The impact of meteorological factors on involuntary admission in Attica, Greece.
Few studies in the literature have examined the effect of meteorological factors, especially temperature, on psychiatric hospitalization and even less on their association with involuntary admission. This study aimed to investigate the potential association of meteorological factors with the involuntary psychiatric hospitalization in the region of Attica, Greece. The research was conducted at the Psychiatric Hospital of Attica "Dafni". This was a retrospective time series study of 8 consecutive years of data (2010 to 2017) and included 6887 involuntarily hospitalized patients. Data on daily meteorological parameters were provided from the National Observatory of Athens. Statistical analysis was based on Poisson or negative binomial regression models with adjusted standard errors. Analyses were initially based on univariable models for each meteorological factor separately. All meteorological factors were taken into account through factor analysis and then, through cluster analysis, an objective grouping of days with similar weather type was performed. The resulting types of days were examined for their effect on the daily number of involuntary hospitalizations. Increases in maximum temperature, in average wind speed and in minimum atmospheric pressure values were associated with an increase in the average number of involuntary hospitalizations per day. Increase of the maximum temperature above 23 °C at lag 6 days before admission did not affect significantly the frequency of involuntary hospitalizations. Low temperature and average relative humidity above 60% levels had a protective effect. The predominant day type at lag 1 to 5 days before admission showed the strongest correlation with the daily number of involuntary hospitalizations. The cold season day type, with lower temperatures and a small diurnal temperature range, northerly winds of moderate speed, high atmospheric pressure and almost no precipitation, was associated with the lowest frequency of involuntary hospitalizations, whereas the warm season day type, with low daily temperature and small daily temperature range during the warm season, high values of relative humidity and daily precipitation, moderate wind speed/gust and atmospheric pressure, was associated with the highest. As climate change increases the frequency of extreme weather events, it is necessary to develop a different organizational and administrative culture of mental health services.


Adsorption of Nanoceria by Phosphocholine Liposomes.
Nanoceria (CeO2 nanoparticle) possesses a number of enzyme-like activities. In particular, it scavenges reactive oxygen species based on in vitro and in vivo antioxidation studies. An important aspect of fundamental physical understanding is its interaction with lipid membranes that are the main components of the cell membrane. In this work, adsorption of nanoceria onto phosphocholine (PC) liposomes was performed. PC lipids are the main constituents of the cell outer membrane. Using a fluorescence quenching assay, a nanoceria adsorption isotherm was determined at various pH values and ionic strengths. A non-Langmuir isotherm occurred at pH 4 because of lateral electrostatic repulsion among the adsorbed cationic nanoceria. The phosphate group in the PC lipid is mainly responsible for the interaction, and the adsorbed nanoceria can be displaced by free inorganic phosphate. The tendency of the system to form large aggregates is a function of pH and the concentration of nanoceria, attributable to nanoceria being positively charged at pH 4 and neutral at physiological pH. Calcein leakage tests indicate that nanoceria induces liposome leakage because of transient lipid phase transition, and cryo-transmission electron microscopy indicates that the overall shape of the liposome is retained although deformation is still observed. This study provides fundamental biointerfacial information at a molecular level regarding the interaction of nanoceria and model cell membranes.


Conditional deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activity.
Melanin-concentrating hormone (MCH) plays a key role in regulating energy balance. MCH acts via its receptor MCHR1, and MCHR1 deletion increases energy expenditure and locomotor activity, which is associated with a hyperdopaminergic state. Since MCHR1 expression is widespread, the neurons supporting the effects of MCH on energy expenditure are not clearly defined. There is a high density of MCHR1 neurons in the striatum, and these neurons are known to be GABAergic. We thus determined if MCH acts via this GABAergic neurocircuit to mediate energy balance. We generated a Mchr1-flox mouse and crossed it with the Vgat-cre mouse to assess if MCHR1 deletion from GABAergic neurons expressing the vesicular GABA transporter (vGAT) in female Vgat-Mchr1-KO mice resulted in lower body weights or increased energy expenditure. Additionally, we determined if MCHR1-expressing neurons within the accumbens form part of the neural circuit underlying MCH-mediated energy balance by delivering an adeno-associated virus expressing Cre recombinase to the accumbens nucleus of Mchr1-flox mice. To evaluate if a dysregulated dopaminergic tone leads to their hyperactivity, we determined if the dopamine reuptake blocker GBR12909 prolonged the drug-induced locomotor activity in Vgat-Mchr1-KO mice. Furthermore, we also performed amperometry recordings to test whether MCHR1 deletion increases dopamine output within the accumbens and whether MCH can suppress dopamine release. Vgat-Mchr1-KO mice have lower body weight, increased energy expenditure, and increased locomotor activity. Similarly, restricting MCHR1 deletion to the accumbens nucleus also increased locomotor activity. Vgat-Mchr1-KO mice show increased and prolonged sensitivity to GBR12909-induced locomotor activity, and amperometry recordings revealed that GBR12909 elevated accumbens dopamine levels to twice that of controls, thus MCHR1 deletion may lead to a hyperdopaminergic state that mediates their observed hyperactivity. Consistent with the inhibitory effect of MCH, we found that MCH acutely suppresses dopamine release within the accumbens. As with established models of systemic MCH or MCHR1 deletion, we found that MCHR1 deletion from GABAergic neurons, specifically those within the accumbens nucleus, also led to increased locomotor activity. A hyperdopaminergic state underlies this increased locomotor activity, and is consistent with our finding that MCH signaling within the accumbens nucleus suppresses dopamine release. In effect, MCHR1 deletion may disinhibit dopamine release leading to the observed hyperactivity.


Nine-year incidence and risk factors for retinal vein occlusion in a general Japanese population: the Hisayama Study.
To estimate the long-term cumulative incidence and risk factors for retinal vein occlusion (RVO) in a population-based cohort study of Japanese. In 1998, a total of 1775 individuals aged 40 years or older underwent a baseline eye examination. Of those, 1369 subjects (77.1%) took part in the follow-up eye examination in 2007 and were enrolled in the present study. Each participant underwent a comprehensive examination. The diagnosis of RVO, including branch (BRVO) and central RVO (CRVO), was determined by grading color fundus photographs. Logistic regression analysis was performed to determine risk factors for RVO. The 9-year cumulative incidence of RVO was 3.0% (2.7% for BRVO and 0.3% for CRVO). The age-specific cumulative incidence of RVO significantly increased with age (P for trend = 0.03). After adjusting for age and sex, higher diastolic blood pressure and chronic kidney disease (CKD) were significantly associated with RVO. In multivariate analysis, higher diastolic blood pressure (per 10 mm Hg) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.14 to 2.01) and CKD (OR, 2.23; 95% CI, 1.02 to 4.89) remained independently significant risk factors for RVO. In stratified analysis, the risk of RVO was higher in subjects with CKD than that in subjects without CKD in both the nonhypertension and the hypertension groups. These findings suggest that the incidence of RVO is higher in Japanese than that in other Asians and Caucasians, and that higher blood pressure and CKD are independent risk factors for RVO in the Japanese.


Reverse transcription recombinase polymerase amplification assay for the detection of middle East respiratory syndrome coronavirus.
The emergence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the eastern Mediterranean and imported cases to Europe has alerted public health authorities. Currently, detection of MERS-CoV in patient samples is done by real-time RT-PCR. Samples collected from suspected cases are sent to highly-equipped centralized laboratories for screening. A rapid point-of-care test is needed to allow more widespread mobile detection of the virus directly from patient material. In this study, we describe the development of a reverse transcription isothermal Recombinase Polymerase Amplification (RT-RPA) assay for the identification of MERS-CoV. A partial nucleocapsid gene RNA molecular standard of MERS-coronavirus was used to determine the assay sensitivity. The isothermal (42°C) MERS-CoV RT-RPA was as sensitive as real-time RT-PCR (10 RNA molecules), rapid (3-7 minutes) and mobile (using tubescanner weighing 1kg). The MERS-CoV RT-RPA showed cross-detection neither of any of the RNAs of several coronaviruses and respiratory viruses affecting humans nor of the human genome. The developed isothermal real-time RT-RPA is ideal for rapid mobile molecular MERS-CoV monitoring in acute patients and may also facilitate the search for the animal reservoir of MERS-CoV.


Complementary therapies and the medical profession: a study of medical students' attitudes.
Despite the popularity of complementary therapies with the public, knowledge and use of these therapies among doctors appear limited. However, studies show that physicians and medical students are positive toward complementary therapies and have a high level of interest in learning about them. The attitudes of medical students toward complementary therapies were examined using a questionnaire distributed to 800 first-, third-, and fifth-year medical students at two universities in Melbourne, Australia. The survey revealed that whereas Australian medical students were positive toward complementary therapies, their self-reported knowledge was low, with 56% having no knowledge of the principles of complementary therapies. Attitudes toward different therapies were found to vary widely, with students having little knowledge of chiropractic and naturopathy, the two therapies most commonly used by Australians. Students consistently scored meditation, massage, and acupuncture the highest with regard to knowledge, perceived usefulness, intended patterns of referral after graduation, and desire for education in the undergraduate degree. When the medical course included some tuition on complementary therapies, students were more positive toward them. A single lecture on complementary therapies was found to have significant impact on medical students' views. Medical students have a high level of interest in complementary therapies that is not being satisfied by their undergraduate curricula.


