Developing and implementing core competencies for integrative medicine fellowships.
The Consortium of Academic Health Centers for Integrative Medicine defines integrative medicine as "the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, health care professionals, and disciplines to achieve optimal health and healing." Over the past three decades, the U.S. public increasingly has sought integrative medicine approaches. In an effort to train medical professionals to adequately counsel patients on the safe and appropriate use of these approaches, medical schools and residencies have developed curricula on integrative medicine for their trainees. In addition, integrative medicine clinical fellowships for postresidency physicians have emerged to provide training for practitioners interested in gaining greater expertise in this emerging field. Currently, 13 clinical fellowships in integrative medicine exist in the United States, and they are predominantly connected to academic medical centers or teaching affiliate hospitals. In 2010, the Consortium of Academic Health Centers for Integrative Medicine, represented by 56 member academic health care institutions with a shared commitment to advance the principles and practices of integrative medicine, convened a two-year task force to draft integrative medicine fellowship core competencies. These competencies would guide fellowship curriculum development and ensure that graduates possessed a common body of knowledge, skills, and attitudes. In this article, the authors discuss the competencies and the task force's process to develop them, as well as associated teaching and assessment methods, faculty development, potential barriers, and future directions.


Developmental roles of Auxin Binding Protein 1 in Arabidopsis thaliana.
Auxin is a major plant growth regulator, but current models on auxin perception and signaling cannot explain the whole plethora of auxin effects, in particular those associated with rapid responses. A possible candidate for a component of additional auxin perception mechanisms is the AUXIN BINDING PROTEIN 1 (ABP1), whose function in planta remains unclear. Here we combined expression analysis with gain- and loss-of-function approaches to analyze the role of ABP1 in plant development. ABP1 shows a broad expression largely overlapping with, but not regulated by, transcriptional auxin response activity. Furthermore, ABP1 activity is not essential for the transcriptional auxin signaling. Genetic in planta analysis revealed that abp1 loss-of-function mutants show largely normal development with minor defects in bolting. On the other hand, ABP1 gain-of-function alleles show a broad range of growth and developmental defects, including root and hypocotyl growth and bending, lateral root and leaf development, bolting, as well as response to heat stress. At the cellular level, ABP1 gain-of-function leads to impaired auxin effect on PIN polar distribution and affects BFA-sensitive PIN intracellular aggregation. The gain-of-function analysis suggests a broad, but still mechanistically unclear involvement of ABP1 in plant development, possibly masked in abp1 loss-of-function mutants by a functional redundancy.


Metabolite profiling identifies markers of uremia.
ESRD is a state of small-molecule disarray. We applied liquid chromatography/tandem mass spectrometry-based metabolite profiling to survey>350 small molecules in 44 fasting subjects with ESRD, before and after hemodialysis, and in 10 age-matched, at-risk fasting control subjects. At baseline, increased levels of polar analytes and decreased levels of lipid analytes characterized uremic plasma. In addition to confirming the elevation of numerous previously identified uremic toxins, we identified several additional markers of ESRD, including dicarboxylic acids (adipate, malonate, methylmalonate, and maleate), biogenic amines, nucleotide derivatives, phenols, and sphingomyelins. The pattern of lipids was notable for a universal decrease in lower-molecular-weight triacylglycerols, and an increase in several intermediate-molecular-weight triacylglycerols in ESRD compared with controls; standard measurement of total triglycerides obscured this heterogeneity. These observations suggest disturbed triglyceride catabolism and/or beta-oxidation in ESRD. As expected, the hemodialysis procedure was associated with significant decreases in most polar analytes. Unexpected increases in several metabolites, however, indicated activation of a broad catabolic program, including glycolysis, lipolysis, ketosis, and nucleotide breakdown. In summary, this study demonstrates the application of metabolite profiling to identify markers of ESRD, provide perspective on uremic dyslipidemia, and broaden our understanding of the biochemical effects of hemodialysis.


Gender and crime victimization modify neighborhood effects on adolescent mental health.
Leverage an experimental study to determine whether gender or recent crime victimization modify the mental health effects of moving to low-poverty neighborhoods. The Moving to Opportunity (MTO) study randomized low-income families in public housing to an intervention arm receiving vouchers to subsidize rental housing in lower-poverty neighborhoods or to controls receiving no voucher. We examined 3 outcomes 4 to 7 years after randomization, among youth aged 5 to 16 years at baseline (n = 2829): lifetime major depressive disorder (MDD), psychological distress (K6), and Behavior Problems Index (BPI). Treatment effect modification by gender and family's baseline report of recent violent crime victimization was tested via interactions in covariate-adjusted intent-to-treat and instrumental variable adherence-adjusted regression models. Gender and crime victimization significantly modified treatment effects on distress and BPI (P < .10). Female adolescents in families without crime victimization benefited from MTO treatment, for all outcomes (Distress B = -0.19, P = .008; BPI B = -0.13, P = .06; MDD B = -0.036, P = .03). Male adolescents in intervention families experiencing crime victimization had worse distress (B = 0.24, P = .004), more behavior problems (B = 0.30, P < .001), and nonsignificantly higher MDD (B = 0.022, P = .16) versus controls. Other subgroups experienced no effect of MTO treatment. Instrumental variable estimates were similar but larger. Girls from families experiencing recent violent crime victimization were significantly less likely to achieve mental health benefits, and boys were harmed, by MTO, suggesting need for cross-sectoral program supports to offset multiple stressors.


Heart failure with preserved ejection fraction.
Progressive aging of the population and prolongation of life expectancy have led to the rising prevalence of heart failure (HF). Despite the improvements in medical therapy, the mortality rate of this condition has remained unacceptably high, becoming the primary cause of death in the elderly population. Almost half of patients with signs and symptoms of HF are found to have a nearly normal ejection fraction, which delineates a distinct clinical syndrome, known as HF with preserved ejection fraction (HF-PEF). While early research focused on the importance of diastolic dysfunction, more recent studies reported the pathophysiological complexity of the disease with multiple cardiovascular abnormalities contributing to its development and progression. HF-PEF is a challenging major health problem with yet no solution as there is no evidence-based treatment which improves clinical outcomes. This review summarizes the state of current knowledge on diagnosis, prognosis and treatment of HF-PEF, with particular insights on the pathological characteristics in the elderly population.


Glucose test provenance recording in UK primary care: was that fasted or random?
To describe the proportion of glucose tests with unrecorded provenance in routine primary care data and identify the impact on clinical practice. A cross-sectional analysis was conducted of blood glucose measurements from the Royal College of General Practitioner Research and Surveillance Centre database, which includes primary care records from >100 practices across England and Wales. All blood glucose results recorded during 2013 were identified. Tests were grouped by provenance (fasting, oral glucose tolerance test, random, none specified and other). A clinical audit in a single primary care practice was also performed to identify the impact of failing to record glucose provenance on diabetes diagnosis. A total of 2 137 098 people were included in the cross-sectional analysis. Of 203 350 recorded glucose measurements the majority (117 893; 58%) did not have any provenance information. The most commonly reported provenance was fasting glucose (75 044; 37%). The distribution of glucose values where provenance was not recorded was most similar to that of fasting samples. The glucose measurements of 256 people with diabetes in the audit practice (size 11 514 people) were analysed. The initial glucose measurement had no provenance information in 164 cases (64.1%). A clinician questioned the provenance of a result in 41 cases (16.0%); of these, 14 (34.1%) required repeating. Lack of provenance led to delays in the diagnosis of diabetes [median (range) 30 (3-614) days]. The recording of glucose provenance in UK primary care could be improved. Failure to record provenance causes unnecessary repeated testing, delayed diagnosis and wasted clinician time.


An evaluation of the effectiveness of the Injury Minimization Programme for Schools (IMPS).
To evaluate the effect of an injury prevention programme (Injury Minimization Programme for Schools, IMPS) on children's primary and secondary prevention, and basic life support, knowledge, attitudes, skills, and behaviour. Prospective non-randomised matched control. Radcliffe NHS Trust and primary and middle schools in Oxfordshire, UK. 1,200 year 6 children (10 and 11 years old); 600 received IMPS, a primary and secondary injury prevention programme taught in the school and hospital environments; 600 children in the control group received no planned intervention. Safety knowledge, measured using a quiz. Resuscitation skills and behaviour observed and assessed using a simulated emergency scenario. Attitude and hypothetical behaviour towards safety assessed by the "draw and write" technique. Before intervention, both groups had similar levels of knowledge. Five months after the intervention, significantly more IMPS trained children demonstrated a greater increase in knowledge in administering first aid and the correct procedure for making a call to the emergency services. They also demonstrated better basic life support techniques-for example, mouth-to-mouth and cardiac compressions. They identified more subtle dangers, were more likely to seek help, and tell others that their behaviour was dangerous. The results demonstrate the benefits of the IMPS programme on injury prevention knowledge, attitudes, and behaviours.


