Modeling sparse connectivity between underlying brain sources for EEG/MEG.
We propose a novel technique to assess functional brain connectivity in electroencephalographic (EEG)/magnetoencephalographic (MEG) signals. Our method, called sparsely connected sources analysis (SCSA), can overcome the problem of volume conduction by modeling neural data innovatively with the following ingredients: 1) the EEG/MEG is assumed to be a linear mixture of correlated sources following a multivariate autoregressive (MVAR) model; 2) the demixing is estimated jointly with the source MVAR parameters; and 3) overfitting is avoided by using the group lasso penalty. This approach allows us to extract the appropriate level of crosstalk between the extracted sources and, in this manner, we obtain a sparse data-driven model of functional connectivity. We demonstrate the usefulness of SCSA with simulated data and compare it to a number of existing algorithms with excellent results.


Effects of preoperative endoscopic pneumatic balloon dilatation on postoperative achalasia symptoms after Heller esophageal myotomy plus Dor fundoplication.
Currently, forceful endoscopic pneumatic balloon dilatation (PBD), laparoscopic Heller myotomy (LHM) with or without an anti-reflux procedure, and peroral endoscopic myotomy are the preferred treatment options for achalasia. The aim of the present study was to retrospectively compare postoperative outcomes after LHM plus Dor fundoplication (DF) between patients who underwent prior endoscopic balloon dilatation and those who did not. Sixty-five patients who underwent HM+DF between January 2008 and December 2016 were retrospectively analyzed. Of these, 45 had a history of endoscopic PBD. Pre- and postoperative achalasia symptoms, including weight loss, dysphagia, heartburn, and regurgitation, were evaluated using the Eckardt score. Fifty (76.9%) patients underwent laparoscopic surgery and 15 (23.1%) underwent open surgery. When patients were compared according to the presence of preoperative endoscopic PBD, no significant difference were observed in terms of age, sex, preoperative lower esophageal sphincter pressure, operation time, hospitalization period, and follow-up period (p>0.05). The mean Eckardt score at the first postoperative year was significantly lower than the preoperative Eckardt score (4.51±1.8 vs. 0.52±0.7; p<0.001). In contrast, no significant difference was found between patients with and without previous PBD on the pre- and postoperative Eckardt scores (p=0.43). HM+DF is an effective procedure in relieving achalasia symptoms as a first-line therapy as well as in individuals unresponsive to repeated endoscopic PBDs.


The controversy surrounding penile rehabilitation after radical prostatectomy.
Radical prostatectomy (RP) techniques have been refined in the last few decades. Despite nerve-sparing surgery, erectile dysfunction (ED) still seems to be affecting more than half of patients undergoing RP. Penile rehabilitation consists of understanding the mechanisms that affect erectile function (EF) and utilizing pharmacologic agents, devices or interventions to promote male sexual function before and after any insult to the penile erectile physiologic axis. There currently is a limited amount of clinical trials that assess treatments with the goal of recovering post-prostatectomy EF. The goal of this article is to assess a contemporary series of trials that study penile rehabilitation. Although the current evidence lacks to prove its irrefutable effectiveness, advancements in research and technology forecast a promising future in penile rehabilitation management.


Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.
To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.


RON Receptor Tyrosine Kinase as a Therapeutic Target for Eradication of Triple-Negative Breast Cancer: Efficacy of Anti-RON ADC Zt/g4-MMAE.
Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC50 values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON+/CD44+/CD24- phenotypes and RON-negative TNBC cells through the bystander effect. In vivo, Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment.


Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.
Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.


Sympathetic and nonsympathetic neuropeptide Y-containing nerves in the rat myocardium and coronary arteries.
We have examined the neuropeptide Y-containing intrinsic nerves of the heart in young (6-week-old) and adult (4-month-old) rats to determine whether they project to the coronary arteries or are capable of doing so if the neuropeptide Y-containing extrinsic nerves are removed. Chronic treatment of neonates with guanethidine was used to permanently destroy the sympathetic nerves. In the young treated animals, 33-54% of the neuropeptide Y remained in the heart despite a 90-99% reduction in norepinephrine; these proportions did not change in the animals that were allowed to develop to adulthood. The level of neuropeptide Y in the right atrium of young animals was unexpectedly high (252 +/- 28.7 pmol/g) compared with adults (75.4 +/- 18.8 pmol/g). The coronary arteries in the control rats received a moderately dense supply of neuropeptide Y-containing nerves; after guanethidine, all neuropeptide Y-containing nerves innervating the large coronary arteries disappeared, but some were still seen in association with small resistance vessels. No compensatory proliferation of the intrinsic neuropeptide Y-containing neurons occurred in the adult sympathectomized animals, and the intrinsic nerves did not reinnervate the large coronary arteries. These results are discussed in relation to the clinical syndrome of coronary artery spasm.


Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure.
Diuretics are frequently required to treat fluid retention in patients with congestive heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohumoral activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V2 receptor, and its levels are increased in CHF. This study was designed to assess the effects of a single oral dose of tolvaptan, a selective V2-receptor blocker, in the absence of other medications, on renal function in human CHF and to compare this to the effects of a single oral dose of furosemide. We hypothesized that V2-receptor antagonism would yield a diuresis comparable to furosemide but would not adversely affect renal hemodynamics, plasma electrolyte concentration, or neurohumoral activation in stable human CHF. Renal and neurohumoral effects of tolvaptan and furosemide were assessed in an open-label, randomized, placebo-controlled crossover study in 14 patients with NYHA II-III CHF. Patients received placebo or 30 mg of tolvaptan on day 1 and were crossed over to the other medication on day 3. On day 5, all subjects received 80 mg of furosemide. Tolvaptan and furosemide induced similar diuretic responses. Unlike tolvaptan, furosemide increased urinary sodium and potassium excretion and decreased renal blood flow. Tolvaptan, furosemide, and placebo did not differ with respect to mean arterial pressure, glomerular filtration rate, or serum sodium and potassium. We conclude that tolvaptan is an effective aquaretic with no adverse effects on renal hemodynamics or serum electrolytes in patients with mild to moderate heart failure.


Multiscale effect of hierarchical self-assembled nanostructures on superhydrophobic surface.
In this work, we describe self-assembled surfaces with a peculiar multiscale organization, from the nanoscale to the microscale, exhibiting the Cassie-Baxter wetting regime with extremely low water adhesion: floating drops regime with roll-off angles < 5°. These surfaces comprise bundles of hierarchical, quasi-one-dimensional (1D) TiO2 nanostructures functionalized with a fluorinated molecule (PFNA). While the hierarchical nanostructures are the result of a gas-phase self-assembly process, their bundles are the result of the capillary forces acting between them when the PFNA solvent evaporates. Nanometric features are found to influence the hydrophobic behavior of the surface, which is enhanced by the micrometric structures up to the achievement of the superhydrophobic Cassie-Baxter state (contact angle (CA) ≫ 150°). Thanks to their high total and diffuse transmittance and their self-cleaning properties, these surfaces could be interesting for several applications such as smart windows and photovoltaics where light management and surface cleanliness play a crucial role. Moreover, the multiscale analysis performed in this work contributes to the understanding of the basic mechanisms behind extreme wetting behaviors.


Projected geographic disparities in healthcare worker absenteeism from COVID-19 school closures and the economic feasibility of child care subsidies: a simulation study.
School closures have been enacted as a measure of mitigation during the ongoing COVID-19 pandemic. It has been shown that school closures could cause absenteeism amongst healthcare workers with dependent children, but there remains a need for spatially granular analyses of the relationship between school closures and healthcare worker absenteeism to inform local community preparedness. We provide national- and county-level simulations of school closures and unmet child care needs across the United States. We develop individual simulations using county-level demographic and occupational data, and model school closure effectiveness with age-structured compartmental models. We perform multivariate quasi-Poisson ecological regressions to find associations between unmet child care needs and COVID-19 vulnerability factors. At the national level, we estimate the projected rate of unmet child care needs for healthcare worker households to range from 7.5% to 8.6%, and the effectiveness of school closures to range from 3.2% (R0 = 4) to 7.2% (R0 = 2) reduction in fewer ICU beds at peak demand. At the county-level, we find substantial variations of projected unmet child care needs and school closure effects, ranging from 1.9% to 18.3% of healthcare worker households and 5.7% to 8.8% reduction in fewer ICU beds at peak demand (R0 = 2). We find significant positive associations between estimated levels of unmet child care needs and diabetes prevalence, county rurality, and race (p < 0.05). We estimate costs of absenteeism and child care and observe from our models that an estimated 71.1% to 98.8% of counties would find it less expensive to provide child care to all healthcare workers with children than to bear the costs of healthcare worker absenteeism during school closures. School closures are projected to reduce peak ICU bed demand, but could disrupt healthcare systems through absenteeism, especially in counties that are already particularly vulnerable to COVID-19. Child care subsidies could help circumvent the ostensible tradeoff between school closures and healthcare worker absenteeism.