S-100B and FDG-PET/CT in therapy response assessment of melanoma patients.
To compare the value of the tumor marker S-100B protein and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients treated for melanoma metastases. In 41 patients with proven melanoma metastases, S-100B measurements and FDG-PET/CT were performed before and after therapy. The change of S-100B levels (DeltaS-100B) was assessed. In all patients, therapy response was assessed with PET/CT using visual criteria and change of maximal standard uptake value (DeltaSUV(max.)) or total lesion glycolysis (DeltaTLG). In 15 of 41 patients (37%), S-100B values were not suitable because they were normal before and after therapy. In 26 patients, S-100B was suitable for therapy response assessment. PET/CT was suitable for response assessment in all patients. Correlations between DeltaS-100B and DeltaTLG (r = 0.850, p < 0.001) and between DeltaS-100B and DeltaSUV(max.) (r = 0.818, p < 0.001) were both excellent. A complete agreement between S-100B and PET/CT response assessment was achieved in 22 of 26 patients. In 4 patients, therapy response differed between the S-100B and PET/CT findings, but subsequent S-100B measurements realigned the S-100B results with the later PET/CT findings. In a third of our patients with metastases, the S-100B tumor marker was not suitable for therapy assessment. In these patients, imaging techniques remain necessary, and FDG-PET/CT can be used for response assessment.


Evaluation of the effects of plant-derived essential oils on central nervous system function using discrete shuttle-type conditioned avoidance response in mice.
Although plant-derived essential oils (EOs) have been used to treat various mental disorders, their central nervous system (CNS) acting effects have not been clarified. The present study compared the effects of 20 kinds of EOs with the effects of already-known CNS acting drugs to examine whether the EOs exhibited CNS stimulant-like effects, CNS depressant-like effects, or neither. All agents were tested using a discrete shuttle-type conditioned avoidance task in mice. Essential oils of peppermint and chamomile exhibited CNS stimulant-like effects; that is, they increased the response rate (number of shuttlings/min) of the avoidance response. Linden also increased the response rate, however, the effect was not dose-dependent. In contrast, EOs of orange, grapefruit, and cypress exhibited CNS depressant-like effects; that is, they decreased the response rate of the avoidance response. Essential oils of eucalyptus and rose decreased the avoidance rate (number of avoidance responses/number of avoidance trials) without affecting the response rate, indicating that they may exhibit some CNS acting effects. Essential oils of 12 other plants, including juniper, patchouli, geranium, jasmine, clary sage, neroli, lavender, lemon, ylang-ylang, niaouli, vetivert and frankincense had no effect on the avoidance response in mice.


Post-treatment of secondary wastewater treatment plant effluent using a two-stage fluidized bed bioreactor system.
The aim of this study was to investigate the performance of a two-stage fluidized bed reactor (FBR) system for the post-treatment of secondary wastewater treatment plant effluents (Shahrak Gharb, Tehran, Iran). The proposed treatment scheme was evaluated using pilot-scale reactors (106-L of capacity) filled with PVC as the fluidized bed (first stage) and gravel for the filtration purpose (second stage). Aluminum sulfate (30 mg/L) and chlorine (1 mg/L) were used for the coagulation and disinfection of the effluent, respectively. To monitor the performance of the FBR system, variation of several parameters (biochemical oxygen demand (BOD5), chemical oxygen demand (COD), turbidity, total phosphorous, total coliform and fecal coliform) were monitored in the effluent wastewater samples. The results showed that the proposed system could effectively reduce BOD5 and COD below 1.95 and 4.06 mg/L, respectively. Turbidity of the effluent could be achieved below 0.75 NTU, which was lower than those reported for the disinfection purpose. The total phosphorus was reduced to 0.52 mg/L, which was near the present phosphorous standard for the prevention of eutrophication process. Depending on both microorganism concentration and applied surface loading rates (5-10 m/h), about 35 to 75% and 67 to 97% of coliform were removed without and with the chlorine addition, respectively. Findings of this study clearly confirmed the efficiency of the FBR system for the post-treatment of the secondary wastewater treatment plant effluents without any solid problem during the chlorination.


Cannabis Use in Young Adult Cancer Patients.
Background: The use of cannabis by young adult (YA) cancer patients is likely to increase as medical cannabis becomes more available. Clinically relevant data on cannabis use are needed to establish benchmarks for use, to identify patients who are more likely to use cannabis, and to assess outcomes associated with use. Objective: The current study sought to determine the rate of cannabis use in YA cancer patients ages 18 to 39, identify demographic and clinical correlates of use, and examine differences in moderate-to-severe symptoms between users and nonusers. Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC), self-reported cannabis use, and cancer-related symptomatology in YA cancer patients in active treatment referred for comprehensive supportive care. Results: Approximately 30% of YA cancer patients tested positive for THC on urine drug testing. At the univariate level, cannabis users were more likely to be male, to have a lifetime history of smoking at least 100 cigarettes, and to be more recently diagnosed. Cannabis use was associated with moderate-to-severe symptomatology, including pain, nausea, lack of appetite, constipation, difficulty sleeping, and poorer overall well-being. Conclusions: YAs referred for comprehensive supportive care may be managing their cancer-related symptoms with cannabis. Further research is needed to better understand patients' perceptions of cannabis's therapeutic and adverse effects, in patients who used cannabis before diagnosis, and in patients who commenced use in response to a cancer diagnosis.


Functional dissection of systemic lupus erythematosus using congenic mouse strains.
We describe the in vivo phenotypes associated with three genomic intervals containing systemic lupus erythematosus (SLE)-susceptibility genes derived from the SLE-prone NZM2410 strain on a C57BL/6 genome. These intervals were identified previously via a genome-wide analysis of SLE susceptibility in a (NZM2410 x C57BL/6)F1 x NZM2410 backcross, and transferred independently on a C57BL/6 background to produce three congenic strains: B6.NZMc1 carrying Sle1, B6.NZMc4 carrying Sle2, and B6.NZMc7 carrying Sle3. B6.NZMc1 develops high titers of IgG anti-nuclear autoantibodies in the absence of any severe nephritis. B6.NZMc4 spontaneously develops elevated levels of IgM, but not IgG Abs against several Ags, indicative of polyclonal activation or polyreactivity affecting the B cell lineage. B6.NZMc7 causes the production of IgM and IgG Abs against both nuclear and non-nuclear Ags and the development of severe lupus nephritis. Therefore, our results show that three defined genomic intervals from the NZM2410 SLE-prone strain each contribute specific component phenotypes that have been associated with SLE, which in combination can mediate severe disease.


Wearable technology-based metrics for predicting operator performance during cardiac catheterisation.
Unobtrusive metrics that can auto-assess performance during clinical procedures are of value. Three approaches to deriving wearable technology-based metrics are explored: (1) eye tracking, (2) psychophysiological measurements [e.g. electrodermal activity (EDA)] and (3) arm and hand movement via accelerometry. We also measure attentional capacity by tasking the operator with an additional task to track an unrelated object during the procedure. Two aspects of performance are measured: (1) using eye gaze and psychophysiology metrics and (2) measuring attentional capacity via an additional unrelated task (to monitor a visual stimulus/playing cards). The aim was to identify metrics that can be used to automatically discriminate between levels of performance or at least between novices and experts. The study was conducted using two groups: (1) novice operators and (2) expert operators. Both groups made two attempts at a coronary angiography procedure using a full-physics virtual reality simulator. Participants wore eye tracking glasses and an E4 wearable wristband. Areas of interest were defined to track visual attention on display screens, including: (1) X-ray, (2) vital signs, (3) instruments and (4) the stimulus screen (for measuring attentional capacity). Experts provided greater dwell time (63% vs 42%, p = 0.03) and fixations (50% vs 34%, p = 0.04) on display screens. They also provided greater dwell time (11% vs 5%, p = 0.006) and fixations (9% vs 4%, p = 0.007) when selecting instruments. The experts' performance for tracking the unrelated object during the visual stimulus task negatively correlated with total errors (r = - 0.95, p = 0.0009). Experts also had a higher standard deviation of EDA (2.52 µS vs 0.89 µS, p = 0.04). Eye tracking metrics may help discriminate between a novice and expert operator, by showing that experts maintain greater visual attention on the display screens. In addition, the visual stimulus study shows that an unrelated task can measure attentional capacity. Trial registration This work is registered through clinicaltrials.gov, a service of the U.S. National Health Institute, and is identified by the trial reference: NCT02928796.


Persistent attenuation of brain oxidative stress through aging in perinatal maternal separated rat pups supplemented with choline and docosahexaenoic acid or Clitoria ternatea aqueous root extract.
Perinatal maternal separation stress (PMSS) induces brain lipid peroxidation and reduction in endogenous antioxidants. The present study was designed to assess the brain oxidative stress (MDA) and protein thiol levels through various stages of aging in PMSS rat pups supplemented with choline with docosahexaenoic acid (DHA) or Clitoria ternatea (Linn) aqueous root extract (CTR). Study groups, control, PMSS, PMSS + choline with DHA, PMSS + CTR (n = 6/group) were included in the study. Pups of PMSS groups were separated from their mothers for a period of 6 h/day for 30 days. PMSS + supplemented groups were treated as appropriate during the same period. Rats were sacrificed on day 30, 60, 90, 210 and 360. Brains were processed for MDA and protein thiol levels. Brain MDA levels were significantly increased in PMSS rats at day 30, 60 (p < 0.001), 90 (p < 0.01) and attenuated in PMSS pups supplemented with choline with DHA and CTR at day 30, 60 (p < 0.01), 90 (p < 0.01, p < 0.05) and 360 (p < 0.001) when compared to the same in age-matched controls and PMSS rats, respectively. Alternatively, brain protein thiol levels in PMSS rats were reduced in all age groups when compared to the same in age-matched controls. A significant increase in brain thiol levels was observed in supplemented groups at day 60 (p < 0.01) and 210 (p < 0.01, p < 0.05) when compared to the same in age-matched PMSS rats. PMSS causes enhanced brain lipid peroxidation (MDA levels) and reduces endogenous antioxidants. Supplementation of choline and DHA or CTR during PMSS in rats persistently attenuates brain oxidative stress through aging.