A ten-year audit of perforated sigmoid diverticulitis: highlighting the outcomes of laparoscopic lavage.
This study was designed to review the results of laparoscopic lavage for the management of perforated sigmoid diverticulitis. A 10-year retrospective review was conducted of 78 consecutive cases of sigmoid diverticulitis warranting emergency surgical intervention (1999-2008). Hinchey grades were I (12 patients), II (31 patients), III (29 patients), and IV (6 patients). The patients' mean age was 72 years. Procedures performed were laparoscopic washout (35), Hartmann procedure (31), percutaneous drainage of abscess (4), and resection and primary anastomosis (8). Overall mortality was 5 of 78 (7%); all of these patients were in the Hartmann group. Washout was successful in 27 of 35 cases, meaning recovery from the initial episode of peritonitis without resection. The short-term failures of washout in 8 patients were because of perforated cancer (1), fecal fistula formation (2), and inadequate washout and ongoing sepsis (5). In long-term follow-up, 8 patients in the washout group developed symptoms of recurrent complicated diverticulitis, including painful phlegmon (3), stricture (1), fistulas (3), and repeat perforation (1); all 8 patients underwent delayed resection. Eight patients underwent early planned resection without experiencing further symptoms. Eleven patients were observed without further symptoms with a mean follow-up of 20 months (range, 6-60 mo). Laparoscopic washout is an emerging technique that is particularly applicable to the management of Hinchey III perforated peritonitis. Short- and long-term problems exist with the technique that may be overcome with further improvement in technique and case selection. Resection and radiological drainage remain widely used in managing perforated sigmoid diverticulitis.


Contrast enhancement in widefield CARS microscopy by tailored phase matching using a spatial light modulator.
We introduce a widefield CARS microscope implementation that uses a spatial light modulator to obtain extremely precise control over the pump/probe-beam incidence geometry, which provides the possibility to enhance the image contrast at specific target resonances by fine-tuning the incidence angles. We show how this technique can be used to optimize the image contrast between objects of different size and to practically eliminate the undesired signal from the solvent that embeds small target specimens. Changing the numerical aperture of the illumination from 1.27 to 1.24 improved the ratio of the signals of 500 nm polystyrene beads and the agarose solvent by about 20 dB.


Stamina pistilloida, the Pea ortholog of Fim and UFO, is required for normal development of flowers, inflorescences, and leaves.
Isolation and characterization of two severe alleles at the Stamina pistilloida (Stp) locus reveals that Stp is involved in a wide range of developmental processes in the garden pea. The most severe allele, stp-4, results in flowers consisting almost entirely of sepals and carpels. Production of ectopic secondary flowers in stp-4 plants suggests that Stp is involved in specifying floral meristem identity in pea. The stp mutations also reduce the complexity of the compound pea leaf, and primary inflorescences often terminate prematurely in an aberrant sepaloid flower. In addition, stp mutants were shorter than their wild-type siblings due to a reduction in cell number in their internodes. Fewer cells were also found in the epidermis of the leaf rachis of stp mutants. Examination of the effects of stp-4 in double mutant combinations with af, tl, det, and veg2-2-mutations known to influence leaf, inflorescence, and flower development in pea-suggests that Stp function is independent of these genes. A synergistic interaction between weak mutant alleles at Stp and Uni indicated that these two genes act together, possibly to regulate primordial growth. Molecular analysis revealed that Stp is the pea homolog of the Antirrhinum gene Fimbriata (Fim) and of UNUSUAL FLORAL ORGANS (UFO) from Arabidopsis. Differences between Fim/UFO and Stp mutant phenotypes and expression patterns suggest that expansion of Stp activity into the leaf was an important step during evolution of the compound leaf in the garden pea.


Increased scale-free dynamics in salience network in adult high-functioning autism.
Autism spectrum disorder (ASD) is clinically characterized by extremely slow and inflexible behavior. The neuronal mechanisms of these symptoms remain unclear though. Using fMRI, we investigate the resting state's temporal structure in the frequency domain (scale-free activity as measured with Power-Law Exponent, PLE, and Spectral Entropy, SE) and temporal variance (neural variability) in high-functioning, adult ASD comparing them with schizophrenic and neurotypical subjects. We show that ASD is characterized by high PLE in salience network, especially in dorsal anterior cingulate. This increase in PLE was 1) specific for salience network; 2) independent of other measures such as neuronal variability/SD and functional connectivity, which did not show any significant difference; 3) detected in two independent samples of ASD but not in the schizophrenia sample. Among salience network subregions, dorsal anterior cingulate cortex exhibited PLE differences between ASD and neurotypicals in both samples, showing high robustness in ROC curves values. Salience network abnormal temporal structure was confirmed by SE, which was strongly anticorrelated with PLE and thus decreased in ASD. Taken together, our findings show abnormal temporal structure (but normal temporal variance) in resting state salience network in adult high-functioning ASD. The abnormally high PLE indicates a relative predominance of slower over faster frequencies, which may underlie the slow adaptation to unexpected changes and the inflexible behavior observed in autistic individuals. The specificity of abnormal PLE in salience network suggests its potential utility as biomarker in ASD.


Rac GTPases control axon growth, guidance and branching.
Growth, guidance and branching of axons are all essential processes for the precise wiring of the nervous system. Rho family GTPases transduce extracellular signals to regulate the actin cytoskeleton. In particular, Rac has been implicated in axon growth and guidance. Here we analyse the loss-of-function phenotypes of three Rac GTPases in Drosophila mushroom body neurons. We show that progressive loss of combined Rac1, Rac2 and Mtl activity leads first to defects in axon branching, then guidance, and finally growth. Expression of a Rac1 effector domain mutant that does not bind Pak rescues growth, partially rescues guidance, but does not rescue branching defects of Rac mutant neurons. Mosaic analysis reveals both cell autonomous and non-autonomous functions for Rac GTPases, the latter manifesting itself as a strong community effect in axon guidance and branching. These results demonstrate the central role of Rac GTPases in multiple aspects of axon development in vivo, and suggest that axon growth, guidance and branching could be controlled by differential activation of Rac signalling pathways.


Single dose of intra-muscular platelet rich plasma reverses the increase in plasma iron levels in exercise-induced muscle damage: A pilot study.
Platelet rich plasma (PRP) therapy is widely used in enhancing the recovery of skeletal muscle from injury. However, the impact of intramuscular delivery of PRP on hematologic and biochemical responses has not been fully elucidated in exercise-induced muscle damage. The purpose of this investigation the effects of intramuscular delivery of PRP on hematologic and biochemical responses and recovery strategy muscle damage induced by high intensity muscle exercise (exercise-induced muscle damage, EIMD). Moderately active male volunteers participated in this study and were assigned to a control group (control, n = 6) and PRP administration group (PRP, n = 6). The subjects performed exercise with a load of 80% one repetition maximum (1RM) maximal voluntary contraction of the elbow flexors until point of exhaustion of the non-dominant arm was reached. The arms were treated with saline or autologous PRP post-24 h EIMD. Venous blood samples were obtained in the morning to establish a baseline value and 1-4 days post-exercise and were analyzed for serum ferritin, iron, iron binding capacity (IBC), creatinine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The baseline levels of plasma iron, ferritin, IBC, CK, LDH, AST, and ALT were similar in both the control and PRP groups. However, 24-h following exercise a significant increase in these parameters was observed in both groups between 1 and 4 days during the recovery period. Interestingly, PRP administration decreased plasma iron levels compared to the control on the second day post-exercise. Plasma IBC increased in PRP group from Days 2 to 4 post-exercise compared to the control group whilst PRP administration had no effect on plasma ferritin, CK, AST, ALT, or LDH. Acute exhaustive exercise increased muscle damage markers, including plasma iron, IBC, and ferritin levels, indicating muscle damage induced by exercise. PRP administration improves inflammation by reversing the increase in the iron levels post-exercise without displaying any myotoxicity and may have a role to play in the recovery of exercise-induced muscle damage.


Modeling sequencing errors by combining Hidden Markov models.
Among the largest resources for biological sequence data is the large amount of expressed sequence tags (ESTs) available in public and proprietary databases. ESTs provide information on transcripts but for technical reasons they often contain sequencing errors. Therefore, when analyzing EST sequences computationally, such errors must be taken into account. Earlier attempts to model error prone coding regions have shown good performance in detecting and predicting these while correcting sequencing errors using codon usage frequencies. In the research presented here, we improve the detection of translation start and stop sites by integrating a more complex mRNA model with codon usage bias based error correction into one hidden Markov model (HMM), thus generalizing this error correction approach to more complex HMMs. We show that our method maintains the performance in detecting coding sequences.