Enantiomer analysis of a new street drug, 3,4-methylenedioxy-N-methyl-butanamine, in rat urine.
A new street drug, 3,4-methylenedioxy-N-methyl-butanamine (MBDB), has been found in Japan recently. The stereoisomer monitoring and the urinary excretion kinetics are not determined in biological fluids even though abused MBDB is a racemic form [enantiomer ratio (-/+) = 1.00]. The present studies were done by high-performance liquid chromatography (HPLC) equipped with a chiral activity column at 40 degrees C using urine specimens from five Wistar rats. Urine samples were collected over six time intervals after a single oral administration of racemic MBDB (30 mg/kg). Unchanged MBDB and 3,4-methylenedioxybutanamine (BDB), an N-demethylated metabolite, were found in the rats' urine. Each enantiomer of MBDB and BDB was monitored (peak resolution > 1.00) by HPLC analysis within 30 min. For both MBDB and BDB, the (+)-isomers were excreted a little more than the (-)-isomers. The stereoselective disposition of BDB was more remarkable than that of MBDB and was observed in the urine throughout the study (p < 0.05). The urinary excretion of MBDB showed significant difference between the two enantiomers from 4 to 20 h (p < 0.05). The amount of MBDB excreted up to 24 h was 34.7+/-2.8% of the administered dose: 17.6+/-1.4% for (+)-isomer and 17.1+/-1.5% for (-)-isomer. The amount of BDB was 4.9+/-1.0%; 2.9+/-0.6% for (+)-isomer and 2.0+/-0.4% for (-)-isomer. The enantiomer ratio (-/+) of MBDB and BDB was 1.00 or a little smaller. The ratio (-/+) of MBDB changed from 1.00+/-0.02 to 0.88+/-0.09 by 24 h, and that of BDB from 0.68+/-0.03 to 0.78+/-0.02. The ratio (-/+) for MBDB and BDB accumulated up to 24 h was 0.97+/-0.01 and 0.70+/-0.06, respectively, and the total ratio (-/+) of the two substances was 0.93+/-0.02 (p < 0.05). These findings suggested that the stereoselective disposition of racemic MBDB was different from that of 3,4-dimethylenedioxyamphetamine and 3,4-dimethylenedioxymethamphetamine and was similar to that of methamphetamine.


Image reconstruction for thin observation module by bound optics by using the iterative backprojection method.
A method for reconstructing high-spatial-resolution images in an imaging system known as thin observation module by bound optics (TOMBO) is reported. We investigate a novel procedure combining a pixel-rearrangement method and iterative backprojection (IBP). Pixel rearrangement has been used until now in TOMBO, and IBP is a digital superresolution technique. We verify the effectiveness of the combined procedure with simulated and experimental results.


Tissue-specific PAI-1 gene expression and glycosylation pattern in insulin-resistant old rats.
Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with obesity, aging, insulin resistance, and type 2 diabetes, conditions that contribute to increased cardiovascular risk. PAI-1 is expressed in a variety of tissues, but the cellular origin of plasma PAI-1 is unknown. To link insulin resistance, aging, and cardiovascular disease, we examined the expression and glycosylation pattern of PAI-1 in liver and white adipose tissue (WAT) from adult (3 mo) and insulin-resistant old (24 mo) Wistar rats. Glycosylated PAI-1 protein was also purified by affinity chromatography from endothelial culture supernatans to analyze its inhibitory activity. We also analyzed the contribution of adipocytes and stromal vascular cells from WAT to PAI-1 levels with aging. Aging caused a significant increase of PAI-1 mRNA (P < 0.001) in WAT that was predominantly due to the adipocytes and not to stroma-vascular cells, while there was no modification in liver from aged rats. Moreover, PAI-1 expression increased during preadipocyte differentiation (P < 0.001). Furthermore, we found a tissue-dependent PAI-1 glycosylation pattern: adipose tissue only expresses the glycosylated PAI-1 form, whereas the liver mainly expresses the nonglycosylated form. Finally, we also found evidences suggesting that the glycosylated PAI-1 form shows higher inhibitory activity than the nonglycosylated. Our data suggest that WAT may be a major source of the elevated plasma levels of PAI-1 in insulin-resistant old rats. Additionally, the high degree of PAI-1 glycosylation and activity, together with the significant increase in visceral fat in old rats, may well contribute to an increased cardiovascular risk associated with insulin-resistant states.


The efficacy of Liv-52 on liver cirrhotic patients: a randomized, double-blind, placebo-controlled first approach.
Cirrhosis is the irreversible sequel of various disorders that damage liver cells permanently over time. Presently, the use of herbal medicines for prevention and control of chronic liver diseases is in the focus of attention for both the physicians and the patients; the reasons for such shift toward the use of herbals include the expensive cost of conventional drugs, adverse drug reactions, and their inefficacy. In the present study, the efficacy of herbal medicine Liv-52 (consisting of Mandur basma, Tamarix gallica and herbal extracts of Capparis spinosa, Cichorium intybus, Solanum nigrum, Terminalia arjuna and Achillea millefolium) on liver cirrhosis outcomes was compared with the placebo for 6 months in 36 cirrhotic patients referred to Tehran Hepatic Center. The outcome measures included child-pugh score, ascites, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total billirubin, albumin, prothrombin time, platelet and white blood cells counts. The indices were recorded in all patients before and after 6 months of drug or placebo treatment. The results demonstrated that the patients treated with Liv-52 for 6 months had significantly better child-pugh score, decreased ascites, decreased serum ALT and AST. In placebo administered patients all the clinical parameters recorded at beginning of the study were not significantly different than after 6 months. We conclude that Liv-52 possess hepatoprotective effect in cirrhotic patients. This protective effect of Liv-52 can be attributed to the diuretic, anti-inflammatory, anti-oxidative, and immunomodulating properties of the component herbs.


Delayed-Onset Muscle Soreness: Temporal Assessment With Quantitative MRI and Shear-Wave Ultrasound Elastography.
The objective of our study was to assess delayed-onset muscle soreness (DOMS) over time using quantitative MRI and shear-wave ultrasound (US) elastography. Five male (mean age ± SD, 39.6 ± 4.6 years) and five female (30.6 ± 13.5 years) volunteers underwent 1.5-T MRI before and after (15 minutes, 1 day, 3 days, 7 days) performing unilateral eccentric resistance exercise of the elbow flexor muscles. The MRI examinations included fluid-sensitive, DWI, and diffusion-tensor imaging sequences of the distal upper arm. Muscle edema, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were assessed. US of the brachialis muscle was performed before and after (15 minutes, 12 hours, 1 day, 2 days, 3 days, 7 days) exercise to measure mean shear-wave velocity (SWV). Pain and muscle tightness were assessed. For men, muscle edema was moderate and peaked 3 days after exercise; for women, muscle edema was mild and peaked 1-3 days after exercise. ADC was highest 3 days after exercise in men (mean, 1809.22 × 10-6 mm2/s; before exercise, 1529.88 × 10-6 mm2/s) and women (1741.90 × 10-6 mm2/s; before exercise, 1475.80 × 10-6 mm2/s). FA dropped from 361.00 in men and 389.00 in women before exercise to a minimum of 252.12 and 321.28, respectively, 3 days after exercise. Mean SWV increased after exercise in men (before exercise, 3.00 ± 0.30 m/s; peak [15 minutes after exercise], 4.04 ± 0.90 m/s) and women (before, 2.82 ± 0.40 m/s; peak [1 day after exercise], 3.23 ± 0.40 m/s) and subsequently returned to normal. In men, the ADC values of the brachialis muscle positively correlated with mean SWV (r = 0.92, p = 0.028). FA negatively correlated with pain in men (r = -0.993, p = 0.001) Muscle edema outlasted clinical symptoms in most volunteers. FA inversely correlates with pain and may be a useful imaging parameter for assessment of DOMS. Shear-wave US elastography shows a temporary increase of muscle stiffness after DOMS-inducing exercise but does not correlate with quantitative MRI parameters or clinical symptoms.


Studying the effects of transcranial direct-current stimulation in stroke recovery using magnetic resonance imaging.
Transcranial direct-current stimulation (tDCS) is showing increasing promise as an adjunct therapy in stroke rehabilitation. However questions still remain concerning its mechanisms of action, which currently limit its potential. Magnetic resonance (MR) techniques are increasingly being applied to understand the neural effects of tDCS. Here, we review the MR evidence supporting the use of tDCS to aid recovery after stroke and discuss the important open questions that remain.


Levels of resilience, anxiety and depression in nurses working in respiratory clinical areas during the COVID pandemic.
The delivery of healthcare during the COVID pandemic has had a significant impact on front line staff. Nurses who work with respiratory patients have been at the forefront of the pandemic response. Lessons can be learnt from these nurses' experiences in order to support these nurses during the existing pandemic and retain and mobilise this skilled workforce for future pandemics. This study explores UK nurses' experiences of working in a respiratory environment during the COVID-19 pandemic. An e-survey was distributed via professional respiratory societies; the survey included a resilience scale, the GAD7 (anxiety) and the PHQ9 (depression) tools. Demographic data was collected on age, gender, ethnicity, nursing experience and background, clinical role in the pandemic, and home-life and work balance. Two hundred and fifty-five responses were received for the survey, predominately women (89%, 226/255), aged over 35 (79%, 202/255). Nearly 21% (40/191) experiencing moderate to severe or severe symptoms of anxiety. Similar levels are seen for depression (17.2%, 31/181). 18.9% (34/180) had a low or very low resilience score. Regression analysis showed that for both depression and anxiety variables, age and years of qualification provided the best model fit. Younger nurses with less experience have higher levels of anxiety and depression and had lower resilience. This cohort experienced significant levels of anxiety and depression, with moderate to high levels of resilience. Support mechanisms and interventions need to be put in place to support all nurses during pandemic outbreaks, particularly younger or less experienced staff.


