Associations between serum selenium and total plasma homocysteine during the acute phase of ischaemic stroke.
Risk of ischaemic stroke (IS) was associated with total homocysteine (tHCY). On the other hand, serum selenium (Se) exhibited anti-aging and cardiopreventive effects. Se and tHCY showed relationships in animals but these were contradictory or inconclusive in humans; therefore, we searched for such associations in acute IS. Ninety-four participants aged around 47 years were identified and 39 patients versus 46 healthy controls were analysed. Clinical, laboratory (blinded) and risk factor questionnaire methods were used. Comparison, correlation and multifactorial regression analyses were applied. IS patients were similar to controls concerning age and gender. IS was prevalent in the carotid system (76.9%); 82.1% had a subacute onset. IS patients expressed higher tHCY (14.65 +/- 9.79 micromol/l) and lower Se levels (1.3 +/- 0.5 micromol/l). Twice as many IS patients (23%) had optimal Se levels of <1.01 mumol/l. Subjects with hyperhomocysteinaemia (tHCY > or =15 micromol/l) showed lower Se levels during IS; Se accounted for 15.4% of tHCY variations (R = -0.393; p = 0.015) with unit change increasing tHCY by 8.25 units. Se remained predictive of tHCY levels after adjustments (vitamin B6, fibrinogen, triglycerides). Lower Se was observed during acute IS, being inversely associated with and predicting increased tHCY levels. Of note, there were more IS patients with suboptimal Se than controls.


Quantum Chemical Calculation of Molecular and Periodic Peptide and Protein Structures.
Special-purpose classical force fields (FFs) provide good accuracy at very low computational cost, but their application is limited to systems for which potential energy functions are available. This excludes most metal-containing proteins or those containing cofactors. In contrast, the GFN2-xTB semiempirical quantum chemical method is parametrized for almost the entire periodic table. The accuracy of GFN2-xTB is assessed for protein structures with respect to experimental X-ray data. Furthermore, the results are compared with those of two special-purpose FFs, HF-3c, PM6-D3H4X, and PM7. The test sets include proteins without any prosthetic groups as well as metalloproteins. Crystal packing effects are examined for a set of smaller proteins to validate the molecular approach. For the proteins without prosthetic groups, the special purpose FF OPLS-2005 yields the smallest overall RMSD to the X-ray data but GFN2-xTB provides similarly good structures with even better bond-length distributions. For the metalloproteins with up to 5000 atoms, a good overall structural agreement is obtained with GFN2-xTB. The full geometry optimizations of protein structures with on average 1000 atoms in wall-times below 1 day establishes the GFN2-xTB method as a versatile tool for the computational treatment of various biomolecules with a good accuracy/computational cost ratio.


The effects of smartphone use on upper extremity muscle activity and pain threshold.
[Purpose] The purpose of this study was to determine whether muscle activity and pressure-induced pain in the upper extremities are affected by smartphone use, and to compare the effects of phone handling with one hand and with both hands. [Subjects] The study subjects were asymptomatic women 20-22 years of age. [Methods] The subjects sat in a chair with their feet on the floor and the elbow flexed, holding a smartphone positioned on the thigh. Subsequently, the subjects typed the Korean anthem for 3 min, one-handed or with both hands. Each subject repeated the task three times, with a 5-min rest period between tasks to minimize fatigue. Electromyography (EMG) was used to record the muscle activity of the upper trapezius (UT), extensor pollicis longus (EPL), and abductor pollicis (AP) during phone operation. We also used a dolorimeter to measure the pressure-induced pain threshold in the UT. [Results] We observed higher muscle activity in the UT, AP, and EPL in one-handed smartphone use than in its two-handed use. The pressure-induced pain threshold of the UT was lower after use of the smartphone, especially after one-handed use. [Conclusion] Our results show that smartphone operation with one hand caused greater UT pain and induced increased upper extremity muscle activity.


Determination of the spatial distribution of wetting in the pore networks of rocks.
The macroscopic movement of subsurface fluids involved in CO2 storage, groundwater, and petroleum engineering applications is controlled by interfacial forces in the pores of rocks. Recent advances in modelling these systems has arisen from approaches simulating flow through a digital representation of the complex pore structure. However, further progress is limited by difficulties in characterising the spatial distribution of the wetting state within the pore structure. In this work, we show how observations of the fluid coverage of mineral surfaces within the pores of rocks can be used as the basis for a quantitative 3D characterisation of heterogeneous wetting states throughout rock pore structures. We demonstrate the approach with water-oil fluid pairs on rocks with distinct lithologies (sandstone and carbonate) and wetting states (hydrophilic, intermediate wetting, and heterogeneously wetting). Fluid surface coverage the within rock pores is a robust signal of the wetting state across varying rock types and wetting states. The wetting state can be quantified and the resulting 3D maps can be used as a deterministic input to pore scale models. These may be applied to multiphase flow problems in porous media ranging from soil science to fuel cells.


Pulmonary hypertension in systemic lupus erythematosus: pulmonary thromboembolism is the leading cause.
Pulmonary hypertension (PH) is a life-threatening complication of systemic lupus erythematosus (SLE). Pulmonary hypertension in SLE has a variety of causes. Diagnosing early and defining the cause of PH accurately can provide better clinical outcome in SLE. We investigated the causes and characteristics of PH in patients with SLE. One hundred twenty-one patients with SLE who had a visit in a 6-month period were assessed retrospectively. Patients who ever had a systolic pulmonary arterial pressure of 40 mm Hg or greater by Doppler echocardiography were considered to have PH. Among 122 patients, 65 had echocardiography for some reason, and 10 (8.2%) were diagnosed as having PH by echocardiographic examination. This number reduced to 9 (7.4%) when we excluded the patient with normal pulmonary artery pressure at right heart catheterization. Causes of PH were as follows: thromboembolic events in 4 patients (44.4%) (2 of them had chronic thromboembolic PH), left-sided heart disease in 2 patients (22.2%), pulmonary arterial hypertension in 1 patient (11.1%), high cardiac output state in 1 patient (11.1%), and transient elevation of systolic pulmonary artery pressure in 1 patient (11.1%) who had a history of venous thromboembolism. Venous thromboembolic disease was significantly higher in patients with SLE with PH in comparison to patients with SLE without PH (7 patients [6.3%] vs 5 patients [50.0%]; P = 0.001). All patients improved clinically during their short-term follow-up. Patients with SLE are at increased risk for PH. This study highlights the complexity of the differential diagnosis of PH in patients with SLE once again and emphasizes the importance of pulmonary thromboembolism as a cause of PH. One should investigate patients with SLE with unexplained symptoms and/or signs related to PH for possible treatable causes.


Visualizing an Allosteric Intermediate Using CuAAC Stabilization of an NMR Mixed Labeled Dimer.
Homodimers are the most abundant type of enzyme in cells, and as such, they represent the most elemental system for studying the phenomenon of allostery. In these systems, in which the allosteric features are manifest by the effect of the first binding event on a similar event at the second site, the most informative state is the asymmetric singly bound (lig1) form, yet it tends to be thermodynamically elusive. Here we obtain milligram quantities of lig1 of the allosteric homodimer, chorismate mutase, in the form of a mixed isotopically labeled dimer stabilized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between the subunits. Below, we outline several critical steps required to generate high yields of both types of unnatural amino acid-containing proteins and overcome multiple pitfalls intrinsic to CuAAC to obtain high yields of a highly purified, fully intact, active mixed labeled dimer, which provides the first glimpse of the lig1 intermediate. These data not only will make possible NMR-based investigations of allostery envisioned by us but also should facilitate other structural applications in which specific linkage of proteins is helpful.


Development of the gut microbiota in early life: The impact of cystic fibrosis and antibiotic treatment.
Patients with Cystic Fibrosis (CF) suffer from pancreatic insufficiency, lipid malabsorption and gastrointestinal complaints, next to progressive pulmonary disease. Altered mucosal homoeostasis due to malfunctioning chloride channels results in an adapted microbial composition of the gastrointestinal and the respiratory tract. Additionally, antibiotic treatment has the potential to distort resident microbial communities dramatically. This study aims to investigate early life development of the gut microbial community composition of children with CF compared to healthy infants and to study the independent effects of antibiotics taking into account other clinical and lifestyle factors. Faecal samples from 20 infants with CF and 45 healthy infants were collected regularly during the first 18 months of life and microbial composition was determined using 16S rRNA based sequencing. We observed significant differences in the overall microbiota composition between infants with CF and healthy infants (p<0.001). Akkermansia and Anaerostipes were significantly more abundant in control infants, whereas Streptococci and E. coli were significantly more abundant in infants with CF, also after correction for several clinical factors (p<0.05). Antibiotic use in infants with CF was associated with a lower alpha diversity, a reduced abundance of Bifidobacterium and Bacteroides, and a higher abundance of Enterococcus. Microbial development of the gut is different in infants with CF compared to healthy infants from the first months of life on, and further deviates over time, in part as a result of antibiotic treatment. The resulting dysbiosis may have significant functional consequences for the microbial ecosystem in CF patients.


