Roles of MIWI, MILI and PLD6 in small RNA regulation in mouse growing oocytes.
The mouse PIWI-interacting RNA (piRNA) pathway produces a class of 26-30-nucleotide (nt) small RNAs and is essential for spermatogenesis and retrotransposon repression. In oocytes, however, its regulation and function are poorly understood. In the present study, we investigated the consequences of loss of piRNA-pathway components in growing oocytes. When MILI (or PIWIL2), a PIWI family member, was depleted by gene knockout, almost all piRNAs disappeared. This severe loss of piRNA was accompanied by an increase in transcripts derived from specific retrotransposons, especially IAPs. MIWI (or PIWIL1) depletion had a smaller effect. In oocytes lacking PLD6 (or ZUCCHINI or MITOPLD), a mitochondrial nuclease/phospholipase involved in piRNA biogenesis in male germ cells, the piRNA level was decreased to 50% compared to wild-type, a phenotype much milder than that in males. Since PLD6 is essential for the creation of the 5΄ ends of primary piRNAs in males, the presence of mature piRNA in PLD6-depleted oocytes suggests the presence of compensating enzymes. Furthermore, we identified novel 21-23-nt small RNAs, termed spiRNAs, possessing a 10-nt complementarity with piRNAs, which were produced dependent on MILI and independent of DICER. Our study revealed the differences in the biogenesis and function of the piRNA pathway between sexes.


Renal function equations before and after living kidney donation: a within-individual comparison of performance at different levels of renal function.
The Modification of Diet in Renal Disease (MDRD) study equation and the Cockcroft-Gault (CG) equation perform poorly in the (near-) normal range of GFR. Whether this is due to the level of GFR as such or to differences in individual characteristics between healthy individuals and patient with chronic kidney disease (CKD) is unknown. We evaluated the performance of MDRD, CG per BSA (CG/(BSA)) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with measured GFR (mGFR; I-iothalamate) at 4 months before and 2 months after donation in 253 consecutive living kidney donors. mGFR declined from 103 ± 15 to 66 ± 11 ml/min per 1.73 m(2) after donation. All equations underestimated mGFR at both time points. Arithmetic performance analysis showed improved performance after donation of all equations, with significant reduction of bias after donation. Expressed as percentage difference, mGFR-estimated GFR (eGFR) bias was reduced after donation only for CG/(BSA). Finally, in 295 unselected individuals who were screened for donation, mGFR was below the cutoff for donation of 80 ml/min per 1.73 m(2) in 19 individual but in 166, 98, and 74 for MDRD, CDK-EPI, and CG/(BSA), respectively. A higher level of GFR as such is associated with larger absolute underestimation of true GFR by eGFR. For donor screening purposes, eGFR should be interpreted with great caution; when in doubt, true GFR should be performed to prevent unjustified decline of prospective kidney donors.


Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review.
OBJECTIVE Spinal metastases that recur after conventional palliative radiotherapy have historically been difficult to manage due to concerns of spinal cord toxicity in the retreatment setting. Spine stereotactic body radiation therapy (SBRT), also known as stereotactic radiosurgery, is emerging as an effective and safe means of delivering ablative doses to these recurrent tumors. The authors performed a systematic review of the literature to determine the clinical efficacy and safety of spine SBRT specific to previously irradiated spinal metastases. METHODS A systematic literature review was conducted, which was specific to SBRT to the spine, using MEDLINE, Embase, Cochrane Evidence-Based Medicine Database, National Guideline Clearinghouse, and CMA Infobase, with further bibliographic review of appropriate articles. Research questions included: 1) Is retreatment spine SBRT efficacious with respect to local control and symptom control? 2) Is retreatment spine SBRT safe? RESULTS The initial literature search retrieved 2263 articles. Of these articles, 160 were potentially relevant, 105 were selected for in-depth review, and 9 studies met all inclusion criteria for analysis. All studies were single-institution series, including 4 retrospective, 3 retrospective series of prospective databases, 1 prospective, and 1 Phase I/II prospective study (low- or very low-quality data). The results indicated that spine SBRT is effective, with a median 1-year local control rate of 76% (range 66%-90%). Improvement in patients' pain scores post-SBRT ranged from 65% to 81%. Treatment delivery was safe, with crude rates of vertebral body fracture of 12% (range 0%-22%) and radiation-induced myelopathy of 1.2%. CONCLUSIONS This systematic literature review suggests that SBRT to previously irradiated spinal metastases is safe and effective with respect to both local control and pain relief. Although the evidence is limited to low-quality data, SBRT can be a recommended treatment option for reirradiation.


Preservation of root cementum: a comparative evaluation of power-driven versus hand instruments.
The purpose of this study was to evaluate the effects of three distinct periodontal treatment methods in comparison with hand instrumentation on residual cementum of periodontal diseased teeth. Cementum can influence the activities of periodontal cells and may play an important regulatory role in periodontal treatment. The ideal method for periodontal therapy involves removal of biofilm, calculus and endotoxin while preserving root cementum. Forty-eight caries free, single-rooted teeth in patients diagnosed with severe chronic periodontitis were treated using four different methods prior to extraction. The teeth were instrumented subgingivally at one approximal site either by hand curettes (HC), piezoelectric ultrasonic scalers (U), piezoelectric ultrasonic scalers following air polishing (U + AP) or air polishing (AP) alone. Following extraction of teeth, instrumented and non-instrumented sites were analysed with a dissecting microscope and SEM for measurement of the amount of and surface characteristics of residual cementum. The percentage of coronal cementum remaining following subgingival instrumentation was 84% for U, 80% for U + AP, 94% for AP and 65% for HC. Although subgingival instrumentation of apical portions of the cementum demonstrated 6% less retained cementum in comparison with coronal portions, the amount of retained cementum with AP was still significantly greater than with HC. SEM results found the smoothest root surfaces were produced by the HC followed by the AP, while root surfaces instrumented by U or U + AP presented grooves and scratches. This study demonstrated that AP was superior to U devices in preserving cementum, whereas HC were the most effective instruments in removing cementum.


Intra-arterial delivery of superparamagnetic iron-oxide nanoshell and polyvinyl alcohol based chemoembolization system for the treatment of liver tumor.
A superparamagnetic iron oxide (SPIO) nanoshell and polyvinyl alcohol (PVA) based chemoembolization system for anti-cancer drug doxorubicin (DOX) delivery has previously been presented. We have also previously confirmed the feasibility and safety of this multifunctional system for carrying both DOX and SPIO nanoparticles in vitro. However, the pharmacokinetic and the therapeutic efficacy of this novel drug-delivery system in vivo is not yet clear, and as such was the subject of this study. A rabbit liver tumor model was utilized, whereby the tumors were targeted by SPIO/DOX/PVA composite infused via a catheter into the hepatic arteries which supplying blood to the tumor. The result was compared to saline, DOX+PVA, or SPIO/DOX infusion alone. SPIO/DOX/PVA displayed sustained chemotherapeutic agent release into the tumor. In comparison to other treatment groups, tumor growth rate was significantly slowed down by SPIO/DOX/PVA with a smaller tumor volume and a prolonged survival time of the experimental rabbits. Liver function results demonstrated SPIO/DOX/PVA has no apparent toxicity to the normal liver. Pharmacokinetic studies and histological evaluations in SPIO/DOX/PVA group revealed that long-term retention and drug release within the tumor associated with SPIO/DOX/PVA therapy, and thereafter induced significantly enhanced tumor necrosis and apoptosis. We conclude SPIO/DOX/PVA provides a highly effective therapeutic strategy for management of liver tumors.


Diversity and distribution of Blastocystis sp. subtypes in non-human primates.
Blastocystis SSU-rDNA sequence data from 317 captive and free-living non-human primates (NHPs) representing 30 genera of apes, Old and New World (OW and NW) monkeys and prosimians were analysed to investigate subtype (ST) and allele distribution among hosts. Excluding 20 mixed ST infections, 27% of the sequences belonged to ST1, 22% to ST2, 34% to ST3, 1% to ST4, 4% to ST5, 11% to ST8, <1% to ST13 and 1% to ST15. The study confirmed cryptic host specificity of ST1 and ST3; conversely, considerable overlap in ST2 alleles exists among humans and NHPs. Subtype distribution in humans and NHPs differs mainly in that ST4 is rarely reported in NHPs while ST5 and ST8 are both unusual in humans. This may be due to host specificity and/or the apparent geographically restricted range of some subtypes. While the distribution of ST1, ST2 and ST3 was independent of NHP group or geographical association, ST5 was seen only in apes and OW monkeys and ST8 primarily in arboreal NHPs and only in species native to Asia or South America.


Intention Estimation Using Set of Reference Trajectories as Behaviour Model.
Autonomous robotic systems operating in the vicinity of other agents, such as humans, manually driven vehicles and other robots, can model the behaviour and estimate intentions of the other agents to enhance efficiency of their operation, while preserving safety. We propose a data-driven approach to model the behaviour of other agents, which is based on a set of trajectories navigated by other agents. Then, to evaluate the proposed behaviour modelling approach, we propose and compare two methods for agent intention estimation based on: (i) particle filtering; and (ii) decision trees. The proposed methods were validated using three datasets that consist of real-world bicycle and car trajectories in two different scenarios, at a roundabout and at a t-junction with a pedestrian crossing. The results validate the utility of the data-driven behaviour model, and show that decision-tree based intention estimation works better on a binary-class problem, whereas the particle-filter based technique performs better on a multi-class problem, such as the roundabout, where the method yielded an average gain of 14.88 m for correct intention estimation locations compared to the decision-tree based method.


