, a mutM knockout strain significantly increased the amount of stationary-phase-associated his, met, and leu revertants produced. In summary, our results support the notion that the absence of MutM promotes mutagenesis that allows nutritionally stressed B. subtilis cells to escape from growth-limiting conditions. The present study describes the role played by a DNA repair protein (MutM) in protecting the soil bacterium Bacillus subtilis from the genotoxic effects induced by reactive oxygen species (ROS) promoter agents. Moreover, it reveals that the genetic inactivation of mutM allows nutritionally stressed bacteria to escape from growth-limiting conditions, putatively by a mechanism that involves the accumulation and error-prone processing of oxidized DNA bases.


MANAGEMENT OF ENDOCRINE DISEASE: Transition of care for young adult patients with Turner syndrome
Turner syndrome (TS), affecting 1/2000 to 1/2500 live born girls, is a chromosomal aberration with a total or partial loss of one of the X chromosomes. The diagnosis can be established from the intra-uterine life to adulthood. TS is a chronic disease with particular morbidity and mortality. The loss to follow-up rate, during transition, between children and adult units, remains a crucial issue. This review focusses on the adolescent and young adult patients with TS. The different goals of TS transition are presented as well as some of the tools available in order to improve this transition. The involvement of the patient's family, advocacy groups and therapeutic educational programs are discussed. A specificity concerning TS transition, as compared to other chronic diseases, relies on the fact that patients with TS may present a peculiar neurocognitive profile. They are in general more anxious than the general population. Therefore, psychological support should be offered to optimize transition. Data illustrating the beneficial impact of an organised transition of TS, from paediatric units to multidisciplinary adult care systems, within the same reference centre are presented. Further studies are required to evaluate the mid-to-long-term transition of paediatric patients with TS referred to adult units.


Effect of Azadinium spinosum on the feeding behaviour and azaspiracid accumulation of Mytilus edulis.
Azadinium spinosum, a small toxic dinoflagellate, was recently isolated and identified as a primary producer of azaspiracid toxins (AZAs). Previous experiments related to AZA accumulation in blue mussels upon direct feeding with A. spinosum revealed increased mussel mortality and had negative effects on the thickness of the digestive gland tubules. Therefore we conducted follow up experiments in order to study effects of A. spinosum on mussel feeding behaviour. Individual assessment of mussel feeding time activity (FTA), clearance rate (CR), filtration rate (TFR), absorption rate (AR), faeces and pseudofaeces production were carried out on mussel fed either toxic (A. spinosum) or non-toxic (Isochrisis aff. galbana (T-Iso)) diets. Furthermore, AZA accumulation and biotransformation in mussels were followed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A. spinosum had a significant effect on mussel feeding behaviour compared to T-Iso: CR was lower by a factor of 6, FTA by a factor of 5, TFR by a factor of 3 and AR even decreased to negative values for the last day of exposure. Even so, a rapid AZA accumulation was observed during the first hours of the trial; less than 6h of feeding were required to reach AZA concentration in mussel above regulatory level. In consistence with physiological observations, AZA concentration of about 200 μg kg(-1) did not increase further until the end of the study. AZA bioconversion was also found to be a fast process: after 3h of exposure AZA17, -19 and AZA7-10 were already found, with a proportion of AZA17 equal to AZA2. These results show a negative effect of A. spinosum on blue mussel feeding activity and indicate a possible regulation of AZA uptake by decreasing filtration and increasing pseudofaeces production.


Crocetin Improves Dengue Virus-Induced Liver Injury.
Dengue virus (DENV) infection is one of the most widespread mosquito-borne viral infections. Liver injury is commonly observed in severe DENV infection, and the present study aimed to examine the efficacy of crocetin treatment in an immunocompetent mouse model of DENV infection exhibiting liver injury. The efficacy of crocetin treatment in DENV-induced liver injury was assessed via both transaminase levels and histopathology analysis. A real-time polymerase chain reaction array was then used to describe the expression of 84 apoptosis-related genes. Using real-time RT-PCR and Western blot analysis, the gene expressions of host factors were investigated. Additionally, the effect of crocetin in NF-kB signaling during DENV infection was studied. We did not observe any significant reduction in virus production when DENV-infected mice were treated with crocetin. However, DENV-infected mice treated with crocetin showed reduced DENV-induced apoptosis. The real-time polymerase chain reaction array revealed pro-inflammatory cytokine expressions to be significantly reduced in the crocetin-treated DENV-infected mice. We also found that crocetin could effectively modulate antioxidant status in DENV-infected mice. Moreover, crocetin demonstrated the ability to reduce the nuclear translocation of NF-kB in DENV-infected mice. Our results suggest that crocetin treatment does not inhibit DENV replication in the liver of DENV-infected mice; however, we did find that crocetin improves host responses that reduce liver injury.


