Two different charge transfer states of photoexcited 9,9'-bianthryl in polar and nonpolar solvents characterized by nanosecond time-resolved near-IR spectroscopy in the 4500-10,500 cm(-1) region.
Transient absorption spectra of 9,9'-bianthryl (BA) in heptane, in acetonitrile, and in 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (bmimTf(2)N) are observed with a nanosecond time-resolved near-IR absorption spectrometer for the wavenumber range of 4500-10,500 cm(-1) (2200-950 nm). In nonpolar heptane solution, a broad absorption band is observed at 6700 cm(-1) (1500 nm), in addition to a strong absorption band of the locally excited (LE) state centered at 9800 cm(-1) (1020 nm). The broad band is assigned to a partial charge transfer (PCT) band. The decay time constants of the PCT band and the LE band are both (13 +/- 1) ns. The agreement of the two decay constants strongly suggests that the PCT state is in equilibrium with the LE state in heptane. In acetonitrile, an absorption band of the charge transfer (CT) state is observed at 8000 cm(-1) (1250 nm). This band decays in (41 +/- 2) ns. In bmimTf(2)N, the CT band appears at 8500 cm(-1) (1180 nm) and decays in (34 +/- 1) ns. The difference in peak position for the CT bands in acetonitrile and in bmimTf(2)N, and the PCT bands in heptane, is explained well by the model based on the charge resonance between the two equivalent electronic structures of the CT state.


Evaluation of the BD Phoenix M50 Automated Microbiology System for Antimicrobial Susceptibility Testing with Clinical Isolates in Korea.
The objectives of this study were to evaluate the performance of the BD Phoenix™ M50 system with two antimicrobial susceptibility testing (AST) panels against clinical isolates in South Korea and the accuracy of determining carbapenem and colistin susceptibility compared with reference methods. A total of 825 nonduplicated clinical isolates were included in this study. Bacterial identification was performed using Bruker Biotyper and 16S rDNA sequencing. Antimicrobial susceptibilities were tested by disk diffusion, broth microdilution, and agar dilution methods. AST with the Phoenix system was performed following the manufacturer's instructions. The categorical agreement (CA), very major error (VME), major error (ME), and minor error (mE) rates were calculated for each antibiotic. CA rates between the results of the Phoenix system and reference methods were more than 90% for most antibiotics except for ciprofloxacin in enterococci (82.7%, 163/197) and cefepime in Acinetobacter species (88.9%, 88/99). VME and ME rates were less than 3% for all the antibiotics tested in this study. Minimum inhibitory concentration (MIC) values for carbapenem and colistin determined by the Phoenix system were highly correlated with those of dilution methods, exhibiting 99.2% (384/387), 96.7% (374/387), and 98.5% (129/131) of the agreement rate within onefold dilution difference for imipenem, meropenem, and colistin, respectively. The BD Phoenix M50™ system showed reliable performance for AST in clinical microbiology laboratories and for detecting carbapenem and colistin resistance in Gram-negative clinical isolates.


FOXP1-related intellectual disability syndrome: a recognisable entity.
Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.


Scent of a disorder: olfactory functioning in schizophrenia.
The use of olfactory probes to assess frontal and temporal-limbic system functioning in patients with schizophrenia has garnered increasing interest among basic and clinical investigators. Deficits in odor identification, detection threshold sensitivity, discrimination, and memory have been reported and are thought to represent a centrally mediated deficit in the processing of this information. These impairments are seen in affected probands, first-degree family members, and those at risk for developing the illness, suggesting a genetic vulnerability or predisposition to chemosensory abnormalities. The observed deficits are not explained by gender, medication use, cognitive impairment, or smoking status, and support the hypothesis of primary dysfunction in the olfactory system. Along this same line, structural abnormalities in the peripheral and central olfactory brain regions, as well as disruptions of the basic physiology of this system, have been described. The study of olfactory processing in schizophrenia has already advanced the knowledge of the neural substrate for this disorder. Because the olfactory system continuously regenerates throughout life, it allows for a unique view of an ongoing neurodevelopmental process.


[Regional features of present-day polymorbidity of internal diseases].
Analysis of transnosological and trans-systemic polymorbidity for 2003-2011 in a general therapy clinic included 23310 patients (9111 men and 14199 women). It was supplemented by comparative analysis of morbidity in southern West Siberia and Yakutiya. The assessment was performed for three age groups (16-39, 40-59, over 60 years). The mean number of nosological forms (transnosological morbidity) and affected systems of organs (trans-systemic morbidity) averaged 5.19 +/- 0.01 and 4.09 +/- 0.01 per patient respectively (4.93 +/- 0.02 and 3.92 +/- 0.02 in men, 5.36 +/- 0.02 and 4.19 +/- 0.01 in women). The prevalence of polymorbidity was significantly higher in women than in men and in Yakutia higher than in West Siberia. The differences tend to be smoothed in recent years. Transnosological morbidity coefficients in male and female residents of Novosibirsk region increased from 4.14 +/- 0.03 and 4.60 +/- 0.04 respectively in 2003-2005 to 5.48 +/- 0.05 and 6.70 +/- 0.06 in 2009-2011 (p < 0.0001). In Yakutiya this growth in men was less pronounced than in a more temperate climate and was practically inapparent in women.


Antigravity hills are visual illusions.
Antigravity hills, also known as spook hills or magnetic hills, are natural places where cars put into neutral are seen to move uphill on a slightly sloping road, apparently defying the law of gravity. We show that these effects, popularly attributed to gravitational anomalies, are in fact visual illusions. We re-created all the known types of antigravity spots in our laboratory using tabletop models; the number of visible stretches of road, their slant, and the height of the visible horizon were systematically varied in four experiments. We conclude that antigravity-hill effects follow from a misperception of the eye level relative to gravity, caused by the presence of either contextual inclines or a false horizon line.


FGF23 and Left Ventricular Hypertrophy in Children with CKD.
High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. Median age was 12 years (interquartile range, 8-15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38-64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P<0.01) in participants with FGF23 concentrations ≥170 RU/ml compared with those with FGF23<100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR≥45 ml/min per 1.73 m2, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 <100 RU/ml, 100-169 RU/ml, and ≥170 RU/ml, respectively (Ptrend=0.01). When eGFR was ≥45 ml/min per 1.73 m2, higher FGF23 concentrations were independently associated with LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24; P<0.05; fully adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; P<0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m2, FGF23 did not associate with LVH. Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m2.


Interference effects in learning similar sequences of discrete movements.
Three experiments were conducted to examine proactive and retroactive interference effects in learning two similar sequences of discrete movements. In each experiment, the participants in the experimental group practiced two movement sequences on consecutive days (1 on each day, order counterbalanced across participants) followed by retention tests on the third day. In all, 2 out of 8 target locations differed between the 2 sequences. Experiment 1 established the nature of the interference effects in the present setup. Clear evidence was found for button-specific proactive and retroactive interference effects. Experiments 2 and 3 further probed the mechanisms underlying those effects, by varying the numbers of repetitions (50 or 250) of the 1st and 2nd sequence (Experiment 2) and the hand, dominant or nondominant, with which the sequences were practiced (Experiment 3). Experiment 2 showed that after a mere 50 repetitions, the representation of the movement structure was strong enough to evoke the effects observed in Experiment 1. Experiment 3 revealed that learning with the dominant hand did not result in more pronounced interference effects compared with learning with the nondominant hand. In combination, these results suggest that changes in the representation of the movement structure are primarily responsible for the observed interference effects.


Dual-sensor fluorescent probes of surfactant-induced unfolding of human serum albumin.
Two extrinsic fluorescent probes, 3-(dimethylamino)-8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalen-7-one (1) and 7-(dimethylamino)-2,3-dihydrophenanthren-4(1H)-one (2), are used to probe the unfolding of human serum albumin by sodium dodecyl sulfate (SDS). These probes respond separately to the polarity and H-bond-donating ability of their surroundings. Competitive binding experiments show that fluorophore 1 binds to site I (domain IIA) and 2 binds to site II (domain IIIA). The local acidity of 1 in site I is out of the sensing range of 1, whereas the local acidity of 2 in site II is calculated to be nearly zero on Catalan's solvent acidity index. Both probes show that the first two equivalents of bound SDS result in a decrease in the local polarity of the binding sites. Each subsequent equivalent of SDS gives rise to a dramatic increase in polarity until HSA is saturated with seven molecules of SDS at the end of the specific binding domain. Compound 2 experiences an increase of acidity of 0.10 on Catalan's solvent acidity index through seven equivalents of SDS, but the local acidity for 1 is still out of range. The increase in acidity experienced by 2 is greater than the increase in polarity. This result is consistent with greater exposure of the carbonyl group in 2, but not the bulk of 2, to the aqueous solvent in site II of the SDS-saturated HSA complex.


Association Between Slow and Delayed Graft Function With Graft Outcomes in Pediatric and Adolescent Deceased Donor Kidney Transplant Recipients.
Delayed graft function (DGF) is associated with an increased risk of graft loss in adult kidney transplant recipients but the association remains inconsistent in pediatric recipients. The aim of this study is to examine the association between DGF and graft loss in pediatric and adolescent deceased donor kidney transplant recipients aged 21 years or younger using Australia and New Zealand Dialysis and Transplant registry. The associations between DGF status, overall and death-censored graft loss (DCGL) were examined using adjusted Cox regression analyses. There were 367 recipients followed up for a median of 9.7 years between 1990 and 2012, with 82 (22%) experiencing DGF requiring dialysis (DGF-D) in the first 72 hours after transplant. Compared with recipients who did not experienced DGF-D, the adjusted hazard ratios for overall graft loss and DCGL in recipients who have experienced DGF-D was 2.08 (95% confidence interval [95% CI], 1.39-3.11; P < 0.001) and 2.09 (95% CI, 1.38-3.17; P < 0.001), respectively, independent of era, age, and initial immunosuppression. Slow graft function, defined as no immediate function but not requiring dialysis, was associated with adjusted hazard ratios of 2.60 (95% CI, 1.50-4.51; P = 0.001) for overall graft loss and 2.49 (95% CI, 1.39-4.47; P = 0.002) for DCGL. This study has shown that DGF, encompassing a spectrum of renal dysfunction after kidney transplantation including those who may or may not require dialysis, is an independent risk factor for long-term graft loss.


Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies.
Inhibition of the androgen receptor (AR) is the mainstay treatment for advanced prostate cancer. Ralaniten (formally EPI-002) prevents AR transcriptional activity by binding to its N-terminal domain (NTD) which is essential for transcriptional activity. Ralaniten acetate (EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD inhibitor to have entered clinical trials (NCT02606123). While well tolerated, the trial was ultimately terminated due to poor pharmacokinetic properties and resulting pill burden. Here we discovered that ralaniten was glucuronidated which resulted in decreased potency. Long-term treatment of prostate cancer cells with ralaniten results in upregulation of UGT2B enzymes with concomitant loss of potency. This has proven to be a useful model with which to facilitate the development of more potent second-generation AR-NTD inhibitors. Glucuronidated metabolites of ralaniten were also detected in the serum of patients in Phase 1 clinical trials. Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.


Cavernous sinus syndrome. Analysis of 151 cases.
To characterize lesions causing cavernous sinus syndrome. Review of 26 years of personal experience in a large city hospital. Among 151 patients, tumors (45 patients, 30%) were the most frequent cause of cavernous sinus syndrome. However, when surgical causes (17 patients, 11%) were included, trauma (36 patients, 24%) became most common. Self-limited inflammation was the third frequent cause (34 patients, 23%), while carotid aneurysms and fistulas, infection, and other causes composed the remaining 12%. The age at onset varied with the cause, and patients with aneurysms (average age, 52 years) and patients with tumors (average age, 47 years) were older than those with self-limited inflammation (average age, 35 years) and trauma (average age, 29 years). Spontaneous remissions defined "self-limited inflammation" but were also seen following an acute onset of symptoms due to aneurysms and pituitary apoplexy. In an unselected series from a city hospital, tumor, trauma, and self-limited inflammation were the predominant causes of cavernous sinus syndrome, and classic causes such as aneurysm, meningioma, and bacterial infection were uncommon. Contrast-enhanced magnetic resonance imaging and watchful waiting proved the most effective diagnostic procedures.


On the Population Dynamics of Junk: A Review on the Population Genomics of Transposable Elements.
Transposable elements (TEs) play an important role in shaping genomic organization and structure, and may cause dramatic changes in phenotypes. Despite the genetic load they may impose on their host and their importance in microevolutionary processes such as adaptation and speciation, the number of population genetics studies focused on TEs has been rather limited so far compared to single nucleotide polymorphisms (SNPs). Here, we review the current knowledge about the dynamics of transposable elements at recent evolutionary time scales, and discuss the mechanisms that condition their abundance and frequency. We first discuss non-adaptive mechanisms such as purifying selection and the variable rates of transposition and elimination, and then focus on positive and balancing selection, to finally conclude on the potential role of TEs in causing genomic incompatibilities and eventually speciation. We also suggest possible ways to better model TEs dynamics in a population genomics context by incorporating recent advances in TEs into the rich information provided by SNPs about the demography, selection, and intrinsic properties of genomes.


Prospective evaluation of flexible ureteroscopes with a novel evaluation tool.
Assess the function and handling in the clinical setting of three different types of reusable or disposable ureteroscopes using a novel, comprehensive flexible ureteroscope evaluation tool. Urologists used a fiberoptic (Olympus URF-P5/P6), digital reusable (Storz Flex Xc), or a new digital disposable ureteroscope (Boston Scientific LithoVue) during ureteroscopic laser lithotripsy. An investigator-designed evaluation tool was used to prospectively assess the performance and handling of the ureteroscopes related to user comfort, maneuverability, efficiency, and various mechanical qualities. After each procedure, surgeons involved in each case who used the ureteroscope completed the written evaluation of the ureteroscope he/she used independently of one another. We reviewed 79 evaluations that were completed after 34 surgical cases; residents and post-graduate MDs were involved in each case. On the characteristics evaluated, significant differences between ureteroscopes were noted. The Storz reusable digital ureteroscope received the highest ratings overall while the new LithoVue disposable ureteroscope generally scored lowest. Our evaluation tool demonstrated good internal consistency, suggesting reliable results. Ureteroscope maneuverability correlated most to overall satisfaction. The clinical evaluation of flexible ureteroscopes for stone removal is critical in equipment purchase decision-making and in planning surgical approaches. We created a comprehensive evaluation tool to standardize and quantify the assessment of ureteroscopes used at our institution. Results revealed significant differences between ureteroscopes for several user and performance characteristics and good reliability of the evaluation tool itself.


Comparing the Predictive Effects of Patient Medication Adherence Indices in Electronic Health Record and Claims-Based Risk Stratification Models.
Multiple indices are available to measure medication adherence behaviors. Medication adherence measures, however, have rarely been extracted from electronic health records (EHRs) for population-level risk predictions. This study assessed the value of medication adherence indices in improving predictive models of cost and hospitalization. This study included a 2-year retrospective cohort of patients younger than age 65 years with linked EHR and insurance claims data. Three medication adherence measures were calculated: medication regimen complexity index (MRCI), medication possession ratio (MPR), and prescription fill rate (PFR). The authors examined the effects of adding these measures to 3 predictive models of utilization: a demographics model, a conventional model (Charlson index), and an advanced diagnosis-based model. Models were trained using EHR and claims data. The study population had an overall MRCI, MPR, and PFR of 14.6 ± 17.8, .624 ± .310, and .810 ± .270, respectively. Adding MRCI and MPR to the demographic and the morbidity models using claims data improved forecasting of next-year hospitalization substantially (eg, AUC of the demographic model increased from .605 to .656 using MRCI). Nonetheless, such boosting effects were attenuated for the advanced diagnosis-based models. Although EHR models performed inferior to claims models, adding adherence indices improved EHR model performances at a larger scale (eg, adding MRCI increased AUC by 4.4% for the Charlson model using EHR data compared to 3.8% using claims). This study shows that medication adherence measures can modestly improve EHR- and claims-derived predictive models of cost and hospitalization in non-elderly patients; however, the improvements are minimal for advanced diagnosis-based models.


Avian influenza overview December 2020 - February 2021.
Between 8 December 2020 and 23 February 2021, 1,022 highly pathogenic avian influenza (HPAI) virus detectionswere reported in 25 EU/EEA countries and the UK in poultry (n=592), wild (n=421) and captive birds (n=9).The majority of the detections were reported by Francethat accounted for 442 outbreaks in poultry,mostly located inthe Landes regionandaffecting the foie gras production industry,and six wild bird detections; Germany,who reported 207 detections in wild birds and 50 poultry outbreaks; Denmark,with 63 detections in wild birds and one poultry outbreak; and Poland,with 37 poultry outbreaks and 24 wild bird detections. Due to the continued presence of HPAI A(H5) viruses in wild birds and the environment,there is still a risk of avian influenza incursions with the potential further spread between establishments, primarily in areas with high poultry densities. As the currently circulating HPAI A(H5N8) virus cancause high mortality also in affected duck farms, mortality eventscan be seen as a good indicator of virus presence. However,also subclinical virusspread in this type of poultry production system have been reported.To improve early detection of infection in poultry within the surveillance zone, the clinical inspection of duck establishments should be complemented by encouraging farmers to collect dead birds to be pooled and tested weekly (bucket sampling).Six different genotypes were identified to date in Europe and Russia, suggesting a high propensity of these viruses to undergo multiple reassortment events. To date, no evidence of fixation of known mutations previously described as associated to zoonotic potential has been observed in HPAI viruses currently circulanting in Europe based on the available sequences.Seven cases due to A(H5N8) HPAI virus have been reported from Russia, all were poultry workerswith mild or no symptoms. Five human cases due to A(H5N6) HPAI and 10 cases due to A(H9N2) LPAI viruseshave been reported from China. The risk for the general population as well as travel-related imported human cases is assessed as very lowand the risk forpeople occupationally exposedpeople as low.Any human infections with avian influenza viruses are notifiablewithin 24 hoursthrough the Early Warning and Response System (EWRS) and the International Health Regulations (IHR) notification system.


Hybrid Collision Avoidance for ASVs Compliant With COLREGs Rules 8 and 13-17.
This paper presents a three-layered hybrid collision avoidance (COLAV) system for autonomous surface vehicles, compliant with rules 8 and 13-17 of the International Regulations for Preventing Collisions at Sea (COLREGs). The COLAV system consists of a high-level planner producing an energy-optimized trajectory, a model-predictive-control-based mid-level COLAV algorithm considering moving obstacles and the COLREGs, and the branching-course model predictive control algorithm for short-term COLAV handling emergency situations in accordance with the COLREGs. Previously developed algorithms by the authors are used for the high-level planner and short-term COLAV, while we in this paper further develop the mid-level algorithm to make it comply with COLREGs rules 13-17. This includes developing a state machine for classifying obstacle vessels using a combination of the geometrical situation, the distance and time to the closest point of approach (CPA) and a new CPA-like measure. The performance of the hybrid COLAV system is tested through numerical simulations for three scenarios representing a range of different challenges, including multi-obstacle situations with multiple simultaneously active COLREGs rules, and also obstacles ignoring the COLREGs. The COLAV system avoids collision in all the scenarios, and follows the energy-optimized trajectory when the obstacles do not interfere with it.