[3]Ferrocenophanes with the bisphosphanotetryl bridge: inorganic rings on the way to tetrylenes.
A series of [3]ferrocenophanes with functional P-E-P motifs (E = group 14 fragments) is reported. Out of these, the silicon compounds with the general formula Fe(C5H4PtBu)2SiXY (XY = Cl2, Br2, I2, H2, HCl) have been characterized by spectroscopic means and the bonding situation was analyzed using X-ray crystallography and quantum chemical calculations. Despite the two stereogenic phosphanyl centers, most of the [3]ferrocenophanes have been obtained as single isomers in the course of stereospecific reactions. The corresponding stannylene Fe(C5H4PtBu)2Sn has been obtained in the form of its dimeric adduct.


Spinal radiological findings in nine patients with spontaneous intracranial hypotension.
Cranial magnetic resonance imaging (MRI) findings in spontaneous intracranial hypotension (SIH) are well known, while spinal studies have received less attention. Radiological spinal findings in nine patients with SIH are presented, looking for possible characteristic features. Five of the nine patients had histories of previous minor trauma, one of previous surgery; in three patients possible relevant preceding events were completely absent. All nine patients had cervical, seven thoracic, and four lumbar spine MRI studies; post-contrast studies were obtained in seven cases, MRI myelograms in five. Radioisotope myelocisternography was performed in four patients and myelo-CT in four. Epidural fluid collections were found in seven patients. In six cases the dural sac had collapsed, with a festooned appearance; intense epidural enhancement on post-contrast studies demonstrated marked dilatation of the epidural venous plexus. In three cases an irregular root sleeve suggested a possible point of cerebrospinal fluid (CSF) leakage. Myelo-CT demonstrated the CSF fistula in two cases, radioisotope myelocisternography in three. The pattern of spinal abnormalities is different from that seen in cranial MRI for anatomical reasons: in the spinal canal the dura is not adherent to the bone; therefore, collapse of the dural sac and dilatation of epidural venous plexus occur, rather than subdural hematomas. In most cases the search for the dural tear is difficult. Radioisotope cisternography is probably the most sensitive examination for documenting the leakage of CSF out of the subarachnoid space; myelo-CT may precisely demonstrate the point of the CSF fistula, whereas MRI may only suggest it.


Surface-controlled electroless deposition method in the preparation of stacked silver nanoparticles on germanium for surface-enhanced infrared absorption measurements.
A new method to prepare highly sensitive sensing elements for surface-enhanced infrared absorption (SEIRA) measurements was investigated. A surface-controlled procedure was employed to grow round and stacked silver nanoparticles (Ag-NPs) on germanium substrates. In this method, an initial layer of Ag-NPs was prepared using a common method of electroless deposition. After subsequently placing a controlled layer of p-aminothiophenol (pATP) on the surface of the initial layer of Ag-NPs, the substrates were placed in a silver nitrate solution to grow a second layer of Ag-NPs. By repeating these growing procedures, multi-layers of stacked Ag-NPs can be obtained. To examine the influence of morphology of the formed Ag-NPs on the resulting SEIRA signals, the factors affecting the reactions were systematically examined. These factors included the concentrations of silver nitrates, the reaction times to prepare both the initial layer and the second layer of Ag-NPs, and the coverage of pATP. Results indicate that the Ag-NPs making up the second layer were round in shape and much more densely distributed than those in the initial layer. The observed SEIRA spectra did not show derivative-shaped absorption bands for pATP on the Ag-NPs after re-growth, indicating that pATP was sandwiched between the two layers of Ag-NPs, preventing the nanoparticles from coming into direct contact with one another. Also, the SEIRA signals of the controlled molecules between the particles were found to be two to five times more intense than the signals before growing another layer of Ag-NPs. The reaction conditions can be adjusted to vary the morphology and thickness of the Ag-NP layers, and, by repeating the growing procedures, a thick layer of stacked Ag-NPs with suitable size for SEIRA measurements can be obtained that is highly suited to chemical sensing applications.


Adherence to a healthy lifestyle and all-cause and cause-specific mortality in Chinese adults: a 10-year prospective study of 0.5 million people.
Adherence to a healthy lifestyle is associated with substantially lower risks of mortality from all causes, cardiovascular diseases, and cancer in white populations. However, little is known about the health benefits among non-white populations. Also, no previous studies have focused on respiratory disease mortality in both white and non-white populations. We assessed the relationships between a combination of healthy lifestyle factors and multiple death outcomes in Chinese adults. This study included 487,198 adults aged 30-79 years from the China Kadoorie Biobank without heart disease, stroke, and cancer at study enrolment. We defined five healthy lifestyle factors as never smoking or smoking cessation not due to illness; non-daily drinking or moderate alcohol drinking; median or higher level of physical activity; a diet rich in vegetables, fruits, legumes and fish, and limited in red meat; a body mass index of 18.5 to 27.9 kg/m2 and a waist circumference < 90 cm (men)/85 cm (women). Cox regression was used to produce adjusted hazard ratios (HRs) relating these healthy lifestyle factors to all-cause and cause-specific mortality. During a median follow-up of 10.2 years (IQR 9.2-11.1), we documented 37,845 deaths. After multivariable adjustment, the number of healthy lifestyle factors exhibited almost inverse linear relationships with the risks of all-cause and cause-specific mortality. Compared with participants without any healthy factors, the hazard ratio of participants with five healthy factors was 0.32 [95% confidence interval (CI): 0.28, 0.37] for all-cause mortality. The corresponding HRs in specific cause of death were 0.42 (95% CI: 0.26, 0.67) for ischaemic heart disease, 0.21 (95% CI: 0.09, 0.49) for ischaemic stroke, 0.37 (95% CI: 0.22, 0.60) for haemorrhage stroke, 0.36 (95% CI: 0.29, 0.45) for cancer, 0.26 (95% CI: 0.14, 0.48) for respiratory diseases, and 0.29 (95% CI: 0.22, 0.39) for other causes. Theoretically, 38.5% (95% CI: 33.0, 43.8%) of all-cause mortality was attributable to nonadherence to a healthy lifestyle, and the proportions of preventable deaths through lifestyle modification ranged from 26.9 to 47.9% for cause-specific mortality. Adherence to a healthy lifestyle was associated with substantially lower risks of all-cause, cardiovascular, respiratory, and cancer mortality in Chinese adults. Promotion of a healthy lifestyle may considerably reduce the burden of non-communicable diseases in China.


Astragaloside suppresses tumor necrosis factor receptor-associated factor 5 signaling pathway and alleviates neurodegenerative changes in retinal pigment epithelial cells induced by isoflurane.
Epidemiological studies showed that isoflurane, a general anesthetic widely used in surgery including those for the children, is associated with impairment of neurodevelopment and neurodegenerative diseases, such as Alzheimer's disease (AD) and age-related macular degeneration (AMD), which are related to the accumulation of reactive oxygen species (ROS). Astragaloside (AS) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge. In this study, we used retinal pigment epithelial cells, which share plenty of features with neurodegenerative diseases such as AD and AMD to investigate the effect of AS. Cell cycle re-entry and proapoptosis were seen in retinal pigment epithelium (RPE) cells treated with isoflurane, which was alleviated by pretreatment of AS. Further, tumor necrosis factor receptor-associated factor 5 (TRAF5) and downstream nuclear factor-κB (NF-κB) were investigated to elucidate the molecular mechanism underlying protective effect of AS. RPE cells exposed to isoflurane expressed higher TRAF5 and NF-κB than those pretreated with AS, suggesting a critical role of TRAF5 therein. In Morris water maze (MWM) assay, Sprague-Dawley rats pretreated with AS and then exposed to isoflurane spent less time in swimming to the platform, and their TRAF5 expression was significantly lower than those received anesthesia alone. Further studies on the consequence of forced downregulation or upregulation are warranted that may employ cutting-edge technologies such as optogenetics to overcome the difficulties in manipulating expression of TRAF5. Although the link between TRAF5 and neurodegeneration requires more in-depth investigations, our study provide a novel hint on the pathological mechanism of isoflurane and suggest a potential target for eliminating persistent side effect of anesthesia.