Management of pediatric hypertrophic cardiomyopathy.
As the underlying genetic basis of hypertrophic cardiomyopathy is being characterized, there has been increasing recognition of the wide spectrum and variable evolution of this disease within the pediatric age range. This review outlines recent evidence relevant to the diagnosis, management, and prognosis of hypertrophic cardiomyopathy specific to children and adolescents. Studies of putative causal genes are leading to the discovery of factors affecting the variability of phenotypic expression and possible avenues for new therapies. Nonetheless, the use of genetic testing currently remains for research purposes only. Echocardiography is the primary means for evaluation, with an increasing focus on diastolic performance. Useful prognostic information can be obtained from the safe performance of cardiopulmonary stress testing. Sudden death can occur in children, although the risk factors are likely different than in adults. The role and mechanisms for possible ischemia remain controversial, and likely differ between individuals. Activity restrictions are recommended, with medical therapy reserved for those who are symptomatic. For those with important left ventricular outflow obstruction, surgical myectomy may be indicated, with little current role for alcohol septal ablation. Advances in implantable defibrillators now make this therapy feasible in younger children. There are important differences from adults in the approach to the diagnosis and management of hypertrophic cardiomyopathy in children and adolescents. Care regarding prognostication and therapy must be taken given the potential life-long implications.


Usability and Acceptability of a Text Message-Based Developmental Screening Tool for Young Children: Pilot Study.
Only 30% of parents of children aged 9-35 months report that their child received a developmental screening in the previous year. Screening rates are even lower in low-income households, where the rates of developmental delays are typically higher than those in high-income households. Seeking to evaluate ways to increase developmental screening, Text4baby, a national perinatal texting program, created an interactive text message-based version of a validated developmental screening tool for parents. This study aimed to assess whether a text message-based developmental screening tool is usable and acceptable by low-income mothers. Low-income mothers of infants aged 8-10 months were recruited from the Women, Infants and Children Program clinics in Prince George's County, MD. Once enrolled, participants used text messages to receive and respond to six developmental screening questions from the Parents' Evaluation of Developmental Status: Developmental Milestones. After confirming their responses, participants received the results and feedback. Project staff conducted a follow-up phone survey and invited a subset of survey respondents to attend focus groups. A representative of the County's Infants and Toddlers Program met with or called participants whose results indicated that their infants "may be behind." Eighty-one low-income mothers enrolled in the study, 93% of whom reported that their infants received Medicaid (75/81). In addition, 49% of the mothers were Hispanic/Latina (40/81) and 42% were African American (34/81). A total of 80% participated in follow-up surveys (65/81), and 14 mothers attended focus groups. All participants initiated the screening and responded to all six screening questions. Of the total, 79% immediately confirmed their responses (64/81), and 21% made one or more changes (17/81). Based on the final responses, 63% of participants received a text that the baby was "doing well" in all six developmental domains (51/81); furthermore, 37% received texts listing domains where their baby was "doing well" and one or more domains where their baby "may be behind" (30/81). All participants received a text with resources for follow-up. In a follow-up survey reaching 65 participants, all respondents said that they would like to answer screening questions again when their baby was older. All but one participant would recommend the tool to a friend and rated the experience of answering questions and receiving feedback by text as "very good" or "good." A mobile text version of a validated developmental screening tool was both usable and acceptable by low-income mothers, including those whose infants "may be behind." Our results may inform further research on the use of the tool at older ages and options for a scalable, text-based developmental screening tool such as that in Text4baby.


Quality of life in hypertension management using olmesartan in primary care.
Differences in quality of life (QoL) using antihypertensive drugs may account for differences in compliance, persistence and blood pressure control. As this is the prerequisite for cardiovascular risk reduction, QoL was investigated using highly tolerable drugs (such as olmesartan). The non-interventional study was carried out in 4252 primary care patients with 6 weeks of follow up. Documentation of patient characteristics included concomitant diseases and antihypertensive medication, blood pressure, pulse pressure, pulse rate and evaluation of QoL using the SF-12 questionnaire. Comparison of data at 6 weeks after adding or switching to olmesartan treatment (median dose: 20 mg) with baseline values. Patients had mild-to-moderate hypertension, 52.6% of whom were male and the mean age was 60.5 +/- 11.9 years. Dyslipidaemia (38.3%), diabetes (20.9%) and coronary heart disease (16.4%) were the most frequent concomitant diseases. After 6 weeks, blood pressure was reduced by -22.8 +/- 14.1/-11.5 +/- 8.3 mmHg (p < 0.001 versus baseline). All items of the SF-12 questionnaire and both sum scores improved over the course of treatment (p < 0.001 versus baseline), and were well compatible with non-hypertensive controls. Improvements were higher when switching from alpha-blockers, calcium channel blockers, beta-blockers, diuretics and angiotensin-converting enzyme inhibitors as compared with angiotensin II type 1 receptors blockers (ARBs), in particular on the mental health scale (p < 0.001). Adverse events were rare (0.66%), with dizziness (n = 8; 0.19%) being the most frequent. As was shown in the current study, patients on olmesartan treatment not only achieve adequate blood pressure control but also experienced a substantial improvement of QoL. This may contribute to long-term blood pressure control using ARBs.


Exploring how cation entropy influences electric double layer formation and electrochemical reactivity.
Electric double layers are crucial to energy storage and electrocatalytic device performance. While double layer formation originates in electrostatic interactions, electric double layer properties are governed by a balance of both electrostatic and entropic driving forces. Favorable ion-surface electrostatic interactions attract counterions to charged surfaces to compensate, or "screen," potentials, but the confinement of these same ions from a bulk reservoir to the interface incurs an entropic penalty. Here, we use a dicationic imidazolium ionic liquid and its monovalent analogue to explore how cation valence and entropy influence double layer formation and electrochemical reactivity using CO2 electroreduction as a model reaction. We find that divalent and monovalent cations display similar CO2 reduction kinetics but differ vastly in steady-state reactivity due to rapid electrochemically induced precipitation of insulating dicationic (bi)carbonate films. Using in situ surface-enhanced Raman scattering spectroscopy, we find that potential-dependent cation reorientation occurs at similar potentials between the two ionic liquids, but the introduction of a covalent link in the divalent cation imparts a more ordered double layer structure that favors (bi)carbonate precipitation. In mixed monovalent-divalent electrolytes, we find that the divalent cations dominate interfacial properties by preferentially accumulating at surfaces even at very low relative concentrations. Our findings confirm that ion entropy plays a key role in modulating local electrochemical environments. Furthermore, we highlight how double layer properties are sensitive to the properties of counterions that pay the lowest entropic penalty to accumulate at interfaces. Overall, we illustrate that ion entropy provides a new knob to tune reaction microenvironments and unveil how entropy plays a major role in modulating electrochemical reactivity in mixed ion electrolytes.


Actin filament barbed-end capping activity in neutrophil lysates: the role of capping protein-beta 2.
A barbed-end capping activity was found in high speed supernates of neutrophils lysed in submicromolar calcium. In dilute supernate (> or = 100-fold dilution of cytoplasm), this activity accounted for most of the inhibition of barbed-end elongation of pyrenyl-G-actin from spectrin-F-actin seeds. Pointed-end elongation from gelsolin-capped F-actin seeds was not inhibited at comparable concentrations of supernate, thus excluding actin monomer sequestration as a cause of the observed inhibition. Most of the capping activity was due to capping protein-beta 2 (a homologue of cap Z). Thus, while immunoadsorption of > or = 95% of the gelsolin in the supernate did not decrease capping activity, immunoadsorption of capping protein-beta 2 reduced capping activity proportionally to the amount of capping protein-beta 2 adsorbed. Depletion of > 90% of capping protein-beta 2 from the supernate removed 90% of its capping activity. The functional properties of the capping activity were defined. The dissociation constant for binding to barbed ends (determined by steady state and kinetic analyses) was approximately 1-2 nM; the on-rate of capping was between 7 x 10(5) and 5 x 10(6) M-1 s-1; and the off-rate was approximately 2 x 10(-3) s-1. The concentration of capper free in the intact cell (determined by adsorption of supernate with spectrin-actin seeds) was estimated to be approximately 1-2 microM. Thus, there appeared to be enough high affinity capper to cap all the barbed ends in vivo. Nevertheless, immediately after lysis with detergent, neutrophils contained sites that nucleate barbed-end elongation of pyrenyl-G-actin. These barbed ends subsequently become capped with a time course and concentration dependence similar to that of spectrin-F-actin seeds in high speed supernates. These observations suggest that, despite the excess of high affinity capper, some ends either are not capped in vivo or are transiently uncapped upon lysis and dilution.