Invasive mammals and habitat modification interact to generate unforeseen outcomes for indigenous fauna.
Biotic invasions and habitat modification are two drivers of global change predicted to have detrimental impacts on the persistence of indigenous biota worldwide. Few studies have investigated how they operate synergistically to alter trophic interactions among indigenous and nonindigenous species in invaded ecosystems. We experimentally manipulated a suite of interacting invasive mammals, including top predators (cat Felis catus, ferret Mustela furo, stoat M. erminea), herbivores (rabbit Oryctolagus cuniculus, hare Lepus europaeus), and an insectivore (hedgehog Erinaceus europaeus occidentalis), and measured their effects on indigenous lizards and invertebrates and on an invasive mesopredator (house mouse Mus musculus). The work was carried out in a grassland/shrubland ecosystem that had been subjected to two types of habitat modification (widespread introduction of high-seed-producing pasture species, and areas of land use intensification by fertilization and livestock grazing). We also quantified food productivity for indigenous and invasive fauna by measuring pasture biomass, as well as seed and fruit production by grasses and shrubs. Indigenous fauna did not always increase following top-predator suppression: lizards increased on one of two sites; invertebrates did not increase on either site. Mesopredator release of mice was evident at the site where lizards did not increase, suggesting negative effects of mice on lizard populations. High mouse abundance occurred only on the predator-suppression site with regular production of pasture seed, indicating that this food resource was the main driver of mouse populations. Removal of herbivores increased pasture and seed production, which further enhanced ecological release of mice, particularly where pasture swards were overtopped by shrubs. An effect of landscape supplementation was also evident where nearby fertilized pastures boosted rabbit numbers and the associated top predators. Other studies have shown that both suppression of invasive predators and retiring land from grazing can benefit indigenous species, but our results suggest that the ensuing vegetation changes and complex interactions among invasive species can block recovery of indigenous fauna vulnerable to mesopredators. Top-down and bottom-up ecological release of mesopredators and landscape supplementation of top predators are key processes to consider when managing invaded communities in complex landscapes.


[Experimental simulation of blunt cardiac trauma].
This paper was designed to analyse the main experimental models of blunt cardiac trauma proposed during a period of more than 100 years beginning from the study of the Italian scientist Felice Meola dated to the 1870s till the present time. The analysis demonstrated that even a mild injury to the anterior chest wall in the projection of the heart may cause serious changes in hemodynamics and ECG characteristics. It was shown that various methods employed to simulate blunt cardiac trauma place potential constraints related to the design of experiments.


Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation.
The authors investigated ideal acoustic conditions on a clinical scanner custom-programmed for ultrasound (US) cavitation-mediated flow augmentation in preclinical models. We then applied these conditions in a first-in-human study to test the hypothesis that contrast US can increase limb perfusion in normal subjects and patients with peripheral artery disease (PAD). US-induced cavitation of microbubble contrast agents augments tissue perfusion by convective shear and secondary purinergic signaling that mediates release of endogenous vasodilators. In mice, unilateral exposure of the proximal hindlimb to therapeutic US (1.3 MHz, mechanical index 1.3) was performed for 10 min after intravenous injection of lipid microbubbles. US varied according to line density (17, 37, 65 lines) and pulse duration. Microvascular perfusion was evaluated by US perfusion imaging, and in vivo adenosine triphosphate (ATP) release was assessed using in vivo optical imaging. Optimal parameters were then used in healthy volunteers and patients with PAD where calf US alone or in combination with intravenous microbubble contrast infusion was performed for 10 min. In mice, flow was augmented in the US-exposed limb for all acoustic conditions. Only at the lowest line density was there a stepwise increase in perfusion for longer (40-cycle) versus shorter (5-cycle) pulse duration. For higher line densities, blood flow consistently increased by 3-fold to 4-fold in the US-exposed limb irrespective of pulse duration. High line density and long pulse duration resulted in the greatest release of ATP in the cavitation zone. Application of these optimized conditions in humans together with intravenous contrast increased calf muscle blood flow by >2-fold in both healthy subjects and patients with PAD, whereas US alone had no effect. US of microbubbles when using optimized acoustic environments can increase perfusion in limb skeletal muscle, raising the possibility of a therapy for patients with PAD. (Augmentation of Limb Perfusion With Contrast Ultrasound; NCT03195556).


Characteristics and job satisfaction of general practitioners using complementary and alternative medicine in Germany--is there a pattern?
The use of Complementary and Alternative medicine (CAM) has increased over the past years. In Germany, many general practitioners (GPs) use CAM in their daily practice. However, little is known about possible differences of GPs using CAM compared to GPs not using CAM. The aim of the study was to explore differences in personal and practice characteristics, work load and job satisfaction of GPs depending on their use of and attitude towards CAM. Furthermore, predictors for CAM use should be explored. A questionnaire was developed based on qualitatively derived data. In addition, a validated instrument assessing job satisfaction was included in the questionnaire, which was sent to 3000 randomly selected GPs in Germany. 1027 returned the questionnaire of which 737 indicated to use CAM in daily practice. We found that GPs using CAM are more female, younger and have a trend towards a healthier life style. Their practices have higher proportions of privately insured patients and are slightly better technically equipped with ultrasound. GPs with a positive attitude had significant better values within the job satisfaction scale and lower working hours per week compared to GPs with neutral/negative attitude. Significant predictors for CAM use were a positive attitude towards CAM, holding a special qualification in CAM, own CAM use and the availability of an ultrasound in practice. The identified differences suggest that those GPs using and believing in CAM have a different medical orientation and approach which in turn may influence their job satisfaction. With this finding CAM use turns out to be a relevant factor regarding job satisfaction and, with this, may be a possible lever to counteract the growing dissatisfaction of GPs in Germany. This finding could also be important for designing strategies to promote the recruitment of young doctors to general practice.


Characterization of angiotensin II-receptor subtypes in podocytes.
Glomerular podocytes play a key role in maintaining the integrity of the glomerular filtration barrier. This function may be regulated by angiotensin II (Ang II) through activation of cell-surface receptors. Although studies suggest that podocytes express receptors for Ang II, the Ang II binding site has not been characterized with radioligand binding techniques. We therefore used iodine 125-labeled Ang II to monitor Ang II-receptor density during differentiation of a mouse podocyte cell line. Scatchard analyses of equilibrium binding data revealed a single class of high-affinity binding sites (dissociation constant approximately 3 nmol/L) in both differentiated and nondifferentiated cells. During differentiation, the density of Ang II-receptor sites increased roughly 15-fold in differentiated podocytes (maximal density of specific binding sites 881 fmol/mg protein) compared with that in nondifferentiated cells (52 fmol/mg protein; P<.005). Glomerular podocytes expressed messenger RNA for AT1A, AT1B, and AT2 receptor subtypes, and competitive binding studies found that differentiated podocytes expressed mostly AT1 receptors (approximately 75%) with lesser amounts of AT2 (approximately 25%). Up-regulation of Ang II-receptor number was associated with increased Ang II-receptor responsiveness, as evidenced by enhanced Ang II-stimulated inositol phosphate (IP) generation and incorporation of tritiated thymidine. Both [3H]thymidine incorporation and IP generation were mediated by AT1-receptor activation. These data suggest that glomerular podocytes express a high-affinity binding site for Ang II with pharmacologic characteristics of both AT1 and AT2 receptors. This receptor site is up-regulated during podocyte differentiation, and receptor activation induces both IP generation and DNA synthesis by AT1-dependent mechanisms. We speculate that activation of podocyte Ang II receptors contributes to glomerular damage in disease states.


Likelihood ratio based tests for longitudinal drug safety data.
This article presents longitudinal likelihood ratio test (LongLRT) methods for large databases with exposure information. These methods are applied to a pooled large longitudinal clinical trial dataset for drugs treating osteoporosis with concomitant use of proton pump inhibitors (PPIs). When the interest is in the evaluation of a signal of an adverse event for a particular drug compared with placebo or a comparator, the special case of the LongLRT, referred to as sequential LRT (SeqLRT), is also presented. The results show that there is some possible evidence of concomitant use of PPIs leading to more adverse events associated with osteoporosis. The performance of the proposed LongLRT and SeqLRT methods is evaluated using simulated datasets and shown to be good in terms of (conditional) power and control of type I error over time. The proposed methods can also be applied to large observational databases with exposure information under the US Food and Drug Administration Sentinel Initiative for active surveillance. Published 2014. This article is a US Government work and is in the public domain in the USA.


Clostridium hungatei sp. nov., a mesophilic, N2-fixing cellulolytic bacterium isolated from soil.
Two strains of obligately anaerobic, mesophilic, cellulolytic, N2-fixing, spore-forming bacteria were isolated from soil samples collected at two different locations near Amherst, MA, USA. Single cells of both strains were slightly curved rods that measured between 2 and 6 microm in length and approximately 0.5 microm in diameter. The spores were spherical, terminally located, distended the sporangium and measured 0.8-1.0 microm in diameter. The cells of both isolates (designated strain ADT and strain B3B) stained Gram-negative, but did not have a typical Gram-negative cell wall structure as demonstrated by transmission electron microscope analysis. The cells of both strains were motile with subpolarly inserted flagella and exhibited chemotactic behaviour towards cellobiose and D-glucose. Both strains fermented cellulose, xylan, cellobiose, cellodextrins, D-glucose, D-xylose, D-fructose, D-mannose and gentiobiose. In addition, strain B3B fermented L-arabinose. For both strains, fermentation products from cellulose were acetate, ethanol, H2 and CO2, as well as small amounts of lactate and formate. The G+C content of strain AD was 40 mol% and that of strain B3B was 42 mol%. Based on their morphological, physiological and phylogenetic characteristics, it was concluded that the two isolates are representatives of a novel species of Clostridium. The name Clostridium hungatei is proposed for the new species. The type strain of Clostridium hungatei sp. nov. is strain ADT (= ATCC 700212T).