Haemonchus contortus (Nematoda: Trichostrongylidae) infection in lambs elicits an unequivocal Th2 immune response.
Selection of resistant animals and host immunization have been proposed as alternative methods for the control of gastrointestinal nematode parasites. However, a better knowledge of the mechanisms involved in protective immunity against these parasites is required for the development of optimal strategies. In this study, 3 month old INRA 401 lambs (n = 81) were allocated into three groups: uninfected control, challenged either once (primary-infected animals) or twice (previously-infected animals) with 10,000 Haemonchus contortus L3. Uninfected control and challenged animals were sequentially sacrificed at 3, 7, 15 and 28 days post challenge. In both challenged groups, a clear Th2-oriented immune response was observed in the abomasal lymph node and mucosa. IL-4 and IL-13 mRNA over-expression, recruitment of eosinophils, mast cells and globule leukocytes and production of specific systemic IgG and mucosal IgA were observed earlier in previously-infected animals than in primary-infected ones. At 28 days post infection, no differences between intensities of these responses were observed between the challenged groups. Worm establishment rates were similar in previously-infected and primary-infected lambs. However, reductions of worm development, female fecundity and fecal egg output were observed in previously-infected sheep. We conclude that H. contortus infection in young INRA 401 lambs induced an unequivocal Th2 immune response resulting in the regulation of worm egg production without affecting their establishment.


Post-bariatric abdominoplasty resulting in wound infection and dehiscence-Conservative treatment with medical grade honey: A case report and review of literature.
Wound complications in post-bariatric patients undergoing body-contouring surgery after massive weight loss are not uncommon and often, surgical debridement or conservative management is necessary. Honey is one of the most ancient remedies for wound care and it is also considered to possess debriding effects. Current research has demonstrated promising results showing that honey can improve wound granulation and epithelialization, reduce exudate and shorten healing times. This case report has been reported in line with the CARE criteria. A 40 year-old female suffered wound infection and dehiscence after undergoing post-bariatric abdominoplasty. The patient was not interested in surgical revision and split skin grafting. Therefore, conservative wound treatment with topical Manuka honey was instituted resulting in significant clinical improvement and effective healing concurrently with good patient satisfaction. Surgical wound complications in post-bariatric patients undergoing abdominoplasty are common and often require surgical revision or conservative wound treatment. No previous publication has addressed outpatient treatment of post-bariatric abdominoplasty wound complications with medical grade honey. Although more research is needed for definitive conclusions of honey's efficacy, it is safe and as presented in our case, it may under certain circumstances reduce the need of surgical wound debridement and serve as a remedy for conservative treatment.


Escherichia coli TatA and TatB proteins have N-out, C-in topology in intact cells.
The twin arginine protein transport (Tat) system translocates folded proteins across the cytoplasmic membrane of prokaryotes and the thylakoid membrane of chloroplasts. In Escherichia coli, TatA, TatB, and TatC are essential components of the machinery. A complex of TatB and TatC acts as the substrate receptor, whereas TatA is proposed to form the Tat transport channel. TatA and TatB are related proteins that comprise an N-terminal transmembrane helix and an adjacent amphipathic helix. Previous studies addressing the topological organization of TatA have given conflicting results. In this study, we have addressed the topological arrangement of TatA and TatB in intact cells by labeling of engineered cysteine residues with the membrane-impermeable thiol reagent methoxypolyethylene glycol maleimide. Our results show that TatA and TatB share an N-out, C-in topology, with no evidence that the amphipathic helices of either protein are exposed at the periplasmic side of the membrane. We further show that the N-out, C-in topology of TatA is fixed and is not affected by the absence of other Tat components or by the overproduction of a Tat substrate. These data indicate that topological reorganization of TatA is unlikely to accompany Tat-dependent protein transport.


An experimental investigation of the combustion performance of human faeces.
Poor sanitation is one of the major hindrances to the global sustainable development goals. The Reinvent the Toilet Challenge of the Bill and Melinda Gates Foundation is set to develop affordable, next-generation sanitary systems that can ensure safe treatment and wide accessibility without compromise on sustainable use of natural resources and the environment. Energy recovery from human excreta is likely to be a cornerstone of future sustainable sanitary systems. Faeces combustion was investigated using a bench-scale downdraft combustor test rig, alongside with wood biomass and simulant faeces. Parameters such as air flow rate, fuel pellet size, bed height, and fuel ignition mode were varied to establish the combustion operating range of the test rig and the optimum conditions for converting the faecal biomass to energy. The experimental results show that the dry human faeces had a higher energy content (∼25 MJ/kg) than wood biomass. At equivalence ratio between 0.86 and 1.12, the combustion temperature and fuel burn rate ranged from 431 to 558 °C and 1.53 to 2.30 g/min respectively. Preliminary results for the simulant faeces show that a minimum combustion bed temperature of 600 ± 10 °C can handle faeces up to 60 wt.% moisture at optimum air-to-fuel ratio. Further investigation is required to establish the appropriate trade-off limits for drying and energy recovery, considering different stool types, moisture content and drying characteristics. This is important for the design and further development of a self-sustained energy conversion and recovery systems for the NMT and similar sanitary solutions.


Physical activity and enhanced fitness to improve cognitive function in older people without known cognitive impairment.
Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, fitness and cognition are reported in the same individuals could help to resolve this question. To assess the effectiveness of physical activity, aimed at improving cardiorespiratory fitness, on cognitive function in older people without known cognitive impairment. We searched MEDLINE, EMBASE, PEDro, SPORTDiscus, PsycINFO, CINAHL, Cochrane Controlled Trials Register (CENTRAL), Dissertation abstracts international and ongoing trials registers on 15 December 2005 with no language restrictions. All published randomised controlled trials comparing aerobic physical activity programmes with any other intervention or no intervention with participants older than 55 years of age were eligible for inclusion. Eleven RCTs fulfilling the inclusion criteria are included in this review. Two reviewers independently extracted the data from these included studies. Eight out of 11 studies reported that aerobic exercise interventions resulted in increased cardiorespiratory fitness of the intervention group (an improvement on the maximum oxygen uptake test which is considered to be the single best indicator of the cardiorespiratory system) of approximately 14% and this improvement coincided with improvements in cognitive capacity. The largest effects on cognitive function were found on motor function and auditory attention (effect sizes of 1.17 and 0.50 respectively). Moderate effects were observed for cognitive speed (speed at which information is processed; effect size 0.26) and visual attention (effect size 0.26). There is evidence that aerobic physical activities which improve cardiorespiratory fitness are beneficial for cognitive function in healthy older adults, with effects observed for motor function, cognitive speed, auditory and visual attention. However, the majority of comparisons yielded no significant results. The data are insufficient to show that the improvements in cognitive function which can be attributed to physical exercise are due to improvements in cardiovascular fitness, although the temporal association suggests that this might be the case. Larger studies are still required to confirm whether the aerobic training component is necessary, or whether the same can be achieved with any type of physical exercise. At the same time, it would be informative to understand why some cognitive functions seem to improve with (aerobic) physical exercise while other functions seem to be insensitive to physical exercise. Clinicians and scientists in the field of neuropsychology should seek mutual agreement on a smaller battery of cognitive tests to use, in order to render research on cognition clinically relevant and transparent and heighten the reproducibility of results for future research.


Interaction of Pseudomonas aeruginosa with A549 pneumocyte cells.
The interaction of Pseudomonas aeruginosa with a human lung pneumocyte cell line (A549) was studied. Wild-type strain PAK adhered efficiently to the A549 cells, while an isogenic mutant, carrying a mutation in the pilin structural gene, adhered at 10 to 20% of the wild-type levels. Another nonpiliated mutant of P. aeruginosa PAK, defective in the pleiotropic regulatory gene rpoN, did not adhere to A549 cells, suggesting the presence of a second, RpoN-controlled adhesin on the bacterial surface. Endocytosis of wild-type P. aeruginosa PAK by A549 cells was also demonstrated. A significant fraction of the internalized bacteria were recovered in a viable form after several hours of residence within the A549 cells. When examined by electron microscopy, intracellular bacteria were located in membranous vesicles, and no evidence of killing by lysosomal mechanisms was observed. These studies raise the possibility that during chronic respiratory tract infections in immunocompromised patients, P. aeruginosa may persist in intracellular compartments and therefore be protected from the defense mechanisms of the host.


Gene transfer for erythropoiesis enhancement.
The spectrum of anemias treated with recombinant human erythropoietin is rapidly broadening. Lifelong treatment with very high doses is now under evaluation for beta-thalassemia and sickle cell anemia. These indications make it worthwhile to search for methods that will allow a permanent systemic delivery of the hormone. Here, we review experimental gene-transfer-based procedures for erythropoietin delivery in vivo. In mice, both ex vivo and direct in vivo approaches for gene transfer have resulted in the long-term production of therapeutic levels of the hormone. Gene transfer of erythropoietin could become a viable alternative to the injection of the purified recombinant protein once reliable procedures for controlling transgene expression are available.