Anaerobic survival potential of four bivalves from different habitats. A comparative survey.
A comparative survey of the anaerobic survival potential of four different bivalve species and the interference of associated bacteria has been carried out. Individuals from both subtidal and intertidal environments were considered by selecting the following species: Mytilus edulis (subtidal epifaunal), Spisula subtruncata (subtidal infaunal), Macoma balthica (intertidal infaunal) and Cerastoderma edule (intertidal infaunal). Anaerobiosis was simulated in the laboratory by subjecting individuals to the following conditions: nitrogen atmosphere, air atmosphere and anoxic seawater incubation. Moreover, the effect of the antibiotic CA (chloramphenicol) was investigated, either as a pre-treatment of individuals kept under normoxic conditions for a week or directly added to the anoxic incubation media. According to survival performances of the individuals, intertidal animals that use to cope with tidal fluctuations in the coastline (emersion processes) had an extraordinary greater capacity to survive aerial exposure as compared to both nitrogen gas and anoxic seawater incubations most likely due to their capacity to perform aerobiosis at certain rate from atmospheric oxygen availability. Specifically, Macoma balthica enlarged its survival potential up to 24.8 days (LT(50)) under air exposure at 12 degrees C as compared to other specific treatments used here (4.9 days). The latter pattern was also observed, although in a much lower magnitude, for the other intertidal species Cerastoderma edule that survived 3.7 and 4.6 days (LT(50)) under nitrogen atmosphere and anoxic seawater incubation, respectively as compared to 9.5 days for emersed individuals. In contrast to the subtidal species, aerial exposure of both intertidal species led to a much higher survival performances than incubation of individuals in anoxic media with the presence of antibiotic. Survival capacity of the subtidal species Mytilus edulis and Spisula subtruncata was statistically similar under air and nitrogen atmospheres and anoxic seawater incubation. Then, subtidal species have a limited ability to air breathing as a conclusion of a similar survival in atmospheric and anoxic seawater incubations. Remarkably, M. edulis represented the only exception when considering longer-term survival capacity compared to the LT(50) values. Indeed, differences in LT(90) values for M. edulis were statistically different, values decreasing significantly from 19.7-19.9 days (under both nitrogen and air atmospheres) to 16.7 days when individuals are incubated in anoxic seawater. This may be due to the adverse effects of anaerobic bacteria that spontaneously proliferate within the static seawater incubations. As well as for S. subtruncata, possible aerobic processes under aerial exposure of mussels seemed to be not significant for the enlargement of its survival potential, since results obtained for both air and nitrogen atmospheres are similar. Pre-treatment with the antibiotic chloramphenicol caused survival capacity to increase by a factor of approx. 2 (M. edulis) and 34-44% (S. subtruncata). In contrast to intertidal species, the direct addition of the antibiotic to the incubation media caused the highest survival performances in both subtidal species. Habitat differences and species-dependent variability must be considered as significant sources of variation when studying the anaerobic performance of individuals using the most common experimental anaerobic techniques to test survival potential.


Periodic Lateral Root Priming: What Makes It Tick?
Conditioning small groups of root pericycle cells for future lateral root formation has a major impact on overall plant root architecture. This priming of lateral roots occurs rhythmically, involving temporal oscillations in auxin response in the root tip. During growth, this process generates a spatial pattern of prebranch sites, an early stage in lateral root formation characterized by a stably maintained high auxin response. To date, the molecular mechanism behind this rhythmicity has remained elusive. Some data implicate a cell-autonomous oscillation in gene expression, while others strongly support the importance of tissue-level modulations in auxin fluxes. Here, we summarize the experimental data on periodic lateral root priming. We present a theoretical framework that distinguishes between a priming signal and its subsequent memorization and show how major roles for auxin fluxes and gene expression naturally emerge from this framework. We then discuss three mechanisms that could potentially induce oscillations of auxin response: cell-autonomous oscillations, Turing-type patterning, and tissue-level oscillations in auxin fluxes, along with specific properties of lateral root priming that may be used to discern which type of mechanism is most likely to drive lateral root patterning. We conclude with suggestions for future experiments and modeling studies.


TrackMate: An open and extensible platform for single-particle tracking.
We present TrackMate, an open source Fiji plugin for the automated, semi-automated, and manual tracking of single-particles. It offers a versatile and modular solution that works out of the box for end users, through a simple and intuitive user interface. It is also easily scriptable and adaptable, operating equally well on 1D over time, 2D over time, 3D over time, or other single and multi-channel image variants. TrackMate provides several visualization and analysis tools that aid in assessing the relevance of results. The utility of TrackMate is further enhanced through its ability to be readily customized to meet specific tracking problems. TrackMate is an extensible platform where developers can easily write their own detection, particle linking, visualization or analysis algorithms within the TrackMate environment. This evolving framework provides researchers with the opportunity to quickly develop and optimize new algorithms based on existing TrackMate modules without the need of having to write de novo user interfaces, including visualization, analysis and exporting tools. The current capabilities of TrackMate are presented in the context of three different biological problems. First, we perform Caenorhabditis-elegans lineage analysis to assess how light-induced damage during imaging impairs its early development. Our TrackMate-based lineage analysis indicates the lack of a cell-specific light-sensitive mechanism. Second, we investigate the recruitment of NEMO (NF-κB essential modulator) clusters in fibroblasts after stimulation by the cytokine IL-1 and show that photodamage can generate artifacts in the shape of TrackMate characterized movements that confuse motility analysis. Finally, we validate the use of TrackMate for quantitative lifetime analysis of clathrin-mediated endocytosis in plant cells.


The impact of age on effects of pre-hospital initiation of high bolus dose of tirofiban before primary angioplasty for ST-elevation myocardial infarction.
Glycoprotein IIb/IIIa inhibitors are favourable in ST-elevation myocardial infarction (STEMI) patients, and the additional value of early pre-hospital high bolus dose tirofiban has recently been established. The aim of this study was to determine the impact of age on myocardial reperfusion and clinical outcomes of pre-hospital administration of high bolus dose tirofiban. This is a pre-specified sub-analysis of the multicentre, double-blind, placebo-controlled, randomised On-TIME 2 trial and it's open label phase. The primary endpoint was mean residual ST segment deviation 1 h after primary PCI and was evaluated in three age groups. Of the 466 patients in the highest tertile (≥68 years), median age was 74.4 years (IQR 71.3-78.6 years) and 231 (50%) were randomised to tirofiban. Mean residual ST segment deviation 1 h after PCI was significantly lower in elderly patients pre-treated with tirofiban compared to elderly patients without tirofiban pre-treatment (4.2 ± 5.2 mm vs 6.4 ± 7.5 mm, p = 0.001). Furthermore, elderly patients pre-treated with tirofiban had a non-significantly higher rate of 30-day major or minor bleeding compared to elderly patients without tirofiban pre-treatment (14.2% vs 9.0%, p = 0.088). 30-day net adverse clinical events in elderly patients with- or without tirofiban was not significantly different (11.9% vs 15.2%, p = 0.300). The effect of pre-hospital initiation of high bolus dose tirofiban on myocardial reperfusion, as determined by ST-segment resolution is highest in the elderly patients. However, this was associated with a trend towards more bleeding complications, resulting in a balanced clinical effect after 30-day follow-up. Future studies should evaluate whether the elderly STEMI patient may benefit from highly effective and safer antiplatelet therapy.


Niacin Inhibits Apoptosis and Rescues Premature Ovarian Failure.
Over 99% of mouse and human ovarian follicles will undergo specialized cell death including atresia and apoptosis. Reduction of apoptosis may help reduce infertility and maintain the reproductive ability in women. 3-day B6D2F1 mice were used to culture small follicle and ovary tissue with niacin and 18-day mice were intraperitoneal injected with niacin to determine its effect on follicle development. Then establish 8-weeks POF animal model with cytoxan (CTX) or radiation. Treatment group was given 0.1 mL of 100 mM niacin by an intraperitoneal injection twice before ovulation. The ovaries were collected and the follicles were counted and categorized, and ovarian histologic sections were stained for TUNEL. Ovarian function was then evaluated by monitoring ovulation. Microarray analyses, Western blot, immunofluorescence and real-time quantitative PCR were used to assess the mechanism of ovarian injury and repair. We found that niacin promotes follicle growth in the immature oocyte and it increased the levels of a germ-line cell marker DDX4, and a cell proliferation marker PCNA in the ovary. Addition of niacin to the cell culture reduced oocyte apoptosis in vitro. Administration of niacin to treat premature ovarian failure (POF) in mouse models showed inhibition of follicular apoptosis under harmful conditions, such as radiation and chemotherapy damage, by markedly reducing cumulus cell apoptosis. Additionally, the number of developing follicles increased after administration of niacin. Niacin may have an important function in treating POF by reducing apoptosis in clinical applications.


Activity-based diubiquitin probes for elucidating the linkage specificity of deubiquitinating enzymes.
We report a new class of deubiquitinating enzyme (DUB) probes that resemble the native diubiquitin with a same linkage size and contain a Michael addition acceptor for trapping the DUB active-site cysteine. Both K63- and K48-linked diubiquitin probes were generated using a facile chemical ligation method. The diUb probes were demonstrated to label DUBs from different families and revealed intrinsic linkage specificities of DUBs.


Cortical and subcortical correlates of functional electrical stimulation of wrist extensor and flexor muscles revealed by fMRI.
The main scope of this study was to test the feasibility and reliability of FES in a MR-environment. Functional Electrical Stimulation (FES) is used in the rehabilitation therapy of patients after stroke or spinal cord injury to improve their motor abilities. Its principle lies in applying repeated electrical stimulation to the relevant nerves or muscles for eliciting either isometric or concentric contractions of the treated muscles. In this study we report cerebral activation patterns in healthy subjects undergoing fMRI during FES stimulation. We stimulated the wrist extensor and flexor muscles in an alternating pattern while BOLD-fMRI was recorded. We used both block and event-related designs to demonstrate their feasibility for recording FES activation in the same cortical and subcortical areas. Six out of fifteen subjects repeated the experiment three times within the same session to control intraindividual variance. In both block and event-related design, the analysis revealed an activation pattern comprising the contralateral primary motor cortex, primary somatosensory cortex and premotor cortex; the ipsilateral cerebellum; bilateral secondary somatosensory cortex, the supplementary motor area and anterior cingulate cortex. Within the same subjects we observed a consistent replication of the activation pattern shown in overlapping regions centered on the peak of activation. Similar time course within these regions were demonstrated in the event-related design. Thus, both techniques demonstrate reliable activation of the sensorimotor network and eventually can be used for assessing plastic changes associated with FES rehabilitation treatment.