Biomass fuel exposure and respiratory diseases in India.
One half of the world's population relies on biomass fuel as the primary source of domestic energy. Biomass fuel exposure causes a high degree of morbidity and mortality in humans. This is especially true in the context of developing countries, which account for 99% of the world's biomass fuel use. Biomass fuel consists of fire wood, dung cakes, agricultural crop residues such as straw, grass, and shrubs, coal fuels and kerosene. Together, they supply 75% of the domestic energy in India. An estimated three-quarters of Indian households use biomass fuel as the primary means for domestic cooking. Ninety percent of rural households and 32% of urban households cook their meals on a biomass stove. There are wide variations between the rural and urban households regarding the specific type of biomass fuel used. Globally, almost 2 million deaths per year are attributable to solid fuel use, with more than 99% of these occurring in developing countries. Biomass fuel accounts for 5-6% of the national burden of disease. Burning biomass fuels emits toxic fumes into the air that consist of small solid particles, carbon monoxide, polyorganic and polyaromatic hydrocarbons, and formaldehyde. Exposure to biomass fuels has been found to be associated with many respiratory diseases such as acute lower respiratory infections, chronic obstructive pulmonary disease, lung cancer, pulmonary tuberculosis, and asthma. Biomass fuel exposure is closely related to the burden of disease in India. Hopes are that future studies will examine the morbidity associated with biomass exposure and seek to prevent it. Concerted efforts to improve stove design and transition to high-efficiency low-emission fuels may reduce respiratory disease associated with biomass fuel exposure.


The hippocampus and the regulation of human food intake.
Human and animal data suggest that the hippocampus plays certain roles in regulating food intake. However, its actual role may be far broader than currently envisaged, a claim suggested by the centrality of the hippocampus to so many aspects of human/animal cognition. Understanding these ingestion-related functions is especially significant. This is because some degree of hippocampal impairment may be quite common, resulting for example from a Western-style diet, insomnia, diabetes, and depression-among many other causes. One potential consequence of hippocampal impairment could be a loosening of food intake regulation, leading in the longer-term to weight gain and its health-related impacts. Here we review known, suspected and newly hypothesized hippocampal-dependent functions involved in regulating human food intake: (a) declarative memory processes, and their use in explicitly evaluating when, what and how much to eat; (b) interoception, as it relates to hunger, fullness and thirst; (c) inhibitory processes, especially as applied to physiological state, place, and time, and their role in modulating memory retrieval; (d) craving and imagery for food; (e) perception of time and its role in preparing the body for food intake and estimating meal length; (f) trace conditioning and nutrient-related learning; and (g) inhibition of the hypothalamic-pituitary-adrenal stress response and stress-related eating. For each we present evidence for hippocampal involvement, describe the putative regulatory role, and the hypothesized effects of hippocampal impairment. We conclude that the hippocampus is intimately involved in regulating human food intake via multiple interconnected pathways, many of which are unstudied and understudied. (PsycINFO Database Record


Motor coding in floccular climbing fibers.
The climbing fibers (CFs) that project from the dorsal cap of the inferior olive (IO) to the flocculus of the cerebellar cortex have been reported to be purely sensory, encoding "retinal slip." However, a clear oculomotor projection from the nucleus prepositus hypoglossi (NPH) to the IO has been shown. We therefore studied the sensorimotor information that is present in the CF signal. We presented rabbits with visual motion noise stimuli to break up the tight relation between instantaneous retinal slip and eye movement. Strikingly, the information about the motor behavior in the CF signal more than doubled that of the sensory component and was time-locked more tightly. The contribution of oculomotor signals was independently confirmed by analysis of spontaneous eye movements in the absence of visual input. The motor component of the CF code is essential to distinguish unexpected slip from self-generated slip, which is a prerequisite for proper oculomotor learning.


The degradation and performance of electrospun supramolecular vascular scaffolds examined upon in vitro enzymatic exposure.
To maintain functionality during in situ vascular regeneration, the rate of implant degradation should be closely balanced by neo-tissue formation. It is unknown, however, how the implant's functionality is affected by the degradation of the polymers it is composed of. We therefore examined the macro- and microscopic features as well as the mechanical performance of vascular scaffolds upon in vitro enzymatic degradation. Three candidate biomaterials with supramolecularly interacting bis-urea (BU) hard blocks ('slow-degrading' polycarbonate-BU (PC-BU), 'intermediate-degrading' polycarbonate-ester-BU (PC(e)-BU), and 'fast-degrading' polycaprolactone-ester-BU (PCL-BU)) were synthesized and electrospun into microporous scaffolds. These materials possess a sequence-controlled macromolecular structure, so their susceptibility to degradation is tunable by controlling the nature of the polymer backbone. The scaffolds were incubated in lipase and monitored for changes in physical, chemical, and mechanical properties. Remarkably, comparing PC-BU to PC(e)-BU, we observed that small changes in macromolecular structure led to significant differences in degradation kinetics. All three scaffold types degraded via surface erosion, which was accompanied by fiber swelling for PC-BU scaffolds, and some bulk degradation and a collapsing network for PCL-BU scaffolds. For the PC-BU and PC(e)-BU scaffolds this resulted in retention of mechanical properties, whereas for the PCL-BU scaffolds this resulted in stiffening. Our in vitro study demonstrates that vascular scaffolds, electrospun from sequence-controlled supramolecular materials with varying ester contents, not only display different susceptibilities to degradation, but also degrade via different mechanisms. STATEMENT OF SIGNIFICANCE: One of the key elements to successfully engineer vascular tissues in situ, is to balance the rate of implant degradation and neo-tissue formation. Due to their tunable properties, supramolecular polymers can be customized into attractive biomaterials for vascular tissue engineering. Here, we have exploited this tunability and prepared a set of polymers with different susceptibility to degradation. The polymers, which were electrospun into microporous scaffolds, displayed not only different susceptibilities to degradation, but also obeyed different degradation mechanisms. This study illustrates how the class of supramolecular polymers continues to represent a promising group of materials for tissue engineering approaches.


Management of the lymph nodes in penile cancer.
A comprehensive literature study was conducted to evaluate the levels of evidence (LEs) in publications on the diagnosis and staging of penile cancer. Recommendations from the available evidence were formulated and discussed by the full panel of the International Consultation on Penile Cancer in November 2008. The final grades of recommendation (GRs) were assigned according to the LE of the relevant publications. The following consensus recommendations were accepted. Fine needle aspiration cytology should be performed in all patients (with ultrasound guidance in those with nonpalpable nodes). If the findings are positive, therapeutic, rather than diagnostic, inguinal lymph node dissection (ILND) can be performed (GR B). Antibiotic treatment for 3-6 weeks before ILND in patients with palpable inguinal nodes is not recommended (GR B). Abdominopelvic computed tomography (CT) and magnetic resonance imaging (MRI) are not useful in patients with nonpalpable nodes. However, they can be used in those with large, palpable inguinal nodes (GR B). The statistical probability of inguinal micrometastases can be estimated using risk group stratification or a risk calculation nomogram (GR B). Surveillance is recommended if the nomogram probability of positive nodes is <0.1 (10%). Surveillance is also recommended if the primary lesion is grade 1, pTis, pTa (verrucous carcinoma), or pT1, with no lymphovascular invasion, and clinically nonpalpable inguinal nodes, but only provided the patient is willing to comply with regular follow-up (GR B). In the presence of factors that impede reliable surveillance (obesity, previous inguinal surgery, or radiotherapy) prophylactic ILND might be a preferable option (GR C). In the intermediate-risk group (nomogram probability .1-.5 [10%-50%] or primary tumor grade 1-2, T1-T2, cN0, no lymphovascular invasion), surveillance is acceptable, provided the patient is informed of the risks and is willing and able to comply. If not, sentinel node biopsy (SNB) or limited (modified) ILND should be performed (GR B). In the high-risk group (nomogram probability >.5 [50%] or primary tumor grade 2-3 or T2-T4 or cN1-N2, or with lymphovascular invasion), bilateral ILND should be performed (GR B). ILND can be performed at the same time as penectomy, instead of 2-6 weeks later (GR C). SNB based on the anatomic position can be performed, provided the patient is willing to accept the potential false-negative rate of </=25% (GR C). Dynamic SNB with lymphoscintigraphic and blue dye localization can be performed if the technology and expertise are available (GR C). Limited ILND can be performed instead of complete ILND to reduce the complication rate, although the false-negative rate might be similar to that of anatomic SNB (GR C). Frozen section histologic examination can be used during SNB or limited ILND. If the results are positive, complete ILND can be performed immediately (GR C). In patients with cytologically or histologically proven inguinal metastases, complete ILND should be performed ipsilaterally (GR B). In patients with histologically confirmed inguinal metastases involving >/=2 nodes on one side, contralateral limited ILND with frozen section analysis can be performed, with complete ILND if the frozen section analysis findings are positive (GR B). If clinically suspicious inguinal metastases develop during surveillance, complete ILND should be performed on that side only (GR B), and SNB or limited ILND with frozen section analysis on the contralateral side can be considered (GR C). Endoscopic ILND requires additional study to determine the complication and long-term survival rates (GR C). Pelvic lymph node dissection is recommended if >/=2 proven inguinal metastases, grade 3 tumor in the lymph nodes, extranodal extension (ENE), or large (2-4 cm) inguinal nodes are present, or if the femoral (Cloquet's) node is involved (GR C). Performing ILND before pelvic lymph node dissection is preferable, because pelvic lymph node dissection can be avoided in patients with minimal inguinal metastases, thus avoiding the greater risk of chronic lymphedema (GR B). In patients with numerous or large inguinal metastases, CT or MRI should be performed. If grossly enlarged iliac nodes are present, neoadjuvant chemotherapy should be given and the response assessed before proceeding with pelvic lymph node dissection (GR C). Antibiotic treatment should be started before surgery to minimize the risk of wound infection (GR C). Perioperative low-dose heparin to prevent thromboembolic complications can be used, although it might increase lymph leakage (GR C). The skin incision for ILND should be parallel to the inguinal ligament, and sufficient subcutaneous tissue should be preserved to minimize the risk of skin flap necrosis (GR B). Sartorius muscle transposition to cover the femoral vessels can be used in radical ILND (GR C). Closed suction drainage can be used after ILND to prevent fluid accumulation and wound breakdown (GR B). Early mobilization after ILND is recommended, unless a myocutaneous flap has been used (GR B). Elastic stockings or sequential compression devices are advisable to minimize the risk of lymphedema and thromboembolism (GR C). Radiotherapy to the inguinal areas is not recommended in patients without cytologically or histologically proven metastases nor in those with micrometastases, but it can be considered for bulky metastases as neoadjuvant therapy to surgery (GR B). Adjuvant radiotherapy after complete ILND can be considered in patients with multiple or large inguinal metastases or ENE (GR C). Adjuvant chemotherapy after complete ILND can be used instead of radiotherapy in patients with >/=2 inguinal metastases, large nodes, ENE, or pelvic metastases (GR C). Follow-up should be individualized according to the histopathologic features and the management chosen for the primary tumor and inguinal nodes (GR B).