Physiological and Physical Responses According to the Game Surface in a Soccer Simulation Protocol.
Recent studies have shown that soccer players' responses are similar on natural grass (NG) and artificial turf (AT), but they did not control the mechanical properties of these surfaces. This work aimed to analyze the influence of the game surface on amateur soccer players' physical and physiological responses using a soccer simulation protocol. A total of 16 amateur players performed 3 bouts of the soccer simulation protocol on AT, and, on another day, 3 bouts on NG. The mechanical properties of both surfaces were recorded. The order of surfaces was randomly established for each participant. Physiological responses of players were assessed before and after the 6-repeated-sprints test existing at the midpoint of each bout. Fatigue (% best; % diff) and general variables (total time; best time, mean time; maximum speed) for both the repeated sprint test (RST) and the agility tests (nonlinear actions at maximum speed) incorporated into the soccer simulation protocol were also analyzed. The 2 surfaces displayed different mechanical properties. Physical responses were found similar for both surfaces (P > .05) before and after the RST. There were no surface differences in sprint times or fatigue variables for the RST (P > .05). The agility test was faster on AT than on NG in bout 1 (average speed [+1.17 km/h;P = .037]; agility test cut time [-0.31 s; P = .027] and best time [-0.52 s; P = .042]). The differences in the mechanical properties of the 2 surfaces are not sufficient to cause differences in the physiological and physical responses of soccer players, although they may affect turns and cuts.


Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study).
It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. ISRCTN11442263.


Ca(2+)-induced Ca2+ release mediates Ca2+ transients evoked by single action potentials in rabbit vagal afferent neurones.
1. Standard intracellular recording techniques with 'sharp' micropipettes were used to evoke action potentials (APs) in acutely dissociated adult nodose neurones. 2. APs induced a transient increase in [Ca2+]i (a calcium transient), recorded with fura-2, that was dependent upon [Ca2+]o and the number of APs. Over the range of one to sixty-five APs, the relation between the amplitude of the calcium transient and the number of APs was well fitted by a rectangular hyperbola (chi 2 = 3.53, r = 0.968). From one to four APs, the calcium transient-AP relation can be described by a line with a slope of 9.6 nM AP-1 (r = 0.999). 3. Charge movement corresponding to Ca2+ influx evoked by a single AP was 39 +/- 2.8 pC (mean +/- S.E.M.) and did not change significantly during trains of one to thirty-one APs (P < 0.05). 4. Caffeine (10 mM), a known agonist of the ryanodine receptor, produced an increase in [Ca2+]i. The caffeine-induced rise in [Ca2+]i was attenuated (by > 90%) by lowering [Ca2+]o, and by ryanodine (10 microM), 2,5-di(t-butyl)hydroquinone (DBHQ, 10 microM), or thapsigargin (100 nM). 5. Neurones incubated with ryanodine, DBHQ or thapsigargin required at least eight APs to evoke a detectable calcium transient. These reagents did not significantly affect Ca2+ influx (P < 0.05). In the presence of these inhibitors, the calcium transient-AP relation exhibited slopes of 1.2, 1.1 and 1.9 nM AP-1 for ryanodine, DBHQ and thapsigargin, respectively. When compared with the slope of 9.6 nM AP-1 in non-treated neurones, it appears that Ca2+ influx produced by a single AP is amplified by ca 5- to 10-fold.


Noninvasive 3-dimensional imaging of liver regeneration in a mouse model of hereditary tyrosinemia type 1 using the sodium iodide symporter gene.
Cell transplantation is a potential treatment for the many liver disorders that are currently only curable by organ transplantation. However, one of the major limitations of hepatocyte (HC) transplantation is an inability to monitor cells longitudinally after injection. We hypothesized that the thyroidal sodium iodide symporter (NIS) gene could be used to visualize transplanted HCs in a rodent model of inherited liver disease: hereditary tyrosinemia type 1. Wild-type C57Bl/6J mouse HCs were transduced ex vivo with a lentiviral vector containing the mouse Slc5a5 (NIS) gene controlled by the thyroxine-binding globulin promoter. NIS-transduced cells could robustly concentrate radiolabeled iodine in vitro, with lentiviral transduction efficiencies greater than 80% achieved in the presence of dexamethasone. Next, NIS-transduced HCs were transplanted into congenic fumarylacetoacetate hydrolase knockout mice, and this resulted in the prevention of liver failure. NIS-transduced HCs were readily imaged in vivo by single-photon emission computed tomography, and this demonstrated for the first time noninvasive 3-dimensional imaging of regenerating tissue in individual animals over time. We also tested the efficacy of primary HC spheroids engrafted in the liver. With the NIS reporter, robust spheroid engraftment and survival could be detected longitudinally after direct parenchymal injection, and this thereby demonstrated a novel strategy for HC transplantation. This work is the first to demonstrate the efficacy of NIS imaging in the field of HC transplantation. We anticipate that NIS labeling will allow noninvasive and longitudinal identification of HCs and stem cells in future studies related to liver regeneration in small and large preclinical animal models.


Eating and shift work - effects on habits, metabolism and performance.
Compared to individuals who work during the day, shift workers are at higher risk of a range of metabolic disorders and diseases (eg, obesity, cardiovascular disease, peptic ulcers, gastrointestinal problems, failure to control blood sugar levels, and metabolic syndrome). At least some of these complaints may be linked to the quality of the diet and irregular timing of eating, however other factors that affect metabolism are likely to play a part, including psychosocial stress, disrupted circadian rhythms, sleep debt, physical inactivity, and insufficient time for rest and revitalization. In this overview, we examine studies on food and nutrition among shift workers [ie, dietary assessment (designs, methods, variables) and the factors that might influence eating habits and metabolic parameters]. The discussion focuses on the quality of existing dietary assessment data, nutritional status parameters (particularly in obesity), the effect of circadian disruptions, and the possible implications for performance at work. We conclude with some dietary guidelines as a basis for managing the nutrition of shift workers.


Memory performance, wireless communication and exposure to radiofrequency electromagnetic fields: A prospective cohort study in adolescents.
The aim of this study is to investigate whether memory performance in adolescents is affected by radiofrequency electromagnetic fields (RF-EMF) from wireless device use or by the wireless device use itself due to non-radiation related factors in that context. We conducted a prospective cohort study with 439 adolescents. Verbal and figural memory tasks at baseline and after one year were completed using a standardized, computerized cognitive test battery. Use of wireless devices was inquired by questionnaire and operator recorded mobile phone use data was obtained for a subgroup of 234 adolescents. RF-EMF dose measures considering various factors affecting RF-EMF exposure were computed for the brain and the whole body. Data were analysed using a longitudinal approach, to investigate whether cumulative exposure over one year was related to changes in memory performance. All analyses were adjusted for relevant confounders. The kappa coefficients between cumulative mobile phone call duration and RF-EMF brain and whole body dose were 0.62 and 0.67, respectively for the whole sample and 0.48 and 0.28, respectively for the sample with operator data. In linear exposure-response models an interquartile increase in cumulative operator recorded mobile phone call duration was associated with a decrease in figural memory performance score by -0.15 (95% CI: -0.33, 0.03) units. For cumulative RF-EMF brain and whole body dose corresponding decreases in figural memory scores were -0.26 (95% CI: -0.42, -0.10) and -0.40 (95% CI: -0.79, -0.01), respectively. No exposure-response associations were observed for sending text messages and duration of gaming, which produces tiny RF-EMF emissions. A change in memory performance over one year was negatively associated with cumulative duration of wireless phone use and more strongly with RF-EMF dose. This may indicate that RF-EMF exposure affects memory performance.


Compressive sensing DNA microarrays.
Compressive sensing microarrays (CSMs) are DNA-based sensors that operate using group testing and compressive sensing (CS) principles. In contrast to conventional DNA microarrays, in which each genetic sensor is designed to respond to a single target, in a CSM, each sensor responds to a set of targets. We study the problem of designing CSMs that simultaneously account for both the constraints from CS theory and the biochemistry of probe-target DNA hybridization. An appropriate cross-hybridization model is proposed for CSMs, and several methods are developed for probe design and CS signal recovery based on the new model. Lab experiments suggest that in order to achieve accurate hybridization profiling, consensus probe sequences are required to have sequence homology of at least 80% with all targets to be detected. Furthermore, out-of-equilibrium datasets are usually as accurate as those obtained from equilibrium conditions. Consequently, one can use CSMs in applications in which only short hybridization times are allowed.


Prevalence and associations of potentially inappropriate prescriptions in Austrian nursing home residents: secondary analysis of a cross-sectional study.
Potentially inappropriate prescriptions (PIP) are an important cause of adverse medication-related events and increases morbidity, hospitalization, and health care costs, especially in nursing home residents. However, little is known about the associations between PIP and residents' characteristics. The aim of our study was to analyse the prevalence and associations of PIP with residents' and facilities' characteristics. We performed a secondary analysis of a cross-sectional study with 48 out of 50 eligible nursing homes and 1,844 out of 2,005 eligible residents in a defined rural-urban area in Austria. The Austrian list of potentially inappropriate medications was applied for the evaluation of inappropriate prescribing. Cluster-adjusted multiple regression analysis was used to investigate institutional and residents' characteristics associated with PIP. Mean cluster-adjusted prevalence of residents with at least one PIP was 70.3 % (95 % CI 67.2-73.4). The number of residents with at least one psychotropic PIP was 1.014 (55 %). The most often prescribed PIP were Prothipendyl (25.9 % residents), Lorazepam (14.5 %) and Diclofenac (6.1 %). Multiple regression analysis showed an inverse association of PIP with cognitive impairment and significant positive associations with permanent restlessness and permanent negative attitude. The associations of PIP with age and male gender were inconsistent. No significant associations were found for PIP and the ratio of staff nurses to residents. Our study results confirm that PIP is highly prevalent in the nursing home population. These results urgently call for effective interventions. Initiatives and successful interventions performed in other countries could serve as examples for safer prescribing in residents in Austria.