The intrinsic microglial clock system regulates interleukin-6 expression.
Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198-208.


Raven-II: an open platform for surgical robotics research.
The Raven-II is a platform for collaborative research on advances in surgical robotics. Seven universities have begun research using this platform. The Raven-II system has two 3-DOF spherical positioning mechanisms capable of attaching interchangeable four DOF instruments. The Raven-II software is based on open standards such as Linux and ROS to maximally facilitate software development. The mechanism is robust enough for repeated experiments and animal surgery experiments, but is not engineered to sufficient safety standards for human use. Mechanisms in place for interaction among the user community and dissemination of results include an electronic forum, an online software SVN repository, and meetings and workshops at major robotics conferences.


Source country-specific burden on health due to high concentrations of PM2.5.
Asian countries face frequent spikes in concentrations of particulate matter smaller than 2.5 μm (PM2.5), which may consist of domestic emissions, transported pollutants from neighboring countries, and secondary aerosol formation (SAF). We aimed to estimate the burden on health in South Korea due to PM2.5 exposure from source countries. We computed the health benefits of meeting air quality guidelines during high pollution periods or spike periods. We used daily mortality counts, PM2.5 concentrations, and primary and secondary contributions to pollutant levels in seven cities and nine provinces in South Korea during 2006-2016. Generalized additive mixed modeling with a Poisson distribution and random effects in 16 regions was used to examine the short-term effects of PM2.5 on mortality. We computed attributable burden due to PM2.5 exposure and the potential benefits of meeting the air quality guidelines set by the World Health Organization (WHO, 25 μg/m3) and the Korea Ministry of Environment (50 and 35 μg/m3 before and after 2015, respectively). A concentration-response curve showed a non-linear relationship between daily mortality counts and PM2.5 levels. The short-term health impacts of PM2.5 were suggested to be 1638 non-accidental deaths in 2016 in South Korea due to daily domestic emissions and pollutants transported from neighboring countries. Of these, 1509, 995, or 238 deaths could have been prevented if the daily mean PM2.5 concentration had been kept below 25, 35, or 50 μg/m3. After accounting for the contribution of SAF to PM2.5, primary sources of PM2.5 resulted in 258-860 and 26-88 deaths due to pollution transported from China and North Korea, respectively, and 162-538 deaths were due to domestic emissions. Meeting the air quality guidelines of the WHO could have prevented most of these deaths.


Insulin-induced desensitization at the receptor and postreceptor level in mitogen-activated human T-lymphocytes.
Human T-lymphocytes activated by phytohemagglutin acquire insulin receptors in culture. Saturation analysis of insulin-binding activity in the presence of competing ligand revealed curvilinear Scatchard plots. Insulin receptors were not regulated by insulin before mitogen activation and culture of T-lymphocytes. However, insulin-induced downregulation of insulin receptors was: (1) demonstrable in receptor-positive cells, (2) dependent on insulin concentration, (3) temporally unrelated to insulin internalization, and (4) prevented by culture at 4 degrees C but not by cycloheximide at 37 degrees C. Recovery of insulin receptors required further culture of cells in media depleted of insulin for 24 h. Scatchard analysis revealed loss of receptor number without changes in receptor affinity. Insulin-induced increases in glucose transport and oxidation were demonstrable in receptor-positive cells but not in receptor-negative cells. However, these effects were extremely time-dependent. After a 2-h exposure of cells to 10(-8) M insulin, increases in glucose transport were no longer demonstrable. Elution of bound insulin from these cells followed by re-exposure to insulin depressed glucose transport in them. Recovery from this hyporesponsive, desensitized state required a 6-h culture in insulin-depleted media. Glucose oxidation of desensitized cells could be stimulated by spermine but not by insulin. These studies demonstrate the activated human T-lymphocyte is an insulin-sensitive tissue that is capable of limiting its physiologic response to insulin by receptor- and postreceptor-mediated mechanisms.


A warm jet in a cold ocean.
Unprecedented quantities of heat are entering the Pacific sector of the Arctic Ocean through Bering Strait, particularly during summer months. Though some heat is lost to the atmosphere during autumn cooling, a significant fraction of the incoming warm, salty water subducts (dives beneath) below a cooler fresher layer of near-surface water, subsequently extending hundreds of kilometers into the Beaufort Gyre. Upward turbulent mixing of these sub-surface pockets of heat is likely accelerating sea ice melt in the region. This Pacific-origin water brings both heat and unique biogeochemical properties, contributing to a changing Arctic ecosystem. However, our ability to understand or forecast the role of this incoming water mass has been hampered by lack of understanding of the physical processes controlling subduction and evolution of this this warm water. Crucially, the processes seen here occur at small horizontal scales not resolved by regional forecast models or climate simulations; new parameterizations must be developed that accurately represent the physics. Here we present novel high resolution observations showing the detailed process of subduction and initial evolution of warm Pacific-origin water in the southern Beaufort Gyre.