Effect of internet-based attention bias modification on the anxiety of Japanese workers: A randomized controlled trial.
This study comprised a randomized controlled trial to examine the effect of internet-based attention bias modification (iABM) on reducing workers' anxiety. In total, 300 eligible participants were randomized according to sex and age; 180 were assigned to the intervention group and 120 to the control group. The word stimuli used in the iABM included eight positive words and eight neutral words. Participants were instructed to indicate the positive word's position as quickly and accurately as possible by tapping one of the two directions on display. The intervention included five sessions per participant over 1 month, resulting in a total of 600 trials. The main outcome measure was the total state anxiety score of the State-Trait Anxiety Inventory (STAI). There was no significant difference in the net change in STAI scores between the intervention and control groups. The mean reaction time of the fifth session was significantly shorter than the mean reaction time of the first session. Furthermore, although there was no effect on the index of effect size Δ, the paired t-test showed a significant decrease in the anxiety score. The iABM intervention in this study did not enhance the amelioration of workers' anxiety when compared with the control condition.


Leelamine mediates cancer cell death through inhibition of intracellular cholesterol transport.
Leelamine is a promising compound for the treatment of cancer; however, the molecular mechanisms leading to leelamine-mediated cell death have not been identified. This report shows that leelamine is a weakly basic amine with lysosomotropic properties, leading to its accumulation inside acidic organelles such as lysosomes. This accumulation leads to homeostatic imbalance in the lysosomal endosomal cell compartments that disrupts autophagic flux and intracellular cholesterol trafficking as well as receptor-mediated endocytosis. Electron micrographs of leelamine-treated cancer cells displayed accumulation of autophagosomes, membrane whorls, and lipofuscin-like structures, indicating disruption of lysosomal cell compartments. Early in the process, leelamine-mediated killing was a caspase-independent event triggered by cholesterol accumulation, as depletion of cholesterol using β-cyclodextrin treatment attenuated the cell death and restored the subcellular structures identified by electron microscopy. Protein microarray-based analyses of the intracellular signaling cascades showed alterations in RTK-AKT/STAT/MAPK signaling cascades, which was subsequently confirmed by Western blotting. Inhibition of Akt, Erk, and Stat signaling, together with abnormal deregulation of receptor tyrosine kinases, was caused by the inhibition of receptor-mediated endocytosis. This study is the first report demonstrating that leelamine is a lysosomotropic, intracellular cholesterol transport inhibitor with potential chemotherapeutic properties leading to inhibition of autophagic flux and induction of cholesterol accumulation in lysosomal/endosomal cell compartments. Importantly, the findings of this study show the potential of leelamine to disrupt cholesterol homeostasis for treatment of advanced-stage cancers.


Optimal decision network with distributed representation.
On the basis of detailed analysis of reaction times and neurophysiological data from tasks involving choice, it has been proposed that the brain implements an optimal statistical test during simple perceptual decisions. It has been shown recently how this optimal test can be implemented in biologically plausible models of decision networks, but this analysis was restricted to very simplified localist models which include abstract units describing activity of whole cell assemblies rather than individual neurons. This paper derives the optimal parameters in a model of a decision network including individual neurons, in which the alternatives are represented by distributed patterns of neuronal activity. It is also shown how the optimal weights in the decision network can be learnt via iterative rules using information accessible for individual synapses. Simulations demonstrate that the network with the optimal synaptic weights achieves better performance and matches fundamental behavioural regularities observed in choice tasks (Hick's law and the relationship between the error rate and the time for decision) better than a network with synaptic weights set according to a standard Hebb rule.


Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection.
Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.


Rotation-Covariant Texture Learning Using Steerable Riesz Wavelets.
We propose a texture learning approach that exploits local organizations of scales and directions. First, linear combinations of Riesz wavelets are learned using kernel support vector machines. The resulting texture signatures are modeling optimal class-wise discriminatory properties. The visualization of the obtained signatures allows verifying the visual relevance of the learned concepts. Second, the local orientations of the signatures are optimized to maximize their responses, which is carried out analytically and can still be expressed as a linear combination of the initial steerable Riesz templates. The global process is iteratively repeated to obtain final rotation-covariant texture signatures. Rapid convergence of class-wise signatures is observed, which demonstrates that the instances are projected into a feature space that leverages the local organizations of scales and directions. Experimental evaluation reveals average classification accuracies in the range of 97% to 98% for the Outex_TC_00010, the Outex_TC_00012, and the Contrib_TC_00000 suites for even orders of the Riesz transform, and suggests high robustness to changes in images orientation and illumination. The proposed framework requires no arbitrary choices of scales and directions and is expected to perform well in a large range of computer vision applications.


Deaf moths employ acoustic Müllerian mimicry against bats using wingbeat-powered tymbals.
Emitting ultrasound upon hearing an attacking bat is an effective defence strategy used by several moth taxa. Here we reveal how Yponomeuta moths acquire sophisticated acoustic protection despite being deaf themselves and hence unable to respond to bat attacks. Instead, flying Yponomeuta produce bursts of ultrasonic clicks perpetually; a striated patch in their hind wing clicks as the beating wing rotates and bends. This wing structure is strikingly similar to the thorax tymbals with which arctiine moths produce their anti-bat sounds. And indeed, Yponomeuta sounds closely mimic such arctiine signals, revealing convergence in form and function. Because both moth taxa contain noxious compounds, we conclude they are mutual Müllerian acoustic mimics. Yponomeuta's perpetual clicking would however also attract bat predators. In response, their click amplitude is reduced and affords acoustic protection just as far as required, matching the distance over which bat biosonar would pick up Yponomeuta echoes anyway - advanced acoustic defences for a deaf moth.


Efficacy of a herbal toothpaste on patients with established gingivitis--a randomized controlled trial.
The aim of this randomised, double blind controlled trial was to verify the efficacy of a herbal dentifrice on the reduction of plaque and gingivitis. Forty eight volunteers with established gingivitis were randomly assigned to either a test group (herbal dentifrice) or positive control group (dentifrice with triclosan and fluoride). The dentifrices were distributed in plain white tubes by an independent pharmacy, which revealed the contents of each tube only after the experimental period. Plaque and gingivitis assessments were carried out on baseline and after 28 days of product use. All examinations were conducted by the same calibrated investigator. Subjects were instructed to brush their teeth three times daily using their assigned dentifrice for 28 days. There was a significant reduction in plaque levels in both the test and control groups. However, there was no significant difference between the groups. A significant reduction in gingivitis was observed in both groups, although there was no significant difference between them. No adverse reactions were reported. The authors concluded that both dentifrices were effective in reducing plaque and gingivitis in subjects with established gingivitis.


Broadband emission spectrum dynamics of large water droplets exposed to intense ultrashort laser radiation.
We report on experiments on the interaction of a gigawatt femtosecond laser pulse train with hanging isolated millimeter-sized water droplets. A transparent droplet experienced explosive boiling-up and emitted light in the visible spectrum as a result of laser-induced plasma formed inside the droplet volume. The droplet emission spectra showed remarkable broadening, depending on the laser power. The role of pulse self-phase modulation in measured spectral broadening when the pulse propagates through the droplet is discussed.