Screening for small for gestational age using third-trimester ultrasound markers: protocol for a systematic review and meta-analysis of screening test accuracy.
Fetal growth restriction (FGR) is a complication of pregnancy associated with major neonatal morbidity and commonly diagnosed at birth based on birth weight below the 5th or the 10th centile. There is no consensus on the use of routine third-trimester ultrasound for the detection of FGR in a general population. This systematic review aims to estimate the performance of third-trimester ultrasound markers in the screening for babies who are small for gestational age in low-risk or general population. A systematic review of screening test accuracy will be conducted. The databases MEDLINE, Embase, Cochrane Library, and Web of Science will be searched from their inception until December 2017, as well as reference lists of included studies and previous related review articles. Studies screening for FGR in a low-risk or general population using third-trimester ultrasound markers and reporting low birth weight for gestational age (small for gestational age at birth) as a reference will be eligible. Two reviewers will independently screen references for inclusion, assess the risk of bias, and extract data. The Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tool will be used to assess the methodological quality and validity of individual studies. The hierarchal summary receiver operating characteristic and random effects hierarchal bivariate models (Bivariate) will be used to estimate the pooled sensitivity and specificity of each ultrasound marker and to compare the discriminative ability of the different ultrasound markers. Subgroup and sensitivity analyses will be performed to explore the heterogeneity between studies and to assess the effect of screening tests' characteristics (e.g., timing) on their discriminative ability. This systematic review will determine the relevance of routine third-trimester ultrasound markers in the screening for FGR in low-risk or general population and their usefulness in standard pregnancy care. Additionally, this knowledge synthesis represents a step in the optimization of the discriminative ability of third-trimester ultrasound and predictive tools, allowing for targeted interventions aiming at the reduction of FGR complications and ultimately improving infants' health. This protocol has been registered at PROSPERO: international prospective register of systematic reviews. The register number is CRD42018085564 .


A simple and novel volumetric method to metre low gas flows from laboratory-scale bioreactors and its application on laboratory sludge digesters.
A novel, cheap and easy to use method has been developed to measure low gas yields in bioreactors, based on the principle of bubble counting via digital imaging techniques and pattern recognition. No external hardware control is required for the measurements, and the device can be turned into a multichannel tool without further detector accessories. The method proved to perform outstandingly according to the testing and calibrating measurements against standard gas flow and revealed a short periodicity in the gas yields of two parallel laboratory-scale mesophilic biogas reactors providing well analysable data about them. For exact characterization of the oscillation, the data were converted into Morell wavelet spectra, which showed that every feeding period had a characteristic and similarly shaped wavelet profile, thereby this rhythm must have had an immanent source in the community metabolism, and it was not an artefact.


Quantitative Imaging in Cancer Clinical Trials.
As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies.


Is there a relation between genetic susceptibility with cancer? A study about paraoxanase (PON1) enzyme activity in breast cancer cases.
Human serum paraoxonase 1 (PON1, EC 188.8.131.52) is a high density lipoprotein (HDL)-associated antioxidant enzyme that not only decreases oxidative stress, but it is also implicated in development of many cancers. Genetic information provides a means of identifying people who have an increased risk of cancer, thus this knowledge of cancer genetics helps to identify the ability to characterize malignancies leading to the development of new therapeutic approaches. Because of this reason, in this preliminary study we aimed to investigate the role of human serum PON1 enzyme activity and phenotypic distribution in 32 breast cancer (BC) patients (age range 28-82) and 35 cancer free (CF) control group (age range 21-67). PON1 enzyme was prepared from the serum pool of BC patients using hydrophobic interaction chromatography on L-tyrosine-9-aminophenanthrene-coupled Sepharose 4Bgel. The PON1 enzyme activity towards paraoxon substrate was quantified spectrophotometrically. The basal activity of PON1 was statistically decreased in cancer cases compared to the control group. In addition, individuals were classified according to phenotyping of human PON1 Q and R types. In the cohort of BC patients, an increase in the frequency of the PON homozygote Q (AA) genotype was observed (31% in the BC group versus 14% in the CF controls). The frequency of the PON heterozygote QR (AB) genotype was 34.5% in the patients with BC and 37% in the CF group. The same trend was observed in PON homozygote R (BB) genotype frequency (BC cases 34.5% versus controls 49%). We determined that the kinetic parameters of the purified enzyme by Lineweaver-Burk method. We obtained Km and Vmax values of 0.227 mM and 62 U/mL min for the BC enzyme, compared with 0.775 mM and 206 U/mL min for the CF control enzyme. As a conclusion, it is clear from our results that while the PON1 AA allele frequency in BC cases is much higher, that of BB allele is much lower, in comparison with the control group. The most significant finding of this study is AA allele activity which is low in BC cases was found high. We concluded that decreased AA allele PON1 activity might have a relation with BC.


Label-free, color-indicating, and sensitive biosensors of cholesteric liquid crystals on a single vertically aligned substrate.
Biosensors based on liquid crystal (LC) materials can be made by employing the sensitive interfacial effect between LC molecules and alignment layers on substrates. In the past, the optical texture observation method was used in the LC biosensor field. However, the method is limited by a complicated fabrication process and quantitative reproducibility of results that bv evidence that both the reliability and accuracy of LC biosensors need to be improved. In this report, we demonstrate that cholesteric LC (CLC) cells in which one substrate is coated with a vertically aligned layer can be used as a new sensing technology. The chirality of the single vertically anchored (SVA)/CLC biosensor was tested by detecting bovine serum albumin (BSA), a protein standard commonly used in the lab. The colors and corresponding spectrum of the SVA/CLC biosensor changed with the BSA concentrations. A detection limit of 1 ng/ml was observed for the SVA/CLC biosensor. The linear optical properties of the SVA/CLC biosensor produced cheap, inexpensive, and color-indicating detection of biomolecules, and may promote the technology of point-of-care devices for disease-related biomarker detection.


The effect of observation on cranial computed tomography utilization for children after blunt head trauma.
Children with minor blunt head trauma often are observed in the emergency department before a decision is made regarding computed tomography use. We studied the impact of this clinical strategy on computed tomography use and outcomes. We performed a subanalysis of a prospective multicenter observational study of children with minor blunt head trauma. Clinicians completed case report forms indicating whether the child was observed before making a decision regarding computed tomography. We defined clinically important traumatic brain injury as an intracranial injury resulting in death, neurosurgical intervention, intubation for longer than 24 hours, or hospital admission for 2 nights or longer. To compare computed tomography rates between children observed and those not observed before a decision was made regarding computed tomography use, we used a generalized estimating equation model to control for hospital clustering and patient characteristics. Of 42 412 children enrolled in the study, clinicians noted if the patient was observed before making a decision on computed tomography in 40 113 (95%). Of these, 5433 (14%) children were observed. The computed tomography use rate was lower in those observed than in those not observed (31.1% vs 35.0%; difference: -3.9% [95% confidence interval: -5.3 to -2.6]), but the rate of clinically important traumatic brain injury was similar (0.75% vs 0.87%; difference: -0.1% [95% confidence interval: -0.4 to 0.1]). After adjustment for hospital and patient characteristics, the difference in the computed tomography use rate remained significant (adjusted odds ratio for obtaining a computed tomography in the observed group: 0.53 [95% confidence interval: 0.43-0.66]). Clinical observation was associated with reduced computed tomography use among children with minor blunt head trauma and may be an effective strategy to reduce computed tomography use.


Internet-based outpatient telerehabilitation for patients following total knee arthroplasty: a randomized controlled trial.
total knee arthroplasty is an effective means for relieving the symptoms associated with degenerative arthritis of the knee. Rehabilitation is a necessary adjunct to surgery and is important in regaining optimum function. Access to high-quality rehabilitation services is not always possible, especially for those who live in rural or remote areas. The aim of this study was to evaluate the equivalence of an Internet-based telerehabilitation program compared with conventional outpatient physical therapy for patients who have had a total knee arthroplasty. this investigation was a single-blinded, prospective, randomized, controlled noninferiority trial. Sixty-five participants were randomized to receive a six-week program of outpatient physical therapy either in the conventional manner or by means of an Internet-based telerehabilitation program. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) measured at baseline and six weeks by a blinded independent assessor. Secondary outcomes included the Patient-Specific Functional Scale, the timed up-and-go test, pain intensity, knee flexion and extension, quadriceps muscle strength, limb girth measurements, and an assessment of gait. Noninferiority was assessed through the comparison of group differences with a noninferiority margin and with linear mixed model statistics. baseline characteristics between groups were similar, and all participants had significant improvement on all outcome measures with the intervention (p < 0.01 for all). After the six-week intervention, participants in the telerehabilitation group achieved outcomes comparable to those of the conventional rehabilitation group with regard to flexion and extension range of motion, muscle strength, limb girth, pain, timed up-and-go test, quality of life, and clinical gait and WOMAC scores. Better outcomes for the Patient-Specific Functional Scale and the stiffness subscale of the WOMAC were found in the telerehabilitation group (p < 0.05). The telerehabilitation intervention was well received by participants, who reported a high level of satisfaction with this novel technology. the outcomes achieved via telerehabilitation at six weeks following total knee arthroplasty were comparable with those after conventional rehabilitation. therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.