Robust reversible watermarking via clustering and enhanced pixel-wise masking.
Robust reversible watermarking (RRW) methods are popular in multimedia for protecting copyright, while preserving intactness of host images and providing robustness against unintentional attacks. However, conventional RRW methods are not readily applicable in practice. That is mainly because 1) they fail to offer satisfactory reversibility on large-scale image datasets; 2) they have limited robustness in extracting watermarks from the watermarked images destroyed by different unintentional attacks; and 3) some of them suffer from extremely poor invisibility for watermarked images. Therefore, it is necessary to have a framework to address these three problems, and further improve its performance. This paper presents a novel pragmatic framework, wavelet-domain statistical quantity histogram shifting and clustering (WSQH-SC). Compared with conventional methods, WSQH-SC ingeniously constructs new watermark embedding and extraction procedures by histogram shifting and clustering, which are important for improving robustness and reducing run-time complexity. Additionally, WSQH-SC includes the property inspired pixel adjustment (PIPA) to effectively handle overflow and underflow of pixels. This results in satisfactory reversibility and invisibility. Furthermore, to increase its practical applicability, WSQH-SC designs an enhanced pixel-wise masking (EPWM) to balance robustness and invisibility. We perform extensive experiments over natural, medical, and synthetic aperture radar (SAR) images to show the effectiveness of WSQH-SC by comparing with the histogram rotation (HR)-based and histogram distribution constrained (HDC) methods.


Dosing efficiency and particle-size characteristics of pressurized metered-dose inhaler aerosols in narrow catheters.
An experimental in vitro model was used to determine the effects of intraluminal catheter diameter and length on the delivered dose and particle-size characteristics of salbutamol (albuterol) aerosol delivered by metered dose inhaler (MDI) (Ventolin, 100 micrograms per puff). The dose of aerosolized drug that exited a 16-cm-long tracheal tube with an inner diameter (ID) of 6 mm was compared with that from 4 catheters of differing diameters and lengths that were inserted individually into the tracheal tube. The salbutamol MDI canister was actuated ten times into each delivery system, and the effluent aerosol was trapped onto a filter. The filtrate was dissolved in methanol, and the salbutamol concentration was determined using high-performance liquid chromatography. For the 3 22-cm-long catheters, the delivered dose (mean +/- SD) of salbutamol per actuation for the 22-standard wire gauge (SWG) catheter was 97.5 +/- 3.9 micrograms, which was similar to that for the 19-SWG catheter (102.3 +/- 2.5 micrograms) but was significantly less than that for the 14-SWG catheter (108.2 +/- 4.2 micrograms) (p < 0.05). These delivered doses exceeded those of the 6.0-mm-ID tracheal tube alone (2.33 +/- 0.76 micrograms) and the 13-cm-long 19-SWG catheter (2.17 +/- 0.29 micrograms) (p < 0.001). In a second experiment using a cascade impactor, the distribution of aerosol particle diameters that exited the 6-mm-ID tracheal tube was compared with that exiting a 13-cm-long 19-SWG catheter that extended halfway down the tracheal tube and with that exiting a 22-cm-long 19-SWG catheter inserted into the distal end of the 6-mm-ID tracheal tube. The mass median aerodynamic diameter (mean +/- SD) of the salbutamol aerosols delivered through both the 6.0-mm-ID tracheal tube (1.1 +/- 0.1 microns) and that of the 13-cm-long 19-SWG catheter (1.2 +/- 0.2 microns) were significantly less than that delivered through the 22-cm-long 19-SWG catheter (2.0 +/- 0.1 microns) (p < 0.05). The authors conclude that delivery of respirable aerosol can occur through narrow catheters that function as extended nozzles for MDIs. Optimal dosing will be obtained when the catheter extends the full length of the tracheal tube.


Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of eight hundred and twenty-one cases.
The natural history of congenital muscular torticollis and the outcome of different treatment modalities have been poorly investigated, and the results of treatment have varied considerably. The main objective of this prospective study was to evaluate the outcomes of 821 consecutive patients with congenital muscular torticollis who were first seen when they were less than one year old, were treated with a standardized program of manual stretching, and were followed for a mean of 4.5 years. Before treatment, the patients were classified into one of three clinical groups: (1) palpable sternomastoid tumor, (2) muscular torticollis (thickening and tightness of the sternocleidomastoid muscle), and (3) postural torticollis (torticollis but no tightness or tumor). Of the 821 patients, 452 (55%) had a sternomastoid tumor; 276 (34%), muscular torticollis; and ninety-three (11%), postural torticollis. Multivariate analysis of the outcomes showed that (1) the duration of treatment was significantly associated with the clinical group (p < 0.0001), a passive rotation deficit of the neck (p < 0.0001), involvement of the right side (p < 0.0001), difficulties with the birth (p < 0.009), and age at presentation (p < 0.0001); (2) the overall final assessment score was associated with the rotation deficit (p = 0.02), age at presentation (p = 0.014), and duration of treatment (p < 0.0001); and (3) subsequent surgical treatment was required by 8% (thirty-four) of the 452 patients in the sternomastoid tumor group compared with 3% (eight) of the 276 patients in the muscular torticollis group and 0% (none) of the ninety-three patients in the postural torticollis group. This large prospective study demonstrated that controlled manual stretching is safe and effective in the treatment of congenital muscular torticollis when a patient is seen before the age of one year. The most important factors that predict the outcome of manual stretching are the clinical group, the initial deficit in rotation of the neck, and the age of the patient at presentation. Surgical treatment is indicated when a patient has undergone at least six months of controlled manual stretching and has residual head tilt, deficits of passive rotation and lateral bending of the neck of >15 degrees, a tight muscular band or tumor, and a poor outcome according to our special assessment chart.


Automated EEG Artifact Handling With Application in Driver Monitoring.
Automated analyses of electroencephalographic (EEG) signals acquired in naturalistic environments are becoming increasingly important in areas such as brain-computer interfaces and behavior science. However, the recorded EEG in such environments is often heavily contaminated by motion artifacts and eye movements. This poses new requirements on artifact handling. The objective of this paper is to present an automated EEG artifacts handling algorithm, which will be used as a preprocessing step in a driver monitoring application. The algorithm, named Automated aRTifacts handling in EEG (ARTE), is based on wavelets, independent component analysis, and hierarchical clustering. The algorithm is tested on a dataset obtained from a driver sleepiness study including 30 drivers and 540 30-min 30-channel EEG recordings. The algorithm is evaluated by a clinical neurophysiologist, by quantitative criteria (signal quality index, mean square error, relative error, and mean absolute error), and by demonstrating its usefulness as a preprocessing step in driver monitoring, here exemplified with driver sleepiness classification. All results are compared with a state-of-the-art algorithm called FORCe. The quantitative and expert evaluation results show that the two algorithms are comparable, and that both algorithms significantly reduce the impact of artifacts in recorded EEG signals. When artifact handling is used as a preprocessing step in driver sleepiness classification, the classification accuracy increased by 5% when using ARTE and by 2% when using FORCe. The advantage with ARTE is that it is data driven and does not rely on additional reference signals or manually defined thresholds, making it well suited for use in dynamic settings where unforeseen and rare artifacts are commonly encountered.


Bacteremia in a long-term-care facility: a five-year prospective study of 163 consecutive episodes.
The clinical features, microbiological characteristics, and outcomes of 163 episodes of bacteremia occurring at a long-term-care facility were evaluated. The rate of nosocomial bacteremia increased from 0.20 to 0.36 cases/1,000 patient-days from 1985 to 1989; there was a parallel increase in the rate of all nosocomial infections combined. Bacteremia was documented in 6.5% of all hospital-acquired infections. The majority of isolates were gram-negative, and Providencia stuartii was the most common gram-negative species. Staphylococcus aureus was the most frequent isolate; one-third of S. aureus strains were resistant to methicillin. Bacteremia was polymicrobial in 36 episodes (22%), 14 of which involved an enterococcal species. Portals of entry included the urinary tract (55%), the respiratory tract (11%), and soft tissue (9%). Overall mortality was 21.5%. Death was significantly associated with residence on the intermediate-care unit, the presence of a respiratory infection, a change in mental status, and relatively recent admission. Optimal management of bacterial infection in a long-term-care setting requires the availability of blood culture results. Initial decisions about antibiotic therapy should be made in light of the likelihood of infection with multiresistant organisms and of polymicrobial infection.


Constrained pseudo-Brownian motion and its application to image enhancement.
Brownian motion is a random process that finds application in many fields, and its relation to certain color perception phenomena has recently been observed. On this ground, Marini and Rizzi developed a retinex algorithm based on Brownian motion paths. However, while their approach has several advantages and delivers interesting results, it has a high computational complexity. We propose an efficient algorithm that generates pseudo-Brownian paths with a very important constraint: we can guarantee a lower bound to the number of visits to each pixel, as well as its average. Despite these constraints, we show that the paths generated have certain statistical similarities to random walk and Brownian motion. Finally, we present a retinex implementation that exploits the paths generated with our algorithm, and we compare some images it generates with those obtained with the McCann99 and Frankle and McCann's algorithms (two multiscale retinex implementations that have a low computational complexity). We find that our approach causes fewer artifacts and tends to require a smaller number of pixel comparisons to achieve similar results, thus compensating for the slightly higher computational complexity.


Proximal placement of the acetabular component in total hip arthroplasty. A long-term follow-up study.
A retrospective review was undertaken of thirty-seven hips (thirty-four patients) that had had a complex cemented total hip arthroplasty. In these hips, circumstances had necessitated that the center of the hip be placed farther proximally, as measured from the interteardrop line, than the anatomical position that is normally used. The mean duration of clinical and roentgenographic follow-up was eleven years (range, seven to seventeen years), and the mean age of the patients was fifty-one years (range, sixteen to seventy-three years). Most of these hips had a major deficiency or defect of the acetabular bone stock, or both. Of the six acetabular components (16 per cent) that became loose and were followed for ten years, only one needed revision. Because this study was aimed specifically at assessment of the acetabular component, if the femoral component alone needed revision, the final clinical rating that was used was the one obtained after the femoral revision. Thirty-one hips (84 per cent) were rated as having a good or excellent result; they had an average Harris hip-rating score of 43 points preoperatively and 93 points postoperatively. Thirty-three of the thirty-seven acetabular components were not substantially displaced laterally as compared with the anatomical location that is normally used. Our findings suggest that, when circumstances dictate, proximal positioning of the acetabular component without lateral displacement can give an acceptable result in cemented total hip-replacement procedures.