The serotonin 5-HT7Dro receptor is expressed in the brain of Drosophila, and is essential for normal courtship and mating.
The 5-HT(7) receptor remains one of the less well characterized serotonin receptors. Although it has been demonstrated to be involved in the regulation of mood, sleep, and circadian rhythms, as well as relaxation of vascular smooth muscles in mammals, the precise mechanisms underlying these functions remain largely unknown. The fruit fly, Drosophila melanogaster, is an attractive model organism to study neuropharmacological, molecular, and behavioral processes that are largely conserved with mammals. Drosophila express a homolog of the mammalian 5-HT(7) receptor, as well as homologs for the mammalian 5-HT(1A), and 5-HT(2), receptors. Each fly receptor couples to the same effector pathway as their mammalian counterpart and have been demonstrated to mediate similar behavioral responses. Here, we report on the expression and function of the 5-HT(7)Dro receptor in Drosophila. In the larval central nervous system, expression is detected postsynaptically in discreet cells and neuronal circuits. In the adult brain there is strong expression in all large-field R neurons that innervate the ellipsoid body, as well as in a small group of cells that cluster with the PDF-positive LNvs neurons that mediate circadian activity. Following both pharmacological and genetic approaches, we have found that 5-HT(7)Dro activity is essential for normal courtship and mating behaviors in the fly, where it appears to mediate levels of interest in both males and females. This is the first reported evidence of direct involvement of a particular serotonin receptor subtype in courtship and mating in the fly.


Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration.
Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.


Embutramide, a Component of Tanax(®) (T-61) as a New Drug of Abuse?
Tanax(®) (T-61) is a euthanasia solution commonly used in veterinary medicine in Europe. It consists of three active components: embutramide, mebezonium iodide, and tetracaine hydrochloride. Human consumption of Tanax(®) (T-61) is usually associated with suicide attempts. In our 15-year-long practice, embutramide was detected only three times but within a short period. First, it was found in the urine of a 42-year-old veterinarian, and the other two observations were made in a 16-year-old young man. Urine samples were analyzed using Shimadzu Prominence TOX.I.S.II. HPLC-DAD system with online SPE extraction system. Both of the two patients denied any intention to die. These cases show that this veterinary drug may also be considered as potential drugs of abuse.


Beta modulation reflects name retrieval in the human anterior temporal lobe: an intracranial recording study.
Naming people, places, and things is a fundamental human ability that is often impaired in patients with language-dominant anterior temporal lobe (ATL) dysfunction or ATL resection as part of epilepsy treatment. Convergent lines of evidence point to the importance of the ATL in name retrieval. The physiologic mechanisms that mediate name retrieval in the ATL, however, are not well understood. The purpose of this study was to characterize the electrophysiologic responses of the human ATL during overt cued naming of famous people and objects. Eight neurosurgical patients with suspected temporal lobe epilepsy who underwent implantation of intracranial electrodes for seizure focus localization were the subjects of this study. Specialized coverage of the ATL was achieved in each subject. The subjects named pictures of U.S. presidents and images of common hand-held tools. Event-related band power was measured for each ATL recording site. Both the left and right ATL demonstrated robust and focal increases in beta-band (14-30 Hz) power during person and tool naming. The onset of this response typically occurred at 400 ms but sometimes as early as 200 ms. Visual naming of famous people and tools is associated with robust and localized modulation of the beta band in both the left and right ATL. Measurement of visual naming responses may provide the groundwork for future mapping modalities to localize eloquent cortex in the ATL.


A randomized clinical trial evaluating online interventions to improve fruit and vegetable consumption.
We assessed change in fruit and vegetable intake in a population-based sample, comparing an online untailored program (arm 1) with a tailored behavioral intervention (arm 2) and with a tailored behavioral intervention plus motivational interviewing-based counseling via e-mail (arm 3). We conducted a randomized controlled intervention trial, enrolling members aged 21 to 65 years from 5 health plans in Seattle, Washington; Denver, Colorado; Minneapolis, Minnesota; Detroit, Michigan; and Atlanta, Georgia. Participants reported fruit and vegetable intake at baseline and at 3, 6, and 12 months. We assessed mean change in fruit and vegetable servings per day at 12 months after baseline, using a validated self-report fruit and vegetable food frequency questionnaire. Of 2540 trial participants, 80% were followed up at 12 months. Overall baseline mean fruit and vegetable intake was 4.4 servings per day. Average servings increased by more than 2 servings across all study arms (P<.001), with the greatest increase (+2.8 servings) among participants of arm 3 (P=.05, compared with control). Overall program satisfaction was high. This online nutritional intervention was well received, convenient, easy to disseminate, and associated with sustained dietary change. Such programs have promise as population-based dietary interventions.


Clot retraction.
The study of clot retraction in vitro has been adopted as a simple and reproducible approach to assess platelet function. Plasma clots should retract away from the sides of a glass tube within a few hours allowing the rapid characterization of outside-in signaling through platelet integrin α(IIb)β(3). In this chapter, we describe the role of platelets in fibrin clot retraction and provide a detailed description of the methods used to assess this process.


Inhibition of anthrax lethal factor by curcumin and chemically modified curcumin derivatives.
Curcumin (diferuloylmethane), the active ingredient in the eastern spice turmeric (Curcuma longa), has been shown to inhibit the activities of numerous enzymes and signaling molecules involved in cancer, bacterial and viral infections and inflammatory diseases. We have investigated the inhibitory activities of curcumin and chemically modified curcumin (CMC) derivatives toward lethal factor (LF), the proteolytic component of anthrax toxin produced by the bacterium Bacillus anthracis. Curcumin (Compound 1) appears to inhibit the catalytic activity of LF through a mixture of inhibitory mechanisms, without significant compromise to the binding of oligopeptide substrates, and one CMC derivative in particular, Compound 3 (4-phenylaminocarbonylbis-demethoxycurcumin), is capable of inhibiting LF with potency comparable with the parent compound, while also showing improved solubility and stability. The quantitative reduction in catalytic activity achieved by the different CMC derivatives appears to be a function of the proportion of the multiple mechanisms through which they inhibit the enzyme.


Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism.
Activated Protein C (APC) is an anticoagulant with strong cytoprotective properties that has been shown to promote wound healing. In this study APC was investigated for its potential orthopedic application using a Bone Morphogenetic Protein 2 (rhBMP-2) induced ectopic bone formation model. Local co-administration of 10 µg rhBMP-2 with 10 µg or 25 µg APC increased bone volume at 3 weeks by 32% (N.S.) and 74% (p<0.01) compared to rhBMP-2 alone. This was associated with a significant increase in CD31+ and TRAP+ cells in tissue sections of ectopic bone, consistent with enhanced vascularity and bone turnover. The actions of APC are largely mediated by its receptors endothelial protein C receptor (EPCR) and protease-activated receptors (PARs). Cultured pre-osteoblasts and bone nodule tissue sections were shown to express PAR1/2 and EPCR. When pre-osteoblasts were treated with APC, cell viability and phosphorylation of ERK1/2, Akt, and p38 were increased. Inhibition with PAR1 and sometimes PAR2 antagonists, but not with EPCR blocking antibodies, ameliorated the effects of APC on cell viability and kinase phosphorylation. These data indicate that APC can affect osteoblast viability and signaling, and may have in vivo applications with rhBMP-2 for bone repair.


Healthy migration: a public health and development imperative for south(ern) Africa.
South Africa (SA), like the rest of the Southern African Development Community, has a high prevalence of communicable diseases, an increasing non-communicable disease burden, and diverse internal and cross-border population movements. Healthy migration is good for development, but current prevention, testing and treatment responses within public health systems - particularly for chronic conditions - fail to engage with migration. Understanding of migration is poor within sectors responsible for developing appropriate responses; negative, unsupported assumptions relating to the prevalence of cross-border migration, the spread of disease, and the burden on receiving health systems prevail. In SA, public health responses fail to address internal and cross-border mobilities, and non-nationals face challenges in accessing healthcare. Of particular concern is the lack of nationally and regionally co-ordinated strategies to ensure treatment continuity for chronic conditions. Co-ordinated, evidence-informed responses to migration, mobility and health are urgently needed. These will have developmental and public health benefits for all.


Modulation of auditory gamma-band responses using transcranial electrical stimulation.
Auditory gamma-band (>30 Hz) activity is a biomarker of cortical excitation/inhibition (E/I) balance in autism, schizophrenia, and bipolar disorder. We provide a comprehensive account of the effects of transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) on gamma responses. Forty-five healthy young adults listened to 40-Hz auditory click trains while electroencephalography (EEG) data were collected to measure stimulus-related gamma activity immediately before and after 10 min of 1 mA tACS (40 Hz), tDCS, or sham stimulation to left auditory cortex. tACS, but not tDCS, increased gamma power and phase locking to the auditory stimulus. However, both tACS and tDCS strengthened the gamma phase connectome, and effects persisted beyond the stimulus. Finally, tDCS strengthened the coupling of gamma activity to alpha oscillations after termination of the stimulus. No effects were observed in prestimulus gamma power, the gamma amplitude connectome, or any band-limited alpha measure. Whereas both stimulation techniques synchronize gamma responses between regions, tACS also tunes the magnitude and timing of gamma responses to the stimulus. Results reveal dissociable neurophysiological changes following tACS and tDCS and demonstrate that clinical biomarkers can be altered with noninvasive neurostimulation, especially frequency-tuned tACS.NEW & NOTEWORTHY Gamma frequency-tuned transcranial alternating current stimulation (tACS) adjusts the magnitude and timing of auditory gamma responses, as compared with both sham stimulation and transcranial direct current stimulation (tDCS). However, both tACS and tDCS strengthen the gamma phase connectome, which is disrupted in numerous neurological and psychiatric disorders. These findings reveal dissociable neurophysiological changes following two noninvasive neurostimulation techniques commonly applied in clinical and research settings.