Three-dimensional spherical spatial boundary conditions differentially regulate osteogenic differentiation of mesenchymal stromal cells.
The spatial boundary condition (SBC) arising from the surrounding microenvironment imposes specific geometry and spatial constraints that affect organogenesis and tissue homeostasis. Mesenchymal stromal cells (MSCs) sensitively respond to alterations of mechanical cues generated from the SBC. However, mechanical cues provided by a three-dimensional (3D) environment are deprived in a reductionist 2D culture system. This study investigates how SBC affects osteogenic differentiation of MSCs using 3D scaffolds with monodispersed pores and homogenous spherical geometries. MSCs cultured under SBCs with diameters of 100 and 150 μm possessed the greatest capability of osteogenic differentiation. This phenomenon was strongly correlated with MSC morphology, organization of actin cytoskeleton, and distribution of focal adhesion involving α2 and α5 integrins. Further silencing either α2 or α5 integrin significantly reduced the above mentioned mechanosensitivity, indicating that the α2 and α5 integrins as mechano-sensitive molecules mediate MSCs' ability to provide enhanced osteogenic differentiation in response to different spherical SBCs. Taken together, the findings provide new insights regarding how MSCs respond to mechanical cues from the surrounding microenvironment in a spherical SBC, and such biophysical stimuli should be taken into consideration in tissue engineering and regenerative medicine in conjunction with biochemical cues.


Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma.
An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes. Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.


Analysis of adjusting effects of mounting force on frequency conversion of mounted nonlinear optics.
Motivated by the need to increase the second harmonic generation (SHG) efficiency of nonlinear optics with large apertures, a novel mounting configuration with active adjusting function on the SHG efficiency is proposed and mechanically and optically studied. The adjusting effects of the mounting force on the distortion and stress are analyzed by the finite element methods (FEM), as well as the contribution of the distortion and stress to the change in phase mismatch, and the SHG efficiency are theoretically stated. Further on, the SHG efficiency is calculated as a function of the mounting force. The changing trends of the distortion, stress, and the SHG efficiency with the varying mounting force are obtained, and the optimal ones are figured out. Moreover, the mechanism of the occurrence of the optimal values is studied and the adjusting strategy is put forward. Numerical results show the robust adjustment of the mounting force, as well as the effectiveness of the mounting configuration, in increasing the SHG efficiency.


Assessing the Control of Preservational Environment on Taphonomic and Ecological Patterns in an Oligocene Mammal Fauna from Badlands National Park, South Dakota.
Comparisons of paleofaunas from different facies are often hampered by the uncertainty in the variation of taphonomic processes biasing the paleoecological parameters of interest. By examining the taphonomic patterns exhibited by different facies in the same stratigraphic interval and area, it is possible to quantify this variation, and assess inter-facies comparability. The fossil assemblages preserved in Badlands National Park (BNP), South Dakota, have long been a rich source for mammalian faunas of the White River Group. To investigate the influence of the variation of taphonomic bias with lithology whilst controlling for the influence of changes in patterns of taphonomic modification with time, taphonomic and paleoecological data were collected from four mammal-dominated fossil assemblages (two siltstone hosted and two sandstone hosted) from a narrow stratigraphic interval within the Oligocene Poleslide Member of the Brule Formation, in the Palmer Creek Unit of BNP. Previous work in the region confirmed that the two major lithologies represent primarily aeolian- and primarily fluvial-dominated depositional environments, respectively. A suite of quantifiable taphonomic and ecological variables was recorded for each of the more than 800 vertebrate specimens studied here (857 specimens were studied in the field, 9 specimens were collected and are reposited at BNP). Distinctly different patterns of taphonomic biasing were observed between the aeolian and fluvial samples, albeit with some variability between all four sites. Fluvial samples were more heavily weathered and abraded, but also contained fewer large taxa and fewer tooth-bearing elements. No quantifiable paleofaunal differences in generic richness or evenness were observed between the respective facies. This suggests that while large vertebrate taxonomic composition in the region did vary with paleodepositional environment, there is no evidence of confounding variation in faunal structure, and therefore differences between the assemblages are attributed to differing preservational environments producing a taphonomic overprint on the assemblages. The lack of apparent taphonomic bias on paleofaunal structure suggests that such paleoecological data can be compared throughout the Poleslide Member, irrespective of lithology.


Maize plastid gene expressed during photoregulated development.
RNAs larger than about 6 S prepared from etioplasts of dark-grown maize seedlings, and from plastids at later stages of light-induced development, were labeled in vitro and hybridized to separated fragments of maize chloroplast DNA digested with endonucleases. The major nonribosomal RNA present in developing plastids, but virtually undetectable in etioplasts, hybridizes to chloroplast DNA Bam fragment 8 and has been mapped on the maize plastid chromosome. Other aliquots of RNA from plastids were translated in a rabbit reticulocyte-derived system. Developing plastids, and mature chloroplasts, but not etioplasts, contain mRNA for an approximately 34,500 dalton polypeptide. The simultaneous appearance, during light-induced maize plastid development, of RNA which hybridizes to Bam 8 and is translated into a 34,500 dalton protein indicates that photoregulated expression of a single gene is being observed.


Fast numerical method for electromagnetic scattering by rough layered interfaces: propagation-inside-layer expansion method.
Electromagnetic scattering from a stack of two one-dimensional rough surfaces separating homogeneous media is modeled with a rigorous integral formulation solved by the method of moments. We present an efficient numerical method for computing the field scattered by such rough layers, in reflection as well as in transmission. We call this method propagation-inside-layer expansion (PILE) due to its straightforward physical interpretation. To our knowledge, it is the first method able to handle problems for this configuration with a huge number of unknowns. We study the convergence of this method versus a coupling condition and validate it by comparison with results from the literature.


Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research.
In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice-certified cell manufacturing facilities- and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients.


Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study.
Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml(-1) in Greenland (0.2-385.8 ng ml(-1)), 1.0 ng ml(-1) in Poland (0.2-6.4 ng ml(-1)) and 1.0 ng ml(-1) in Ukraine (0.2-4.9 ng ml(-1)). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (β=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (β=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH × testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml(-1) has adverse effects on biomarkers of male reproductive health.


Introducing rapid diagnostic tests for malaria into drug shops in Uganda: design and implementation of a cluster randomized trial.
An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop vendors and implemented supporting interventions to orientate local communities (patients) and the public sector (health facility staff and district officials) to the behavioral changes in diagnosis, treatment and referral being introduced in drug shops. The intervention was designed to be evaluated through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions on diagnosis and treatment of malaria at drug shops, and affordable prices for mRDTs and ACTs in order to inform the design of the intervention and implementation modalities. The intervention required careful design with the intention to be acceptable, sustainable and effective. Critical components of intervention were: community sensitization and creating awareness, training of drug shop vendors to diagnose malaria with mRDTs, treat and refer customers to formal health facilities, giving pre-referral rectal artesunate and improved record-keeping. The primary outcome was the proportion of patients receiving appropriately-targeted treatment with ACT, evaluated against microscopy on a research blood slide. Introducing mRDTs in drug shops may seem simple, but our experience of intervention design, conduct and evaluation showed this to be a complex process requiring multiple interventions and evaluation components drawing from a combination of epidemiological, social science and health economics methodologies. The trial was conducted in phases sequenced such that each benefited from the other. The main challenges in designing this trial were maintaining a balance between a robust intervention to support effective behaviour change and introducing practices that would be sustainable in a real-life situation in tropical Africa; as well as achieving a detailed evaluation without inadvertently influencing prescribing behaviour. NCT01194557 registered with ClinicalTrials.gov 2 September 2010.