Laboratory validation and field usability assessment of a point-of-care test for serum bilirubin levels in neonates in a tropical setting.
Background: Screening and monitoring serum bilirubin (SBR) in neonates is crucial to prevent neonatal hyperbilirubinemia (NH)-associated morbidity and mortality worldwide. A lack of resources is often a barrier for measuring SBR in developing countries. Reliable, cost-effective, easy to use point-of-care (POC) SBR tests are needed. This study aimed to evaluate the technical accuracy and usability of the Bilistick System (BS), a new bilirubin POC test, in a tropical setting. Methods: This was a mixed-methods study, including laboratory validation of the BS, direct observation of technical procedures as performed by the midwives and midwives' assessment of the device's easiness of use through focus group discussions (FGD) and a self-administered questionnaire. The study was conducted in a field clinic of the Shoklo Malaria Research Unit along the Thailand-Myanmar border between January and December 2017. Results: A total of 173 samples were tested at a median age of 4 days. BS generated an error message-providing no SBR readout-in 48.6% of the tests performed. For the tests that yielded a result, the correlation coefficient (95% CI) between BS and routine laboratory bilirubinometer SBR was 0.87 (0.77-0.93). The accuracy decreased with increasing haematocrit and at higher humidity (≥75%). Direct observation of the operators using the device and analysis of the focus group discussions and questionnaires indicated that the BS was considered easy to use and required limited training. Conclusions: This evaluation showed that the BS, in its current formulation, does not provide reliable results for measuring SBR in a tropical, low-resource setting but has acceptable usability features.


Effect of weatherization combined with community health worker in-home education on asthma control.
We assessed the benefits of adding weatherization-plus-health interventions to an in-home, community health worker (CHW) education program on asthma control. We used a quasi-experimental design to compare study group homes (n = 34) receiving CHW education and weatherization-plus-health structural interventions with historical comparison group homes (n = 68) receiving only education. Data were collected in King County, Washington, from October 2009 to September 2010. Over the 1-year study period, the percentage of study group children with not-well-controlled or very poorly controlled asthma decreased more than the comparison group percentage (100% to 28.8% vs 100% to 51.6%; P = .04). Study group caregiver quality-of-life improvements exceeded comparison group improvements (P = .002) by 0.7 units, a clinically important difference. The decrease in study home asthma triggers (evidence of mold, water damage, pests, smoking) was marginally greater than the comparison group decrease (P = .089). Except for mouse allergen, the percentage of study group allergen floor dust samples at or above the detection limit decreased, although most reductions were not statistically significant. Combining weatherization and healthy home interventions (e.g., improved ventilation, moisture and mold reduction, carpet replacement, and plumbing repairs) with CHW asthma education significantly improves childhood asthma control.


New species of Cryptosporidium Tyzzer, 1907 (Apicomplexa) from amphibian host: morphology, biology and phylogeny.
Cryptosporidium fragile sp. n. (Apicomplexa) is described from black-spined toads, Duttaphrynus melanostictus (Schneider) (Amphibia, Anura, Bufonidae) from the Malay Peninsula. The parasitized animals were directly imported from Malaysia and harboured C. fragile at the time of arrival. Oocysts were subspherical to elliptical with irregular contour in optical section, measuring 6.2 (5.5-7.0) x 5.5 (5.0-6.5) microm. Oocyst wall was smooth and colourless in light microscopy. The endogenous development of C. fragile in the stomach of black-spined toad was analysed in detail using light and electron microscopy. Cryptosporidian developmental stages were confined to the surface of gastric epithelial cells. In transmission experiments, C. fragile has not been infective for one fish species, four amphibian species, one species of reptile and SCID mice. Full length small subunit rRNA gene sequence was obtained. Phylogenetic reconstruction revealed distinct status of C. fragile within the clade of species with gastric localisation including Cryptosporidium muris Tyzzer, 1907, Cryptosporidium serpentis Levine, 1980 and Cryptosporidium andersoni Lindsay, Upton, Owens, Morgan, Mead et Blagburn, 2000. Described characteristics differentiate C. fragile from the currently recognized Cryptosporidium species. Our experience with the description of C. fragile has led us to revise the recommended criteria for an introduction of a new Cryptosporidium species name. C. fragile is the first species described and named from an amphibian host. Its prevalence of 83% (15/18) in black-spined toads within the 3 months after importation calls for strict quarantine measures and import regulation for lower vertebrates.


Evaluation of a technique for measurement of flow-mediated vasodilation in healthy ponies.
To determine between-pony and within-pony variations and interobserver and intraobserver agreements of a technique for measurement of flow-mediated vasodilation (FMD) in healthy ponies. 6 healthy pony mares (weight range, 236 to 406 kg; body condition score range, 3/9 to 7/9; age range, 14 to 25 years). In each pony, the left median artery was occluded with a blood pressure cuff (inflated to > 300 mm Hg for 5 minutes). Two-dimensional ultrasonographic images of the artery were recorded for 30 seconds before cuff inflation and for 2 minutes after cuff deflation. Maximum luminal diameters of arteries were compared with their baseline diameters to calculate FMD (relative percentage increase in luminal size). Images were obtained from 6 ponies 1 time and from 1 pony 6 times. Independent analysis of images was performed by 2 investigators, 1 of whom analyzed images on 2 occasions. Mean ± SD FMD in 6 ponies (1 time) was 12.57 ± 4.28% and in 1 pony (6 times) was 7.30 ± 2.11%. Between-pony and within-pony coefficients of variation were 34.09% and 28.84%, respectively. Interobserver agreement was fair (intraclass correlation coefficient, 0.47); intraobserver agreement was poor (intraclass correlation coefficient, 0.30). FMD was identified and measured in ponies. Measurement of FMD is used to assess endothelial function in humans and has been investigated in dogs. Measurement of FMD in ponies appeared to be feasible and could be used to assess endothelial function (to determine predisposition for development of laminitis or cardiovascular diseases).


The incidence and distribution of stress fractures in competitive track and field athletes. A twelve-month prospective study.
The incidence and distribution of stress fractures were evaluated prospectively over 12 months in 53 female and 58 male competitive track and field athletes (age range, 17 to 26 years). Twenty athletes sustained 26 stress fractures for an overall incidence rate of 21.1%. The incidence was 0.70 for the number of stress fractures per 1000 hours of training. No differences were observed between male and female rates (P > 0.05). Twenty-six stress fractures composed 20% of the 130 musculoskeletal injuries sustained during the study. Although there was no difference in stress fracture incidence among athletes competing in different events (P > 0.05), sprints, hurdles, and jumps were associated with a significantly greater number of foot fractures; middle- and long-distance running were associated with a greater number of long bone and pelvic fractures (P < 0.05). Overall, the most common sites of bone injuries were the tibia with 12 injuries (46%), followed by the navicular with 4 injuries (15%), and the fibula with 3 injuries (12%). The high incidence of stress fractures in our study suggests that risk factors in track and field athletes should be identified.


Challenges in representation learning: a report on three machine learning contests.
The ICML 2013 Workshop on Challenges in Representation Learning(1) focused on three challenges: the black box learning challenge, the facial expression recognition challenge, and the multimodal learning challenge. We describe the datasets created for these challenges and summarize the results of the competitions. We provide suggestions for organizers of future challenges and some comments on what kind of knowledge can be gained from machine learning competitions.


[Identification and sequence analysis of a novel human leukocyte antigen allele B*54:09].
To identify a novel human leukocyte antigen(HLA) allele in Chinese population. HLA typing was carried out with polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). The HLA-B exons 1-7 of the proband were amplified and the product was cloned using a TOPO TA cloning sequencing kit to separate the two alleles. Both strands of exons 2 and 3 of selected colonies were sequenced. Sequence-based typing (SBT) was used to identify and analyze the difference between the new allele and the closest matching HLA-B allele. HLA typing indicated a SSOP pattern which did not match with known HLA-B alleles. The results of the sequencing suggested the HLA-B alleles of the proband as B*59:01 and a novel allele. The HLA-B exon 3 sequence of the novel allele was different from any known alleles. This allele differs from the closest matching B*54:06 allele by 6 nucleotides, which included nt486 (G to C), nt527 (A to T), nt538 (T to C), nt539 (G to T), nt559 (C to A) and nt560 (T to C) in exon 3, resulting in substitutions of three amino acids including Glu to Val at codon 152, Trp to Leu at codon 156 and Leu to Thr at codon 163. A novel HLA-B allele has been identified and has been designated as HLA-B*54:09 by WHO Nomenclature Committee for Factors of the HLA System.


A mutation in the MATP gene causes the cream coat colour in the horse.
In horses, basic colours such as bay or chestnut may be partially diluted to buckskin and palomino, or extremely diluted to cream, a nearly white colour with pink skin and blue eyes. This dilution is expected to be controlled by one gene and we used both candidate gene and positional cloning strategies to identify the "cream mutation". A horse panel including reference colours was established and typed for different markers within or in the neighbourhood of two candidate genes. Our data suggest that the causal mutation, a G to A transition, is localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine substitution in the encoded protein. This conserved mutation was also described in mice and humans, but not in medaka.