Rhythmic Temporal Expectation Boosts Neural Activity by Increasing Neural Gain.
Temporal orienting improves sensory processing, akin to other top-down biases. However, it is unknown whether these improvements reflect increased neural gain to any stimuli presented at expected time points, or specific tuning to task-relevant stimulus aspects. Furthermore, while other top-down biases are selective, the extent of trade-offs across time is less well characterized. Here, we tested whether gain and/or tuning of auditory frequency processing in humans is modulated by rhythmic temporal expectations, and whether these modulations are specific to time points relevant for task performance. Healthy participants (N = 23) of either sex performed an auditory discrimination task while their brain activity was measured using magnetoencephalography/electroencephalography (M/EEG). Acoustic stimulation consisted of sequences of brief distractors interspersed with targets, presented in a rhythmic or jittered way. Target rhythmicity not only improved behavioral discrimination accuracy and M/EEG-based decoding of targets, but also of irrelevant distractors preceding these targets. To explain this finding in terms of increased sensitivity and/or sharpened tuning to auditory frequency, we estimated tuning curves based on M/EEG decoding results, with separate parameters describing gain and sharpness. The effect of rhythmic expectation on distractor decoding was linked to gain increase only, suggesting increased neural sensitivity to any stimuli presented at relevant time points.SIGNIFICANCE STATEMENT Being able to predict when an event may happen can improve perception and action related to this event, likely due to the alignment of neural activity to the temporal structure of stimulus streams. However, it is unclear whether rhythmic increases in neural sensitivity are specific to task-relevant targets, and whether they competitively impair stimulus processing at unexpected time points. By combining magnetoencephalography and encephalographic recordings, neural decoding of auditory stimulus features, and modeling, we found that rhythmic expectation improved neural decoding of both relevant targets and irrelevant distractors presented and expected time points, but did not competitively impair stimulus processing at unexpected time points. Using a quantitative model, these results were linked to nonspecific neural gain increases due to rhythmic expectation.


Accuracy of non-invasive scoring systems for diagnosing non-alcoholic steatohepatitis-related fibrosis: Multicenter validation study.
Hepatic fibrosis is the most important factor for estimating the prognosis of patients with non-alcoholic fatty liver disease (NAFLD). A novel non-invasive scoring system, the FM-fibro index, showed high accuracy in a pilot study. The purpose of this study was to validate the efficacy of the FM-fibro index in a multicenter cohort. Among 18 institutions, we analyzed 400 Japanese patients with biopsy-proven NAFLD. We evaluated the accuracies of the FM-fibro index, CA-fibro index, and European Liver Fibrosis (ELF) panel by area under the receiver operator characteristics curves (AUROC). The FM-fibro index includes three formulas for type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule-1. Among 400 patients, 205 were women, and the median age was 56 years. The histological distribution of Matteoni types 1, 2, 3, and 4 was 11, 40, 15, and 334, and the distribution of hepatic fibrosis stages 0 to 4 was 67, 183, 55, 63, and 32, respectively. The AUROCs of the FM-fibro index, CA-fibro index, and ELF panel for non-alcoholic steatohepatitis (NASH)-related fibrosis were 0.7178/0.7095/0.7065, 0.7093, and 0.7245, respectively. The sensitivity and specificity of the FM-fibro index for predicting NASH-related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM-fibro index was not significantly different from that of the CA-fibro index or the ELF panel. The FM-fibro index can predict NASH-related fibrosis with sufficient accuracy compared with previous scoring systems. Further analyses that verify the accuracy of the FM-fibro index to distinguish significant or advanced fibrosis in patients with NAFLD are awaited. (UMIN-CTR: UMIN000018158).


A method for measuring Cl efflux from dispersed cells of airway epithelium.
This paper describes a method for measuring the increase in halide permeability of isolated airway epithelial cells induced by adenosine 3',5'-cyclic monophosphate (cAMP). Suspensions of isolated cells, known to contain the cystic fibrosis transmembrane conductance regulator (CFTR), were placed in the upper part of a Swinnex filter holder containing a filter with pores of 0.65 micron diameter. Medium was perfused over the cells at room temperature and collected at minute intervals following its passage through the filter. Experiments were performed on Calu-3 and T84 cells (human lung and colonic epithelial cell lines), primary cultures of dog and human tracheal epithelium, and Swiss 3T3 fibroblasts stably transfected with CFTR. In all cell types, addition of agents that elevate cAMP led to increases in the rates of loss of 36Cl and 125I. However, in human tracheal epithelial cells, warming the medium from room temperature to 37 degrees C was a more effective way of stimulating tracer efflux. Increases in efflux in response to either temperature or cAMP-elevating agents were inhibited by diphenylamine-2-carboxylate, a blocker of CFTR. Reproducible increases in tracer efflux were seen with as few as 10(6) cells. Cells that had been trypsinized off their culture dishes responded better than cells that had been scraped off, although treatment of scraped cells with trypsin enhanced their responsiveness to cAMP-elevating agents. Cystic fibrosis is characterized by the lack of a cAMP-activated Cl conductance in the apical membrane of airway epithlia.(ABSTRACT TRUNCATED AT 250 WORDS)


Serum Magnesium Is Inversely Associated With Heart Failure, Atrial Fibrillation, and Microvascular Complications in Type 2 Diabetes.
We investigated whether serum magnesium (Mg2+) was prospectively associated with macro- or microvascular complications and mediated by glycemic control (hemoglobin A1c [HbA1c]), in type 2 diabetes (T2D). We analyzed in 4,348 participants the association of serum Mg2+ with macrovascular disease and mortality (acute myocardial infarction [AMI], coronary heart disease [CHD], heart failure [HF], cerebrovascular accident [CVA], and peripheral arterial disease [PAD]), atrial fibrillation (AF), and microvascular complications (chronic kidney disease [CKD], diabetic retinopathy, and diabetic foot) using Cox regression, adjusted for confounders. Mediation analysis was performed to assess whether HbA1c mediated these associations. The average baseline serum Mg2+ concentration was 0.80 ± 0.08 mmol/L. During 6.1 years of follow-up, serum Mg2+ was inversely associated with major macrovascular, 0.87 (95% CI 0.76; 1.00); HF, 0.76 (95% CI 0.62; 0.93); and AF, 0.59 (95% CI 0.49; 0.72). Serum Mg2+ was not associated with AMI, CHD, CVA, and PAD. During 5.1 years of follow-up, serum Mg2+ was inversely associated with overall microvascular events, 0.85 (95% CI 0.78; 0.91); 0.89 (95% CI 0.82; 0.96) for CKD, 0.77 (95% CI 0.61; 0.98) for diabetic retinopathy, and 0.85 (95% CI 0.78; 0.92) for diabetic foot. HbA1c mediated the associations of serum Mg2+ with HF, overall microvascular events, diabetic retinopathy, and diabetic foot. Serum Mg2+ concentration is inversely associated with the risk to develop HF and AF and with the occurrence of CKD, diabetic retinopathy, and foot complications in T2D. Glycemic control partially mediated the association of serum Mg2+ with HF and microvascular complications.


Insect symbionts as valuable grist for the biotechnological mill: an alkaliphilic silkworm gut bacterium for efficient lactic acid production.
Insects constitute the most abundant and diverse animal class and act as hosts to an extraordinary variety of symbiotic microorganisms. These microbes living inside the insects play critical roles in host biology and are also valuable bioresources. Enterococcus mundtii EMB156, isolated from the larval gut (gut pH >10) of the model organism Bombyx mori (Lepidoptera: Bombycidae), efficiently produces lactic acid, an important metabolite for industrial production of bioplastic materials. E. mundtii EMB156 grows well under alkaline conditions and stably converts various carbon sources into lactic acid, offering advantages in downstream fermentative processes. High-yield lactic acid production can be achieved by the strain EMB156 from renewable biomass substrates under alkaline pretreatments. Single-molecule real-time (SMRT) sequencing technology revealed its 3.01 Mbp whole genome sequence. A total of 2956 protein-coding sequences, 65 tRNA genes, and 6 rRNA operons were predicted in the EMB156 chromosome. Remarkable genomic features responsible for lactic acid fermentation included key enzymes involved in the pentose phosphate (PP)/glycolytic pathway, and an alpha amylase and xylose isomerase were characterized in EMB156. This genomic information coincides with the phenotype of E. mundtii EMB156, reflecting its metabolic flexibility in efficient lactate fermentation, and established a foundation for future biotechnological application. Interestingly, enzyme activities of amylase were quite stable in high-pH broths, indicating a possible mechanism for strong EMB156 growth in an alkaline environment, thereby facilitating lactic acid production. Together, these findings implied that valuable lactic acid-producing bacteria can be discovered efficiently by screening under the extremely alkaline conditions, as exemplified by gut microbial symbionts of Lepidoptera insects.