Teleost microbiomes: the state of the art in their characterization, manipulation and importance in aquaculture and fisheries.
Indigenous microbiota play a critical role in the lives of their vertebrate hosts. In human and mouse models it is increasingly clear that innate and adaptive immunity develop in close concert with the commensal microbiome. Furthermore, several aspects of digestion and nutrient metabolism are governed by intestinal microbiota. Research on teleosts has responded relatively slowly to the introduction of massively parallel sequencing procedures in microbiomics. Nonetheless, progress has been made in biotic and gnotobiotic zebrafish models, defining a core microbiome and describing its role in development. However, microbiome research in other teleost species, especially those important from an aquaculture perspective, has been relatively slow. In this review, we examine progress in teleost microbiome research to date. We discuss teleost microbiomes in health and disease, microbiome ontogeny, prospects for successful microbiome manipulation (especially in an aquaculture setting) and attempt to identify important future research themes. We predict an explosion in research in this sector in line with the increasing global demand for fish protein, and the need to find sustainable approaches to improve aquaculture yield. The reduced cost and increasing ease of next generation sequencing technologies provides the technological backing, and the next 10 years will be an exciting time for teleost microbiome research.


Mechanism of human dermal fibroblast migration driven by type I collagen and platelet-derived growth factor-BB.
Migration of human dermal fibroblasts (HDFs) is critical for skin wound healing. The mechanism remains unclear. We report here that platelet-derived growth factor-BB (PDGF-BB) is the major promotility factor in human serum for HDF motility on type I collagen. PDGF-BB recapitulates the full promotility activity of human serum and anti-PDGF neutralizing antibodies completely block it. Although collagen matrix initiates HDF migration without growth factors, PDGF-BB-stimulated migration depends upon attachment of the cells to a collagen matrix. The PDGF-BB's role is to provide directionality and further enhancement for the collagen-initiated HDF motility. To study the collagen and PDGF-BB "dual signaling" in primary HDF, we establish "gene cassettes" plus lentiviral gene delivery approach, in which groups of genes are studied individually or in combination for their roles in HDF migration. Focal adhesion kinase, p21(Rac,CDC42)-activated kinase and Akt are grouped into an upstream kinase gene cassette, and the four major mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2, p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase 5) are grouped into a downstream kinase gene cassette. The experiments demonstrate 1) the genes' individual roles and specificities, 2) their combined effects and sufficiency, and 3) the mechanisms of their intermolecular connections in HDF migration driven by collagen and PDGF-BB.


Impact of Real-Time Clinical Decision Support on Blood Utilization and Outcomes in Hospitalized Patients with Solid Tumor Cancer.
Patients with cancer are frequently hospitalized, and anemia is a common complication of cancer care. Transfusion is often required and commonly occurs above guideline-supported thresholds. It was hypothesized that an educational intervention, combined with real-time clinical decision support (CDS), would reduce blood utilization among hospitalized solid tumor cancer patients without adversely affecting outcomes. A retrospective, historical control analysis was conducted comparing transfusion utilization among hospitalized solid tumor cancer patients before and after implementation of the educational intervention and CDS. The primary outcome was receipt of red blood cell (RBC) transfusion. Secondary outcomes included total RBC transfusions per 100 inpatient-days, readmission, outpatient transfusion within seven days of discharge, inpatient mortality, and odds of transfer to the ICU. The odds of receiving a transfusion were significantly reduced in the postintervention cohort (odds ratio [OR] = 0.52, p = 0.005). Among patients receiving transfusion, there was no significant difference between groups in the number of RBC transfusions per 100 inpatient-days (incidence rate ratio = 0.87, p = 0.26). There were also no significant differences in readmission, outpatient transfusion within seven days of discharge, or inpatient mortality, though patients in the postintervention cohort had lower odds of ICU transfer (OR = 0.29, p = 0.04). The combined use of an educational intervention and CDS in a hospitalized solid tumor cancer patient population was associated with lower blood utilization, similar patient outcomes, and unchanged short-term outpatient transfusion requirements. Hospitals should consider similar interventions to work toward appropriate resource allocation and mitigation of transfusion-associated risk in this patient population.


The relationship between genotype, developmental stability and mating performance: disentangling the epigenetic causes.
Developmental stability (DS) may confer an advantage in competition for mates. The present study tests this hypothesis using Drosophila immigrans, and proposes a novel approach to help broadly define the epigenetic factors causing such an effect. We first estimated the magnitude of isofemale heritability in sternopleural bristle fluctuating asymmetry (FA), using replicate genetic lines extracted from nature. Positional FA (PFA) exhibited significant among-line variation, and the heritability estimate of 0.10 (0.046 s.e.m.) was statistically significant. Among individual males, there was a significant positive relationship between PFA and copulation latency (time elapsed between introduction of females and copulation) and duration, but not copulation frequency. Moreover, high-DS lines exhibited significantly shorter copulation latency and duration compared with low-DS lines. When these components of sexual performance were again contrasted between lines with among-individual differences in bristle asymmetry controlled statistically, significant line effects on copulation latency and duration disappeared. The results suggest that deficits in the developmental apparatus underlying one particular trait can compromise individual sexual performance, and weaken the hypothesis that FA is a cue of overall 'genetic quality'.


Protocol for a constructivist metasynthesis of qualitative research of heroism and paramedic practice.
Exceptional demands have been placed on paramedics and other healthcare workers (HCWs) during the COVID-19 pandemic. An overwhelming outpouring of public support has unfolded, bringing into focus the relationship between paramedics, other HCWs and society, where they are portrayed as heroes. Scholars have studied the notion of heroism to society, and characteristics of such heroic status include: the voluntary nature of a heroic act, risk of physical or social harm, willingness to accept the consequences of action, acting for the benefit of others and without the expectation of gain. While some HCWs and paramedics may reflect these characteristics, many may not. Such heroic narratives can be damaging, stifling meaningful discussion around limits to duties, failing to acknowledge the importance of reciprocity and potentially imposing demands on paramedics and HCWs to be heroic. This article prospectively presents the protocol for a metasynthesis which aims to identify, appraise and synthesise the qualitative literature in order to develop theory on heroism and paramedic practice. Evolved grounded theory methodology is followed along with the procedural guidelines of Noblit and Hare (1988) to guide the analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P) have also been adopted when preparing this protocol and will be followed in the study proper. The protocol has been registered with the International Prospective Register of Systematic Reviews PROSPERO 2021, registration number CRD42021234851. We do not currently have results, but PRISMA guidelines will be followed when reporting our findings. Current narratives on heroism and paramedic practice are important in terms of the relationship between paramedics and society. The metasynthesis prospectively reported in this article serves as the first point in our journey of making sense of and developing theory on heroism and paramedic practice.


Influence of thyroid hormone on the concentration of galanin in the rat brain and pituitary.
Galanin (GAL) is a 29-amino acid peptide implicated in neuroendocrine regulation of prolactin, growth hormone and thyrotropin in the rat. GAL-like immunoreactivity and GAL messenger RNA (mRNA) are present in the anterior pituitary (AP) and hypothalamus and the expression of GAL mRNA has been shown to be modulated by peripheral gonadal steroid hormones. In view of possible interactions between members of the steroid/thyroid hormone receptor family and recent data suggesting an effect of GAL on thyrotropin secretion, we investigated the possible influence of thyroid status on GAL concentrations in the hypothalamus and AP of the male rat. Three weeks after the surgical removal of the thyroid gland from male rats, the concentrations of GAL in the median eminence (ME) and AP were reduced 54 and 65%, respectively. Similarly, GAL concentrations were decreased 39% in the ME and 69% in the AP of animals rendered hypothyroid by treatment with propylthiouracil (PTU). The effects of PTU treatment in both regions were reversed by daily T4 injections (50 micrograms/kg). The effects of PTU in the ME were reversed after 2 weeks of T4 treatment, whereas 3 weeks of replacement therapy were required to restore GAL concentrations in the AP. However, T4 treatment of intact control animals did not influence GAL concentrations. This study demonstrates that the presence of thyroid hormones is required for the maintenance of physiological concentrations of GAL in the hypothalamus and AP of the rat. These data also suggest that GAL may be involved in the negative feedback regulation of the hypothalamohypophysial-thyroid axis.


Effect of a knowledge-based and skills-based programme for physicians on risk of sexually transmitted reinfections among high-risk patients in China: a cluster randomised trial.
China is experiencing growing epidemics of HIV and sexually transmitted infections (STIs). Programmes to train physicians in China on HIV and STI knowledge, diagnosis, treatment, and risk reduction counselling can potentially reduce HIV and STI risk among high-risk patients. We aimed to assess a knowledge-based and skills-based programme for physicians in China to reduce patients' STI risk. In this cluster randomised trial, we block randomised counties in two provinces in eastern China to intervention or control groups. In the intervention group, physicians from county general hospitals participated in a structured HIV and STI training programme and received opportunities to enhance their clinical and counselling skills, whereas in the control group, physicians from county hospitals received the training after the intervention group completed final assessments. We recruited STI patients from physicians in both groups, treated baseline gonorrhoea and chlamydia infections, and assessed 9-month gonorrhoea and chlamydia reinfection as the primary outcome. Statistical comparisons between intervention and delayed-control patients used multilevel analyses to account for cluster effects at county and physician levels. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00644150. Between April 1, 2007, and Sept 1, 2008, 51 counties were randomly assigned; 27 to receive immediate intervention and 24 to receive delayed intervention. 249 physicians from the 51 county-level hospitals were enrolled, 121 physicians in the intervention group and 128 in the control group. From these physicians, we enrolled 633 and 491 patients, respectively, of whom 508 (80%) and 402 (82%) were available for reassessment at 9 months. Intervention patients at follow-up had significantly lower odds of combined gonorrhoea or chlamydia reinfection than did control patients (58/508 [11%] vs 123/402 [31%]; adjusted odds ratio 0·62 [95% CI 0·46-0·84]). Integrating HIV and STI training into medical education in China could be an effective strategy to reduce the country's growing HIV risk and STI epidemics. US National Institutes of Health.