Which resources should be used to identify RCT/CCTs for systematic reviews: a systematic review.
Systematic reviewers seek to comprehensively search for relevant studies and summarize these to present the most valid estimate of intervention effectiveness. The more resources searched, the higher the yield, and thus time and costs required to conduct a systematic review. While there is an abundance of evidence to suggest how extensive a search for randomized controlled trials (RCTs) should be, it is neither conclusive nor consistent. This systematic review was conducted in order to assess the value of different resources to identify trials for inclusion in systematic reviews. Seven electronic databases, four journals and Cochrane Colloquia were searched. Key authors were contacted and references of relevant articles screened. Included studies compared two or more sources to find RCTs or controlled clinical trials (CCTs). A checklist was developed and applied to assess quality of reporting. Data were extracted by one reviewer and checked by a second. Medians and ranges for precision and recall were calculated; results were grouped by comparison. Meta-analysis was not performed due to large heterogeneity. Subgroup analyses were conducted for: search strategy (Cochrane, Simple, Complex, Index), expertise of the searcher (Cochrane, librarian, non-librarian), and study design (RCT and CCT). Sixty-four studies representing 13 electronic databases met inclusion criteria. The most common comparisons were MEDLINE vs. handsearching (n = 23), MEDLINE vs. MEDLINE+handsearching (n = 13), and MEDLINE vs. reference standard (n = 13). Quality was low, particularly for the reporting of study selection methodology. Overall, recall and precision varied substantially by comparison and ranged from 0 to 100% and 0 to 99%, respectively. The trial registries performed the best with median recall of 89% (range 84, 95) and median precision of 96.5% (96, 97), although these results are based on a small number of studies. Inadequate or inappropriate indexing was the reason most cited for missing studies. Complex and Cochrane search strategies (SS) performed better than Simple SS. Multiple-source comprehensive searches are necessary to identify all RCTs for a systematic review, although indexing needs to be improved. Although trial registries demonstrated the highest recall and precision, the Cochrane SS or a Complex SS in consultation with a librarian are recommended. Continued efforts to develop CENTRAL should be supported.


Engineering Yarrowia lipolytica as a Chassis for De Novo Synthesis of Five Aromatic-Derived Natural Products and Chemicals.
Yarrowia lipolytica is a novel microbial chassis to upgrade renewable low-cost carbon feedstocks to high-value commodity chemicals and natural products. In this work, we systematically characterized and removed the rate-limiting steps of the shikimate pathway and achieved de novo synthesis of five aromatic chemicals in Y. lipolytica. We determined that eliminating amino acids formation and engineering feedback-insensitive DAHP synthases are critical steps to mitigate precursor competition and relieve the feedback regulation of the shikimate pathway. Further overexpression of heterologous phosphoketolase and deletion of pyruvate kinase provided a sustained metabolic driving force that channels E4P (erythrose 4-phosphate) and PEP (phosphoenolpyruvate) precursors through the shikimate pathway. Precursor competing pathways and byproduct formation pathways were also blocked by inactivating chromosomal genes. To demonstrate the utility of our engineered chassis strain, three natural products, 2-phenylethanol (2-PE), p-coumaric acid, and violacein, which were derived from phenylalanine, tyrosine, and tryptophan, respectively, were chosen to test the chassis performance. We obtained 2426.22 ± 48.33 mg/L of 2-PE, 593.53 ± 28.75 mg/L of p-coumaric acid, 12.67 ± 2.23 mg/L of resveratrol, 366.30 ± 28.99 mg/L of violacein, and 55.12 ± 2.81 mg/L of deoxyviolacein from glucose in a shake flask. The 2-PE production represents a 286-fold increase over the initial strain (8.48 ± 0.50 mg/L). Specifically, we obtained the highest 2-PE, violacein, and deoxyviolacein titer ever reported from the de novo shikimate pathway in yeast. These results set up a new stage of engineering Y. lipolytica as a sustainable biorefinery chassis strain for de novo synthesis of aromatic compounds with economic values.


Periocular and orbital amyloidosis: clinical characteristics, management, and outcome.
To present the clinical features and management outcome in a large series of patients with periocular and orbital amyloidosis. Retrospective, noncomparative, interventional case series. All patients diagnosed with periocular and orbital amyloidosis in 6 oculoplastic and orbital units. Clinical records of all patients were reviewed. Clinical presentation, radiological and histological findings, treatment modalities, and outcome. The study included 24 patients (15 female, 9 male) with a mean age of 57+/-17 years. Nineteen cases were unilateral, and 5 were bilateral. Clinical signs and symptoms included a visible or palpable periocular mass or tissue infiltration (95.8%), ptosis (54.2%), periocular discomfort or pain (25%), proptosis or globe displacement (21%), limitations in ocular motility (16.7%), recurrent periocular subcutaneous hemorrhages (12.5%), and diplopia (8.3%). Seven cases had orbital involvement, and 17 were periocular. Immunohistochemistry in 7 patients showed B cells or plasma cells producing monoclonal immunoglobulin chains that were deposited as amyloid light chains. Only 1 patient was diagnosed with systemic amyloid light chain amyloidosis. Treatment modalities were mainly observation and surgical debulking. During a mean follow-up period of 39 months, 21% showed significant progression after treatment, whereas 79% were stable or showed no recurrence after treatment. Periocular and orbital amyloidosis may present with a wide spectrum of clinical findings and result in significant ocular morbidity. Complete surgical excision is not feasible in many cases, and the goal of treatment is to preserve function and to prevent sight-threatening complications.


The effects of cryopreserved red blood cell transfusion on tissue oxygenation in obese trauma patients.
Low tissue oxygenation (StO2) is associated with poor outcomes in obese trauma patients. A novel treatment could be the transfusion of cryopreserved packed red blood cells (CPRBCs), which the in vitro biochemical profile favors red blood cell (RBC) function. We hypothesized that CPRBC transfusion improves StO2 in obese trauma patients. Two hundred forty-three trauma patients at five Level I trauma centers who required RBC transfusion were randomized to receive one to two units of liquid packed RBCs (LPRBCs) or CPRBCs. Demographics, injury severity, StO2, outcomes, and biomarkers of RBC function were compared in nonobese (body mass index [BMI] < 30) and obese (BMI ≥ 30) patients. StO2 was also compared between obese patients with BMI of 30 to 34.9 and BMI ≥ 35. StO2 was normalized and expressed as % change after RBC transfusion. A p value less than 0.05 indicated significance. Patients with BMI less than 30 (n = 141) and BMI of 30 or greater (n = 102) had similar Injury Severity Score, Glasgow Coma Scale, and baseline StO2. Plasma levels of free hemoglobin, an index of RBC lysis, were lower in obese patients after CPRBC (125 [72-259] μg/mL) versus LPRBC transfusion (230 [178-388] μg/mL; p < 0.05). StO2 was similar in nonobese patients regardless of transfusion type, but improved in obese patients who received CPRBCs (104 ± 1%) versus LPRPCs (99 ± 1%, p < 0.05; 8 hours after transfusion). Subanalysis showed improved StO2 after CPRBC transfusion was specific to BMI of 35 or greater, starting 5 hours after transfusion (p < 0.05 vs. LPRBCs). CPRBCs did not improve clinical outcomes in either group. CPRBC transfusion is associated with increased StO2 and lower free hemoglobin levels in obese trauma patients, but did not improve clinical outcomes. Future studies are needed to determine if CPRBC transfusion in obese patients attenuates hemolysis to improve StO2. Therapeutic, level IV.


Seasonal genotype dynamics of a marine dinoflagellate: Pelagic populations are homogeneous and as diverse as benthic seed banks.
Genetic diversity is the basis for evolutionary adaptation and selection under changing environmental conditions. Phytoplankton populations are genotypically diverse, can become genetically differentiated within small spatiotemporal scales and many species form resting stages. Resting stage accumulations in sediments (seed banks) are expected to serve as reservoirs for genetic information, but so far their role in maintaining phytoplankton diversity and in evolution has remained unclear. In this study we used the toxic dinoflagellate Alexandrium ostenfeldii (Dinophyceae) as a model organism to investigate if (i) the benthic seed bank is more diverse than the pelagic population and (ii) the pelagic population is seasonally differentiated. Resting stages (benthic) and plankton (pelagic) samples were collected at a coastal bloom site in the Baltic Sea, followed by cell isolation and genotyping using microsatellite markers (MS) and restriction site associated DNA sequencing (RAD). High clonal diversity (98%-100%) combined with intermediate to low gene diversity (0.58-0.03, depending on the marker) was found. Surprisingly, the benthic and pelagic fractions of the population were equally diverse, and the pelagic fraction was temporally homogeneous, despite seasonal fluctuation of environmental selection pressures. The results of this study suggest that continuous benthic-pelagic coupling, combined with frequent sexual reproduction, as indicated by persistent linkage equilibrium, prevent the dominance of single clonal lineages in a dynamic environment. Both processes harmonize the pelagic with the benthic population and thus prevent seasonal population differentiation. At the same time, frequent sexual reproduction and benthic-pelagic coupling maintain high clonal diversity in both habitats.


Facing the future of substance use disorders treatment in Vietnam - A case study for international development and cooperation.
Vietnam made progress transitioning from a criminal justice to a health treatment response for substance use disorders (SUD) in recent years. This case study describes the evolution of Vietnam's SUD treatment system from 2005 to 2020 to understand and learn from the phases of its development. The case study is based on data from a predesigned interview guide for 47 respondents, literature and policy desk review and direct experience of the authors. Vietnam saw remarkable growth of opioid use disorder (OUD) treatment from 2005 when methadone was unavailable, to 2020 with 335 methadone clinics in all 63 provinces serving more than 52,200 patients. The growth in OUD treatment accounts for much of Vietnam's success managing its HIV epidemic for which injection drug use was a major vector. An unintended consequence, however, focused only on OUD as a strategy to address HIV and was unable to address multiple substances. Most elements of a modern evidence and community-based SUD treatment system exist in Vietnam; however, they are siloed and influenced by multiple government administrative jurisdictions. Faced with rising amphetamine and persistent alcohol use, the path ahead for Vietnam involves a choice between a reliance on compulsory rehabilitation centers or a plan to broaden the scope of substances and treatments, and further integrate with Vietnam's commune-based primary health system.