Role of persistent sodium current in bursting activity of mouse neocortical networks in vitro.
Most types of electrographic epileptiform activity can be characterized by isolated or repetitive bursts in brain electrical activity. This observation is our motivation to determine mechanisms that underlie bursting behavior of neuronal networks. Here we show that the persistent sodium (Na(P)) current in mouse neocortical slices is associated with cellular bursting and our data suggest that these cells are capable of driving networks into a bursting state. This conclusion is supported by the following observations. 1) Both low concentrations of tetrodotoxin (TTX) and riluzole reduce and eventually stop network bursting while they simultaneously abolish intrinsic bursting properties and sensitivity levels to electrical stimulation in individual intrinsically bursting cells. 2) The sensitivity levels of regular spiking neurons are not significantly affected by riluzole or TTX at the termination of network bursting. 3) Propagation of cellular bursting in a neuronal network depended on excitatory connectivity and disappeared on bath application of CNQX (20 microM) + CPP (10 microM). 4) Voltage-clamp measurements show that riluzole (20 microM) and very low concentrations of TTX (50 nM) attenuate Na(P) currents in the neural membrane within a 1-min interval after bath application of the drug. 5) Recordings of synaptic activity demonstrate that riluzole at this concentration does not affect synaptic properties. 6) Simulations with a neocortical network model including different types of pyramidal cells, inhibitory interneurons, neurons with and without Na(P) currents, and recurrent excitation confirm the essence of our experimental observations that Na(P) conductance can be a critical factor sustaining slow population bursting.


MBene (MnB): a new type of 2D metallic ferromagnet with high Curie temperature.
We extend the 2D MXene family into the boride world, namely, MBenes. High-throughput calculations screen twelve MBenes with excellent stability. Among them, 2D MnB MBene exhibits robust metallic ferromagnetism (∼3.2 μB per Mn atom) and high Curie temperature (345 K). After functionalization with the -F and -OH groups, the ferromagnetic ground state of 2D MnB is well preserved. The Curie temperature is increased to 405 and 600 K, respectively, providing a novel and feasible strategy to tailor the TC of 2D magnetic materials.


Detection of Exotic Mosquito Species (Diptera: Culicidae) at International Airports in Europe.
In Europe, the air-borne accidental introduction of exotic mosquito species (EMS) has been demonstrated using mosquito surveillance schemes at Schiphol International Airport (Amsterdam, The Netherlands). Based upon these findings and given the increasing volume of air transport movements per year, the establishment of EMS after introduction via aircraft is being considered a potential risk. Here we present the airport surveillance results performed by the Centre for Monitoring of Vectors of the Netherlands, by the Monitoring of Exotic Mosquitoes (MEMO) project in Belgium, and by the Public Health England project on invasive mosquito surveillance. The findings of our study demonstrate the aircraft mediated transport of EMS into Europe from a wide range of possible areas in the world. Results show accidental introductions of Aedes aegypti and Ae. albopictus, as well as exotic Anopheles and Mansonia specimens. The findings of Ae. albopictus at Schiphol airport are the first evidence of accidental introduction of the species using this pathway in Europe. Furthermore, our results stress the importance of the use of molecular tools to validate the morphology-based species identifications. We recommend monitoring of EMS at airports with special attention to locations with a high movement of cargo and passengers.


MITE Aba12 , a Novel Mobile Miniature Inverted-Repeat Transposable Element Identified in Acinetobacter baumannii ATCC 17978 and Its Prevalence across the Moraxellaceae Family.
Insertion sequences (IS) are fundamental mediators of genome plasticity with the potential to generate phenotypic variation with significant evolutionary outcomes. Here, a recently active miniature inverted-repeat transposon element (MITE) was identified in a derivative of Acinetobacter baumannii ATCC 17978 after being subjected to stress conditions. Transposition of the novel element led to the disruption of the hns gene, resulting in a characteristic hypermotile phenotype. DNA identity shared between the terminal inverted repeats of this MITE and coresident ISAba12 elements, together with the generation of 9-bp target site duplications, provides strong evidence that ISAba12 elements were responsible for mobilization of the MITE (designated MITE Aba12 ) within this strain. A wider genome-level survey identified MITE Aba12 in 30 additional Acinetobacter genomes at various frequencies and one Moraxella osloensis genome. Ninety MITE Aba12 copies could be identified, of which 40% had target site duplications, indicating recent transposition events. Elements ranged between 111 and 114 bp; 90% were 113 bp in length. Using the MITE Aba12 consensus sequence, putative outward-facing Escherichia coli σ70 promoter sequences in both orientations were identified. The identification of transcripts originating from the promoter in one direction supports the proposal that the element can influence neighboring host gene transcription. The location of MITE Aba12 varied significantly between and within genomes, preferentially integrating into AT-rich regions. Additionally, a copy of MITE Aba12 was identified in a novel 8.5-kb composite transposon, Tn6645, in the M. osloensis CCUG 350 chromosome. Overall, this study shows that MITE Aba12 is the most abundant nonautonomous element currently found in AcinetobacterIMPORTANCE One of the most important weapons in the armory of Acinetobacter is its impressive genetic plasticity, facilitating rapid genetic mutations and rearrangements as well as integration of foreign determinants carried by mobile genetic elements. Of these, IS are considered one of the key forces shaping bacterial genomes and ultimately evolution. We report the identification of a novel nonautonomous IS-derived element present in multiple bacterial species from the Moraxellaceae family and its recent translocation into the hns locus in the A. baumannii ATCC 17978 genome. The latter finding adds new knowledge to only a limited number of documented examples of MITEs in the literature and underscores the plastic nature of the hns locus in A. baumannii MITE Aba12 , and its predicted parent(s), may be a source of substantial adaptive evolution within environmental and clinically relevant bacterial pathogens and, thus, have broad implications for niche-specific adaptation.


Phenytoin-Induced Purple Glove Syndrome: A Case Report and Review of the Literature.
To present a case report and literature review of phenytoin-induced purple glove syndrome (PGS). A 54-year-old African American male presented to our hospital's emergency department (ED) following a seizure episode, cardiac arrest, and loss of consciousness. On arrival to the ED, the patient's total phenytoin level was subtherapeutic at 4.1 mcg/mL and his corrected total phenytoin level was subtherapeutic at 5.1 mcg/mL. In the ED, the patient received a loading dose of intravenous (IV) phenytoin 1,000 mg once via the left cephalic vein, at a rate of 50 mg/min, and was admitted to the medicine service. A day following IV phenytoin administration, a nurse noticed an IV fluid infiltration on the skin tissue around the left cephalic vein. The area appeared dark blue and purple in color, swollen, erythematous, and warm to touch. An ultrasound of the left upper extremity was performed and revealed subcutaneous fluid collection without evidence of thrombosis. The Naranjo Adverse Drug Reaction Probability Scale assigned a score of 7, indicating phenytoin as the probable cause of purple glove syndrome (PGS). The patient's PGS was managed with a combination of dry dressing material, left forearm elevation, collagenase topical cream, 0.1% IV bupivacaine, and IV fentanyl. The patient's injury was resolving at the time of discharge to a rehabilitation facility. PGS is a rare complication of IV phenytoin therapy. The risk of PGS for this patient may have been abated by decreasing the phenytoin infusion rate from 50 mg/min to less than 25 mg/min.


Metabolomics and transcriptomics identify pathway differences between visceral and subcutaneous adipose tissue in colorectal cancer patients: the ColoCare study.
Metabolic and transcriptomic differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments, particularly in the context of obesity, may play a role in colorectal carcinogenesis. We investigated the differential functions of their metabolic compositions. Biochemical differences between adipose tissues (VAT compared with SAT) in patients with colorectal carcinoma (CRC) were investigated by using mass spectrometry metabolomics and gene expression profiling. Metabolite compositions were compared between VAT, SAT, and serum metabolites. The relation between patients' tumor stage and metabolic profiles was assessed. Presurgery blood and paired VAT and SAT samples during tumor surgery were obtained from 59 CRC patients (tumor stages I-IV) of the ColoCare cohort. Gas chromatography time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were used to measure 1065 metabolites in adipose tissue (333 identified compounds) and 1810 metabolites in serum (467 identified compounds). Adipose tissue gene expression was measured by using Illumina's HumanHT-12 Expression BeadChips. Compared with SAT, VAT displayed elevated markers of inflammatory lipid metabolism, free arachidonic acid, phospholipases (PLA2G10), and prostaglandin synthesis-related enzymes (PTGD/PTGS2S). Plasmalogen concentrations were lower in VAT than in SAT, which was supported by lower gene expression of FAR1, the rate-limiting enzyme for ether-lipid synthesis in VAT. Serum sphingomyelin concentrations were inversely correlated (P = 0.0001) with SAT adipose triglycerides. Logistic regression identified lipids in patients' adipose tissues, which were associated with CRC tumor stage. As one of the first studies, we comprehensively assessed differences in metabolic, lipidomic, and transcriptomic profiles between paired human VAT and SAT and their association with CRC tumor stage. We identified markers of inflammation in VAT, which supports prior evidence regarding the role of visceral adiposity and cancer.