From low to high-index facets of noble metal nanocrystals: a way forward to enhance the performance of electrochemical CO2 reduction.
To date, noble metal nanoparticles, mainly the gold (Au) and silver (Ag) nanoparticles, are the most active and selective heterogeneous catalysts that have revealed a tendency to form CO and directly synthesize syngas as a result of the electrochemical CO2 reduction reaction (CO2RR). The CO2RR activity and selectivity are influenced by a wide range of factors, such as morphology, surface structure, shape, composition, type of electrolyte used, and pH. Most of these issues have been reviewed and evaluated critically. Herein, the CO2RR activity and selectivity to CO formation on the low and high-index facets of Au, Ag, and Pt NCs were evaluated with a greater motive to provide new insights into the field. The author refers to different experimental approaches and the corresponding theoretical methods that have been employed to study the product formation activity and selectivity on low and high-index facet noble metal NCs for the CO2RR. In conclusion, some perspectives have been provided on the future research of the low and high-index facets of noble metal NCs for CO2 reduction.


Anti-SARS-CoV-2 IgG levels in relation to disease severity of COVID-19.
The durability of infection-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity has crucial implications for reinfection and vaccine effectiveness. However, the relationship between coronavirus disease 2019 (COVID-19) severity and long-term anti-SARS-CoV-2 immunoglobulin G (IgG) antibody level is poorly understood. Here, we measured the longevity of SARS-CoV-2-specific IgG antibodies in survivors who had recovered from COVID-19 1 year previously. In a cohort of 473 survivors with varying disease severity (asymptomatic, mild, moderate, or severe), we observed a positive correlation between virus-specific IgG antibody titers and COVID-19 severity. In particular, the highest virus-specific IgG antibody titers were observed in patients with severe COVID-19. By contrast, 74.4% of recovered asymptomatic carriers had negative anti-SARS-CoV-2 IgG test results, while many others had very low virus-specific IgG antibody titers. Our results demonstrate that SARS-CoV-2-specific IgG persistence and titer depend on COVID-19 severity.


Evolution and Phylogeny of MicroRNAs - Protocols, Pitfalls, and Problems.
MicroRNAs are important regulators in many eukaryotic lineages. Typical miRNAs have a length of about 22nt and are processed from precursors that form a characteristic hairpin structure. Once they appear in a genome, miRNAs are among the best-conserved elements in both animal and plant genomes. Functionally, they play an important role in particular in development. In contrast to protein-coding genes, miRNAs frequently emerge de novo. The genomes of animals and plants harbor hundreds of mutually unrelated families of homologous miRNAs that tend to be persistent throughout evolution. The evolution of their genomic miRNA complement closely correlates with important morphological innovation. In addition, miRNAs have been used as valuable characters in phylogenetic studies. An accurate and comprehensive annotation of miRNAs is required as a basis to understand their impact on phenotypic evolution. Since experimental data on miRNA expression are limited to relatively few species and are subject to unavoidable ascertainment biases, it is inevitable to complement miRNA sequencing by homology based annotation methods. This chapter reviews the state of the art workflows for homology based miRNA annotation, with an emphasis on their limitations and open problems.


Drinking motives as moderators of the effect of ambivalence on drinking and alcohol-related problems.
The current study seeks to evaluate relationships between drinking motives and alcohol-related ambivalence in the prediction of problem drinking. We expected that: 1) main effects would emerge such that alcohol-related ambivalence would be positively associated with peak drinking and problems; drinking motives would be positively associated with drinking and problems, and 2) interactions would emerge between motives and ambivalence in predicting problematic drinking such that drinking motives would be positively associated with peak drinking and problems, especially among those high in ambivalence over drinking. Six hundred sixty-nine undergraduate students (mean age=22.95, SD=5.47, 82.22% female) completed study materials. Results showed that consistent with expectations, ambivalence was positively associated with peak drinking and problems. Further, consistent with expectations, drinking motives were positively associated with peak drinking and problems. Additionally, ambivalence was positively associated with drinking motives. Significant interactions emerged between drinking motives (social and coping) and ambivalence when predicting peak drinking and alcohol-related problems. These findings highlight the importance of considering motives in the relationship between ambivalence and drinking. Clinical implications include the need for tailoring interventions to target individual difference factors that increase risk for heavy drinking and associated problems. This is especially important among college students who may be at risk for problematic behavior.


Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells.
Eukaryotic cells compartmentalize biochemical processes in different organelles, often relying on metabolic cycles to shuttle reducing equivalents across intracellular membranes. NADPH serves as the electron carrier for the maintenance of redox homeostasis and reductive biosynthesis, with separate cytosolic and mitochondrial pools providing reducing power in each respective location. This cellular organization is critical for numerous functions but complicates analysis of metabolic pathways using available methods. Here we develop an approach to resolve NADP(H)-dependent pathways present within both the cytosol and the mitochondria. By tracing hydrogen in compartmentalized reactions that use NADPH as a cofactor, including the production of 2-hydroxyglutarate by mutant isocitrate dehydrogenase enzymes, we can observe metabolic pathway activity in these distinct cellular compartments. Using this system we determine the direction of serine/glycine interconversion within the mitochondria and cytosol, highlighting the ability of this approach to resolve compartmentalized reactions in intact cells.


Measurement of arsenic and gallium content of gallium arsenide semiconductor waste streams by ICP-MS.
The chemistry of semiconductor wafer processing liquid waste, contaminated by heavy metals, was investigated to determine arsenic content. Arsenic and gallium concentrations were determined for waste slurries collected from gallium arsenide (GaAs) wafer processing at three industrial sources and compared to slurries prepared under laboratory conditions. The arsenic and gallium content of waste slurries was analyzed using inductively coupled plasma mass-spectrometry (ICP-MS) and it is reported that the arsenic content of the waste streams was related to the wafer thinning process, with slurries from wafer polishing having the highest dissolved arsenic content at over 1,900 mgL(-1). Lapping slurries had much lower dissolved arsenic (< 90 mgL(-1)) content, but higher particulate contents. It is demonstrated that significant percentage of GaAs becomes soluble during wafer lapping. Grinding slurries had the lowest dissolved arsenic content at 15 mgL(-1). All three waste streams are classified as hazardous waste, based on their solids content and dissolved arsenic levels and treatment is required before discharge or disposal. It is calculated that as much as 93% of material is discarded through the entire GaAs device manufacturing process, with limited recycling. Although gallium can be economically recovered from waste slurries, there is little incentive to recover arsenic, which is mostly landfilled. Options for treating GaAs processing waste streams are reviewed and some recommendations made for handling the waste. Therefore, although the quantities of hazardous waste generated are miniscule in comparison to other industries, sustainable manufacturing practices are needed to minimize the environmental impact of GaAs semiconductor device fabrication.


The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains.
Many well-represented domains recognize primary sequences usually less than 10 amino acids in length, called Short Linear Motifs (SLiMs). Accurate prediction of SLiMs has been difficult because they are short (often < 10 amino acids) and highly degenerate. In this study, we combined scoring matrixes derived from peptide library and conservation analysis to identify protein classes enriched of functional SLiMs recognized by SH2, SH3, PDZ and S/T kinase domains. Our combined approach revealed that SLiMs are highly conserved in proteins from functional classes that are known to interact with a specific domain, but that they are not conserved in most other protein groups. We found that SLiMs recognized by SH2 domains were highly conserved in receptor kinases/phosphatases, adaptor molecules, and tyrosine kinases/phosphatases, that SLiMs recognized by SH3 domains were highly conserved in cytoskeletal and cytoskeletal-associated proteins, that SLiMs recognized by PDZ domains were highly conserved in membrane proteins such as channels and receptors, and that SLiMs recognized by S/T kinase domains were highly conserved in adaptor molecules, S/T kinases/phosphatases, and proteins involved in transcription or cell cycle control. We studied Tyr-SLiMs recognized by SH2 domains in more detail, and found that SH2-recognized Tyr-SLiMs on the cytoplasmic side of membrane proteins are more highly conserved than those on the extra-cellular side. Also, we found that SH2-recognized Tyr-SLiMs that are associated with SH3 motifs and a tyrosine kinase phosphorylation motif are more highly conserved. The interactome of protein domains is reflected by the evolutionary conservation of SLiMs recognized by these domains. Combining scoring matrixes derived from peptide libraries and conservation analysis, we would be able to find those protein groups that are more likely to interact with specific domains.