A neonate with critical congenital heart disease.
Critical congenital heart disease (CCHD) is defined as a ductal-dependent congenital heart defect requiring surgical or percutaneous intervention via cardiac catheterization before 1 year of age. Most cases of CCHD can be diagnosed with prenatal ultrasound or fetal echocardiogram. If not prenatally diagnosed, CCHD can be stable in the newborn nursery due to persistent ductal patency, and the patient may only be diagnosed after ductal closure and development of cardiac symptoms at home. In this case, a 6-day-old female presented to the emergency department (ED) floppy with agonal respirations, poor capillary refill, and absent femoral pulses. On the day of presentation, the patient became increasingly fussy, refused feeding, and began to gasp. The patient was transported to the ED for evaluation, where a bedside echocardiogram revealed interrupted aortic arch (IAA), ventricular septal defect, minimal flow through a thread-like ductus arteriosus, and severely depressed cardiac function. IAA is very rare, with an incidence of three cases per 1 million live births. Patients require neonatal supportive care, continuous prostaglandin E1 infusion, and urgent referral for neonatal surgical repair in the first days to weeks of life. To reduce the volume of undiagnosed CCHD in the immediate newborn period, the U.S. Department of Health and Human Services Secretary's Advisory Committee on Heritable Diseases in Newborns and Children (SACHDNC) recommended that CCHD screening via pulse oximetry be added to the recommended uniform screening panel. A positive screen results in an immediate referral for an echocardiogram. Fetal diagnosis, newborn screening, and/or careful clinical examination may have resulted in detection of IAA in our patient prior to ductal closure.


[Immunochemical analysis of the cytoplasmic fraction of a cholera-like vibrion].
A soluble cytoplasm and ribosomal fraction which were later subjected to gel-filtration were obtained by disintegration and subsequent differential centrifugation from a cholera-like strain. Immunodiffusion and immunoelectrophoresis in gel showed that the ribosomal fraction contained up to 6 high-molecular antigenic components (including an O-antigen and the antigens identical to those of a cholerogen), and others; its low-molecular components (molecular weight 1.7-10-4 and lower) were inactive in immunodiffusion and immunoelectrophoresis. The soluble fraction of the cytoplasm contained up to 5 antigenic components, two of which represented thermolabile antigens of protein nature, and the rest, apparently--of carbohydrate. The soluble portion of the cytoplasm displayed antigens identical to the cholerogen of a cholera vibrio; low molecular components of the soluble cytoplasm (mol. weight--1.7-10-4 and lower) possessed no antigenic activity. The data obtained pointed to the possible intracellular formation of the cholera vibrio toxin.


Effects of apelin and vascular endothelial growth factor on central retinal vein occlusion in monkey eyes intravitreally injected with bevacizumab: a preliminary study.
To examine the intraocular distribution of bevacizumab at four weeks after intravitreal bevacizumab (IVB) injection and to investigate the effects of IVB on apelin and vascular endothelial growth factor (VEGF) in the central retinal vein occlusion (CRVO) of monkey eyes. Direct laser coagulation was performed on all branch retinal veins in the right eyes of six Rhesus monkeys to establish a CRVO model. The eyes of the first three monkeys were enucleated one week, two weeks, and 24 weeks after the establishment of the CRVO model; this was the CRVO group. Subsequently, IVB was injected into the eyes of the last three monkeys one week, two weeks, and 24 weeks after laser coagulation; this was the IVB group. The left eye of the first monkey was used as normal control. Immunohistochemistry and reverse-transcription PCR was used to examine the expression of apelin and VEGF. The penetration of bevacizumab into the retina and iris was investigated by fluorescence immunostaining. Immunoreactivity for bevacizumab could be detected in the vessel walls of the iris and choroid on day 28 after injecting IVB: apelin and VEGF staining had been more prominent than normal in the CRVO eye, but these decreased following IVB injection. Expression of apelin mRNA (p<0.01) was lower in the IVB group than the CRVO group and did not vary significantly between groups. Bevacizumab could be detected in the iris and choroid after four weeks of intravitreal injection. Apelin may be partially suppressed by bevacizumab, and it may play a role in retinal neovascularization during the development of CRVO.


The effect of a monoclonal antibody coupled to ricin A chain-derived peptides on endothelial cells in vitro: insights into toxin-mediated vascular damage.
Immunotoxins (ITs) containing plant or bacterial toxins have a dose-limiting toxicity of vascular leak syndrome (VLS) in humans. The active A chain of ricin toxin (RTA), other toxins, ribosome-inactivating proteins, and the VLS-inducing cytokine IL-2 contain the conserved sequence motif (x)D(y) where x = L, I, G, or V and y = V, L, or S. RTA-derived LDV-containing peptides attached to a monoclonal antibody, RFB4, induce endothelial cell (EC) damage in vitro and vascular leak in two animal models in vivo. We have now investigated the mechanism(s) by which this occurs and have found that (1) the exposed D75 in the LDV sequence in RTA and the C-terminal flanking threonine play critical roles in the ability of RFB4-conjugated RTA peptide to bind to and damage ECs and (2) the LDV sequence in RTA induces early manifestations of apoptosis in HUVECs by activating caspase-3. These data suggest that RTA-mediated inhibition of protein synthesis (due to its active site) and apoptosis (due to LDV) may be mediated by different portions of the RTA molecule. These results suggest that ITs prepared with RTA mutants containing alterations in LDVT may kill tumor cells in vivo in the absence of EC-mediated VLS.


Towards a comprehensive structural variation map of an individual human genome.
Several genomes have now been sequenced, with millions of genetic variants annotated. While significant progress has been made in mapping single nucleotide polymorphisms (SNPs) and small (<10 bp) insertion/deletions (indels), the annotation of larger structural variants has been less comprehensive. It is still unclear to what extent a typical genome differs from the reference assembly, and the analysis of the genomes sequenced to date have shown varying results for copy number variation (CNV) and inversions. We have combined computational re-analysis of existing whole genome sequence data with novel microarray-based analysis, and detect 12,178 structural variants covering 40.6 Mb that were not reported in the initial sequencing of the first published personal genome. We estimate a total non-SNP variation content of 48.8 Mb in a single genome. Our results indicate that this genome differs from the consensus reference sequence by approximately 1.2% when considering indels/CNVs, 0.1% by SNPs and approximately 0.3% by inversions. The structural variants impact 4,867 genes, and >24% of structural variants would not be imputed by SNP-association. Our results indicate that a large number of structural variants have been unreported in the individual genomes published to date. This significant extent and complexity of structural variants, as well as the growing recognition of their medical relevance, necessitate they be actively studied in health-related analyses of personal genomes. The new catalogue of structural variants generated for this genome provides a crucial resource for future comparison studies.


Central Nervous System Fungal Infection and Acute Lymphoblastic Leukemia in Children: What is the Optimal Duration of Antifungal Therapy?
Invasive fungal infections are rare in children with acute lymphoblastic leukemia. It compromises the antileukemia therapy should it happen. Central nervous system fungal infections carry high mortality. We here report the case of a 6.5-year-old girl who developed multiple central nervous system fungal abscesses possibly due to Aspergillus infection during induction therapy for acute lymphoblastic leukemia who has been successfully managed without compromising antileukemia therapy. She has been receiving antifungal therapy and maintenance chemotherapy for 20 months from diagnosis. We reviewed literature about the optimal duration of therapy for such children as the reported cases duration ranged between 4 and 24 months.


Design, synthesis, biological evaluation, and molecular modeling study of 4-alkoxyquinazoline derivatives as potential VEGFR2 kinase inhibitors.
A series of novel 4-alkoxyquinazoline derivatives were prepared and synthesized and their biological activities were evaluated as potential inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). Of these compounds, compound 3j demonstrated the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, the IC50 values of this compound reaching up to 2.72 nM and 0.35 μM, respectively, compared with Tivozanib (3.40 nM and 0.38 μM). The obtained results, along with a 3D-QSAR study and molecular docking that was used for investigating the probable binding mode, could provide an important basis for further optimization of compound 3j as a potential tyrosine kinase inhibitor.


Bulk optical parameters of porcine skin dermis at eight wavelengths from 325 to 1557 nm.
We introduce a method with which to obtain accurately the bulk optical parameters of fresh biological tissues in vitro by combining measurements of the sample surface profiles, reflectance, and transmittances with Monte Carlo-based inverse calculations. The bulk optical parameters of fresh porcine dermis tissue were determined at eight wavelengths from 325 to 1557 nm and were found to be much different from those determined without consideration of surface roughness.


Astaxanthin prevents and reverses the activation of mouse primary hepatic stellate cells.
Activation of hepatic stellate cells (HSCs) is a critical step that leads to the development of liver fibrosis. We showed that astaxanthin (ASTX), a xanthophyll carotenoid, displays antifibrogenic effects in LX-2 cells, a human HSC cell line. In this study, we further determined the effect of ASTX on HSC activation and inactivation using primary HSCs from C57BL/6J mice. Quiescent and activated HSCs were incubated with ASTX (25μM) at different stages of activation. ASTX prevented the activation of quiescent HSCs, as evidenced by the presence of intracellular lipid droplets and reduction of α-smooth muscle actin, an HSC activation marker. Also, ASTX reverted activated HSCs to a quiescent phenotype with the reappearance of lipid droplets with a concomitant increase in lecithin retinol acyltransferase mRNA. Cellular accumulation of reactive oxygen species was significantly reduced by ASTX, which was attributable to a decrease in NADPH oxidase 2 expression. The antifibrogenic effect of ASTX was independent of nuclear erythroid 2-related factor 2 as it was observed in HSCs from wild-type and Nrf2(-/-) mice. In conclusion, ASTX inhibits HSC activation and reverts activated HSCs to a quiescent state. Further investigation is warranted to determine if ASTX effectively prevents the development of liver fibrosis.