Imaging the adult with simple shunt lesions: position paper from the EACVI and the ESC WG on ACHD. Endorsed by AEPC (Association for European Paediatric and Congenital Cardiology).
In 2018, the position paper 'Imaging the adult with congenital heart disease: a multimodality imaging approach' was published. The paper highlights, in the first part, the different imaging modalities applied in adult congenital heart disease patients. In the second part, these modalities are discussed more detailed for moderate to complex anatomical defects. Because of the length of the paper, simple lesions were not touched on. However, imaging modalities to use for simple shunt lesions are still poorly known. One is looking for structured recommendations on which they can rely when dealing with an (undiscovered) shunt lesion. This information is lacking for the initial diagnostic process, during repair and at follow-up. Therefore, this paper will focus on atrial septal defect, ventricular septal defect, and persistent arterial duct. Pre-, intra-, and post-procedural imaging techniques will be systematically discussed. This position paper will offer algorithms that might help at a glance. The document is prepared for general cardiologists, trainees, medical students, imagers/technicians to select the most appropriate imaging modality and to detect the requested information for each specific lesion. It might serve as reference to which researchers could refer when setting up a (imaging) study.


Conductive and evaporative precooling lowers mean skin temperature and improves time trial performance in the heat.
Self-paced endurance performance is compromised by moderate-to-high ambient temperatures that are evident in many competitive settings. It has become common place to implement precooling prior to competition in an attempt to alleviate perceived thermal load and performance decline. The present study aimed to investigate precooling incorporating different cooling avenues via either evaporative cooling alone or in combination with conductive cooling on cycling time trial performance. Ten trained male cyclists completed a time trial on three occasions in hot (35 °C) ambient conditions with the cooling garment prepared by (a) immersion in water (COOL, evaporative); (b) immersion in water and frozen (COLD, evaporative and conductive); or (c) no precooling (CONT). COLD improved time trial performance by 5.8% and 2.6% vs CONT and COOL, respectively (both P < 0.05). Power output was 4.5% higher for COLD vs CONT (P < 0.05). Mean skin temperature was lower at the onset of the time trial following COLD compared with COOL and CONT (both P < 0.05) and lasted for the first 20% of the time trial. Thermal sensation was perceived cooler following COOL and COLD. The combination of evaporative and conductive cooling (COLD) had the greatest benefit to performance, which is suggested to be driven by reduced skin temperature following cooling.


Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ).
Common symptoms for children with Anderson-Fabry Disease (FD) such as acroparaesthesia and gastrointestinal manifestations can only be objectively assessed in patients using a valid instrument. To date, no such instrument exists. A preliminary 40-item measure of symptoms and experience with FD, the Fabry-specific Paediatric Health and Pain Questionnaire (FPHPQ) was developed, but lacked a formal assessment of its measurement properties. The FPHPQ was used in the Fabry Outcome Survey (FOS), a registry for all patients with a confirmed diagnosis of FD who are receiving agalsidase alfa, or are treatment naïve and who are managed by physicians participating in FOS. After an item analysis to explore how items performed and combined into domains, a battery of psychometric analyses was performed to assess the measurement properties of this new instrument. Eighty-seven children (ages 4-18 years) completed the questionnaire. Twenty-three items in three subscales of the questionnaire emerged: pain associated with heat or exertion, pain associated with cold, and abdominal pain and fatigue symptoms. Internal consistency reliability for all three subscales was good (Cronbach alpha ≥ 0.84). Reliability was equally high for all age groups (4-7, 8-12, and 13-18). Test-retest reliability was high for all three subscales (intraclass correlation coefficient ≥ 0.74). Construct validity was demonstrated by moderate correlation with brief pain inventory (BPI), KINDL, and EQ-5D. Known group validity showed all subscales were able to discriminate between Fabry disease severity groups as classified by above or below median of the FOS MSSI (Mainz Severity Score Index) grade. The heat or exertion subscale was responsive to change in symptoms between responders and non-responders as defined by change in EQ-5D index scores between the first and second visit. Preliminary results indicate that the measurement properties of FPHPQ are valid and reliable for assessing patient-reported symptoms of FD. The questionnaire could be a useful tool for clinicians to understand the progression of disease and monitor treatment effects. FPHPQ will be further validated and refined as the FOS registry is continuously adding more patients.


Conservation priorities for Ethiopian sheep breeds combining threat status, breed merits and contributions to genetic diversity.
Prioritizing livestock breeds for conservation needs to incorporate both genetic and non-genetic aspects important for the survival of the breeds. Here, we apply a maximum-utility-strategy to prioritize 14 traditional Ethiopian sheep breeds based on their threat status, contributions to farmer livelihoods (current breed merits) and contributions to genetic diversity. Contributions of the breeds to genetic diversity were quantified using Eding's marker-estimated kinship approaches. Non-genetic aspects included threats (e.g. low population size, low preferences by farmers) and current merits (economic, ecological and cultural merits). Threat analysis identified eight of the 14 breeds as threatened. Analysis of current merits showed that sub-alpine and arid-lowland breeds contribute most to farmer livelihoods in comparison to other breeds. The highest contribution to the genetic diversity conserved was from the Simien breed. Simien showed high between-breed (low between-breed kinship = 0.04) as well as high within-breed diversity (low within-breed kinship = 0.09 and high H(E) = 0.73 and allelic richness = 6.83). We combined the results on threat status, current breed merits and contributions to genetic diversity to produce a ranking of the 14 breeds for conservation purposes. Our results balance the trade-offs between conserving breeds as insurance against future uncertainties and current sustainable utilization. The ranking of breeds provides a basis for conservation strategies for Ethiopian sheep and contributes to a regional or global conservation plan.


Phase retrieval by iterated projections.
Several strategies in phase retrieval are unified by an iterative "difference map" constructed from a pair of elementary projections and three real parameters. For the standard application in optics, where the two projections implement Fourier modulus and object support constraints, respectively, the difference map reproduces the "hybrid" form of Fienup's input-output map when a particular choice is made for two of the parameters. The geometric construction of the difference map illuminates the distinction between its fixed points and the recovered object, as well as the mechanism whereby the form of stagnation encountered by alternating projection schemes is avoided. When support constraints are replaced by object histogram or atomicity constraints, the difference map lends itself to crystallographic phase retrieval. Numerical experiments with synthetic data suggest that structures with hundreds of atoms can be solved.


Dipole solitons in optically induced two-dimensional photonic lattices.
Dipole solitons in a two-dimensional optically induced photonic lattice are theoretically predicted and experimentally demonstrated for the first time to our knowledge. It is shown that such dipole solitons are stable and robust under appropriate conditions. Our experimental results are in good agreement with theoretical predictions.


Complications of needle electromyography: hematoma risk and correlation with anticoagulation and antiplatelet therapy.
Electromyography (EMG) is considered a relatively safe procedure based primarily on clinical experience. Literature review reveals few reported complications from bleeding or hematoma formation. No evidence-based guidelines exist for EMG procedures in patients who are taking anticoagulant or antiplatelet medications. The purpose of this study was to determine if patients taking anticoagulant or antiplatelet agents exhibit an increased risk of hematoma formation after routine needle EMG of the tibialis anterior muscle when compared to controls. Study subjects underwent routine needle EMG of the tibialis anterior muscle followed by ultrasound examination to evaluate for the presence of hematoma formation. A mean of 30.8 min elapsed between needle insertion and ultrasound evaluation. A total of 101 patients who were taking warfarin were studied. They had International Normalized Ratio (INR) values at or above 1.5, and two were found to have small, subclinical hematomas. Of 57 patients taking clopidogrel and/or aspirin, 1 was found to have a small, subclinical hematoma. In the control group (51 patients taking neither class of medication), no hematomas were found on ultrasound. This study suggests that hematoma formation from a standard needle EMG is rare. In addition, hematoma formation in our study group of patients on anticoagulant or antiplatelet medications was also uncommon, and no patients with documented hematomas experienced symptoms. These findings should be considered when determining the feasibility of electrodiagnostic evaluation of patients who are taking anticoagulant or antiplatelet medications.


Suppression of microRNA 124-3p and microRNA 340-5p ameliorates retinoic acid-induced cleft palate in mice.
The etiology of cleft lip with or without cleft palate (CL/P), a common congenital birth defect, is complex, with genetic and epigenetic, as well as environmental, contributing factors. Recent studies suggest that fetal development is affected by maternal conditions through microRNAs (miRNAs), a group of short noncoding RNAs. Here, we show that miR-129-5p and miR-340-5p suppress cell proliferation in both primary mouse embryonic palatal mesenchymal cells and O9-1 cells, a neural crest cell line, through the regulation of Sox5 and Trp53 by miR-129-5p, and the regulation of Chd7, Fign and Tgfbr1 by miR-340-5p. Notably, miR-340-5p, but not miR-129-5p, was upregulated following all-trans retinoic acid (atRA; tretinoin) administration, and a miR-340-5p inhibitor rescued the cleft palate (CP) phenotype in 47% of atRA-induced CP mice. We have previously reported that a miR-124-3p inhibitor can also partially rescue the CP phenotype in atRA-induced CP mouse model. In this study, we found that a cocktail of miR-124-3p and miR-340-5p inhibitors rescued atRA-induced CP with almost complete penetrance. Taken together, our results suggest that normalization of pathological miRNA expression can be a preventive intervention for CP.