Quartz crystal microbalance investigation of the interaction of bacterial toxins with ganglioside containing solid supported membranes.
The binding of cholera toxin, tetanus toxin and pertussis toxin to ganglioside containing solid supported membranes has been investigated by quartz crystal microbalance measurements. The bilayers were prepared by fusion of phospholipid-vesicles on a hydrophobic monolayer of octanethiol chemisorbed on one gold electrode placed on the 5 MHz AT-cut quartz crystal. The ability of the gangliosides GM1, GM3, GD1a, GD1b, GT1b and asialo-GM1 to act as suitable receptors for the different toxins was tested by measuring the changes of quartz resonance frequencies. To obtain the binding constants of each ligand-receptor-couple Langmuir-isotherms were successfully fitted to the experimental adsorption isotherms. Cholera toxin shows a high affinity for GM1 (Ka = 1.8.10(8)M-1), a lower one for asialo-GM1 (Ka = 1.0.10(7)M-1) and no affinity for GM3. The C-fragment of tetanus toxin binds to ganglioside GD1a, GD1b and GT1b containing membranes with similar affinity (Ka approximately 10(6)M-1), while no binding was observed with GM3. Pertussis toxin binds to membranes containing the ganglioside GD1a with a binding constant of Ka = 1.6.10(6)M-1, but only if large amounts (40 mol%) of GD1a are present. The maximum frequency shift caused by the protein adsorption depends strongly on the molecular structure of the receptor. This is clearly demonstrated by an observed maximum frequency decrease of 99 Hz for the adsorption of the C-fragment of tetanus toxin to GD1b. In contrast to this large frequency decrease, which was unexpectedly high with respect to Sauerbrey's equation, implying pure mass loading, a maximum shift of only 28 Hz was detected after adsorption of the C-fragment of tetanus toxin to GD1a.


NIR-Absorbing Electron Acceptor Based on a Selenium-Heterocyclic Core Attaching to Phenylalkyl Side Chains for Polymer Solar Cells with 17.3% Efficiency.
Selenium-heterocyclic and side-chain strategies for developing near-infrared (NIR) small fused-ring acceptors (FRAs) to further obtain short-circuit current density (Jsc) have proven advantageous in the top-performing polymer solar cells (PSCs). Herein, a new electron-rich central selenium-containing heterocycle core (BTSe) attaching alkyl side chains with a terminal phenyl group was coupled with a difluorinated and dichlorinated electron-accepting terminal 1,1-dicyanomethylene-3-indanone (IC) to afford two types of new FRAs, BTSe-IC2F and BTSe-IC2Cl. Interestingly, in spite of the weaker intramolecular charge transfer, BTSe-IC2F shows a stronger NIR response because of the smaller bandgap (Egopt) up to 1.26 eV, benefiting from the stronger ordered molecular packing in comparison to BTSe-IC2Cl with an Egopt of 1.30 eV. Additionally, thermal annealing induced an evident red shift by ∼50 nm in the absorption of D18:BTSe-IC2F blend films. Such a phenomenon may be attributed to the synergistic impact of the formation of inward constriction toward the molecular backbone because of the combination of bulky side chains and fluorinated IC as well as the reduced aromaticity of the selenium heterocycle. Consequently, the thermally annealed device based on BTSe-IC2F/D18 achieves a champion power conversion efficiency (PCE) of 17.3% with a high fill factor (FF) of 77.22%, which is among the highest reported PCE values for selenium-heterocyclic FRAs in binary PSCs. The improved Jsc and FF values of the D18:BTSe-IC2F film are simultaneously achieved mainly because of the preferred face-on orientations, the well-balanced electron/hole mobility, and the favorable blend morphology compared to D18:BTSe-IC2Cl. This work suggests that the selenium-heterocyclic fused-ring core (with proper side chains) combined with fluorinated terminal groups is an effective strategy for obtaining highly efficient NIR-responsive FRAs.


Development of bis-thiazoles as inhibitors of triosephosphate isomerase from Trypanosoma cruzi. Identification of new non-mutagenic agents that are active in vivo.
The neglected disease American trypanosomiasis is one of the major health problems in Latin America. Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), the etiologic agent of this disease, has been proposed as a druggable target. Some bis-benzothiazoles have been described as irreversible inhibitors of this enzyme. On the other hand, new bioactive furane-containing thiazoles have been described as excellent in vivo anti-T. cruzi agents. This encouraged us to design and develop new bis-thiazoles with potential use as drugs for American trypanosomiasis. The bis-thiazol 5, 3,3'-allyl-2,2'-bis[3-(2-furyl)-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, showed the best in vitro anti-T. cruzi profile with a higher selectivity index than the reference drugs Nifurtimox and Benznidazole against amastigote form of the parasite. This derivative displayed marginal activity against TcTIM however the bis-thiazol 14, 3-allyl-2-[3-(2-furyl)-2-propenylidenehydrazono]-3'-phenyl-2'-(3-phenyl-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, was an excellent inhibitor of the enzyme of the parasite. The absence of both in vitro mutagenic and in vivo toxicity effects, together with the activity of bis-thiazol 5in vivo, suggests that this compound is a promising anti-T. cruzi agent surpassing the "hit-to-lead" stage in the drug development process.


Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice.
Proteolytic cleavage of the amyloid precursor protein (APP) into the Aβ peptide has been an extensively researched mechanism for Alzheimer's disease, but the normal function of the protein is less understood. APP functions to regulate neuronal iron content by stabilizing the surface presentation of ferroportin-the only iron exporter channel of cells. The present study aims to quantify the contribution of APP to brain and peripheral iron by examining the lifetime impact on brain and liver iron levels in APP knockout mice. Consistent with previous reports, we found that wild-type mice exhibited an age-dependent increase in iron and ferritin in the brain, while no age-dependent changes were observed in the liver. APP ablation resulted in an exaggeration of age-dependent iron accumulation in the brain and liver in mice that was assessed at 8, 12, 18, and 22 months of age. Brain ferroportin levels were decreased in APP knockout mice, consistent with a mechanistic role for APP in stabilizing this iron export protein in the brain. Iron elevation in the brain and liver of APP knockout mice correlated with decreased transferrin receptor 1 and increased ferritin protein levels. However, no age-dependent increase in brain ferritin iron saturation was observed in APP-KO mice despite similar protein expression levels potentially explaining the vulnerability of APP-KO mice to parkinsonism and traumatic brain sequelae. Our results support a crucial role of APP in regulating brain and peripheral iron, and show that APP may act to oppose brain iron elevation during aging.


Clinical prediction of normotension in borderline hypertensive men--a 10 year study.
To investigate 24-h ambulatory blood pressure measurements (ABPM) as a tool for long-term prediction of future blood pressure (BP) status in high normal and low stage 1 hypertensives. A total of 165 men from a population screening program with diastolic BP (DBP) 85-94 mmHg and a systolic BP (SBP) < 150 mmHg performed a 24-h ABPM. Ten years later, 120 participants (73%) returned for renewed measurements. Blood pressure status at 10 years. At the 10-year follow-up, 53% of the participants were classified as hypertensive (HT) (BP > or = 140/90 or taking anti-hypertensive medication) and 47% were classified as normotensive (NT) (BP < 140/90 mmHg). There was no significant baseline differences in office SBP levels between those who were normotensive or hypertensive at follow-up (136/91 versus 138/92 mmHg), whereas both SBP and DBP night-time levels were significantly lower in the future normotensives as compared to the future hypertensives (107/69 versus 112/74 mmHg, P < 0.01). Using recommended normalcy night-time ABP levels of < 120/75 mmHg in addition to office BP (140/90) at baseline, over 85% of the subjects were correctly classified provided they met both clinic and ambulatory night-time criteria for HT and NT classification at baseline. The use of ABPM in addition to office BP's in patients with borderline hypertension greatly increases the possibility of identifying those individuals who are at a very small risk of developing future hypertension. This could potentially lead to considerable savings in both patient anxiety, physician time and resource consumption.


Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis.
Crocin is a pharmacologically active component of Crocus sativus L. (saffron) that has been used in traditional Chinese medicine. In a previous study, we demonstrated that crocin inhibits apoptosis in PC-12 cells by affecting the function of tumor necrosis factor-alpha. In this study, we found that depriving cultured PC-12 cells of serum/glucose causes a rapid increase in cellular ceramide levels, followed by an increase in the phosphorylation of c-jun kinase (JNK). The accumulation of ceramide was found to depend on the activation of magnesium-dependent neutral sphingomyelinase (N-SMase), but not on de novo synthesis. The serum/glucose-deprived PC-12 cells also decreased the cellular levels of glutathione (GSH), which is the potent inhibitor of N-SMase. Treating the PC-12 cells with crocin prevented N-SMase activation, ceramide production, and JNK phosphorylation. We also found that the chemical can enhance the activities of GSH reductase and gamma-glutamylcysteinyl synthase (gamma-GCS), contributing to a stable GSH supply that blocks the activation of N-SMase. Thus our data suggest that crocin combats the serum/glucose deprivation-induced ceramide formation in PC-12 cells by increasing GSH levels and prevents the activation of JNK pathway, which is reported to have a role of the signaling cascade downstream ceramide for neuronal cell death.