[Intra- and extramural workshop for care, teaching, and research].
Medical care and its development, education, training and research are closely linked in academic medical centres. Traditionally, hospital-based disciplines can make use of the university hospital as a 'workshop' for the combination of these activities. In the Netherlands, however, there is no structurally financed workshop for the non-hospital based medical disciplines, such as family medicine, public health medicine, and nursing home medicine. In the Academic Medical Centre, University of Amsterdam, an integrated hospital and primary health care oriented academic workshop is being developed, for all medical disciplines, including social medicine (e.g. preventive care) and general practice.


A novel paradigm links mitochondrial dysfunction with muscle stem cell impairment in sepsis.
Sepsis is an acute systemic inflammatory response of the body to microbial infection and a life threatening condition associated with multiple organ failure. Survivors may display long-term disability with muscle weakness that remains poorly understood. Recent data suggest that long-term myopathy in sepsis survivors is due to failure of skeletal muscle stem cells (satellite cells) to regenerate the muscle. Satellite cells impairment in the acute phase of sepsis is linked to unusual mitochondrial dysfunctions, characterized by a dramatic reduction of the mitochondrial mass and hyperactivity of residual organelles. Survivors maintain the impairment of satellite cells, including alterations of the mitochondrial DNA (mtDNA), in the long-term. This condition can be rescued by treatment with mesenchymal stem cells (MSCs) that restore mtDNA alterations and mitochondrial function in satellite cells, and in fine their regenerative potential. Injection of MSCs in turn increases the force of isolated muscle fibers and of the whole animal, and improves the survival rate. These effects occur in the context of reduced inflammation markers that also raised during sepsis. Targeting muscle stem cells mitochondria, in a context of reduced inflammation, may represent a valuable strategy to reduce morbidity and long-term impairment of the muscle upon sepsis.


A case-control study of the risk of cutaneous melanoma associated with three selenium exposure indicators.
A direct association between exposure to the metalloid selenium and risk of cutaneous melanoma has been suggested by some observational and experimental cohort studies, whereas other studies have yielded inconsistent results. Since some of the inconsistencies may be due to exposure misclassification arising from the use of exposure indicators that do not adequately reflect body tissue selenium content or the levels of the biologically relevant species of this metalloid, we examined this issue using multiple indicators of exposure. We analyzed the relation of selenium exposure with risk of cutaneous melanoma using two different biomarkers, plasma and toenail selenium concentration, and estimated dietary selenium intake in a population-based case-control series (54 cases, 56 controls) from an Italian community. In unmatched and matched logistic regression models as well as nonparametric generalized additive models, higher plasma selenium levels were strongly associated with excess disease risk. In contrast, toenail and dietary selenium exhibited little relation with melanoma risk. The pattern of correlation among indicators of exposure differed by disease status, with dietary intake associated with plasma selenium levels in patients but not in controls. Our data showed that different selenium exposure indicators can yield different inferences about melanoma risk. Although the series was small, our results are consistent with a positive association between circulating levels of selenium and melanoma risk. Further investigation of the exposure classification performance of various selenium biomarkers and of metabolic patterns of the metalloid and of its speciation are needed to help elucidate the relation between selenium exposure and human health.


Dexamethasone during ovulation induction for in-vitro fertilization: a pilot study.
The purpose of the present study was to determine whether adrenal androgen suppression with dexamethasone (DEX) during ovulation induction improves the outcome of in-vitro fertilization (IVF) cycles. A total of 25 patients with serum dehydroepiandrosterone sulphate (DHEAS) concentrations > 2.5 micrograms/ml were randomized to receive either 0.5 mg DEX daily or placebo during ovulation induction with leuprolide acetate down-regulation plus human menopausal gonadotrophins (HMG). Nine patients undergoing a subsequent IVF cycle were crossed over to the other treatment group. Ovarian responsiveness and IVF outcome variables analysed included number of follicles > 12 mm in diameter, serum oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) administration, number of ampoules of HMG administered, number of oocytes retrieved, percentage of oocytes fertilized, number of embryos transferred, implantation rate and numbers of clinical pregnancies and live birth pregnancies. The 31 randomized IVF cycles revealed a trend towards a higher implantation rate for the placebo-treated group compared to the DEX-treated group (24 versus 10%; P = 0.07). The remainder of the IVF cycle variables revealed no statistically significant differences. In conclusion, the suppression of adrenal androgens with DEX in women with DHEAS concentrations > 2.5 micrograms/ml appears to have no beneficial effects on ovarian responsiveness or clinical or live birth pregnancy rates.


Expression of matrix metalloproteinases in vasculitic neuropathy.
The aim of this study was to investigate the expression pattern and cellular source of matrix metalloproteinases (MMP) in vasculitic neuropathy. Matrix metalloproteinases are endopeptidases degrading components of extracellular matrix proteins, and they have been implicated in the pathogenesis of inflammatory demyelination. They are induced by cytokines, secreted by inflammatory cells, and enhance T cell migration. Vasculitic neuropathy occurs as a component of systemic vasculitis or as an isolated angiitis of the peripheral nervous system, and T cell-mediated inflammation is detected in its pathogenesis. Nerve biopsy sections of eight patients with nonsystemic vasculitic neuropathy (NSVN) and four with systemic vasculitic neuropathy were examined for the presence of CD4+, CD8+, and CD68+ cells and immunohistochemically for MMP-2 and MMP-9 expression. Nerve biopsies of eight patients with noninflammatory neuropathy were used as a control group. Semiquantitative polymerase chain reaction analysis was performed to detect MMP-2 and MMP-9 mRNA. The predominant cells were CD8+ and CD68+ T cells. Expression of MMP-9, but not MMP-2, was increased in perivascular inflammatory infiltrate in nerve tissues of vasculitic neuropathy patients. This MMP-9 expression correlated positively with immunostaining of CD8+ T cells. No difference was detected between immunostaining patterns of nonsystemic and systemic vasculitic neuropathies with the antibodies used, except in MMP-9 immunostaining, which was found to be enhanced in NSVN group. Polymerase chain reaction analysis revealed elevated mRNA levels of MMP-9 and MMP-2 compared with controls, but this did not reach statistical significance. Our results imply a pathogenic role for MMP-9 secreted from CD8+ cells in vasculitic neuropathy.


Use of the Neuro-Wrap system for severe post-electroconvulsive therapy headaches.
To determine, in a nonblinded trial, if the Neuro-Wrap system is effective in reducing the severity of pain in patients with severe post-electroconvulsive therapy (ECT) headaches not adequately responsive to routine analgesic treatment. A very troubling side effect of ECT is severe post-ECT headaches. Although these headaches usually respond to routine analgesic medication, some patients continue to experience severe headache despite treatment. This very unpleasant sensation, repeated with each ECT, may cause patients to prematurely stop ECT and experience a relapse in their psychiatric symptoms. "Cold therapy" has been used for a long time as an adjunct to treat headache and pain. The Neuro-Wrap system is a method to provide temperature-controlled cooling to the head without the need to frequently reapply ice packs or physically hold the ice packs in position. It has been used successfully for patients with migraine headaches. This is the first report of its use with patients experiencing severe post-ECT headaches. The study comprised a total of 14 patients receiving ECT who experienced a severe headache for 2 successive ECT treatments or 2 of their last 4 treatments and who had only partial or no response to usual analgesic treatment for their headache. After completion of the ECT, the Neuro-Wrap was placed on the head of the patient for a maximum of 40 minutes. Patients continued to receive analgesic medication as needed for relief of headache pain. Patients were their own control group. A total of 85 Neuro-Wrap treatments were given to 14 patients ranging in age from 23 to 71 years old. Nine patients reported clearly positive results on 67 different occasions. Three reported mild alleviation of headaches on 15 occasions. The remaining 2 patients had a total of 3 treatments with no benefit. After the initial treatment, 12 of 14 patients wanted to use the machine after all their subsequent ECT sessions. Cold therapy with Neuro-Wrap is an effective alternative treatment for refractory headaches caused by ECT.


Linking population dynamics models with empirically derived models through phytoplankton primary production.
There are alternative methods for estimation of phytoplankton primary production (PP) that are fundamentally different in the calculation approach. The process-oriented PP model is a mechanistic, empirically derived method based on the photosynthesis-light relationships. The population dynamics-based PP calculation, which is a synthetic method, provides a production estimate based on population dynamics of phytoplankton. These alternative methods were here compared with regard to production estimates and linked to enhance the performance of the existing models of population dynamics applied to a wide variety of lakes worldwide in terms of morphometry, nutrient status, and light environments. Estimates of PP were shown to be sensitive to changes in phytoplankton sinking and zooplankton grazing rates in both methods. Production estimates in the process-oriented PP model were also sensitive to light-associated parameters such as day length. Although the production estimated from the population dynamics-based PP calculation tended to be lower than that from the process-oriented PP model irrespective of lake morphometry, production estimates calculated from both methods with standard parameterization were comparable when production was estimated on an annual timescale. However, it was also shown that the alternative methods could produce different production estimates when estimated on shorter timescales such as cyanobacterial blooms in summer. Cyanobacteria with low mortality due to grazing and sinking losses have been considered as trophic bottlenecks, but there is increasing evidence that their mortality is, to a considerable extent, due to parasitic pathogens. In the case of cyanobacterial blooms, an addition of parasite-related loss term (19%-33% of standing stock) resulted in a resolution of the difference in production estimates between the methods. These analyses theoretically support the critical role of parasitism and resolve the bottleneck problem in aquatic ecosystem metabolism.