Past and present physical activity and endometrial cancer risk.
We examined the relation between physical activity and endometrial cancer using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. Estimates of recreational (i.e. active sport, walks and hikes) and nonrecreational activity (i.e. house cleaning, climbing stairs and walking or standing on the job) were obtained using interview information. After adjustment for age, study area, education, parity, years of use of oral contraceptives, years of use of menopausal oestrogens and cigarette smoking, recent recreational inactivity was associated with increased risk (RR = 1.9 for lowest vs highest tertile). Similarly, recent nonrecreational inactivity was associated with increased risk (RR = 2.2 for lowest vs highest tertile). Further adjustment for body mass and nonrecreational activity attenuated the association between risk and recent recreational inactivity (RR = 1.2; 95% CL = 0.7-2.0) but adjustment for body mass and recreational activity did not alter the association between risk and recent nonrecreational inactivity (RR = 2.0; 95% CL = 1.2-3.1). To evaluate the relation between risk and sustained inactivity, we simultaneously examined activity levels at three periods (RR i.e. age 20-29, age 30-39 and recently) in women age 50 and older. After adjustment for potential confounders and body mass, risk was elevated among women who were always recreationally inactive (RR = 1.5 for always active vs always inactive) and among women who were always nonrecreationally inactive (RR = 1.6 for always active vs always inactive). This study suggests that physically inactive women may be at increased risk of endometrial cancer because they are more likely to be overweight or obese. Our data also suggest that inactivity per se may be associated with an increased risk of endometrial cancer. However, we cannot rule out the possibility that our results, particularly those for nonrecreational activity, reflect unmeasured confounding factors. Future studies should attempt to obtain more detailed assessments of physical activity, including the intensity with which an individual engaged in an activity and the actual time involved in exertion.


In vitro digestion testing of lipid-based delivery systems: calcium ions combine with fatty acids liberated from triglyceride rich lipid solutions to form soaps and reduce the solubilization capacity of colloidal digestion products.
In vitro digestion testing is of practical importance to predict the fate of drugs administered in lipid-based delivery systems. Calcium ions are often added to digestion media to increase the extent of digestion of long-chain triglycerides (LCTs), but the effects they have on phase behaviour of the products of digestion, and consequent drug solubilization, are not well understood. This study investigates the effect of calcium and bile salt concentrations on the rate and extent of in vitro digestion of soybean oil, as well as the solubilizing capacity of the digestion products for two poorly water-soluble drugs, fenofibrate and danazol. In the presence of higher concentrations of calcium ions, the solubilization capacities of the digests were reduced for both drugs. This effect is attributed to the formation of insoluble calcium soaps, visible as precipitates during the digestions. This reduces the availability of liberated fatty acids to form mixed micelles and vesicles, thereby reducing drug solubilization. The use of high calcium concentrations does indeed force in vitro digestion of LCTs but may overestimate the extent of drug precipitation that occurs within the intestinal lumen.


Proinflammatory Action of a New Electronegative Low-Density Lipoprotein Epitope.
The electronegative low-density lipoprotein, LDL (-), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (-) were mapped using a phage display library of peptides and monoclonal antibodies reactive to this modified lipoprotein. Two different peptide libraries (X6 and CX8C for 6- and 8-amino acid-long peptides, respectively) were used in the mapping. Among all tested peptides, two circular peptides, P1A3 and P2C7, were selected based on their high affinities for the monoclonal antibodies. Small-angle X-ray scattering analysis confirmed their structures as circular rings. P1A3 or P2C7 were quickly internalized by bone marrow-derived murine macrophages as shown by confocal microscopy. P2C7 increased the expression of TNFα, IL-1 β and iNOS as well as the secretion of TNFα, CCL2, and nitric oxide by murine macrophages, similar to the responses induced by LDL (-), although less intense. In contrast, P1A3 did not show pro-inflammatory effects. We identified a mimetic epitope associated with LDL (-), the P2C7 circular peptide, that activates macrophages. Our data suggest that this conformational epitope represents an important danger-associated molecular pattern of LDL (-) that triggers proinflammatory responses.


Conditional survival after surgical resection of colorectal liver metastasis: an international multi-institutional analysis of 949 patients.
Traditionally, survival estimates have been reported solely as survival from the time of surgery, but future survival probability likely changes based on the survival time already accumulated after therapy-otherwise known as conditional survival (CS). We sought to assess the comparative performance of various colorectal liver metastasis prognostic scoring systems, as well as to investigate the CS of patients who underwent resection of colorectal liver metastasis. Between 1982 and 2008, 949 patients who underwent colorectal liver metastasis resection were identified from an international multi-institutional database. Various prognostic scoring systems were evaluated using Cox proportional hazards models and calculated concordance index (c). CS estimates were calculated as CS = S((x+5))/S((x)). Overall survival after liver resection was 65% at 3 years and 45% at 5 years, with a median survival of 52 months. All of the prognostic scoring systems had poor-to-moderate prognostic discriminatory ability (Fong c = 0.57, Nordlinger c = 0.56, Memorial Sloan-Kettering Cancer Center nomogram c = 0.58). Using CS, the probability of surviving an additional 5 years, given that the patient had already survived 1, 3, or 5 years, was 41%, 40%, or 50%, respectively. The inadequate performance of the prognostic scoring systems was explained by the fact that as survival from liver resection increased from 0 to 5 years, the 5-year observed CS improved substantially for patients who were initially predicted to have poor survival at the time of surgery. Colorectal liver metastasis prognostic scoring systems have fair-to-moderate performance. CS can provide more accurate prognostic information for patients and physicians after colorectal liver metastasis resection and should be incorporated into the quantification of survival.


Intussusceptive Pillar Formation in Developing Porcine Glomeruli.
Intussusceptive angiogenesis (IA) is a dynamic process which contributes to vascular expansion and remodeling. Intraluminal pillars have long been the distinctive structural indicator of IA. However, the mechanism of their formation has not been fully elucidated. Using light and electron microscopy, we studied intussusceptive vascular growth in the developing porcine metanephric kidney. We observed intraluminal pillars formed by endothelial cells in the vasculature of developing glomeruli. Their diameter was < 2.5 µm, consistent with the diameter of nascent pillars. TEM revealed that the majority of these pillars consisted only of endothelium. However, a central core of extracellular matrix (ECM) covered by endothelium, reminiscent of a more mature intussusceptive pillar, was also found in the lumen of a glomerular capillary. Perivascular cells or pericytes were not involved in the pillar structure during these stages of formation. This study shows ECM presence in a mature intussusceptive pillar without any perivascular cell involvement in the structure. This leads to the hypothesis that ECM deposition precedes the participation of these cells in the formation of intraluminal pillars during IA in porcine metanephric glomerular capillaries.


Treatment of central sleep apnea in U.S. veterans.
There are no standard therapies for the management of central sleep apnea (CSA). Either positive pressure therapy (PAP) or supplemental oxygen (O(2)) may stabilize respiration in CSA by reducing ventilatory chemoresponsiveness. Additionally, increasing opioid use and the presence of comorbid conditions in US veterans necessitates investigations into alternative titration protocols to treat CSA. The goal was to report on the effectiveness of titration with PAP, used alone or in conjunction with O(2), for the management of CSA associated with varying comorbidities and opioid use. This was a retrospective chart review over 3 years, performed at a VA sleep disorders center. The effects of CPAP, CPAP+O(2), and BPAP+O(2), used in a step-wise titration protocol, on consecutive patients diagnosed with CSA were studied. CSA was diagnosed in 162 patients. The protocol was effective in eliminating CSA (CAI ≤ 5/h) in 84% of patients. CPAP was effective in 48%, while CPAP+O(2) combination was effective in an additional 25%, and BPAP+O(2) in 11%. The remaining 16% were non-responders. Forty-seven patients (29%) were on prescribed opioid therapy for chronic pain, in whom CPAP, CPAP+O(2), or BPAP+O(2) eliminated CSA in 54%, 28%, and 10% cases, respectively. CPAP, CPAP+O(2), and BPAP+O(2) each produced significant declines in the AHI, CAI, and arousal index, and an increase in the SpO(2). The data demonstrate that using a titration protocol with CPAP and then PAP with O(2) effectively eliminates CSA in individuals with underlying comorbid conditions and prescription opioid use. Comparative studies with other therapeutic modalities are required.


Association of a 62 Variants Type 2 Diabetes Genetic Risk Score With Markers of Subclinical Atherosclerosis: A Transethnic, Multicenter Study.
Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci.