Genetic polymorphisms associated with anti-malarial antibody levels in a low and unstable malaria transmission area in southern Sri Lanka.
The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions. Sera were collected from 1,011 individuals residing in Kataragama and anti-malarial antibodies and total IgE levels were measured by a standardized ELISA technique. Host DNA was extracted and used for genotyping of selected SNPs in known genes associated with malaria. The antibody levels were analysed in relation to the past history of malaria (during past 10 years), age, sex, the location of residence within Kataragama and selected host genetic markers. A significant increase in antibodies against Plasmodium falciparum antigens AMA1, MSP2, NANP and Plasmodium vivax antigen MSP1 in individuals with past history of malaria were observed when compared to those who did not. A marked increase of anti-MSP1(Pf) and anti-AMA1(Pv) was also evident in individuals between 45-59 years (when compared to other age groups). Allele frequencies for two SNPs in genes that code for IL-13 and TRIM-5 were found to be significantly different between those who have experienced one or more malaria attacks within past 10 years and those who did not. When antibody levels were classified into a low-high binary trait, significant associations were found with four SNPs for anti-AMA1(Pf); two SNPs for anti-MSP1(Pf); eight SNPs for anti-NANP(Pf); three SNPs for anti-AMA1(Pv); seven SNPs for anti-MSP1(Pv); and nine SNPs for total IgE. Eleven of these SNPs with significant associations with anti-malarial antibody levels were found to be non-synonymous. Evidence is suggestive of an age-acquired immunity in this study population in spite of low malaria transmission levels. Several SNPs were in linkage disequilibrium and had a significant association with elevated antibody levels, suggesting that these host genetic mutations might have an individual or collective effect on inducing or/and maintaining high anti-malarial antibody levels.


Long-Term Cell Fate Tracking of Individual Renal Cells Using Serial Intravital Microscopy.
Intravital multiphoton microscopy of the kidney is a powerful technique to study alterations in tissue morphology and function simultaneously in the living animal and represents a dynamic and developing research tool in the field. Recent technological advances include serial intravital multiphoton microscopy of the same kidney regions over several weeks and combined with ex vivo histology for cellular biomarker expression of the same cells, which had been subject to serial imaging before. Thus, serial intravital multiphoton microscopy followed by ex vivo histology provides unique tools to perform long-term cell fate tracing of the same renal cells during physiological and pathophysiological conditions, thereby allowing the detection of structural changes of the same renal cells over time. Examples include renal cell migration and proliferation while linking these events to local functional alterations and eventually to the expression of distinct cellular biomarkers. Here, we provide a detailed step-by-step protocol to facilitate serial intravital multiphoton microscopy for long-term in vivo tracking of renal cells and subsequent ex vivo histology for immunohistological staining of the same cells in the fixed tissue.


Use of and regional variation in initial CT imaging for kidney stones.
We sought to determine the prevalence of initial computed tomography (CT) utilization and to identify regions in the United States where CT is highly used as the first imaging study for children with nephrolithiasis. We performed a cross-sectional study in 9228 commercially insured children aged 1 to 17 years with nephrolithiasis who underwent diagnostic imaging in the United States between 2003 and 2011. Data were obtained from MarketScan, a commercial insurance claims database of 17,827,229 children in all 50 states. We determined the prevalence of initial CT use, defined as CT alone or CT performed before ultrasound in the emergency department, inpatient unit, or outpatient clinic, and identified regions of high CT utilization by using logistic regression. Sixty-three percent of children underwent initial CT study and 24% had ultrasound performed first. By state, the proportion of children who underwent initial CT ranged from 41% to 79%. Regional variations persisted after adjusting for age, gender, year of presentation, and insurance type. Relative to children living in West South Central states, the highest odds of initial CT utilization were observed for children living in the East South Central US Census division (odds ratio: 1.27; 95% confidence interval: 1.06-1.54). The lowest odds of initial CT were observed for children in the New England states (odds ratio: 0.48; 95% confidence interval: 0.38-0.62). Use of CT as the initial imaging study for children with nephrolithiasis is highly prevalent and shows extensive regional variability in the United States. Current imaging practices deviate substantially from recently published guidelines that recommend ultrasound as the initial imaging study.


Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects.
Studies examining vasodilatory responses to acetylcholine (ACh) and its derivatives have been conflicting. Enhanced activation of the cyclo-oxygenase pathway and increased availability of vasodilatory prostanoids may occur in type 1 diabetes, and this may compensate for the observed reduction in nitric oxide (NO) activity We examined the role of cyclo-oxygenase inhibition on vasodilatory responses in 12 healthy normotensive type 1 diabetic adults and 12 nondiabetic control subjects of similar age, sex, and BMI. Forearm blood flow was measured using a venous occlusion plethysmography technique at baseline and after brachial artery infusions of ACh (7.5, 15, and 30 microg/min). Forearm blood flow at baseline and after ACh was then reexamined after local intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm volume), a cyclo-oxygenase inhibitor. Baseline blood flow in the diabetic and control groups were similar (2.65 +/- 0.26 vs. 2.59 +/- 0.20 ml/min per 100 ml, respectively; P = 0.4). After indomethacin infusion, the vasodilatory responses to all doses of ACh were reduced in both the diabetic (by 25.30 +/- 4.90%) and control group (by 11.23 +/- 5.45%). However, the reduction in blood flow response to ACh after indomethacin was greater in diabetic patients compared with control subjects (P = 0.03). Our findings suggest that vasodilatory, prostanoids are important in determining endothelial response to ACh in diabetic and nondiabetic subjects. Increased prostaglandin-mediated vasodilation may compensate for attenuated responses to NO previously reported in diabetic subjects. These findings may partly explain the conflicting reports of endothelial dysfunction in patients with type 1 diabetes.


Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial.
The visual and mental development of preterm infants improved after feeding them milk enriched with docosahexaenoic acid (DHA) in amounts matching the fetal accretion rate. The objective was to evaluate whether feeding preterm infants milk with a higher DHA content than that used in current practice influences language or behavior in early childhood. This was a follow-up study in a subgroup of infants enrolled in the DINO (Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome) trial. In a double-blind randomized controlled trial, infants born at <33 wk of gestation were fed milk containing 1% of total fatty acids as DHA (higher-DHA group) or approximately 0.3% DHA (control group) until reaching full-term equivalent age. The longer-term effects of the intervention on language, behavior, and temperament were measured by using the MacArthur Communicative Development Inventory (MCDI) at 26-mo corrected age, the Strengths and Difficulties Questionnaire (SDQ), and the Short Temperament Scale for Children (STSC) between 3- and 5-y corrected age. Mean (+/-SD) MCDI scores did not differ significantly (adjusted P = 0.8) between the higher-DHA group (308 +/- 179, n = 60) and the control group (316 +/- 192, n = 67) per the Vocabulary Production subscale. Composite scores on the SDQ and STSC did not differ between the higher-DHA group and the control group [SDQ Total Difficulties: higher-DHA group (10.3 +/- 6.0, n = 61), control group (9.5 +/- 5.5, n = 64), adjusted P = 0.5; STSC score: higher-DHA group (3.1 +/- 0.7, n = 61), control group (3.0 +/- 0.7, n = 64), adjusted P = 0.3]. Feeding preterm infants milk containing 3 times the standard amount of DHA did not result in any clinically meaningful change to language development or behavior when assessed in early childhood. Whether longer-term effects of dietary DHA supplementation can be detected remains to be assessed. This trial was registered with the Australia and New Zealand Clinical Trial Registry at www.anzctr.org.au as 12606000327583.


Age-dependent alterations in the inflammatory response to pulmonary challenge.
The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 months or greater than 18 months (approximating humans of 20 and 55-65 years), were challenged, intratracheally, with lipoteichoic acid and peptidoglycan. Cellular and cytokine evaluations were performed on both bronchoalveolar lavage fluid (BAL) and plasma, 24 h post-challenge. The plasma concentration of free thyroxine, a marker of severity in non-thyroidal illness, was also evaluated. The older animals had an increased chemotactic gradient in favor of the airspaces, which was associated with a greater accumulation of neutrophils and protein. Furthermore, macrophage migration inhibitory factor (MIF), an inflammatory mediator and putative biomarker in acute lung injury, was increased in both the plasma and BAL of the older, but not young animals. Conversely, plasma free thyroxine, a natural inhibitor of MIF, was decreased in the older animals. These findings identify age-associated inflammatory/metabolic changes following pulmonary challenge that it may be possible to manipulate to improve outcome in the older, critically ill patient.


Physical health, illicit drug use, and demographic characteristics in rural stimulant users.
There is growing concern about illicit rural stimulant use, especially regarding methamphetamine use and its health consequences. The present study describes associations between aspects of stimulant use and illness experience in rural areas, with additional focus on the role of demographic characteristics in these associations. The research participants were 710 stimulant drug users who were recruited from rural areas of Arkansas, Kentucky, and Ohio using Heckathorn's respondent-driven sampling method. Health was measured by self-reports of perceived health and extent of current, recent, and lifelong health problems. Drug use was measured with self-reports of type and frequency of use. Several associations were found between drug use and illness, controlling for demographics. Stimulant use pattern related significantly with the sum of health problems in the previous 6 months and the sum of lifetime illness diagnoses, after adjustment for demographic factors. Extent of illicit drug use in the past month and self-perceived drug and alcohol problems were associated with several measures of health. In this sample of stimulant users, methamphetamine use was associated with fewer recent medical problems than crack cocaine, combined crack and powder cocaine use, and use of all 3 of these stimulants. These results, across the 3 sites, suggest that prevalent assumptions about the methamphetamine "plague" and its negative health consequences must be viewed cautiously and examined with additional research.


Molecular regulation of myogenic progenitor populations.
Skeletal muscle regeneration and adaptation to exercise require the actions of muscle satellite cells. Muscle satellite cells are thought to play an integral role in the process of exercise adaptation, but have also been shown to possess the capacity to fully regenerate muscle tissue following destructive muscle injury. We now know that molecular regulation of satellite cells involves the coordinated actions of a series of transcriptional networks that leads to myogenic commitment, cell-cycle entry, proliferation, and terminal differentiation. Additionally, Pax7 is a paired-box transcription factor that has been identified as playing a critical role in satellite cell regulation. It remains debatable, however, whether Pax7 is required for the specification of satellite cells and (or) whether it is playing a vital role in self-renewal and maintenance of the satellite cell population. In recent years, the emergence of atypical myogenic progenitor populations has added a new dimension to muscle repair, and significant interest has been focused on identifying populations such as bone-marrow-derived stem cells that have the ability to contribute to muscle. Interestingly, elucidating the molecular regulation of myogenic progenitor populations has involved animal models of muscle regeneration, with questionable relevance for human muscle adaptation to exercise. This paper highlights the current state of knowledge on the molecular regulation of satellite cells, explores the potential contribution of atypical myogenic progenitors, and discusses the information gathered from animal regeneration models in terms of its relevance to the process of exercise adaptation.