Tuning of the structure and parameters of a neural network using an improved genetic algorithm.
This paper presents the tuning of the structure and parameters of a neural network using an improved genetic algorithm (GA). It is also shown that the improved GA performs better than the standard GA based on some benchmark test functions. A neural network with switches introduced to its links is proposed. By doing this, the proposed neural network can learn both the input-output relationships of an application and the network structure using the improved GA. The number of hidden nodes is chosen manually by increasing it from a small number until the learning performance in terms of fitness value is good enough. Application examples on sunspot forecasting and associative memory are given to show the merits of the improved GA and the proposed neural network.


Microvascular decompression for hemifacial spasm: analyses of operative findings and results in 310 patients.
The operative findings and results of microvascular decompression (MVD) on 310 Chinese patients with hemifacial spasm are analyzed in this report. The operations were performed at the Neurological Institute of the Veterans General Hospital-Taipei between January 1983 and June 1990. The length of follow-up ranged from 6 months to 8 years (mean, 4.3 years); 273 patients (88%) had complete relief of spasm within 3 days after one MVD, and the remaining 37 patients (12%) showed no immediate postoperative improvement. Sixteen (5.2%) of these 37 initially unresponsive patients subsequently experienced complete relief, which occurred from 4 days to 22 months (median, 21 days) after one MVD; 13 others (4.2%) had complete relief immediately after the second MVD; another 3 (1%) had delayed complete relief 6, 9, and 11 months after the second MVD, respectively; and the remaining 5 (1.6%) only had delayed partial relief, which occurred 2 to 9 weeks after one MVD. Late recurrence occurred in three patients (1%). These immediate and long-term results lend support to the conclusion that the timing of reoperation can be postponed for a period of 3 to 4 weeks in the event of an initial failure to get improvement, and that a second MVD may be of value.


SAD--a normalized structural alignment database: improving sequence-structure alignments.
We present a structural alignment database that is specifically targeted for use in derivation and optimization of sequence-structure alignment algorithms for homology modeling. We have paid attention to ensure that fold-space is properly sampled, that the structures involved in alignments are of significant resolution (better than 2.5 A) and the alignments are accurate and reliable. Alignments have been taken from the HOMSTRAD, BAliBASE and SCOP-based Gerstein databases along with alignments generated by a global structural alignment method described here. In order to discriminate between equivalent alignments from these different sources, we have developed a novel scoring function, Contact Alignment Quality score, which evaluates trial alignments by their statistical significance combined with their ability to reproduce conserved three-dimensional residue contacts. The resulting non-redundant, unbiased database contains 1927 alignments from across fold-space with high-resolution structures and a wide range of sequence identities. The database can be interactively queried either over the web at http://abagyan.scripps.edu/lab/web/sad/show.cgi or by using MySQL, and is also available to download over the web.


Cerebral venous thrombosis: combined intrathrombus rtPA and intravenous heparin.
We chose to evaluate the safety and efficacy of combined intrathrombus rtPA and intravenous heparin in cerebral venous thrombosis (CVT). We treated 12 patients with symptoms of 1 to 40 days' duration (eg, headache, somnolence, focal deficits, seizures, and nausea and vomiting). Pretreatment MRI disclosed subtle hemorrhagic venous infarction in 4 patients, obvious hemorrhagic infarction in 2, small parenchymal hemorrhage from recent pallidotomy in 1, and no focal lesion in 5. Magnetic resonance venography and contrast venography identified thrombi in the superior sagittal sinus (SSS) in 3 patients; transverse/sigmoid sinus (TS/SS) in 2; SSS and both TS/SS in 1; SSS and 1 TS/SS in 5; and SSS, 1 TS/SS, and straight sinus in 1 patient. A loading dose of rtPA was instilled throughout the clot at 1 mg/cm, followed by continuous intrathrombus infusion at 1 to 2 mg/h. Intravenous heparin was infused concomitantly. Flow was restored completely in 6 patients and partially in 3, with a mean rtPA dose of 46 mg (range, 23 to 128 mg) at a mean time of 29 hours (range, 13 to 77 hours). Symptoms improved in these 9 patients concomitantly with flow restoration. Flow could not be restored in 3 patients. In 1 of them, treatment was stopped when little progress had been made, and fibrinogen level dropped to 118 mg/dL. In the other 2 patients, hemorrhagic worsening occurred, and treatment was abbreviated after initial rtPA dosing. In 1 of these, the hematoma was evacuated. Our experience with intrathrombus rtPA in conjunction with intravenous heparin in patients with CVT is encouraging. This therapy should probably be regarded as unsafe in patients with obvious hemorrhage. Time to restore flow may be faster than with urokinase (an average of 71 hours has been reported for 29 documented patients). Further evaluation of rtPA with heparin in CVT is warranted.


High-dose chemotherapy for breast cancer: is another look warranted?
Controversy has surrounded the use of high-dose chemotherapy for breast cancer for more than a decade. Numerous randomized trials have compared high-dose chemotherapy with standard-dose chemotherapy in metastatic breast cancer and high-risk primary breast cancer, defined by extensive axillary node involvement or inflammatory disease. The authors review the main research results of high-dose chemotherapy for breast cancer in 2002 to 2003. Preliminary analyses of three randomized trials in metastatic breast cancer and seven in high-risk primary breast cancer have been reported during this period. An advantage in event-free survival has been observed in all three studies in metastatic disease and in four of the high-risk primary cancer trials, albeit with no impact on overall survival at short follow-up. These early results are consistent with the most recent Cochrane reviews, which included trials reported through mid 2002. An early event-free survival advantage is apparent in favor of high-dose chemotherapy in both high-risk primary and metastatic breast cancer. Longer follow-up of those and most other trials is required to detect translation of the event-free survival differences into benefits in overall survival. High-dose chemotherapy remains a valid research strategy in event-free survival and high-risk primary breast cancer.


Effectively implementing healthy and sustainable food practices in out-of-home food service locations: The perspective of the catering staff members.
Restaurants, canteens, residential care, hospitals and other out-of-home food service locations can play an important role in improving people's diet quality by offering healthier and more sustainable food choices. However, the effectiveness of implementing sustainable and healthy food practices at these locations is, at least partly, dependent on the extent to which they are accepted and implemented by the staff members. This study aims to assess staff members' motivation, perceived capability, perceived opportunity and their readiness to change their behaviour (i.e., stages of change) in offering more healthy and sustainable food options to their customers or patients. Eleven out-of-home locations that wanted to adjust their assortment towards more healthy and sustainable product offerings participated in this study and were able to distribute a comparable questionnaire among their staff members to assess their perceived readiness to change. Results among 268 participants show that staff members find both a healthy and sustainable food assortment important and also seem to be motivated to improve their food assortment regarding health and sustainability. Perceived opportunity seems to be the largest barrier for staff members, although there is also room for improvement regarding their perceived capability. In addition, personal motivation seems to play the dominant role in staff members' readiness to change the health of the assortment, whereas perceived capability seems to play the dominant role in their perceived readiness to change the sustainability of the assortment. This study shows that taking into account the perspective of the catering staff members may help to effectively implement healthy and sustainable food practices in out-of-home food service locations.


Occurrence and effect of lower extremity ulcer in rheumatoid arthritis -- a population-based Study.
To assess the occurrence, risk factors, morbidity, and mortality associated with lower extremity (LE) ulcers in patients with rheumatoid arthritis (RA). Retrospective review of Olmsted County, Minnesota, USA, residents who first fulfilled the 1987 American College of Rheumatology criteria for RA in 1980-2007 with followup to death, migration, or April 2012. Only LE ulcers that developed after the diagnosis of RA were included. The study included 813 patients with 9771 total person-years of followup. Of them, 125 developed LE ulcers (total of 171 episodes), corresponding to a rate of occurrence of 1.8 episodes per 100 person-years (95% CI: 1.5, 2.0 per 100 person-yrs). The cumulative incidence of first LE ulcers was 4.8% at 5 years after diagnosis of RA and increased to 26.2% by 25 years. Median time for the LE ulcer to heal was 30 days. Ten of 171 episodes (6%) led to amputation. LE ulcers in RA were associated with increased mortality (HR 2.42; 95% CI 1.71, 3.42), adjusted for age, sex, and calendar year. Risk factors for LE ulcers included age (HR 1.73 per 10-yr increase; 95% CI 1.47, 2.04), rheumatoid factor positivity (HR 1.63; 95% CI 1.05, 2.53), presence of rheumatoid nodules (HR 2.14; 95% CI 1.39, 3.31), and venous thromboembolism (HR 2.16; 95% CI 1.07, 4.36). LE ulcers are common among patients with RA. The cumulative incidence increased by 1% per year. A significant number require amputation. Patients with RA who have LE ulcers are at a 2-fold risk for premature mortality.