[Determination of hepatitis B virus genotypes by DNA sequence analysis in patients from Ankara, Turkey].
Hepatitis B virus (HBV) genotypes vary depending on the geographical region. The HBV genotype determined in Turkey has been genotype D which is found as the homogenously disseminated single genotype. The aim of this study was to determine HBV genotypes in a group of HBV infected patients who were admitted to a university hospital in Ankara, Turkey. Serum samples from HBsAg positive and anti-HBs negative 84 (52 male, 32 female) patients with HBV infection were included into the study. Anti-HBc was positive in 95.2%, HBeAg was positive in 47.6% and anti-HBe was positive in 11.9% of the patients. Mean HBV-DNA levels of the patients were 5.7 x 10(7) +/- 4.6 x 10(7) IU/ml; mean ALT levels were 131 +/- 171 IU/ml and mean AST levels were 98 +/- 170 IU/ml. HBV-DNA was extracted from serum by the phenol-chloroform method and PCR was performed to amplify the S gene region of HBV-DNA. Cycle sequencing of PCR products was performed by a commercial "Cy5/Cy5.5 Dye Primer Cycle Sequencing Kit" (Visible Genetics, Canada) based on dideoxy chain termination method. The sequences were read and analyzed in an automated fluorescence-based DNA-sequencing system (Long-Read Tower System, Visible Genetics, Canada). The nucleotide sequences of the patient samples were compared with the previously reported sequences in gene bank for each genotype. According to the comparative analysis of S-sequences of all patient samples with the published sequences of the genotypes in gene bank, all of the 84 hepatitis B strains (100%) were shown to be related to D genotypic group, subtype ayw. A phylogenetic analysis was performed and phylogenetic trees were constructed using programs in the PHYLIP phylogeny inference package. The patient samples clustered within the genotypic group D. According to these results, the main HBV genotype in our patients was genotype D in accordance with the previous molecular epidemiologic information on HBV in this geographic area. HBV genotype determination may help to establish more rational clinical approach in the evaluation of HBV infected patients.


Informing the nursing professions about IT.
In the United Kingdom, over two decades of activity by enthusiasts for nursing informatics appears to have failed to engage the active interest of fellow nurses, midwives, and health visitors. Conferences, journals, and articles in the professional journals have been used. Clinical computing has developed, with the Department of Health in England taking a lead. Changes have occurred in the organization of the health services and in nurse education. One possible model, drawn from general education, is proposed as an explanation and a source for solutions.


Site-specific and temporally controlled initiation of DNA replication in a human cell-free system.
We have recently established a cell-free system from human cells that initiates semi-conservative DNA replication in nuclei isolated from cells which are synchronised in late G1 phase of the cell division cycle. We now investigate origin specificity of initiation using this system. New DNA replication foci are established upon incubation of late G1 phase nuclei in a cytosolic extract from proliferating human cells. The intranuclear sites of replication foci initiated in vitro coincide with the sites of earliest replicating DNA sequences, where DNA replication had been initiated in these nuclei in vivo upon entry into S phase of the previous cell cycle. In contrast, intranuclear sites that replicate later in S phase in vivo do not initiate in vitro. DNA replication initiates in this cell-free system site-specifically at the lamin B2 DNA replication origin, which is also activated in vivo upon release of mimosine-arrested late G1 phase cells into early S phase. In contrast, in the later replicating ribosomal DNA locus (rDNA) we neither detected replicating rDNA in the human in vitro initiation system nor upon entry of intact mimosine-arrested cells into S phase in vivo. As a control, replicating rDNA was detected in vivo after progression into mid S phase. These data indicate that early origin activity is faithfully recapitulated in the in vitro system and that late origins are not activated under these conditions, suggesting that early and late origins may be subject to different mechanisms of control.


Development of a New Molecular Marker for the Resistance to Tomato Yellow Leaf Curl Virus.
Tomato yellow leaf curl virus (TYLCV) responsible for tomato yellow leaf curl disease (TYLCD) causes a substantial decrease in tomato (Solanum lycopersicum L.) yield worldwide. The use of resistant variety as a sustainable management strategy has been advocated. Tremendous progress has been made in genetically characterizing the resistance genes (R gene) in tomato. Breeding tomato for TYLCV resistance has been based mostly on Ty-3 as a race-specific resistance gene by introgression originating from wild tomato species relatives. Improvement or development of a cultivar is achievable through the use of marker-assisted selection (MAS). Therefore, precise and easy use of gene-targeted markers would be of significant importance for selection in breeding programs. The present study was undertaken to develop a new marker based on Ty-3 gene sequence that can be used for MAS in TYLCV resistant tomato breeding program. The new developed marker was named ACY. The reliability and accuracy of ACY were evaluated against those of Ty-3 linked marker P6-25 through screening of commercial resistant and susceptible tomato hybrids, and genetic segregation using F2 population derived from a commercial resistant hybrid AG208. With the use of bioinformatics and DNA sequencing analysis tools, deletion of 10 nucleotides was observed in Ty-3 gene sequence for susceptible tomato variety. ACY is a co-dominant indel-based marker that produced clear and strong polymorphic band patterns for resistant plant distinguishing it from its susceptible counterpart. The obtained result correlates with 3:1 segregation ratio of single resistant dominant gene inheritance, which depicted ACY as gene-tag functional marker. This marker is currently in use for screening 968 hybrids varieties and one thousand breeding lines of tomato varieties stocked in Jiangsu Green Port Modern Agriculture Development Company (Green Port). So far, ACY has been used to identify 56 hybrids and 51 breeding lines. These newly detected breeding lines were regarded as potential source of resistance for tomato breeding. This work exploited the sequence of Ty-3 and subsequently contributed to the development of molecular marker ACY to aid phenotypic selection. We thus recommend this marker to breeders, which is suitable for marker-assisted selection in tomato.


Ferns diversified in the shadow of angiosperms.
The rise of angiosperms during the Cretaceous period is often portrayed as coincident with a dramatic drop in the diversity and abundance of many seed-free vascular plant lineages, including ferns. This has led to the widespread belief that ferns, once a principal component of terrestrial ecosystems, succumbed to the ecological predominance of angiosperms and are mostly evolutionary holdovers from the late Palaeozoic/early Mesozoic era. The first appearance of many modern fern genera in the early Tertiary fossil record implies another evolutionary scenario; that is, that the majority of living ferns resulted from a more recent diversification. But a full understanding of trends in fern diversification and evolution using only palaeobotanical evidence is hindered by the poor taxonomic resolution of the fern fossil record in the Cretaceous. Here we report divergence time estimates for ferns and angiosperms based on molecular data, with constraints from a reassessment of the fossil record. We show that polypod ferns (> 80% of living fern species) diversified in the Cretaceous, after angiosperms, suggesting perhaps an ecological opportunistic response to the diversification of angiosperms, as angiosperms came to dominate terrestrial ecosystems.


Effectiveness of anti-TNFα for Crohn disease: research in a pediatric learning health system.
ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20-1.96) for clinical remission and 1.74 (95% CI, 1.33-2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4-11.1) for clinical remission and 5.0 (95% CI, 3.4-10.0) for corticosteroid-free remission. In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.


A root is a root is a root? Water uptake rates of Citrus root orders.
Knowledge about the physiological function of root orders is scant. In this study, a system to monitor the water flux among root orders was developed using miniaturized chambers. Different root orders of 4-year-old Citrus volkameriana trees were analysed with respect to root morphology and water flux. The eight root orders showed a broad overlap in diameter, but differences in tissue densities and specific root area (SRA) were clearly distinguishable. Thirty per cent of the root branch biomass but 50% of the surface area (SA) was possessed by the first root order, while the fifth accounted for 5% of the SA (20% biomass). The root order was identified as a determinant of water flux. First-order roots showed a significantly higher rate of water uptake than the second and third root orders, whereas the fourth and fifth root orders showed water excess. The water excess suggested the occurrence of hydraulic redistribution (HR) as a result of differences in osmotic potentials. We suggest that plants may utilize hydraulic redistribution to prevent coarse root desiccation and/or to increase nutrient acquisition. Our study showed that the novel 'miniature depletion chamber' method enabled direct measurement of water fluxes per root order and can be a major tool for future studies on root order traits.


[Home care: health professionals at risk for biological exposure].
This prospective, exploratory study was performed using a quantitative approach with the objective of characterizing the healthcare tasks that involved biological risk for professionals working with the Home Care Service of the São Carlos Municipal Hospital (São Carlos, SP, Brazil). We followed 159 visits from June 2008 to January 2009. A total of 347 procedures were considered to present risks for biological exposure, categorized as follows: dressings (31.1%), capillary blood glucose monitoring (14.4%); and vascular access (3.1%). Of all subjects, 21.5% complied with hand cleansing prior to performing a procedure, 66.3% wore gloves and 83.5% disposed of sharps appropriately. In conclusion, these professionals are subject to biological risks similar to those found in the hospital environment, because they are also exposed to blood and sharps often and have a poor adherence to the standard preventive measures. Further studies to evaluate the influence of the features of the household on the referred risk should be encouraged.


Screening methods to measure antioxidant activity of sorghum (sorghum bicolor) and sorghum products.
Specialty sorghums, their brans, and baked and extruded products were analyzed for antioxidant activity using three methods: oxygen radical absorbance capacity (ORAC), 2,2'-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and 2,2-diphenyl-1-picrylhydrazyl (DPPH). All sorghum samples were also analyzed for phenolic contents. Both ABTS and DPPH correlated highly with ORAC (R(2) = 0.99 and 0.97, respectively, n = 18). Phenol contents of the sorghums correlated highly with their antioxidant activity measured by the three methods (R(2) >or= 0.96). The ABTS and DPPH methods, which are more cost effective and simpler, were demonstrated to have similar predictive power as ORAC on sorghum antioxidant activity. There is a need to standardize these methods to allow for data comparisons across laboratories.