Spectrally efficient digitized radio-over-fiber system with k-means clustering-based multidimensional quantization.
We propose a spectrally efficient digitized radio-over-fiber (D-RoF) system by grouping highly correlated neighboring samples of the analog signals into multidimensional vectors, where the k-means clustering algorithm is adopted for adaptive quantization. A 30 Gbit/s D-RoF system is experimentally demonstrated to validate the proposed scheme, reporting a carrier aggregation of up to 40 100 MHz orthogonal frequency division multiplexing (OFDM) channels with quadrate amplitude modulation (QAM) order of 4 and an aggregation of 10 100 MHz OFDM channels with a QAM order of 16384. The equivalent common public radio interface rates from 37 to 150 Gbit/s are supported. Besides, the error vector magnitude (EVM) of 8% is achieved with the number of quantization bits of 4, and the EVM can be further reduced to 1% by increasing the number of quantization bits to 7. Compared with conventional pulse coding modulation-based D-RoF systems, the proposed D-RoF system improves the signal-to-noise-ratio up to ∼9 dB and greatly reduces the EVM, given the same number of quantization bits.


The changing prevalence and incidence of dementia over time - current evidence.
Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.


The pathophysiology of malarial anaemia: where have all the red cells gone?
Malarial anaemia is an enormous public health problem in endemic areas and occurs predominantly in children in the first 3 years of life. Anaemia is due to both a great increase in clearance of uninfected cells and a failure of an adequate bone marrow response. Odhiambo, Stoute and colleagues show how the age distribution of malarial anaemia and the haemolysis of red blood cells may be linked by an age-dependent increase in the capacity of red blood cells to inactivate complement components absorbed or deposited directly on to the surface of the red blood cell. In this commentary, we discuss what has been established about the role of complement deposition on the surface of red blood cells in the pathology of malarial anaemia, how genetic polymorphisms of the complement control proteins influence the outcome of malaria infection and how the findings of Odhiambo, Stoute and colleagues and others shed light on the puzzling age distribution of different syndromes of severe malaria.


Can a couples' intervention reduce unmet needs and caregiver burden after brain injury?
To examine the effectiveness of the Therapeutic Couples Intervention (TCI) on caregiver needs and burden after brain injury. Individuals with brain injury and their intimate partners/caregivers (n = 75) participated in a 2-arm, parallel, randomized trial with a waitlist control. The TCI consisted of 5 2-hr sessions, with a sixth optional session for parents. The Family Needs Questionnaire-R (FNQ-R) and the Zarit Burden Interview (ZBI) were secondary outcome measures. After adjusting for baseline characteristics, caregivers in the TCI group demonstrated reduction in unmet needs for 5 of the 6 FNQ-R subscales, whereas those in the waitlist control group did not. ZBI scores improved significantly for TCI caregivers but not for controls. At the 3-month follow-up, benefits were maintained for the ZBI and 4 of the 6 FNQ-R subscales (Health Information, Emotional Support, Professional Support, and Community Support Network). The present investigation provided evidence that, following brain injury, a structured couples intervention can reduce unmet needs and burden in caregivers. Future multicenter research examining long-term durability of treatment gains and specific characteristics of positive responders is warranted. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Advanced modelled iterative reconstruction for abdominal CT: qualitative and quantitative evaluation.
To determine qualitative and quantitative image-quality parameters in abdominal imaging using advanced modelled iterative reconstruction (ADMIRE) with third-generation dual-source 192 section CT. Forty patients undergoing abdominal portal-venous CT at different tube voltage levels (90, 100, 110, and 120 kVp, n = 10 each) and 10 consecutive patients undergoing abdominal non-enhanced low-dose CT (100 kVp, 60 mAs) using a third-generation dual-source 192 section CT machine in the single-source mode were included. Images were reconstructed with filtered back projection (FBP) and ADMIRE (strength levels 1-5). Two blinded, independent readers subjectively determined image noise, artefacts, visibility of small structures, and image contrast, and measured attenuation in the liver, spleen, kidney, muscle, fat, and urinary bladder, and objective image noise. Subjective noise was significantly lower and image contrast significantly higher for each increasing ADMIRE strength level and also for ADMIRE 1 compared to FBP (all, p < 0.001). No significant differences were found for artefact and visibility ratings among image sets (all, p > 0.05). Attenuation was similar across tube voltage-image datasets in all anatomical regions (all, p > 0.05). Objective noise was significantly lower for each increasing ADMIRE strength level, and for ADMIRE 1 compared to FBP (all, p < 0.001, maximal reduction 53%). Independent predictors of noise were tube voltage (p < 0.05) and current (p < 0.001), diameter (p < 0.05), and reconstruction algorithm (p<0.001); the amount of noise reduction was related only to the reconstruction algorithm (p < 0.001). Abdominal CT using ADMIRE results in an improved image quality with lower image noise as compared with FBP, while the attenuation of various anatomical regions remains constant among reconstruction algorithms.


Analysis of rotavirus antigenemia in hematopoietic stem cell transplant recipients.
Systemic rotavirus infection, such as rotavirus antigenemia, has been found in immunocompetent rotavirus gastroenteritis patients. However, the pathogenesis of rotavirus infection in immunocompromised transplant recipients remains unclear. Enzyme-linked immunosorbent assay was used to measure rotavirus antigen levels in serially collected serum samples obtained from 62 pediatric patients receiving allogeneic hematopoietic stem cell transplants (HSCT). Rotavirus antigen was detected in 43 (6.8%) of 633 serum samples (8 of 62 patients). The duration of rotavirus antigenemia ranged between 1 and 10 weeks, and diarrhea was concurrent with rotavirus antigenemia in Cases 3, 6, 7, and 8. The level of viral antigen in the transplant recipients (0.19 ± 0.20) was significantly lower than that observed in serum samples collected from immunocompetent patients on either day 1 (0.49 ± 0.18, P = 0.0011) or day 3 (0.63 ± 0.09, P = 0.0005). A patient who received a graft from a human leukocyte antigen (HLA)-mismatched donor was at significant risk for rotavirus antigenemia (P = 0.024; odds ratio = 9.44) in comparison to patients who received grafts from HLA-matched donors. Although the duration of antigenemia was clearly longer in HSCT patients than in immunocompetent rotavirus gastroenteritis patients, the levels of viral antigen were not as high. Therefore, mismatched HLA may be a risk factor for rotavirus antigenemia after HSCT.


Predicting human touch sensitivity to single atom substitutions in surface monolayers for molecular control in tactile interfaces.
The mechanical stimuli generated as a finger interrogates the physical and chemical features of an object form the basis of fine touch. Haptic devices, which are used to control touch, primarily focus on recreating physical features, but the chemical aspects of fine touch may be harnessed to create richer tactile interfaces and reveal fundamental aspects of tactile perception. To connect tactile perception with molecular structure, we systematically varied silane-derived monolayers deposited onto surfaces smoother than the limits of human perception. Through mechanical friction testing and cross-correlation analysis, we made predictions of which pairs of silanes might be distinguishable by humans. We predicted, and demonstrated, that humans can distinguish between two isosteric silanes which differ only by a single nitrogen-for-carbon substitution. The mechanism of tactile contrast originates from a difference in monolayer ordering, as quantified by the Hurst exponent, which was replicated in two alkylsilanes with a three-carbon difference in length. This approach may be generalizable to other materials and lead to new tactile sensations derived from materials chemistry.


Gastrointestinal helminths may affect host susceptibility to anthrax through seasonal immune trade-offs.
Most vertebrates experience coinfections, and many pathogen-pathogen interactions occur indirectly through the host immune system. These interactions are particularly strong in mixed micro-macroparasite infections because of immunomodulatory effects of helminth parasites. While these trade-offs have been examined extensively in laboratory animals, few studies have examined them in natural systems. Additionally, many wildlife pathogens fluctuate seasonally, at least partly due to seasonal host immune changes. We therefore examined seasonality of immune resource allocation, pathogen abundance and exposure, and interactions between infections and immunity in plains zebra (Equus quagga) in Etosha National Park (ENP), Namibia, a system with strongly seasonal patterns of gastrointestinal (GI) helminth infection intensity and concurrent anthrax outbreaks. Both pathogens are environmentally transmitted, and helminth seasonality is driven by environmental pressures on free living life stages. The reasons behind anthrax seasonality are currently not understood, though anthrax is less likely directly driven by environmental factors. We measured a complex, interacting set of variables and found evidence that GI helminth infection intensities, eosinophil counts, IgE and IgGb antibody titers, and possibly IL-4 cytokine signaling were increased in wetter seasons, and that ectoparasite infestations and possibly IFN-γ cytokine signaling were increased in drier seasons. Monocyte counts and anti-anthrax antibody titers were negatively associated with wet season eosinophilia, and monocytes were negatively correlated with IgGb and IgE titers. Taken together, this supports the hypothesis that ENP wet seasons are characterized by immune resource allocation toward Th-2 type responses, while Th1-type immunity may prevail in drier seasons, and that hosts may experience Th1-Th2 trade-offs. We found evidence that this Th2-type resource allocation is likely driven by GI parasite infections, and that these trade-offs may render hosts less capable of concurrently mounting effective Th1-type immune responses against anthrax. This study is one of the first to examine laboratory-demonstrated Th1-Th2 trade-offs in a natural system. It provides evidence that seasonally bound pathogens may affect, through immunology, transmission dynamics of pathogens that might otherwise not be seasonally distributed. It suggests that, by manipulating the internal host ecosystem, GI parasites may influence the external ecosystem by affecting the dynamics of another environmentally transmitted pathogen.