Patient specific identification of the cardiac driver function in a cardiovascular system model.
The cardiac muscle activation or driver function, is a major determinant of cardiovascular dynamics, and is often approximated by the ratio of the left ventricle pressure to the left ventricle volume. In an intensive care unit, the left ventricle pressure is usually never measured, and the left ventricle volume is only measured occasionally by echocardiography, so is not available real-time. This paper develops a method for identifying the driver function based on correlates with geometrical features in the aortic pressure waveform. The method is included in an overall cardiovascular modelling approach, and is clinically validated on a porcine model of pulmonary embolism. For validation a comparison is done between the optimized parameters for a baseline model, which uses the direct measurements of the left ventricle pressure and volume, and the optimized parameters from the approximated driver function. The parameters do not significantly change between the two approaches thus showing that the patient specific approach to identifying the driver function is valid, and has potential clinically.


Synchronous and opposite roles of the parietal and prefrontal cortices in bistable perception: a double-coil TMS-EEG study.
Bistable perception occurs when a stimulus is ambiguous and has two distinct interpretations that spontaneously alternate in observers' consciousness. Studies using functional magnetic resonance imaging, electroencephalography (EEG), and transcranial magnetic stimulation (TMS) in healthy subjects and patient studies point towards a right fronto-parietal network regulating the balance between percept stabilization and the arising of alternative interpretations. However, the causal role of the interaction between parietal and prefrontal areas is not clearly understood. Using intermittent presentations of bistable images, we confirmed that maintaining or switching percepts had neural correlates identifiable on EEG. Single-pulse TMS applied over the right anterior intraparietal sulcus (IPS) 70 msec before image presentation interfered with evoked potentials and destabilized the percept. However, with paired-pulse TMS applied over right IPS and dorsolateral prefrontal cortex (DLPFC) 70 and 60 msec before image presentation, both perceptual and neurophysiological effects were canceled. Thus, TMS over IPS and DLPFC interacted with each other and influenced upcoming percepts. We suggest that when the visual world is ambiguous, IPS plays a stabilizing role, whereas DLPFC is important for triggering perceptual switches or for modulating parietal activity. The balance between maintaining and switching visual conscious percepts relies on the dynamic interaction between IPS and DLPFC.


Epidemiology of Extended-Spectrum Beta-Lactamase and Carbapenemase-Producing Enterobacterales in the Greater Mekong Subregion: A Systematic-Review and Meta-Analysis of Risk Factors Associated With Extended-Spectrum Beta-Lactamase and Carbapenemase Isolation.
Background: Despite the rapid spread of extended-spectrum beta-lactamase (ESBL) producing-Enterobacterales (ESBL-E) and carbapenemase-producing Enterobacterales (CPE), little is known about the extent of their prevalence in the Greater Mekong Subregion (GMS). In this systematic review, we aimed to determine the epidemiology of ESBL-E and CPE in clinically significant Enterobacterales: Escherichia coli and Klebsiella pneumoniae from the GMS (comprising of Cambodia, Laos, Myanmar, Thailand, Vietnam and Yunnan province and Guangxi Zhuang region of China). Methods: Following a list of search terms adapted to subject headings, we systematically searched databases: Medline, EMBASE, Scopus and Web of Science for articles published on and before October 20th, 2020. The search string consisted of the bacterial names, methods involved in detecting drug-resistance phenotype and genotype, GMS countries, and ESBL and carbapenemase detection as the outcomes. Meta-analyses of the association between the isolation of ESBL from human clinical and non-clinical specimens were performed using the "METAN" function in STATA 14. Results: One hundred and thirty-nine studies were included from a total of 1,513 identified studies. Despite the heterogeneity in study methods, analyzing the prevalence proportions on log-linear model scale for ESBL producing-E. coli showed a trend that increased by 13.2% (95%CI: 6.1-20.2) in clinical blood specimens, 8.1% (95%CI: 1.7-14.4) in all clinical specimens and 17.7% (95%CI: 4.9-30.4) increase in carriage specimens. Under the log-linear model assumption, no significant trend over time was found for ESBL producing K. pneumoniae and ESBL-E specimens. CPE was reported in clinical studies and carriage studies past 2010, however a trend could not be determined because of the small dataset. Twelve studies were included in the meta-analysis of risk factors associated with isolation of ESBL. Recent antibiotic exposure was the most studied variable and showed a significant positive association with ESBL-E isolation (pooled OR: 2.9, 95%CI: 2.3-3.8) followed by chronic kidney disease (pooled OR: 4.7, 95%CI: 1.8-11.9), and other co-morbidities (pooled OR: 1.6, 95%CI: 1.2-2.9). Conclusion: Data from GMS is heterogeneous with significant data-gaps, especially in community settings from Laos, Myanmar, Cambodia and Yunnan and Guangxi provinces of China. Collaborative work standardizing the methodology of studies will aid in better monitoring, surveillance and evaluation of interventions across the GMS.


Dynamin impacts homology-directed repair and breast cancer response to chemotherapy.
After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.


Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function.
The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease.


Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy.
The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side-effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side-effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2].


Effect of adrenaline on transmesothelial resistance of isolated sheep pleura.
The effect of adrenaline on the transmesothelial resistance (RTM) of sheep's visceral and parietal pleura was studied using the Ussing chamber technique. Basal transmesothelial resistance of visceral pleura was found to be 20.71 +/- 0.31 Omega cm2, whereas that of parietal pleura was found to be 19.53 +/- 0.34 Omega cm2. Immediately after the addition of adrenaline (10(-7) M) both apically and basolaterally on the visceral and parietal pleura, these values were significantly increased (P < 0.05). Addition of the nonselective beta-receptor blocker, propranolol (10(-5) M), suppressed this effect in both visceral and parietal pleura, while addition of the nonselective alpha-receptor blocker, phentolamine (10(-5) M), partly suppressed the above-mentioned increase in the parietal pleura. In conclusion, our results show that adrenaline has a rapid effect on both pleurae. This rapid effect is mediated by the stimulation of beta-adrenergic receptors in the case of visceral pleura, while in the case of parietal pleura this effect seems to be due to a stimulation of alpha- and beta-adrenergic receptors. On the visceral pleura the effect of adrenaline vanishes after some minutes and on the parietal this effect is more permanent than the visceral's one, suggesting differences in the distribution of the adrenergic receptors between the visceral and parietal pleura.


Proton-Coupled Electron Transfer Drives Long-Range Proton Translocation in Bioinspired Systems.
Proton-coupled electron transfer (PCET) combines the movement of fundamental charged species to form an essential link between electron- and proton-transport reactions in bioenergetics and catalysis in general. The length scale over which proton transport may occur within PCET processes and the thermodynamic consequences of the resulting proton chemical potential to the oxidation reaction driving these PCET processes have not been generally established. Here we report the design of bioinspired molecules that employ oxidation-reduction processes to move reversibly two, three, and four protons via a Grotthuss-type mechanism along hydrogen-bonded networks up to ∼16 Å in length. These molecules are composed of benzimidazole moieties linking a phenol to the final proton acceptor, a cyclohexylimine. Following electrochemical oxidation of the phenol, the appearance of an infrared band at 1660 cm-1 signals proton arrival at the terminal basic site. Switching the electrode potential to reducing conditions reverses the proton translocation and resets the structure to the initial species. In addition to mimicking the first step of the iconic PCET process used by the Tyrz-His190 redox relay in photosystem II to oxidize water, this work specifically addresses theoretically and experimentally the length scale over which PCET processes may occur. The thermodynamic findings from these redox-driven, bioinspired "proton wires" have implications for understanding and rationally designing pumps for the generation of proton-motive force in artificial and reengineered photosynthesis, as well as for management of proton activity around catalytic sites, including those for water oxidation and oxygen reduction.


Nuclear membranes control symbiotic calcium signaling of legumes.
Nuclear-associated oscillations in calcium act as a secondary messenger in the symbiotic signaling pathway of legumes. These are decoded by a nuclear-localized calcium and calmodulin-dependent protein kinase, the activation of which is sufficient to drive downstream responses. This implies that the calcium oscillations within the nucleus are the predominant signals for legume symbiosis. However, the mechanisms that allow targeted release of calcium in the nuclear region have not been defined. Here we show that symbiosis-induced calcium changes occur in both the nucleoplasm and the perinuclear cytoplasm and seem to originate from the nuclear membranes. Reaction diffusion simulations suggest that spike generation within the nucleoplasm is not possible through transmission of a calcium wave from the cytoplasm alone and that calcium is likely to be released across the inner nuclear membrane to allow nuclear calcium changes. In agreement with this, we found that the cation channel DMI1, which is essential for symbiotic calcium oscillations, is preferentially located on the inner nuclear membrane, implying an essential function for the inner nuclear membrane in symbiotic calcium signaling. Furthermore, a sarco/endoplasmic reticulum calcium ATPase (SERCA) essential for symbiotic calcium oscillations is targeted to the inner nuclear membrane, as well as the outer nuclear membrane and endoplasmic reticulum (ER). We propose that release of calcium across the inner nuclear membrane allows targeted release of the ER calcium store, and efficient reloading of this calcium store necessitates the capture of calcium from the nucleoplasm and nuclear-associated cytoplasm.


PRactice of VENTilation in Middle-Income Countries (PRoVENT-iMIC): rationale and protocol for a prospective international multicentre observational study in intensive care units in Asia.
Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. NCT03188770; Pre-results.