Supernatant of bacterial fermented soybean induces apoptosis of human hepatocellular carcinoma Hep 3B cells via activation of caspase 8 and mitochondria.
SC-1, the aqueous phase of soybean fermentation products by bacteria (Bacillus subtilis and Bacillus brevis), significantly inhibited the growth and clonogenesity of human hepatocellular (Hep 3B), mouse hepatocellular (ML-1), and human colorectal (HCT 116 and HT-29) carcinoma cells. Cytotoxicity of SC-1 in Hep 3B cells was through the process of apoptosis characterizing by increase in cell population of sub-G(1) phase, fragmentation of DNA, and change of nuclear morphology. Treatment of Hep 3B cells with SC-1 activated caspase 8 and caspase 3. Elevation of nuclear DNA fragmentation factor 40 (DFF40) and cleavage form of poly(ADP-ribose) polymerase (PARP) were also observed. SC-1 also activated intrinsic pathway via increase of pro-apoptotic (tBid, Bak and Bax) and decrease of anti-apoptotic (Bcl-2 and Bcl-x(L)) proteins on mitochondria, disruption of mitochondrial membrane potential, release of cytochrome c and Smac (second mitochondria-derived activator of caspase/direct IAP binding protein with low PI) from mitochondria, and activation of caspase 9. Inhibition on protein expression of Ku70 in cytosol and cyclooxygenase (COX)-2, but not COX-1, in whole cell lystes were revealed in SC-1-treated Hep 3B cells. These results suggest caspase 8, Ku70 and mitochondria are involved in the antitumor mechanism of SC-1 in Hep 3B cells.


Adolescent Plant Product Intake in Relation to Later Prostate Cancer Risk and Mortality in the NIH-AARP Diet and Health Study.
Although fruit and vegetable intake during adolescence, a potentially sensitive time period for prostate cancer (PCa) development, has been proposed to protect against PCa risk, few studies have investigated the role of adolescent plant product intake in PCa development. Intake of various vegetables, fruit, and grains by males at ages 12-13 y was examined in relation to later PCa risk and mortality in the NIH-AARP Diet and Health Study. Cox proportional hazards regression was used to calculate HRs and 95% CIs of nonadvanced (n = 14,238) and advanced (n = 2,170) PCa incidence and PCa mortality (n = 760) during 1,729,896 person-years of follow-up. None of the plant products examined were associated consistently with all PCa outcomes. However, greater adolescent intakes of tomatoes (P-trend = 0.004) and nonstarch vegetables (P-trend = 0.025) were associated with reduced risk of nonadvanced PCa, and greater intakes of broccoli (P-trend = 0.050) and fruit juice (P-trend = 0.019-0.025) were associated with reduced risk of advanced PCa and/or PCa mortality. Positive trends were also observed for greater intakes of fruit juice (P-trend = 0.002), total fruit (P-trend = 0.014), and dark bread (P-trend = 0.035) with nonadvanced PCa risk and for greater intakes of legumes (P-trend < 0.001), fiber (P-trend = 0.001), and vegetable protein (P-trend = 0.013-0.040) with advanced PCa risk or PCa mortality. Our findings do not provide strong evidence to suggest that adolescent plant product intake is associated with reduced PCa risk.


pH-independent optical sensing of heparin based on ionic liquid-capped gold nanoparticles.
A simple pH-independent optical method for the sensing of heparin, as a biomedically important polyionic drug, based on aggregation of gold nanoparticles (AuNPs) is described. The polyanionic heparin induces the aggregation of positively charged ionic liquid stabilized AuNPs, which results in a shift in the surface plasmon band and a consequent color change of the AuNPs from red to blue. The color change was monitored using UV-vis spectrophotometry and image analysis methods. The aggregation was confirmed by transmission electron microscopic measurements. The degree of aggregation was found to be proportional to the concentration of the added heparin, allowing its quantitative detection. The change in the absorbance and color-value has been used to monitor the concentration of heparin. This optical method can quantify heparin as low as 0.010 μg mL(-1) and the calibration is linear for a wide range of concentration.


Investigation of the source of the blue field entoptic phenomenon.
The cellular source of the blue field entoptic phenomenon was investigated in two microvascular preparations using video-microscopy with lighting conditions similar to those under which the entoptic phenomenon is visualized within the human eye. In the wing of the hibernating bat, microvascular flow was simultaneously videotaped under transmission illumination at 430 nm and under unfiltered illumination. In the rat cremaster alternating observations were made using transmission illumination at 430 nm and epi-illumination fluorescence microscopy with leukocytes rendered fluorescent by intravenous Quinacrine. In both preparations, low magnification video-microscopy using 430 nm illumination produced a field of particles, which were brighter than the background, flowing within a network of dark vessels. The appearance of the particles and their movement simulated the blue field entoptic particle motion. Under higher magnification, the particles appeared brighter than the plasma gaps between red blood cells and were demonstrated to be leukocytes by morphology, by specific staining and by typical behavioral movement. The particles were observed in terminal arteriols capillaries, and post-capillary venules where they were not obscured by red blood cells. The results of this study of two microvascular preparations strongly suggest that in the human eye the blue field entoptic phenomenon is produced by leukocytes flowing within the macular retinal microvasculature.


Characterization of urease and carbonic anhydrase producing bacteria and their role in calcite precipitation.
Urease and carbonic anhydrase (CA) are key enzymes in the chemical reaction of living organisms and have been found to be associated with calcification in a number of microorganisms and invertebrates. Three bacterial strains designated as AP4, AP6, and AP9 were isolated from highly alkaline soil samples using the enrichment culture technique. On the basis of various physiological tests and 16S rRNA sequence analysis, these three bacteria were identified as Bacillus sp., B. megaterium, and B. simplex. Further, these Bacillus species have been characterized for the production of urease and CA in the process of biocalcification. One of the isolates, AP6 produced 553 U/ml of urease and 5.61 EU/ml CA. All the strains were able to produce significant amount of exopolymeric substances and biofilm. Further, efficacy of these strains was tested for calcite production ability and results were correlated with urease and CA. Isolate AP6 precipitated 2.26 mg calcite/cell dry mass (mg). Our observations strongly suggest that it is not only urease but CA also plays an important role in microbially induced calcium carbonate precipitation process. The current work demonstrates that urease and CA producing microbes can be utilized in biocalcification as a sealing agent for filling the gaps or cracks and fissures in constructed facilities and natural formations alike.


Dietary Supplement for Core Symptoms of Autism Spectrum Disorder: Where Are We Now and Where Should We Go?
Autism spectrum disorders (ASDs) are a class of severe and chronic conditions and core symptoms are deficits in social interaction, language communication impairments, and repetitive/stereotyped behavior. Given the limitations of available treatments and substantially increased prevalence of the disease, additional interventions are needed. Since the use of dietary supplements for ASD is of high prevalence, up-to-date information about those supplements are required for both parents and clinicians. Relevant articles were identified through a systematic search of PubMed, EMBASE, Cochrane library, and PsychINFO databases (through May 2017). Current best evidences of 22 randomized controlled trials on 8 different dietary supplements for core symptoms of ASD were reviewed. For each supplement, this report focuses on the definition and potential therapeutic mechanisms, the latest advances, and discussion of study limitations and future directions. Most studies were small and short term, and there is little evidence to support effectiveness of dietary supplements for children with ASD.


Loss of Serglycin Promotes Primary Tumor Growth and Vessel Functionality in the RIP1-Tag2 Mouse Model for Spontaneous Insulinoma Formation.
The serglycin proteoglycan is mainly expressed by hematopoietic cells where the major function is to retain the content of storage granules and vesicles. In recent years, expression of serglycin has also been found in different forms of human malignancies and a high serglycin expression level has been correlated with a more migratory and invasive phenotype in the case of breast cancer and nasopharyngeal carcinoma. Serglycin has also been implicated in the development of the tumor vasculature in multiple myeloma and hepatocellular carcinoma where reduced expression of serglycin was correlated with a less extensive vasculature. To further investigate the contribution of serglycin to tumor development, we have used the immunocompetent RIP1-Tag2 mouse model of spontaneous insulinoma formation crossed into serglycin deficient mice. For the first time we show that serglycin-deficiency affects orthotopic primary tumor growth and tumor vascular functionality of late stage carcinomas. RIP1-Tag2 mice that lack serglycin develop larger tumors with a higher proliferative activity but unaltered apoptosis compared to normal RIP1-Tag2 mice. The absence of serglycin also enhances the tumor vessel functionality, which is better perfused than in tumors from serglycin wild type mice. The presence of the pro-angiogenic modulators vascular endothelial growth factor and hepatocyte growth factor were decreased in the serglycin deficient mice which suggests a less pro-angiogenic environment in the tumors of these animals. Taken together, we conclude that serglycin affects multiple aspects of spontaneous tumor formation, which strengthens the theory that serglycin acts as an important mediator in the formation and progression of tumors.


Air quality in developing world disaster and conflict zones--the case of post-earthquake Haiti.
Data on air quality are remarkably limited in the poorest of the world's countries. This is especially true for post-conflict and disaster zones, where international relief efforts focus largely on more salient public health challenges such as water and sanitation, infectious diseases, and housing. Using post-earthquake Haiti as the example case, this commentary explores air quality challenges in the developing world, highlighting concerns related to infrastructure damage from post-conflict and disaster settings. We contend that there is a growing and presently unmet need for further research and attention from the global health community to address these issues.


Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.
Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Increasing small conductance Ca2+-activated potassium channel activity reverses ischemia-induced impairment of long-term potentiation.
Global cerebral ischemia following cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes injury to hippocampal CA1 pyramidal neurons and impairs cognition. Small conductance Ca(2+)-activated potassium channels type 2 (SK2), expressed in CA1 pyramidal neurons, have been implicated as potential protective targets. Here we showed that, in mice, hippocampal long-term potentiation (LTP) was impaired as early as 3 h after recovery from CA/CPR and LTP remained impaired for at least 30 days. Treatment with the SK2 channel agonist 1-Ethyl-2-benzimidazolinone (1-EBIO) at 30 min after CA provided sustained protection from plasticity deficits, with LTP being maintained at control levels at 30 days after recovery from CA/CPR. Minimal changes in glutamate release probability were observed at delayed times after CA/CPR, implicating post-synaptic mechanisms. Real-time quantitative reverse transcriptase-polymerase chain reaction indicated that CA/CPR did not cause a loss of N-methyl-D-aspartate (NMDA) receptor mRNA at 7 or 30 days after CA/CPR. Similarly, no change in synaptic NMDA receptor protein levels was observed at 7 or 30 days after CA/CPR. Further, patch-clamp experiments demonstrated no change in functional synaptic NMDA receptors at 7 or 30 days after CA/CPR. Electrophysiology recordings showed that synaptic SK channel activity was reduced for the duration of experiments performed (up to 30 days) and that, surprisingly, treatment with 1-EBIO did not prevent the CA/CPR-induced loss of synaptic SK channel function. We concluded that CA/CPR caused alterations in post-synaptic signaling that were prevented by treatment with the SK2 agonist 1-EBIO, indicating that activators of SK2 channels may be useful therapeutic agents to prevent ischemic injury and cognitive impairments.


Growth and differentiation in vitro of mast cells from mesenteric lymph nodes of Nippostrongylus brasiliensis-infected rats.
Intestinal mastocytosis begins to develop in rats, depending on the strain, at 14 (outbred Sprague-Dawley, SD) or 16 (inbred Lewis, L) days after infection with the nematode Nippostrongylus brasiliensis (Nippo). We have investigated in vitro mastopoiesis from mesenteric lymph node (MLN) cells cultured at various intervals post-infection, using a modified Marbrook liquid system. Greater increases in mast cells (MC) were observed in cultures of SD-MLN removed on day 14 after Nippo infection (IMLN-14) than from MLN removed from uninfected animals (NMLN): seven- to twenty-fold versus up to two-fold at 2 weeks and forty- to two hundred-fold versus up to twenty-fold at 4 weeks, respectively (P < 0.002). In contrast, similar differential increases in MC and histamine compared to uninfected controls, were demonstrated in 2 week cultures of MLN from L strain rats removed 17 (IMLN-17) and 20 (IMLN-20) but not 14 days after Nippo infection (P < 0.001). the presence of phytohaemagglutinin (PHA) in vitro was associated with enhanced MC differentiation from both IMLN-17 and IMLN-20, while worm antigen (Ag) stimulated mastopoiesis from IMLN-17, but suppressed the response from IMLN-20 (P < 0.02). Conditioned media (CM) prepared from unstimulated or PHA-stimulated IMLN-32 (i.e. removed 32 days after Nippo infection) caused significant mastopoiesis from NMLN in vitro when compared to no CM or Ag-stimulated CM (P < 0.01). Either MC precursors or cells which help MC differentiation exist in increased numbers in MLN of Nippo-infected rats. Mitogenic or antigenic stimulation modulates in vitro mastopoiesis, either directly or through soluble factors derivable from MLN cells. These in vitro methods can be utilized to understand further mechanisms of intestinal mastocytosis in the rat.


Rectification in tunneling junctions: 2,2'-bipyridyl-terminated n-alkanethiolates.
Molecular rectification is a particularly attractive phenomenon to examine in studying structure-property relationships in charge transport across molecular junctions, since the tunneling currents across the same molecular junction are measured, with only a change in the sign of the bias, with the same electrodes, molecule(s), and contacts. This type of experiment minimizes the complexities arising from measurements of current densities at one polarity using replicate junctions. This paper describes a new organic molecular rectifier: a junction having the structure Ag(TS)/S(CH2)11-4-methyl-2,2'-bipyridyl//Ga2O3/EGaIn (Ag(TS): template-stripped silver substrate; EGaIn: eutectic gallium-indium alloy) which shows reproducible rectification with a mean r(+) = |J(+1.0 V)|/|J(-1.0 V)| = 85 ± 2. This system is important because rectification occurs at a polarity opposite to that of the analogous but much more extensively studied systems based on ferrocene. It establishes (again) that rectification is due to the SAM, and not to redox reactions involving the Ga2O3 film, and confirms that rectification is not related to the polarity in the junction. Comparisons among SAM-based junctions incorporating the Ga2O3/EGaIn top electrode and a variety of heterocyclic terminal groups indicate that the metal-free bipyridyl group, not other features of the junction, is responsible for the rectification. The paper also describes a structural and mechanistic hypothesis that suggests a partial rationalization of values of rectification available in the literature.


Asynchronous master-slave parallelization of differential evolution for multi-objective optimization.
In this paper, we present AMS-DEMO, an asynchronous master-slave implementation of DEMO, an evolutionary algorithm for multi-objective optimization. AMS-DEMO was designed for solving time-intensive problems efficiently on both homogeneous and heterogeneous parallel computer architectures. The algorithm is used as a test case for the asynchronous master-slave parallelization of multi-objective optimization that has not yet been thoroughly investigated. Selection lag is identified as the key property of the parallelization method, which explains how its behavior depends on the type of computer architecture and the number of processors. It is arrived at analytically and from the empirical results. AMS-DEMO is tested on a benchmark problem and a time-intensive industrial optimization problem, on homogeneous and heterogeneous parallel setups, providing performance results for the algorithm and an insight into the parallelization method. A comparison is also performed between AMS-DEMO and generational master-slave DEMO to demonstrate how the asynchronous parallelization method enhances the algorithm and what benefits it brings compared to the synchronous method.


Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus.
Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssRNA) stimulation of the TLR-7-MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF)-7 and eosinophil-associated ribonucleases EAR-1 and EAR-2. Hypereosinophilia in the airways of infected mice also correlated with increased expression of IRF-7, IFN-beta, and NOS-2, and inhibition of NO production with the NOS-2 inhibitor L-NMA partially reversed the accelerated virus clearance promoted by eosinophils. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.


Protein-protein interactions generate hidden feedback and feed-forward loops to trigger bistable switches, oscillations and biphasic dose-responses.
Protein-protein interactions (PPIs) defined as reversible association of two proteins to form a complex, are undoubtedly among the most common interaction motifs featured in cells. Recent large-scale proteomic studies have revealed an enormously complex interactome of the cell, consisting of tens of thousands of PPIs with numerous signalling hubs. PPIs have functional roles in regulating a wide range of cellular processes including signal transduction and post-translational modifications, and de-regulation of PPIs is implicated in many diseases including cancers and neuro-degenerative disorders. Despite the ubiquitous appearance and physiological significance of PPIs, our understanding of the dynamic and functional consequences of these simple motifs remains incomplete, particularly when PPIs occur within large biochemical networks. We employ quantitative, dynamic modelling to computationally analyse salient dynamic features of the PPI motifs and PPI-containing signalling networks varying in topological architecture. Our analyses surprisingly reveal that simple reversible PPI motifs, when being embedded into signalling cascades, could give rise to extremely rich and complex regulatory dynamics in the absence of explicit positive and negative feedback loops. Our work represents a systematic investigation of the dynamic properties of PPIs in signalling networks, and the results shed light on how this simple event may potentiate diverse and intricate behaviours in vivo.


Audit and feedback in mental healthcare: staff experiences.
Audit and feedback (A&F) often underlie implementation projects, described as a circular process; i.e. an A&F cycle. They are widely used, but effect varies with no apparent explanation. We need to understand how A&F work in real-life situations. The purpose of this paper, therefore, is to describe and explore mental healthcare full A&F cycle experiences. This is a naturalistic qualitative study that uses four focus groups and qualitative content analysis. Staff accepted the initial A&F stages, perceiving it to enhance awareness and reassure them about good practice. They were willing to participate in the full cycle and implement changes, but experienced poor follow-up and prioritization, not giving them a chance to own to the process. An important finding is the need for an A&F cycle facilitator. Research teams cannot be expected to be involved in implementing clinical care. Guidelines will keep being produced to improve service quality and will be expected to be practiced. This study gives insights into planning and tailoring A&F cycles. Tools to ease implementation are not enough, and the key seems to lie with facilitating a process using A&F. This study underscores leadership, designated responsibility and facilitation throughout a full audit cycle.