Rural Veterans' Experiences With Outpatient Care in the Veterans Health Administration Versus Community Care.
The 2014 Veterans Access, Choice and Accountability Act was intended to improve Veterans' access to timely health care by expanding their options to receive community care (CC) paid for by the Veterans Health Administration (VA). Although CC could particularly benefit rural Veterans, we know little about rural Veterans' experiences with CC. The objective of this study was to compare rural Veterans' experiences with CC and VA outpatient health care services to those of urban Veterans and examine changes over time. Retrospective, cross-sectional study using data from the Survey of Healthcare Experiences of Patients (SHEP) and VA Corporate Data Warehouse. Subjects: All Veterans who responded to the SHEP survey in Fiscal Year (FY) 16 or FY19. Outcomes were 4 measures of care experience (Access, Communication, Coordination, and Provider Rating). Independent variables included care setting (CC/VA), rural/urban status, and demographic and clinical characteristics. Compared with urban Veterans, rural Veterans rated CC the same (for specialty care) or better (for primary care). Rural Veterans reported worse experiences in CC versus VA, except for specialty care Access. Rural Veterans' care experiences improved between FY16 and FY19 in both CC and VA, with greater improvements in CC. Rural Veterans' reported comparable or better experiences in CC compared with urban Veterans, but rural Veterans' CC experiences still lagged behind their experiences in VA for primary care. As growing numbers of Veterans use CC, VA should ensure that rural and urban Veterans' experiences with CC are at least comparable to their experiences with VA care.


Early Childhood Dental Caries, Mouth Pain, and Malnutrition in the Ecuadorian Amazon Region.
Malnutrition and dental caries in early childhood remain persistent and intertwined global health challenges, particularly for indigenous and geographically-remote populations. To examine the prevalence and associations between early childhood dental caries, parent-reported mouth pain and malnutrition in the Amazonian region of Ecuador, we conducted a cross-sectional study of the oral health and nutrition status of 1407 children from birth through age 6 in the "Alli Kiru" program (2011-2013). We used multivariate regression analysis to examine relationships between severe caries, parent-reported mouth pain measures, and nutritional status. The prevalence of dental caries was 65.4%, with 44.7% of children having deep or severe caries, and 33.8% reporting mouth pain. The number of decayed, missing and filled teeth (dmft) increased dramatically with age. Malnutrition was prevalent, with 35.9% of children stunted, 1.1% wasted, 7.4% underweight, and 6.8% overweight. As mouth pain increased in frequency, odds for severe caries increased. For each unit increase in mouth pain frequency interfering with sleeping, children had increased odds for being underweight (Adjusted Odds Ratio (AOR): 1.27; 95% CI: 1.02-1.54) and decreased odds for being overweight (AOR: 0.76; 95% CI: 0.58-0.97). This relationship was most pronounced among 3-6 year-olds. Early childhood caries, mouth pain and malnutrition were prevalent in this sample of young children. Parent-reported mouth pain was associated with severe caries, and mouth pain interfering with sleeping was predictive of poor nutritional status. We demonstrate the utility of a parsimonious parent-reported measure of mouth pain to predict young children's risk for severe early childhood caries and malnutrition, which has implications for community health interventions.


CRISPR as a Diagnostic Tool.
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has recently gained growing attention as a diagnostic tool due to its capability of specific gene targeting. It consists of Cas enzymes and a guide RNA (gRNA) that can cleave the target DNA or RNA based on the sequence of the gRNA, making it an attractive genetic engineering technique. In addition to the target-specific binding and cleavage, the trans-cleavage activity was reported for some Cas proteins, including Cas12a and Cas13a, which is to cleave the surrounding single-stranded DNA or RNA upon the target binding of Cas-gRNA complex. All these activities of the CRISPR-Cas system are based on its target-specific binding, making it applied to develop diagnostic methods by detecting the disease-related gene as well as microRNAs and the genetic variations such as single nucleotide polymorphism and DNA methylation. Moreover, it can be applied to detect the non-nucleic acids target such as proteins. In this review, we cover the various CRISPR-based diagnostic methods by focusing on the activity of the CRISPR-Cas system and the form of the target. The CRISPR-based diagnostic methods without target amplification are also introduced briefly.


Integer lapped transforms and their applications to image coding.
This paper proposes new integer approximations of the lapped transforms, called the integer lapped transforms (ILT), and studies their applications to image coding. The ILT are derived from a set of orthogonal sinusoidal transforms having short integer coefficients, which can be implemented with simple integer arithmetic. By employing the same scaling constants in these integer sinusoidal transforms, integer versions of the lapped orthogonal transform (LOT), the lapped biorthogonal transform (LBT), and the hierarchical lapped biorthogonal transform (HLBT) are developed. The ILTs with 5-b integer coefficients are found to have similar coding gain (within 0.06 dB) and image coding performances as their real-valued counterparts. Furthermore, by representing these integer coefficients as sum of powers-of-two coefficients (SOPOT), multiplier-less lapped transforms with very low implementation complexity are obtained. In particular, the implementation of the eight-channel multiplier-less integer LOT (ILOT), LBT (ILBT), and HLBT (IHLBT) require 90 additions and 44 shifts, 98 additions and 59 shifts, and 70 additions and 38 shifts, respectively.


[Search for biological remedies for fungi of the Candida genus].
51 bacterial strains were studied with a view to find out anticandidial activity; of these, 15 strains were found to have activity, more on less expressed with respect to fungi of the genus Candida. In most cases the anticandidial activity of an antagonist strain was manifested to a similar degree against several Candida strains. The preliminary analysis of antifungal substances produced by microbial strains makes it possible to suggest their antibiotic nature.


Ecotone shifts in southern Madagascar: first barcoding data and six new species of the endemic millipede genus Riotintobolus (Spirobolida, Pachybolidae).
Six new species of the Spirobolida millipede genus Riotintobolus Wesener, 2009, are described from the spiny forest in southern Madagascar utilising genetic barcoding, drawings and scanning electron microscopy: Riotintobolus tsimelahy sp. nov., R. mangatsiaka sp. nov., R. lavanono sp. nov., R. bovinus sp. nov., R. antafoky sp. nov. and R. makayi sp. nov. One other Riotintobolus population from the spiny forest might represent an additional species based on genetic data, but it cannot be described as no male specimens were collected. At present, the genus Riotintobolus Wesener, 2009 has eight species from the spiny forest and two species from the littoral rainforest. A determination key to all ten species of the genus is provided. Molecular data reveal that the two critically endangered species from the humid littoral rainforest are not closely related to one another, but have their closest relative in the dry spiny forest ecosystem. Riotintobolus mandenensis Wesener, 2009, only known from the southern littoral rainforest of Mandena is related to R. tsimelahy sp. nov. from the nearby spiny forest at Tsimelahy with a p-distance of 11%, while R. minutus Wesener, 2009 from the littoral forest of Sainte Luce is more distant to all other Riotintobolus species, but more closely related to R. bovinus sp. nov. from the southwestern forest of the Makay.


Latitudinal patterns in plant defense: evolution of cardenolides, their toxicity and induction following herbivory.
Attempts over the past 50 years to explain variation in the abundance, distribution and diversity of plant secondary compounds gave rise to theories of plant defense. Remarkably, few phylogenetically robust tests of these long-standing theories have been conducted. Using >50 species of milkweed (Asclepias spp.), we show that variation among plant species in the induction of toxic cardenolides is explained by latitude, with higher inducibility evolving more frequently at lower latitudes. We also found that: (1) the production of cardenolides showed positive-correlated evolution with the diversity of cardenolides, (2) greater cardenolide investment by a species is accompanied by an increase in an estimate of toxicity (measured as chemical polarity) and (3) instead of trading off, constitutive and induced cardenolides were positively correlated. Analyses of root and shoot cardenolides showed concordant patterns. Thus, milkweed species from lower latitudes are better defended with higher inducibility, greater diversity and added toxicity of cardenolides.


Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms.
The decision to perform lumbar puncture in patients with asymptomatic human immunodeficiency virus (HIV) infection and syphilis is controversial. The Centers for Disease Control and Prevention recommend certain criteria that warrant lumbar puncture. Here, we assess the performance of these criteria for detecting asymptomatic neurosyphilis (ANS). Eligible subjects consisted of all patients with concurrent HIV infection and syphilis in a prospective clinical cohort who had no neurologic symptoms at the time of lumbar puncture. We retrospectively applied different stratification criteria to calculate the performance of lumbar puncture in detecting ANS: (1) lumbar puncture in patients with late latent syphilis or syphilis of an unknown duration, regardless of the CD4 cell count or rapid plasma reagin titer; (2) lumbar puncture if the CD4 cell count was 350 cells/mL and/or the rapid plasma reagin titer was 1:32, regardless of the syphilis stage; and (3) lumbar puncture in the context of serologic nonresponse to syphilis therapy. Two hundred two of 231 patients with syphilis did not have neurologic symptoms. Immediate lumbar puncture was performed for 46 patients, and 10 cases (22%) of ANS were detected. With use of the first criterion, 2 (14%) of 10 cases of ANS in patients with early-stage syphilis would have been missed (sensitivity, 80% [95% confidence interval [CI], 44%-97%]; specificity, 23% (95% confidence interval [CI], 11.4%-40.2%) [corrected] Criterion 2 would not have missed any cases of ANS (sensitivity, 100% [95% CI, 70%-100%]; specificity, 13.2% (95% CI, 4.4%-29.1%) [corrected] but would have required that a lumbar puncture be performed for 88% of patients. Performance of lumbar puncture performed in 13 cases based on serologic nonresponse to syphilis therapy yielded 4 cases (31%) of ANS. In patients with concurrent HIV infection and syphilis, the use of criteria based on rapid plasma reagin titer and CD4 cell count, instead of stage-based criteria, improved the ability to identify ANS.


Limit cycles in predator-prey communities.
Essentially all models that have been proposed for predator-prey systems are shown to possess either a stable point equilibrium or a stable limit cycle. This stable limit cycle, an explicitly nonlinear feature, is commonly overlooked in conventional analyses of these models. Such a stable limit cycle provides a satisfying explanation for those animal communities in which populations are observed to oscillate in a rather reproducible periodic manner.