The anti-inflammatory effect of kaempferol on early atherosclerosis in high cholesterol fed rabbits.
Atherosclerosis has been widely accepted as an inflammatory disease of vascular, adhesion molecules play an important role in the early progression of it. The aim of the present study was to evaluate the effect of kaempferol on the inflammatory molecules such as E-selectin (E-sel), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesionmolecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in high cholesterol induced atherosclerosis rabbit models. Thirty male New Zealand white (NZW) rabbits were randomly divided into five groups, control group, model group, fenofibrate (12 mg/kg) group and kaempferol groups (150 mg/kg and 30 mg/kg). The rabbits were fed with a normal diet or a high cholesterol diet for 10 weeks. Levels of blood lipids, serum tumour-necrosis factor-alpha (TNF-α) and serum interleukin-1beta (IL-1β) were detected at the end of the sixth and tenth week. Malonaldehyde (MDA) level and superoxide dismutase (SOD) activity in serum were also determined. Lesion areas of the aorta were measured with morphometry analysis after ten weeks. Gene expression of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas was determined by RT-PCR (reverse transcription-polymerase chain reaction). Immunohistochemical staining was employed to measure protein expression of E-sel, ICAM-1, VCAM-1 and MCP-1. Model rabbits fed with ten weeks of high-cholesterol diet developed significant progression of atherosclerosis. Compared with the control, levels of blood lipids, TNF-α, IL-1β and MDA increased markedly in serum of model rabbits, while SOD levels decreased. Gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas increased remarkably in model group. However, comparing to the model rabbits, levels of TNF-α, IL-1β and MDA decreased significantly and serum SOD activity increased, gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas decreased significantly with the treatment of kaempferol. Kaempferol shows anti-atherosclerotic effect by modulating the gene and protein expression of inflammatory molecules.


Effects of tensile strain and fluid flow on osteoarthritic human chondrocyte metabolism in vitro.
This study examined the hypothesis that tensile strain and fluid flow differentially influence osteoarthritic human chondrocyte metabolism. Primary high-density monolayer chondrocytes cultures were exposed to varying magnitudes of tensile strain and fluid-flow using a four-point bending system. Metabolic changes were quantified by real-time PCR measurement of aggrecan, IL-6, SOX-9, and type II collagen gene expression, and by determination of nitric oxide levels in the culture medium. A linear regression model was used to investigate the roles of strain, fluid flow, and their interaction on metabolic activity. Aggrecan, type II collagen, and SOX9 mRNA expression were negatively correlated to increases in applied strain and fluid flow. An effect of the strain on the induction of nitric oxide release and IL-6 gene expression varied by level of fluid flow (and visa versa). This interaction between strain and fluid flow was negative for nitric oxide and positive for IL-6. These results confirm that articular chondrocyte metabolism is responsive to tensile strain and fluid flow under in vitro loading conditions. Although the articular chondrocytes reacted to the mechanically applied stress, it was notable that there was a differential effect of tensile strain and fluid flow on anabolic and catabolic markers.


Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody.
The dengue virus (DENV) complex is composed of four distinct but serologically related flaviviruses, which together cause the present-day most important emerging viral disease. Although DENV infection induces lifelong immunity against viruses of the same serotype, the antibodies raised appear to contribute to severe disease in cases of heterotypic infections. Understanding the mechanisms of DENV neutralization by antibodies is, therefore, crucial for the design of vaccines that simultaneously protect against all four viruses. Here, we report a comparative, high-resolution crystallographic analysis of an "A-strand" murine monoclonal antibody, Mab 4E11, in complex with its target domain of the envelope protein from the four DENVs. Mab 4E11 is capable of neutralizing all four serotypes, and our study reveals the determinants of this cross-reactivity. The structures also highlight the mechanism by which A-strand Mabs disrupt the architecture of the mature virion, inducing premature fusion loop exposure and concomitant particle inactivation.


The impact of a routine late third trimester growth scan on the incidence, diagnosis, and management of breech presentation in Oxfordshire, UK: A cohort study.
Breech presentation at term contributes significantly to cesarean section (CS) rates worldwide. External cephalic version (ECV) is a safe procedure that reduces term breech presentation and associated CS. A principal barrier to ECV is failure to diagnose breech presentation. Failure to diagnose breech presentation also leads to emergency CS or unplanned vaginal breech birth. Recent evidence suggests that undiagnosed breech might be eliminated using a third trimester scan. Our aim was to evaluate the impact of introducing a routine 36-week scan on the incidence of breech presentation and of undiagnosed breech presentation. We carried out a population-based cohort study of pregnant women in a single unit covering Oxfordshire, United Kingdom. All women delivering between 37+0 and 42+6 weeks gestational age, with a singleton, nonanomalous fetus over a 4-year period (01 October 2014 to 30 September 2018) were included. The mean maternal age was 31 years, mean BMI 26, 44% were nulliparous, and 21% were of non-white ethnicity. Comparisons between the 2 years before and after introduction of routine 36-week scan were made for 2 primary outcomes of (1) the incidence of breech presentation and (2) undiagnosed breech presentation. Secondary outcomes related to ECV, mode of birth, and perinatal outcomes. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. A total of 27,825 pregnancies were analysed (14,444 before and 13,381 after). A scan after 35+0 weeks was performed in 5,578 (38.6%) before, and 13,251 (99.0%) after (p < 0.001). The incidence of breech presentation at birth did not change significantly (2.6% and 2.7%) (RR 1.02; 95% CI 0.89, 1.18; p = 0.76). The rate of undiagnosed breech before labour reduced, from 22.3% to 4.7% (RR 0.21; 95% CI 0.12, 0.36; p < 0.001). Vaginal breech birth rates fell from 10.3% to 5.3% (RR 0.51; 95% CI 0.30, 0.87; p = 0.01); nonsignificant increases in elective CS rates and decreases in emergency CS rates for breech babies were seen. Neonatal outcomes were not significantly altered. Study limitations include insufficient numbers to detect serious adverse outcomes, that we cannot exclude secular changes over time which may have influenced our results, and that these findings are most applicable where a comprehensive ECV service exists. In this study, a universal 36-week scan policy was associated with a reduction in the incidence but not elimination of undiagnosed term breech presentation. There was no reduction in the incidence of breech presentation at birth, despite a comprehensive ECV service.


Evaluating ecosystem response to oyster restoration and nutrient load reduction with a multispecies bioenergetics model.
Many of the world's coastal ecosystems are impacted by multiple stressors each of which may be subject to different management strategies that may have overlapping or even conflicting objectives. Consequently, management results may be indirect and difficult to predict or observe. We developed a network simulation model intended specifically to examine ecosystem-level responses to management and applied this model to a comparison of nutrient load reduction and restoration of highly reduced stocks of bivalve suspension feeders (eastern oyster, Crassostrea virginica) in an estuarine ecosystem (Chesapeake Bay, USA). Model results suggest that a 50% reduction in nutrient inputs from the watershed will result in lower phytoplankton production in the spring and reduced delivery of organic material to the benthos that will limit spring and summer pelagic secondary production. The model predicts that low levels of oyster restoration will have no effect in the spring but does result in a reduction in phytoplankton standing stocks in the summer. Both actions have a negative effect on pelagic secondary production, but the predicted effect of oyster restoration is larger. The lower effect of oysters on phytoplankton is due to size-based differences in filtration efficiency and seasonality that result in maximum top-down grazer control of oysters at a time when the phytoplankton is already subject to heavy grazing. These results suggest that oyster restoration must be achieved at levels as much as 25-fold present biomass to have a meaningful effect on phytoplankton biomass and as much as 50-fold to achieve effects similar to a 50% nutrient load reduction. The unintended effect of oyster restoration at these levels on other consumers represents a trade-off to the desired effect of reversing eutrophication.


Underutilization of hepatitis C-positive kidneys for hepatitis C-positive recipients.
Hepatitis C-positive (HCV(+)) candidates likely derive survival benefit from transplantation with HCV(+) kidneys, yet evidence remains inconclusive. We hypothesized that lack of good survival benefit data has led to wide practice variation. Our goal was to characterize national utilization of HCV(+) kidneys for HCV(+) recipients, and to quantify the risks/benefits of this practice. Of 93,825 deceased donors between 1995 and 2009, HCV(+) kidneys were 2.60-times more likely to be discarded (p < 0.001). However, of 6830 HCV(+) recipients, only 29% received HCV(+) kidneys. Patients over 60 relative rate (RR 0.86), women (RR 0.73) and highly sensitized patients (RR 0.42) were less likely to receive HCV(+) kidneys, while African Americans (RR 1.56), diabetics (RR 1.29) and those at centers with long waiting times (RR 1.19) were more likely to receive them. HCV(+) recipients of HCV(+) kidneys waited 310 days less than the average waiting time at their center, and 395 days less than their counterparts at the same center who waited for HCV(-) kidneys, likely offsetting the slightly higher patient (HR 1.29) and graft loss (HR 1.18) associated with HCV(+) kidneys. A better understanding of the risks and benefits of transplanting HCV(+) recipients with HCV(+) kidneys will hopefully improve utilization of these kidneys in an evidence-based manner.


Three-dimensional adaptive filtering in magnetic resonance angiography.
In order to enhance 3D image data from magnetic resonance angiography (MRA), a novel method based on the theory of multidimensional adaptive filtering has been developed. The purpose of the technique is to suppress image noise while enhancing important structures. The method is based on local structure estimation using six 3D orientation selective filters, followed by an adaptive filtering step controlled by the local structure information. The complete filtering procedure requires approximately 3 minutes of computational time on a standard workstation for a 256 x 256 x 64 data set. The method has been evaluated using a mathematical vessel model and in vivo MRA data (both phase contrast and time of flight (TOF)). 3D adaptive filtering results in a better delineation of small blood vessels and efficiently reduces the high-frequency noise. Depending on the data acquisition and the original data type, contrast-to-noise ratio (CNR) improvements of up to 179% (8.9 dB) were observed. 3D adaptive filtering may provide an alternative to prolonging the scan time or using contrast agents in MRA when the CNR is low.