Ex vivo depletion of T cells from bone marrow grafts with CAMPATH-1 in acute leukemia: graft-versus-host disease and graft-versus-leukemia effect.
Preventing graft-versus-host disease (GVHD) by depletion of T lymphocytes from the stem cell graft for transplantation remains controversial, mainly because of the perceived increase in disease recurrence. We retrospectively analyzed the outcome of 50 consecutive individuals in remission of acute lymphoblastic leukemia (n=13; 8 in complete remission [CR]1) or acute myeloblastic leukemia (n=37; 33 in CR1), who had received marrow grafts from HLA-identical siblings. The conditioning regimen included six 2-Gy fractions of total body irradiation, succeeded by cyclophosphamide at 120 mg/kg (with mesna) followed by four fractions of 1.5 Gy to lymphoid areas. Bone marrow (n=38) or peripheral blood mobilized donor mononuclear cells (n=12) were exposed ex vivo to CAMPATH-1 (IgM and complement, or IgG; antiCD52) antibodies, without any further posttransplantation immunosuppression. Median patient age was 31 (range 14-51) years; 12 patients were 40 or older. Thirty-two patients were male. One patient died of pulmonary hemorrhage on day 10; another died on day 29 of interstitial pneumonitis. Except for one early death, all patients engrafted. Ten (21%) of the remaining 48 who were at risk, developed GVHD. In none was it greater than grade II. Eight patients developed serious viral infections. Four died of cytomegalovirus pneumonia, adenovirus hepatitis, and human immunodeficiency. Overall, 11 patients (22%) relapsed (4 of 33 acute myeloblastic leukemia in CR1) at a median of 235 (range 46-528) days. Mean posttransplantation follow-up was 1062 (median 560; range 10-4177) days. Thirty-three patients (66%) remained disease free at a mean of 1,118 (median 1439; range 159-4,177) days. For all patients, the performance status was between 82% and 100% (median 100). T-cell depletion with CAMPATH-1 effectively prevents GVHD, particularly the severe acute forms, without leading to excessive risk of relapse in acute leukemia.


Study of histamine wheal suppression by dexamethasone with and without iontophoresis.
Iontophoresis increases the penetration of drugs into the skin by electric current. The ability of topical steroids to reduce the size of the histamine wheal was used to assess the efficacy of topical dexamethasone delivered with and without iontophoresis. To determine the wheal suppressing ability of dexamethasone delivered with and without iontophoresis. A template with three squares of 3x3 cm was placed on both forearms of 20 volunteers and the edges marked. A gauze piece soaked in 2 ml of dexamethasone solution was placed on the flexor aspect of the left forearm and the electrode, an aluminum foil was placed on it and connected to the negative pole (since dexamethasone is negatively charged). An electric current was passed for 15 minutes. Similarly, on the right forearm, a dexamethasone soaked gauze piece was placed without iontophoresis. Histamine wheal suppression was assessed at the end of 30 min, 1 hr and 2 hrs, on both sides. Statistical analysis was done using an independent t-test. There was a statistically significant difference in wheal suppression at 30 min (p=0.006) on the left hand where iontophoresis was used. Our experiment showed that topical dexamethasone with iontophoresis has the maximum effect at the end of 30 minutes and is more effective than dexamethasone without iontophoresis.


Cooperation between the hippocampus and the striatum during episodic encoding.
The hippocampus and the striatum are thought to play distinct roles in learning and memory, each supporting an independent memory system. A fundamental question is whether, and how, these systems interact to jointly contribute to learning and memory. In particular, it remains unknown whether the striatum contributes selectively to implicit, habitual learning, or whether the striatum may also contribute to long-term episodic memory. Here, we show with functional magnetic resonance imaging (fMRI) that the hippocampus and the striatum interact cooperatively to support episodic memory formation. Participants were scanned during a memory encoding paradigm and, subsequently, were tested for memory of encoded items. fMRI data revealed that successful memory was associated with greater activity in both the hippocampus and the striatum (putamen) during encoding. Furthermore, activity in the hippocampus and the striatum was correlated within subjects for items that were later remembered, but not for items that were forgotten. Finally, across subjects, the strength of the correlation between the hippocampus and the striatum predicted memory success. These findings provide novel evidence for contributions of both the striatum and the hippocampus to successful episodic encoding and for a cooperative interaction between them.


Updated guideline on the management of common bile duct stones (CBDS).
Common bile duct stones (CBDS) are estimated to be present in 10-20% of individuals with symptomatic gallstones. They can result in a number of health problems, including pain, jaundice, infection and acute pancreatitis. A variety of imaging modalities can be employed to identify the condition, while management of confirmed cases of CBDS may involve endoscopic retrograde cholangiopancreatography, surgery and radiological methods of stone extraction. Clinicians are therefore confronted with a number of potentially valid options to diagnose and treat individuals with suspected CBDS. The British Society of Gastroenterology first published a guideline on the management of CBDS in 2008. Since then a number of developments in management have occurred along with further systematic reviews of the available evidence. The following recommendations reflect these changes and provide updated guidance to healthcare professionals who are involved in the care of adult patients with suspected or proven CBDS. It is not a protocol and the recommendations contained within should not replace individual clinical judgement.


Long-term comparison of everolimus-eluting stents with sirolimus- and paclitaxel-eluting stents for percutaneous coronary intervention of saphenous vein grafts.
Newer-generation everolimus-eluting stents (EES) have been shown to improve clinical outcomes compared with early-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in patients undergoing percutaneous coronary intervention (PCI). Whether this benefit is maintained among patients with saphenous vein graft (SVG) disease remains controversial. We assessed cumulative incidence rates (CIR) per 100 patient years after inverse probability of treatment weighting to compare clinical outcomes. The pre-specified primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target vessel revascularisation (TVR). Out of 12,339 consecutively treated patients, 288 patients (5.7%) underwent PCI of at least one SVG lesion with EES (n=127), SES (n=103) or PES (n=58). Up to four years, CIR of the primary endpoint were 58.7 for EES, 45.2 for SES and 45.6 for PES with similar adjusted risks between groups (EES vs. SES; HR 0.94, 95% CI: 0.55-1.60, EES vs. PES; HR 1.07, 95% CI: 0.60-1.91). Adjusted risks showed no significant differences between stent types for cardiac death, MI and TVR. Among patients undergoing PCI for SVG lesions, newer-generation EES have similar safety and efficacy to early-generation SES and PES during long-term follow-up to four years.


Modifications to the composition of the hyphal outer layer of Aspergillus fumigatus modulates HUVEC proteins related to inflammatory and stress responses.
Aspergillus fumigatus, the main etiologic agent causing invasive aspergillosis, can induce an inflammatory response and a prothrombotic phenotype upon contact with human umbilical vein endothelial cells (HUVECs). However, the fungal molecules involved in this endothelial response remain unknown. A. fumigatus hyphae produce an extracellular matrix composed of galactomannan, galactosaminogalactan and α-(1,3)-glucan. In this study, we investigated the consequences of UGM1 gene deletion in A. fumigatus, which produces a mutant with increased galactosaminogalactan production. The ∆ugm1 mutant exhibited an HUVEC-hyperadhesive phenotype and induced increased endothelial TNF-α secretion and tissue factor mRNA overexpression in this "semi-professional" immune host cell. Using a shotgun proteomics approach, we show that the A. fumigatus ∆ugm1 strain can modulate the levels of proteins in important endothelial pathways related to the inflammatory response mediated by TNF-α and to stress response pathways. Furthermore, a purified galactosaminogalactan fraction was also able to induce TNF-α secretion and the coincident HUVEC pathways regulated by the ∆ugm1 mutant, which overexpresses this component, as demonstrated by fluorescence microscopy. This work contributes new data regarding endothelial mechanisms in response to A. fumigatus infection. Invasive aspergillosis is the main opportunistic fungal infection described in neutropenic hematologic patients. One important clinical aspect of this invasive fungal infection is vascular thrombosis, which could be related, at least in part, to the activation of endothelial cells, as shown in previous reports from our group. It is known that direct contact between the A. fumigatus hyphal cell wall and the HUVEC cell surface is necessary to induce an endothelial prothrombotic phenotype and secretion of pro-inflammatory cytokines, though the cell surface components of this angioinvasive fungus that trigger this endothelial response are unknown. The present work employs a discovery-driven proteomics approach to reveal the role of one important cell wall polysaccharide of A. fumigatus, galactosaminogalactan, in the HUVEC interaction and the consequent mechanisms of endothelial activation. This is the first report of the overall panel of proteins related to the HUVEC response to a specific and purified cell wall component of the angioinvasive fungus A. fumigatus.


Lack of evidence for infection with known human and animal retroviruses in patients with chronic fatigue syndrome.
We investigated 21 patients with chronic fatigue syndrome who were identified through the surveillance system of the Centers for Disease Control and Prevention (CDC) in Atlanta for the presence of several human and animal retroviruses. In addition, we evaluated 21 CDC employee controls matched with the patients for age (+/- 5 years), gender, and race. The viruses tested included human T-lymphotropic viruses types I and II; human spuma retrovirus; simian T-lymphotropic virus type I; simian retroviruses types 1, 2, and 3; bovine leukemia virus; feline leukemia virus; and gibbon ape leukemia virus. Samples of peripheral blood lymphocytes and leukocytes from patients and controls were analyzed in a blinded fashion for retroviral sequences; polymerase chain reaction (PCR) amplification assays and Southern blot hybridization to 32P-labeled internal oligoprobes were used. All PCR assays were optimized for maximal sensitivity on respective infected cell lines or plasmids, and sensitivity controls were included in each experiment. All samples from patients and controls were negative for the tested retroviral sequences. Our data indicate that none of these retroviruses plays an etiologic role or is a cofactor in the chronic fatigue syndrome illnesses of our study population.