The effect of fear of movement on muscle activation in posttraumatic neck pain disability.
Studies using surface electromyography have demonstrated a reorganization of muscle activation patterns of the neck and shoulder muscles in patients with posttraumatic neck pain disability. The neurophysiologically oriented "pain adaptation" model explains this reorganization as a useful adaptation to prevent further pain and injury. The cognitive-behavioral-oriented "fear avoidance" model suggests that fear of movement, in addition to the effects of pain, modulates the muscle activation level. We analyzed the extent to which pain and fear of movement influenced the activation patterns of the upper trapezius muscle during the transition from acute to chronic posttraumatic neck pain. Ninety-two people with an acute traumatic neck injury after a motor vehicle accident were followed up for 24 weeks. Visual analog scale ratings of pain intensity, response on the Tampa Scale of Kinesophobia--fear of movement, and surface electromyography of the upper trapezius muscles during a submaximal isometric physical task were obtained at 1, 4, 8, 12, and 24 weeks after the motor vehicle accident. Multilevel analysis revealed that an increased level of both fear of movement (t value=-2.19, P=0.030) and pain intensity (t value=-2.94, P=0.004) were independently associated with a decreased level of muscle activation. Moreover, the results suggest that the association between fear of movement and lower muscle activity level is stronger in patients reporting high pain intensity (t value=2.15, P=0.033). The contribution of pain intensity to the muscle activation level appeared to decrease over time after the trauma (t value=2.58, P=0.011). The results support both the "pain adaptation" and the "fear avoidance" models. It is likely that the decrease in muscle activation level is aimed at "avoiding" the use of painful muscles.


Antioxidant capacity in the lipophilic fraction of Alzheimer's brain tissues.
The aim of this study was to investigate the antioxidant capacity (AC) in the lipophilic fraction of postmortem motorcortex (MC), nucleus caudatus (NC) and gyrus temporalis (GT) from controls (C) and Alzheimer's disease (AD) patients. The initial samples consisted of 50 human brain tissues of AD and C. AC of the different region of human brain were measured by using the fluorescent method of the oxygen radical absorbance capacity (ORAC). Peroxyl and hydroxyl radical generators were used in the analysis. All ORAC analysis were carried out on the Perkin-Elmer spectrofluorometer LS 55 with fluorescent filters, Ex: 485 nm; Em: 520 nm. Final results were calculated using the differences between area under the quenching curve of fluorescein (FL), blank and analyzed biological samples. AC against peroxyl radicals (ORAC-ROO degrees ) of lipophilic fraction in MC of AD was statistically significantly lower in comparison with MC of C (p < 0.008). No changes in the AC against hydroxyl radicals (ORAC- degrees OH) of lipophilic fraction of AD were found in comparison with C. Reduction of total protein in GT of AD (p < 0.03) was found. The results showed that in the MC of AD brain the balance between production of free radicals and the neutralization by a complex antioxidant system is disturbed. The manual fluorescent method for AC measurements proved to be sufficiently appropriate and sensitive for the AC measurements of lipophilic fraction of postmortem brain tissues from different patologic conditions.


Ubiquitin- and MDM2 E3 ligase-independent proteasomal turnover of nucleostemin in response to GTP depletion.
Nucleostemin (NS) is a nucleolar GTP-binding protein essential for ribosomal biogenesis, proliferation, and animal embryogenesis. It remains largely unclear how this protein is regulated. While working on its role in suppression of MDM2 and activation of p53, we observed that NS protein (but not mRNA) levels decreased drastically in response to GTP depletion. When trying to further elucidate the molecular mechanism(s) underlying this unusual phenomenon, we found that NS was degraded independently of ubiquitin and MDM2 upon GTP depletion. First, depletion of GTP by treating cells with mycophenolic acid decreased the level of NS without apparently affecting the levels of other nucleolar proteins. Second, mutant NS defective in GTP binding and exported to the nucleoplasm was much less stable than wild-type NS. Although NS was ubiquitinated in cells, its polyubiquitination was independent of Lys-48 or Lys-63 in the ubiquitin molecule. Inactivation of E1 in E1 temperature-sensitive mouse embryonic fibroblast (MEF) cells failed to prevent the proteasomal degradation of NS. The proteasomal turnover of NS was also MDM2-independent, as its half-life in p53/MDM2 double knock-out MEF cells was the same as that in wild-type MEF cells. Moreover, NS ubiquitination was MDM2-independent. Mycophenolic acid or doxorubicin induced NS degradation in various human cancerous cells regardless of the status of MDM2. Hence, these results indicate that NS undergoes a ubiquitin- and MDM2-independent proteasomal degradation when intracellular GTP levels are markedly reduced and also suggest that ubiquitination of NS may be involved in regulation of its function rather than stability.


Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper.
Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.