Assessment of Musculoskeletal Strength and Levels of Fatigue during Different Phases of Menstrual Cycle in Young Adults.
Some of the physiological factors and athletic performance might show variation along the phases of menstrual cycle. The alterations seen in these physiological parameters of various systems relating to oscillations in hormonal levels do affect the autonomic nervous system and metabolic functions. Former studies heave inconclusively about the influence of hormones on exercise performance, predominantly muscle strength and rate of fatigue during different phases of the menstrual cycle. Studies regarding influence of these variations during bleeding phase were not done. To evaluate the muscle strength variations and also the rate of fatigue during various phases of the menstrual cycle in young adults. This was a prospective study conducted among 100 healthy adult female volunteers aged 18-24 years, with normal regular menstrual cycles persistent between 26- 32 days (average of 28 days), for a minimum of last 6 months. Muscle strength was assessed by calculating the work done and fatigue rate using Mosso's ergograph and by handgrip dynamometer strength. Each subject was evaluated consecutively for two menstrual cycles in all three phases which were classified as Phase 1- Menstrual phase, Phase 2- Follicular phase and Phase 3- Luteal phase. The data obtained was analysed by statistical tool One-way ANOVA followed by a post-hoc Tukeys test. A p-value of ≤ 0.05 was considered significant. The amount of work done and handgrip strength was significantly higher in phase 2 (p<0.001) and relatively reduced in phase 1 and 3 (p<0.001) of menstrual cycle. In terms of fatigue rate percentage, phase 2 showed significantly lesser values (p<0.001) as compared to phase 1 and 3 of menstrual cycle. We conclude that the cyclical variation in endogenous reproductive hormones increases the muscle strength in follicular phase of the menstrual cycle. Thus provide support for the influence of these hormones in regulation of these parameters in the premenopausal age group.


The use of self-report exposure measures among novice motorcyclists: appropriateness and best practice recommendations.
While self-report methods to collect exposure information have large practical advantages in many research contexts, little research has specifically investigated the reliability and validity of motorcyclists' self-reported exposure. The present study aimed to examine the reliability and validity of different self-report exposure measures and to provide recommendations on best practice self-report riding exposure questions. The reliability and validity of different self-report exposure measures were examined amongst novice motorcyclists through t-tests, Bland Altman plots, coefficients of variation, and correlations. The most valid and reliable data was provided when riding exposure was asked for the current average week rather than earlier and longer periods, and in units of time rather than distance or number of trips. The greater reliability of riding exposure found amongst commuting and rural riders compared to recreational and metropolitan riders respectively and at the second interview compared to the first suggests that factors such as riding purposes, geographical locations, and riding experience can contribute to measurement error. If self-reported odometer readings are used, questions on whether the respondents share their own bike or ride more than one bike, and a built-in process to ensure respondents report the exact odometer reading on their bike are recommended. It is recommended that self-report riding exposure questions ask about the hours of riding for the current average week, and data on riding purposes, locations, and experience are also collected.


Effects of Size-Fractionated Particulate Matter on Cellular Oxidant Radical Generation in Human Bronchial Epithelial BEAS-2B Cells.
The aim of the present study was to investigate the effects of size-fractionated (i.e., <1; 1-2.5, and 2.5-10 µm in an aerodynamic diameter) ambient particulate matter (PM) on reactive oxygen species (ROS) activity and cell viability in human bronchial epithelial cells (BEAS-2B). The PM samples were collected from an urban site (uPM) in Beijing and a steel factory site (sPM) in Anshan, China, from March 2013 to December 2014. Metal elements, organic and elemental carbon, and water-soluble inorganic ions in the uPM and sPM were analyzed. The cell viability and ROS generation in PM-exposed BEAS-2B cells were measured by MTS and DCFH-DA. The results showed that both uPM and sPM caused a decrease in the cell viability and an increase in ROS generation. The level of ROS measured in sPM1.0 was approximately triple that in uPM1.0. The results of correlation analysis showed that the ROS activity and cytotoxicity were related to different PM composition. Moreover, deferoxamine (DFO) significantly prevented the increase of ROS generation and the decrease of cell viability. Taken together, our results suggest that the metals absorbed on PM induced oxidant radical generation in BEAS-2B cells that could lead to impairment of pulmonary function.


Cultural Differences in Strength of Conformity Explained Through Pathogen Stress: A Statistical Test Using Hierarchical Bayesian Estimation.
The severity of the environment has been found to have played a selective pressure in the development of human behavior and psychology, and the historical prevalence of pathogens relate to cultural differences in group-oriented psychological mechanisms, such as collectivism and conformity to the in-group. However, previous studies have also proposed that the effectiveness of institutions, rather than pathogen stress, can account for regional variation in group-oriented psychological mechanisms. Moreover, previous studies using nations as units of analysis may have suffered from a problem of statistical non-independence, namely, Galton's problem. The present study tested whether or not regional variation in pathogen stress, rather than government effectiveness, affected collectivism and conformity to social norms by adjusting the effect of global regions using hierarchical Bayesian estimation. We found that the overall effect of pathogen stress remained significant in only one out of the four indices of the regional variability of conformity, and the effects of the government effectiveness also disappeared. Instead, we found that significant effects of both pathogen stress and government effectiveness in specific regions of the world, but these effects were not stable across the measurements. These results indicate that both the effects of pathogen stress and government effectiveness need further reevaluation.


Temporal Changes in the Influence of Hospitals and Regional Healthcare Networks on Severe Sepsis Mortality.
There is systematic variation between hospitals in their care of severe sepsis, but little information on whether this variation impacts sepsis-related mortality, or how hospitals' and health-systems' impacts have changed over time. We examined whether hospital and regional organization of severe sepsis care is associated with meaningful differences in 30-day mortality in a large integrated health care system, and the extent to which those effects are stable over time. In this retrospective cohort study, we used risk- and reliability-adjusted hierarchical logistic regression to estimate hospital- and region-level random effects after controlling for severity of illness using a rich mix of administrative and clinical laboratory data. One hundred fourteen U.S. Department of Veterans Affairs hospitals in 21 geographic regions. Forty-three thousand seven hundred thirty-three patients with severe sepsis in 2012, compared to 33,095 such patients in 2008. None. The median hospital in the worst quintile of performers had a risk-adjusted 30-day mortality of 16.7% (95% CI, 13.5%, 20.5%) in 2012 compared with the best quintile, which had a risk-adjusted mortality of 12.8% (95% CI, 10.7%, 15.3%). Hospitals and regions explained a statistically and clinically significant proportion of the variation in patient outcomes. Thirty-day mortality after severe sepsis declined from 18.3% in 2008 to 14.7% in 2012 despite very similar severity of illness between years. The proportion of the variance in sepsis-related mortality explained by hospitals and regions was stable between 2008 and 2012. In this large integrated healthcare system, there is clinically significant variation in sepsis-related mortality associated with hospitals and regions. The proportion of variance explained by hospitals and regions has been stable over time, although sepsis-related mortality has declined.


Significance of detecting Epstein-Barr-specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients.
Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.


Highly active bifunctional oxygen electrocatalysts derived from nickel- or cobalt-phytic acid xerogel for zinc-air batteries.
Developing highly efficient non-noble metal electrocatalysts for oxygen electrode reactions is highly desirable for industrial scale application in energy related devices. Herein, two new kinds of Ni (POxN3-x)2/NPC and Co (POxN3-x)2/NPC (NPC: N, P-co-doped carbon) are synthesized through a facile post-treatment of nickel- or cobalt-phytic acid xerogel, followed by an annealing procedure under an argon and ammonia atmosphere at 800 °C. The as-prepared catalysts exhibit outstanding catalytic activities for both the oxygen reduction and evolution reactions, which are comparable to those of Pt/C and IrO2. Furthermore, the primary zinc-air batteries assembled with Ni (POxN3-x)2/NPC and Co (POxN3-x)2/NPC as the cathodes show gravimetric energy densities of 894 and 836 W h kgZn-1, which are superior to that of Pt/C (793 W h kgZn-1). In addition, the rechargeable zinc-air battery assembled with Ni (POxN3-x)2/NPC exhibits an excellent round-trip efficiency, which is shown by a slight increase in the sum of the overpotentials for discharge-charge cycling at a current density of 20 mA cm-2, even after experiencing 33 h of testing. To the best of our knowledge, there are few reports on metaphosphate salts where oxygen is partially replaced by nitrogen as bifunctional oxygen electrode catalysts for zinc-air batteries. This work provides an easy, low-cost and scalable avenue to develop new kinds of catalyst for application in energy devices.


Evaluation of BSA protein release from hollow hydroxyapatite microspheres into PEG hydrogel.
Implants that simultaneously function as an osteoconductive matrix and as a device for local drug or growth factor delivery could provide an attractive system for bone regeneration. In our previous work, we prepared hollow hydroxyapatite (abbreviated HA) microspheres with a high surface area and mesoporous shell wall and studied the release of a model protein, bovine serum albumin (BSA), from the microspheres into phosphate-buffered saline (PBS). The present work is an extension of our previous work to study the release of BSA from similar HA microspheres into a biocompatible hydrogel, poly(ethylene glycol) (PEG). BSA-loaded HA microspheres were placed in a PEG solution which was rapidly gelled using ultraviolet radiation. The BSA release rate into the PEG hydrogel, measured using a spectrophotometric method, was slower than into PBS, and it was dependent on the initial BSA loading and on the microstructure of the microsphere shell wall. A total of 35-40% of the BSA initially loaded into the microspheres was released into PEG over ~14 days. The results indicate that these hollow HA microspheres have promising potential as an osteoconductive device for local drug or growth factor delivery in bone regeneration and in the treatment of bone diseases.