Arabidopsis SWI/SNF chromatin remodeling complex binds both promoters and terminators to regulate gene expression.
ATP-dependent chromatin remodeling complexes are important regulators of gene expression in Eukaryotes. In plants, SWI/SNF-type complexes have been shown critical for transcriptional control of key developmental processes, growth and stress responses. To gain insight into mechanisms underlying these roles, we performed whole genome mapping of the SWI/SNF catalytic subunit BRM in Arabidopsis thaliana, combined with transcript profiling experiments. Our data show that BRM occupies thousands of sites in Arabidopsis genome, most of which located within or close to genes. Among identified direct BRM transcriptional targets almost equal numbers were up- and downregulated upon BRM depletion, suggesting that BRM can act as both activator and repressor of gene expression. Interestingly, in addition to genes showing canonical pattern of BRM enrichment near transcription start site, many other genes showed a transcription termination site-centred BRM occupancy profile. We found that BRM-bound 3΄ gene regions have promoter-like features, including presence of TATA boxes and high H3K4me3 levels, and possess high antisense transcriptional activity which is subjected to both activation and repression by SWI/SNF complex. Our data suggest that binding to gene terminators and controlling transcription of non-coding RNAs is another way through which SWI/SNF complex regulates expression of its targets.


The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke--II: neurologic outcome and efficacy analysis.
High-dose human albumin (ALB) is robustly neuroprotective in rodent stroke models. A phase I dose-escalation study was conducted to assess the safety of ALB therapy in ischemic stroke. We analyzed the data for preliminary evidence of treatment efficacy. Eighty-two subjects with acute ischemic stroke (NIH Stroke Scale [NIHSS] of 6 or above) received 25% ALB beginning within 16 hours of stroke onset. Six successive ALB dose tiers were assessed (range, 0.34 to 2.05 g/kg). Forty-two patients also received standard-of-care intravenous tissue plasminogen activator (tPA). Efficacy outcomes were determined at 3 months. We compared the highest three, putatively therapeutic ALB dose tiers (1.37 to 2.05 g/kg) with the lowest three, presumed subtherapeutic doses (0.34 to 1.03 g/kg) and with historical cohort data derived from the NINDS rt-PA Stroke Study. After adjusting for the tPA effect, the probability of good outcome (defined as modified Rankin Scale 0 to 1 or NIH Stroke Scale 0 to 1 at 3 months) at the highest three ALB doses was 81% greater than in the lower dose-tiers (relative risk [RR], 1.81; 95% confidence interval [CI], 1.11 to 2.94) and was 95% greater than in the comparable NINDS rt-PA Stroke Study cohort (RR, 1.95; 95% CI, 1.47 to 2.57). The tPA-treated subjects who received higher-dose ALB were three times more likely to achieve a good outcome than subjects receiving lower-dose ALB, suggesting a positive synergistic effect between ALB and tPA. Our data suggest that high-dose ALB therapy may be neuroprotective after ischemic stroke. These results have led to a multicenter, randomized, placebo-controlled efficacy trial of ALB in acute ischemic stroke-the ALIAS Phase III Trial.


Knowing, applying, and reasoning about arithmetic: Roles of domain-general and numerical skills in multiple domains of arithmetic learning.
The longitudinal relations of domain-general and numerical skills at ages 6-7 years to 3 cognitive domains of arithmetic learning, namely knowing (written computation), applying (arithmetic word problems), and reasoning (arithmetic reasoning) at age 11, were examined for a representative sample of 378 Finnish children. The results showed that domain-general skills, including spatial visualization, language, rapid automatized naming, and working memory, contributed independently to arithmetic learning. These relations were mostly mediated via basic number competence (i.e., counting sequence and number system knowledge), although spatial visualization remained predictive of arithmetic outcomes. The findings underscore a similar developmental course of arithmetic learning across different cognitive domains where domain-general skills build a launchpad for advanced arithmetic via enhancing basic number competence. (PsycINFO Database Record


Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.


Condition, not eyespan, predicts contest outcome in female stalk-eyed flies, Teleopsis dalmanni.
In contests among males, body condition is often the key determinant of a successful outcome, with fighting ability signaled by so-called armaments, that is, exaggerated, condition-dependent traits. However, it is not known whether condition and exaggerated traits function in the same way in females. Here, we manipulated adult condition by varying larval nutrition in the stalk-eyed fly, Teleopsis dalmanni, a species in which eyespan is exaggerated in both sexes, and we measured the outcome of contests between females of similar or different body condition and relative eyespan. We found that females in higher condition, with both larger bodies and eyespan, won a higher proportion of encounters when competing against rivals of lower condition. However, when females were of equal condition, neither eyespan nor body length had an effect on the outcome of a contest. An analysis of previously published data revealed a similar pattern in males: individuals with large relative eyespan did not win significantly more encounters when competing with individuals of a similar body size. Contrary to expectations, and to previous findings in males, there was no clear effect of differences in body size or eyespan affecting contest duration in females. Taken together, our findings suggest that although eyespan can provide an honest indicator of condition, large eyespans provide no additional benefit to either sex in intrasexual aggressive encounters; body size is instead the most important factor.


Lipoprotein lipase gene PvuII polymorphism serum lipids and risk for coronary artery disease: meta-analysis.
Our aim was to determine whether lipoprotein lipase gene PvuII polymorphism can be considered as an independent risk factor for coronary artery disease (CAD) by conducting a meta-analysis of all available published trials, including our own study. In 7 seperate studies, 3289 subjects were screened for this substitution; meta-analysis included only some of these individuals. Among the 7 studies, 6 were performed on white subjects, whereas 1 was on patients with Saudi Arabic descent.Subgroup analysis indicated that individuals with PvuII substitution does not have an increased risk for CAD. The LPL-PvuII genotype and allele frequency distributions did not differ significantly between CAD patients and healthy controls. There was no difference in the distribution of LPL-PvuII genotypes between the healthy subjects and the patients with CAD. However, no significant differences in lipid variables (triglyceride and HDL-cholesterol) were determined for the PvuII polymorphisms in the patients with CAD. No significant differences were found in serum triglyceride and HDL-cholesterol levels for LPL-PvuII genotypes when the control and CAD groups were pooled. In conclusion, LPL-Pvu II polymorphism cannot be used as independent genetic risk factor for CAD.


Stimulating and toxic effect of chromium on growth and photosynthesis of a marine chlorophyte.
Marine phytoplankton can interchange trace metals in various biochemical functions, particularly under metal-limiting conditions. Here, we investigate the stimulating and toxicity effect of chromium (Cr) on a marine Chlorophyceae Osetreococcus tauri under Fe-replete and Fe-deficient conditions. We determined the growth, photosynthesis, and proteome expressions of Osetreococcus tauri cultured under different Cr and Fe concentrations. In Fe-replete conditions, the presence of Cr(VI) stimulated significantly the growth rate and the maximum yield of photochemistry of photosystem II (Fv /Fm ) of the phytoplankton, while the functional absorption cross-section of photosystem II (σPSII ) did not change. Minor additions of Cr(VI) partially rescued phytoplankton growth under Fe-limited conditions. Proteomic analysis of this alga grown in Fe-replete normal and Fe-replete with Cr addition media (10 μM Cr) showed that the presence of Cr significantly decreased the expression of phosphate-transporting proteins and photosynthetic proteins, while increasing the expression of proteins related to carbon assimilation. Cr can stimulate the growth and photosynthesis of O. tauri, but the effects are dependent on both the Cr(VI) concentration and the availability of Fe. The proteomic results further suggest that Cr(VI) addition might significantly increase starch production and carbon fixation.


Evaluation of the bitter components of bamboo shoots using a metabolomics approach.
Bamboo shoots, most of which are bitter in taste, are a traditional vegetable eaten in Asia. However, our understanding of the components responsible for this bitterness is limited. In this study, we used metabolomic and phytochemical analyses to scientifically study bamboo shoot bitterness. Based on oral evaluation, 16 common bamboo shoots were categorized into four bitterness groups. The most bitter species was Pleioblastus amarus. Thus, we isolated and performed a detailed spectroscopic analysis of 14 main compounds from this species. The correlation between the concentration of these components and bitterness in four representative bamboo shoot species was then analyzed by UPLC-MRM-MS and PLS-DA. It appears that bamboo shoot bitterness is largely due to l-phenylalanine, uridine, l-omithine, l-tryptophan, and adenine, with l-phenylalanine being the greatest contributor. In addition to identifying the primary component involved in bamboo shoot bitterness, this study also outlines a novel method for evaluating the bitterness of natural foods.


Cutaneous manifestations of metastatic Crohn's disease.
Metastatic Crohn's disease is a rare cutaneous complication of primary Crohn's disease. It is a granulomatous inflammatory process, similar to the pathogenic mechanism of Crohn's disease, that occurs in sites discontiguous from the gastrointestinal tract. Metastatic Crohn's disease can precede the development of Crohn's disease by months to years, and children are more likely to present with metastatic Crohn's disease in the absence of gastrointestinal symptoms. Given that approximately 30% of individuals with Crohn's disease present in childhood, early recognition of extraintestinal manifestations of Crohn's disease such as metastatic Crohn's disease can aid in timely diagnosis and management of bowel disease. We present data from two pediatric cases of metastatic Crohn's disease recently seen at our institution in addition to the 61 reported cases of pediatric metastatic Crohn's disease in the literature. This review article will focus on the epidemiology, pathogenesis, clinical features, and histology of and treatment options for pediatric metastatic Crohn's disease.