Gender distribution in surgery for Parkinson's disease.
Parkinson's disease (PD) affects both women and men. The surgical treatment of this disease has experienced a worldwide increase since the mid-eighties. In order to document eventual differences in gender distribution of patients undergoing various stereotactic surgical procedures for PD, we reviewed scientific papers published during the last 14years.A literature search provided 145 clinical papers, published between January 1985 and February 1999, and dealing with pallidotomy, thalamotomy and deep brain stimulation procedures. These papers were scrutinised with respect to redundancies or other overlap of reported patients. The resulting numbers of patients were compiled according to gender, to surgical procedure, and to geographic area of origin of the publishing centers.In one third of the reviewed publications the gender of the patients was not specified. In the remaining papers, the overall sex distribution of patients who underwent surgery was 35% females and 65% males. These proportions between sexes were relatively consistent regardless of surgical procedure, and regardless of geographic origin of the publications.Male preponderance in patients undergoing surgery for PD cannot be explained by a corresponding difference in gender-prevalence of the disease. The criteria of selection, and patterns of referral, of patients for surgery, as well as the respective attitude of female and male patients toward surgery, may account for the uneven gender distribution in surgical PD patients.


[Postnatal perineal edema assessment: agreement among observers].
Perineal trauma produced during vaginal delivery is frequent, and there are no clinically validated evaluation scales available. The aim was to analyze the reliability of a tool to assess the vulvoperineal region during the postnatal period. This is an observational study conducted at the University Hospital of Universidade de São Paulo, Brazil. Thirty women with vaginal delivery were analyzed. The tool was built and evaluated in three stages: admission, 1-2, and 24-36 hours after delivery. Reliability analysis was carried out, and Kappa coefficient presented excellent, good, or marginal agreement to identify, respectively, 13, 20, and 13 parameters related to the pudendal chink, major and minor labia, clitoris, and perineal body. The conclusions were that the tool may be partially validated due to the reliability showed by the results, and that it must be modified, taking into consideration the individual characteristics of each woman, and changes that do not cause morbidity, which clinical evaluation is irrelevant.


Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease.
Anemia of chronic kidney disease (CKD) is a multifactorial disorder caused by impaired erythropoietin (EPO) production and altered iron homeostasis associated with inflammation. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates erythropoiesis via a coordinated response involving increased EPO production and enhanced iron availability for Hb synthesis. HIF degradation is regulated by HIF-prolyl hydroxylase (HIF-PH) enzymes. We hypothesized that roxadustat, an orally available small-molecule inhibitor of HIF-PH, would increase EPO production and promote erythropoiesis in animal models of anemia. In cells, roxadustat increased both HIF-1α and HIF-2α proteins, leading to an increase in EPO production, even in the presence of EPO-suppressing inflammatory cytokines. Roxadustat administered intermittently to healthy rats and cynomolgus monkeys increased circulating EPO levels, reticulocytes, blood Hb, and hematocrit in a dose-dependent manner. Roxadustat corrected anemia in a rat model of CKD after five-sixth nephrectomy and in a rat model of anemia of inflammation with impaired iron metabolism induced by peptidoglycan-polysaccharide (PG-PS). In the PG-PS model, roxadustat significantly decreased hepatic expression of hepcidin, a hormone responsible for iron sequestration and functional iron deficiency, and increased expression of two genes involved in duodenal iron absorption: divalent metal transporter 1 and duodenal cytochrome b. In conclusion, by activating the HIF pathway, roxadustat increased EPO production, elevated Hb, corrected anemia, and improved iron homeostasis. The coordinated erythropoietic response stimulated by roxadustat, involving both EPO production and mobilization of iron stores, makes this compound a promising treatment of anemia of CKD and anemia associated with functional iron deficiency. SIGNIFICANCE STATEMENT: Roxadustat is a novel orally available small-molecule inhibitor of HIF prolyl hydroxylase enzymes that reversibly stabilizes HIF-α, thus activating transcription of HIF-dependent genes, including EPO and regulators of iron homeostasis. Activation of the HIF pathway by roxadustat induces erythropoiesis in healthy rats and monkeys and corrects experimentally induced anemia in rats. The coordinated erythropoietic response that increases EPO production and mobilizes iron stores makes roxadustat a promising treatment for anemia of chronic kidney disease and anemia associated with functional iron deficiency.


Carbohydrate vaccines for the immunotherapy of cancer.
On the basis of the observation that tumor cells exhibit aberrant glycosylation, carbohydrate vaccines are being developed for the active immunotherapy of cancer. Potential targets include members of the ABH Lewis blood group family (e.g., Lewis(y)), members of the mucin core family (e.g., Tn, sialyl Tn and T-F) and gangliosides (e.g., GM2). Most studies have used glycoconjugate vaccines in which a synthetic oligosaccharide is coupled to a protein carrier, for example, KLH, but completely synthetic constructs are also being examined. Preclinical studies in mice have shown the effectiveness of some of these vaccines. Clinical studies are under way in a number of human cancers but the results are still being evaluated.


Common characteristics and unique features: A comparison of the fusion machinery of the alphaherpesviruses Pseudorabies virus and Herpes simplex virus.
Membrane fusion is a fundamental biological process that allows different cellular compartments delimited by a lipid membrane to release or exchange their respective contents. Similarly, enveloped viruses such as alphaherpesviruses exploit membrane fusion to enter and infect their host cells. For infectious entry the prototypic human Herpes simplex viruses 1 and 2 (HSV-1 and -2, collectively termed HSVs) and the porcine Pseudorabies virus (PrV) utilize four different essential envelope glycoproteins (g): the bona fide fusion protein gB and the regulatory heterodimeric gH/gL complex that constitute the "core fusion machinery" conserved in all members of the Herpesviridae; and the subfamily specific receptor binding protein gD. These four components mediate attachment and fusion of the virion envelope with the host cell plasma membrane through a tightly regulated sequential activation process. Although PrV and the HSVs are closely related and employ the same set of glycoproteins for entry, they show remarkable differences in the requirements for fusion. Whereas the HSVs strictly require all four components for membrane fusion, PrV can mediate cell-cell fusion without gD. Moreover, in contrast to the HSVs, PrV provides a unique opportunity for reversion analyses of gL-negative mutants by serial cell culture passaging, due to a limited cell-cell spread capacity of gL-negative PrV not observed in the HSVs. This allows a more direct analysis of the function of gH/gL during membrane fusion. Unraveling the molecular mechanism of herpesvirus fusion has been a goal of fundamental research for years, and yet important mechanistic details remain to be uncovered. Nevertheless, the elucidation of the crystal structures of all key players involved in PrV and HSV membrane fusion, coupled with a wealth of functional data, has shed some light on this complex puzzle. In this review, we summarize and discuss the contemporary knowledge on the molecular mechanism of entry and membrane fusion utilized by the alphaherpesvirus PrV, and highlight similarities but also remarkable differences in the requirements for fusion between PrV and the HSVs.


Cytogenomic analyses reveal the structural plasticity of the chloroplast genome in higher plants.
A DNA fiber-based fluorescence in situ hybridization (fiber-FISH) technique was developed to analyze the structure and organization of a large number of intact chloroplast DNA (cpDNA) molecules from Arabidopsis, tobacco, and pea. Using this cytogenomic approach, we determined that 25 to 45% of the cpDNA within developing leaf tissue consists of circular molecules. Both linear and circular DNA fibers with one to four copies of the chloroplast genome were present, with monomers being the predominant structure. Arabidopsis and tobacco chloroplasts contained previously unidentified multimers (>900 kb) consisting of six to 10 genome equivalents. We further discovered rearranged cpDNA molecules of incomplete genome equivalents, confirmed by both differential hybridizations and size estimations. The unique cpDNA organization and novel structures revealed in this study demonstrate that higher plant cpDNA is more structurally plastic than previous sequence and electrophoretic analyses have suggested. Additionally, we demonstrate how the fiber-FISH-based cytogenomic approach allows for powerful analysis of very rare events that cannot be detected by traditional techniques such as DNA gel blot hybridization or polymerase chain reaction.


IL-10 inhibits the NF-κB and ERK/MAPK-mediated production of pro-inflammatory mediators by up-regulation of SOCS-3 in Trypanosoma cruzi-infected cardiomyocytes.
Trypanosoma cruzi (T. cruzi) infection produces an intense inflammatory response which is critical for the control of the evolution of Chagas' disease. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines identified as modulator of the inflammatory reaction. This work shows that exogenous addition of IL-10 inhibited ERK1/2 and NF-κB activation and reduced inducible nitric oxide synthase (NOS2), metalloprotease (MMP) -9 and MMP-2 expression and activities, as well as tumour necrosis factor (TNF)-α and interleukin (IL)-6 expression, in T. cruzi-infected cardiomyocytes. We found that T. cruzi and IL-10 promote STAT3 phosphorylation and up-regulate the expression of suppressor of cytokine signalling (SOCS)-3 thereby preventing NF-κB nuclear translocation and ERK1/2 phosphorylation. Specific knockdown of SOCS-3 by small interfering RNA (siRNA) impeded the IL-10-mediated inhibition of NF-κB and ERK1/2 activation. As a result, the levels of studied pro-inflammatory mediators were restored in infected cardiomyocytes. Our study reports the first evidence that T. cruzi up- regulates SOCS-3 expression and highlights the relevance of IL-10 in the modulation of pro-inflammatory response of cardiomyocytes in Chagas' disease.