18F-THK 5351 and 11C-PiB PET of the Thai normal brain template.
The aim of the study was to create a local normal database brain template of Thai individuals for 11C-Pittsburgh compound B (11C-PiB) and 18F-THK 5351 depositions using statistical parametric mapping (SPM) software, and to validate and optimize the established specific brain template for use in clinical practice with a highly reliability and reproducibility. This prospective study was conducted in 24 healthy right-handed volunteers (13 men, 11 women; aged: 42-79 years) who underwent 18F-THK 5351 and 11C-PiB PET/CT scans. SPM was used for the 18F-THK 5351 and 11C-PiB PET/CT image analysis. All PET images were processed individually using Diffusion Tensor Image -Magnetic Resonance Imaging-weighted images (DTI-MRI images), which involved: (1) conversion of Digital Imaging and Communications in Medicine (DICOM) files into an analyzable file extension (.NIFTI) for statistical parametric mapping, (2) setting of the origin (the anterior commissure was used as the anatomical landmark), (3) re-alignment, (4) co-registration of PET with B0 (T1W) and DTI-MRI images, (5) normalization, and (6) normal verification using the Thai MRI standard. We then compared the normal PET template with the abnormal deposition area of different dementia syndromes, including Alzheimer's disease and progressive supranuclear palsy. This method was able to differentiate cognitively normal from Alzheimer's disease and progressive supranuclear palsy subjects. This normal brain template was able to be integrated into clinical practice and research using PET analyses at our center.


Effects of deuterium oxide on the rate and dissociation constants for saxitoxin and tetrodotoxin action. Voltage-clamp studies on frog myelinated nerve.
The actions of tetrodotoxin (TTX) and saxitoxin (STX) in normal water and in deuterium oxide (D2O) have been studied in frog myelinated nerve. Substitution of D2O for H2O in normal Ringer's solution has no effect on the potency of TTX in blocking action potentials but increases the potency of STX by approximately 50%. Under voltage clamp, the steady-state inhibition of sodium currents by 1 nM STX is doubled in D2O as a result of a halving of the rate of dissociation of STX from the sodium channel; the rate of block by STX is not measurably changed by D2O. Neither steady-state inhibition nor the on- or off-rate constants of TTX are changed by D2O substitution. The isotopic effects on STX binding are observed less than 10 min after the toxin has been added to D2O, thus eliminating the possibility that slow-exchange (t 1/2 greater than 10 h) hydrogen-binding sites on STX are involved. The results are consistent with a hypothesis that attributes receptor-toxin stabilization to isotopic changes of hydrogen bonding; this interpretation suggests that hydrogen bonds contribute more to the binding of STX than to that of TTX at the sodium channel.


The nature of the risk faced by pedestrians with neurodevelopmental disorders: A systematic review.
Pedestrians represent one of the most vulnerable road user groups worldwide. Children and adult pedestrians with neurodevelopmental disorders may be at greater risk due to deficits in a range of domains, such as attention, social communication, motor control and executive function. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychological Association, 2013), neurodevelopmental disorders include individuals with a diagnosis of Autism Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Specific Learning Disorder, Motor Difficulties, Communication Disorders and Intellectual Disabilities. The purpose of this systematic review and meta-analysis was to explore existing literature relating to determine the nature of the risk faced by pedestrians with neurodevelopmental disorders. Relevant databases including Web of Science, PhysInfo and CINAHL were searched up to July 2019. All peer reviewed journals that presented data focusing on neurodevelopmental disorders and some aspect of road crossing or roadside behaviour that included a control or comparison group were included. A total of 149 abstracts were assessed and 17 met the inclusion criteria. The identified papers could be grouped into four areas: (1) rate of injury; (2) assessment of risk; (3) eye gaze and understanding of road layout and (4) gap choice. No papers exploring the risk factors at the roadside for individuals with Specific Learning Disorders or Communication Disorders were identified. Overall, the review provide evidence for an elevated risk of injury for individuals with ADHD at the roadside, potentially as a consequence of poor temporal gap choice, although there was evidence that this risk could be mediated by executive dysfunction rather than ADHD symptomology. Furthermore, poor temporal gap choice was found in children with DCD but it remains unclear as to whether this risk translates to the roadside. Finally, both children and adults with ASD and children with ID were found to demonstrate differences in behaviour / understanding at the roadside. In general, co-occurrence between neurodevelopmental disorders has been largely ignored in the current literature relating to pedestrian risk and future research could consider this along with executive functioning.


Spatial imagery preserves temporal order.
Line drawings were presented in either a spatial or a nonspatial format. Subjects recalled each of four sets of 24 items in serial order. Amount recalled in the correct serial order and sequencing errors were scored. In Experiment 1 items appeared either in consecutive locations of a matrix or in one central location. Subjects who saw the items in different locations made fewer sequencing errors than those who saw each item in a central location, but serial recall levels for these two conditions did not differ. When items appeared in nonconsecutive locations in Experiment 2, the advantage of the spatial presentation on sequencing errors disappeared. Experiment 3 included conditions in which both the consecutive and nonconsecutive spatial formats were paired with retrieval cues that either did or did not indicate the sequence of locations in which the items had appeared. Spatial imagery aided sequencing when, and only when, the order of locations in which the stimuli appeared could be reconstructed at retrieval.


Chaos driven fusion enhancement factor at astrophysical energies.
We perform molecular dynamics simulations of screening by bound target electrons in low energy nuclear reactions. Quantum effects corresponding to the Pauli and Heisenberg principles are enforced by constraints. We show that the enhancement of the average cross section and of its variance is due to the perturbations induced by the electrons. This gives a correlation between the maximum amplitudes of the internuclear oscillational motion and the enhancement factor. It suggests that the chaotic behavior of the electronic motion affects the magnitude of the enhancement factor.


Functional SNPs in SYISL promoter significantly affect muscle fiber density and muscle traits in pigs.
Our previous studies showed that SYISL is a negative regulator of muscle growth and regeneration in mice, pigs and humans. SYISL knockout resulted in an increase in the density of muscle fibers and muscle growth. However, it is unclear whether there are natural mutations in pig SYNPO2 intron sense-overlapping lncRNA (pSYISL) that affect the expression of pSYISL and muscle growth traits. In this study, three SNPs in exons and six SNPs within the promoter of pSYISL were identified. Association analysis showed that the two SNPs in exons are significantly associated with loin muscle area (p < 0.05); the six SNPs in the promoter that show complete linkage are significantly associated with live backfat thickness and live loin muscle area in American Large White pigs. Bioinformatics and luciferase reporter assays as well as in vitro binding experiments indicated that the mutation of SNP rs702045770 (g.539G>A) leads to the loss of YY1 binding to the promoter, thus affecting the expression level of pSYISL, and we found that Jiangshan Black pigs with genotype GG have a higher expression level of pSYISL than genotype AA individuals, but the muscle fiber density was significantly lower than in genotype AA individuals. Furthermore, the association analysis showed that the carcass backfat thickness of genotype GG of SNP rs702045770 was significantly higher than that of other genotypes in (Pietrain × Duroc) × (Landrace × Yorkshire) crossbred pigs (p < 0.05). The glycolytic potential of genotype GG was significantly higher than that of other genotypes (p < 0.05). These results provide novel insight into the identification of functional SNPs in non-coding genomic regions.


Lelliottia aquatilis sp. nov., isolated from drinking water.
Five beige-pigmented, oxidase-negative bacterial isolates, 6331-17T, 6332-17, 6333-17, 6334-17 and 9827-07, isolated either from a drinking water storage reservoir or drinking water in 2006 and 2017 in Germany, were examined in detail applying by a polyphasic taxonomic approach. Cells of the isolates were rod-shaped and Gram-stain-negative. Comparison of the 16S rRNA gene sequences of these five isolates showed highest sequence similarities to Lelliottia amnigena (99.98 %) and Lelliottia nimipressuralis (99.99 %). Multilocus sequence analyses based on concatenated partial rpoB, gyrB, infB and atpD sequences confirmed the clustering of these isolates with Lelliottia species, but also revealed a clear distinction to the closest related type strains. Analysis of the genome sequences of these isolates indicated >70 % in silico DNA-DNA hybridization and high average nucleotide identities between strains. Nevertheless, they showed only <70 and <95 % similarity to the type strains of these two Lelliottia species. The fatty acid profiles of these isolates were very similar and consisted of the major fatty acids C16:0, C17 : 0cyclo, C15 : 0iso 2-OH/C16 : 1ω7c and C18 : 1ω7c. In addition, physiological/biochemical tests revealed high phenotypic similarity to each other. These cumulative data indicate that these isolates represent a novel Lelliottia species, for which the name Lelliottia aquatilis sp. nov. is proposed, with strain 6331-17T (=CCM 8846T=CIP 111609T=LMG 30560T) as the type strain.


GGNpTCR: A Generative Graph Structure Neural Network for Predicting Immunogenic Peptides for T-cell Immune Response.
Identifying the interactions between T-cell receptor (TCRs) and human antigens is a crucial step in developing new vaccines, diagnostics, and immunotherapy. Current methods primarily focus on learning binding patterns from known TCR binding repertoires by using sequence information alone without considering the binding specificity of new antigens or exogenous peptides that have not appeared in the training set. Furthermore, the spatial structure of antigens plays a critical role in immune studies and immunotherapy, which should be addressed properly in the identification of interacting TCR-antigen pairs. In this study, we introduced a novel deep learning framework based on generative graph structures, GGNpTCR, for predicting interactions between TCR and peptides from sequence information. Results of real data analysis indicate that our model achieved excellent prediction for new antigens unseen in the training data set, making significant improvements compared to existing methods. We also applied the model to a large COVID-19 data set with no antigens in the training data set, and the improvement was also significant. Furthermore, through incorporation of additional supervised mechanisms, GGNpTCR demonstrated the ability to precisely forecast the locations of peptide-TCR interactions within 3D configurations. This enhancement substantially improved the model's interpretability. In summary, based on the performance on multiple data sets, GGNpTCR has made significant progress in terms of performance, universality, and interpretability.