Circumpolar maternal blood contaminant survey, 1994-1997 organochlorine compounds.
During the past 20 years a number of studies have found neurological and immunological effects in the developing fetus and infants exposed to background or only slightly elevated levels of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs). To address concerns arising from possible increased human exposure in the Arctic and possible effects of POPs, all circumpolar countries agreed in 1994 to monitoring of specific human tissues for contaminants in the Arctic under the Arctic Monitoring and Assessment Program (AMAP). Mothers in eight circumpolar countries contributed blood samples that were analysed at a single laboratory for 14 PCB congeners (IUPAC No. 28, 52, 99, 105, 118, 128, 138, 153, 156, 170, 180, 183, 187) and 13 organochlorine pesticides (aldrin, beta-hexachlorocyclohexane (beta-HCH), dichlordiphenyltrichloroethane (p,p'-DDT), diphenyldichloroethylene (p,p'-DDE), dieldrin, heptachlorepoxide, hexachlorobenzene (HCB), mirex, and the chlordane derivatives alpha-chlordane, gamma-chlordane, cis-nonachlor, oxychlordane and trans-nonachlor). Inuit mothers from Greenland and Canada have significantly higher levels of oxychlordane, transnonachlor and mirex than mothers from Norway, Sweden, Iceland and Russia. Inuit mothers from Greenland also have significantly higher levels of these contaminants than Inuit mothers from Canada and Alaska. These differences among Inuit groups may represent regional dietary preferences or different contaminant deposition patterns across the Arctic. Levels of PCBs are also elevated among some arctic populations due to their consumption of marine mammals and are in the range where subtle effects on learning and the immune system have been reported. The Russian mothers who consume mainly food imported from southern Russia have elevated levels of DDT, DDE, beta-HCH and a higher proportion of lower chlorinated PCB congeners. This study has allowed an assessment of the variation of contaminants such as PCBs and various organochlorine pesticides (DDT, chlordane, etc.) in human populations around the circumpolar north.


Ferrous sulphate gel dosimetry and MRI for proton beam dose measurements.
Ferrous sulphate gel dosimetry has the potential for measurement of absorbed dose distributions in proton therapy. The chemical properties of the gel are altered according to the radiation dose and these changes can be evaluated in three dimensions using MRI. The purpose of this work was to investigate the properties of a ferrous gel used with clinical proton beams. The gel was irradiated with both monoenergetic and range-modulated proton beams. It was then evaluated using MRI. The depth dose by means of the 1/T1 distribution was studied and compared with data from a plane-parallel plate ionization chamber. 1/T1 was shown to be proportional to the dose at a mean proton energy of approximately 90 MeV. The dose response was no different from that obtained using photon beams. However, on normalization at the entrance, the relative 1/T1 at the Bragg peak was 15-20% lower than the corresponding ionization chamber data for the monoenergetic proton beam. Better agreement was found for the modulated beam, but with significant differences close to the distal edge of the 1/T1 distribution. The change in sensitivity with depth was explained by means of a linear energy transfer dependence. This property was further studied using Monte Carlo methods.


Can wireless text messaging improve adherence to preventive activities? Results of a randomised controlled trial.
To determine the effectiveness of cell phone wireless text messaging for improving adherence to a healthy behaviour. A randomised, unblinded, controlled trial was conducted with 102 subjects, 18 years or older, each having a cell phone and willing to take 1 vitamin C pill per day for 1 month for preventive reasons. Intervention group participants received text messaging reminders and were asked to acknowledge receiving their messages after taking the vitamins, whereas control group subjects had no text messaging activity. Self-reported adherence and the number of participant text messages acknowledging vitamins taken. Both groups reported an increased adherence after the trial: by 246% for the intervention group and by 131% for the control group. There was a non-significant difference between the two groups at endpoint: an average difference of 0.8 between the number of pills missed in the last week of the trial (2.5 out of 7 in the intervention and 3.3 out of 7 in the control group) with a power of 0.54. The study revealed a significant correlation (coefficient=-0.352, sig.=0.01) between the average number of text messaging acknowledgements sent by the intervention group participants and the number of pills they reported missed during the last week of the trial. This was a small randomised controlled trial with inconclusive but encouraging results. It suggests a new approach in addressing insufficient adherence in outpatient conditions and shows that the use of information technology tools for compliance warrants further research.


Learning Invariance from Transformation Sequences.
The visual system can reliably identify objects even when the retinal image is transformed considerably by commonly occurring changes in the environment. A local learning rule is proposed, which allows a network to learn to generalize across such transformations. During the learning phase, the network is exposed to temporal sequences of patterns undergoing the transformation. An application of the algorithm is presented in which the network learns invariance to shift in retinal position. Such a principle may be involved in the development of the characteristic shift invariance property of complex cells in the primary visual cortex, and also in the development of more complicated invariance properties of neurons in higher visual areas.


Grand canonical inverse design of multicomponent colloidal crystals.
Inverse design methods are powerful computational approaches for creating colloidal systems which self-assemble into a target morphology by reverse engineering the Hamiltonian of the system. Despite this, these optimization procedures tend to yield Hamiltonians which are too complex to be experimentally realized. An alternative route to complex structures involves the use of several different components, however, conventional inverse design methods do not explicitly account for the possibility of phase separation into compositionally distinct structures. Here, we present an inverse design scheme for multicomponent colloidal systems by combining active learning with a method to directly compute their ground state phase diagrams. This explicitly accounts for phase separation and can locate stable regions of Hamiltonian parameter space which grid-based surveys are prone to miss. Using this we design low-density, binary structures with Lennard-Jones-like pairwise interactions that are simpler than in the single component case and potentially realizable in an experimental setting. This reinforces the concept that ground states of simple, multicomponent systems might be rich with previously unappreciated diversity, enabling the assembly of non-trivial structures with only few simple components instead of a single complex one.


Diagnosis of metastases from testicular germ cell tumours using fine needle aspiration cytology.
The cytological features of testicular germ cell tumours were established in smears from 15 freshly resected tumours. These features were applied to the fine needle aspiration cytology diagnosis of metastases in 27 patients referred for chemotherapy. There were 16 positive reports in 32 aspirates of which 13 were taken before chemotherapy and three in patients with residual or new masses after chemotherapy. Teratomas and typical seminomas showed certain characteristic morphological features in cytological preparations which when present in fine needle aspiration cytology material enabled tumour types to be diagnosed. Spermatocytic and anaplastic seminoma were not represented in this series. It is unlikely that these could be distinguished from malignant teratoma undifferentiated (MTU) in the fine needle aspiration cytology material. Metastases from carcinomatous areas in MTU and malignant teratoma intermediate (MTI) may not be distinguishable in fine needle aspiration cytology material from metastatic adenocarcinoma or undifferentiated carcinoma from a different primary site. Positive cytological findings are of value to the oncologist in the management of patients with metastases from testicular germ cell tumours; negative cytology does not exclude the presence of viable tumour. The sampling of small foci of viable tumour in large necrotic masses persisting after chemotherapy is a problem for radiologists, cytologists, and histopathologists. This paper does not advocate the use of fine needle aspiration cytology for the diagnosis of primary testicular tumour.


Chiral 1,3,4-oxadiazol-2-ones as highly selective FAAH inhibitors.
In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, 51), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 μM). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 μM and 16% inhibition at 10 μM, respectively). The FAAH selectivity of the compound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected S-enantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.


Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.


Sex differences in childhood sexual abuse and suicide-related behaviors.
Child sexual abuse and suicide-related behaviors are associated, but it remains unclear if the strength of this association differs in boys and girls. In a systematic review of this association in children and youth, we identified 16 relevant studies, all cross-sectional surveys of students. The association is stronger in boys specific to suicide attempt(s). Adjustments for potential confounding variables explained some, but not all of this sex difference. While additional research would strengthen causal inferences, this sex difference may be influenced by the nature and timing of child sexual abuse as well as the sex of the perpetrator, which in turn shapes the disclosure of these events.


Experimental and molecular mechanics and ab initio investigation of activated adsorption and desorption of trichloroethylene in mineral micropores.
This research investigated activated adsorption of a hydrophobic organic contaminant(HOC) in mineral micropores using experimental and molecular modeling techniques. Adsorption of trichloroethylene (TCE) on a silica gel adsorbent was measured using a frontal analysis chromatography technique at atmospheric and elevated fluid pressures. Increasing the fluid pressure yielded increased TCE uptake that was not released upon lowering the pressure back to atmospheric conditions. This showed that the increase in pressure was able to rapidly induce the formation of a desorption-resistant fraction that previous investigations have shown requires months to develop at atmospheric pressure. Grand Canonical Monte Carlo (GCMC) modeling was then used to elucidate the nature of water and TCE behavior within silica micropores. The GCMC modeling showed that molecular scale packing restrictions resulted in pore fluid densities that ranged from 0.28 to 0.78 of those in the bulk solution. The modeling also showed that TCE was able to displace water from hydrophilic mineral pores due to molecular scale packing restrictions. Exothermic isosteric heats for TCE adsorption up to -27 kJ/mol were observed and were greatest in pores of 7 and 8 A. This indicated that TCE adsorption was energetically most favorable in pores that were minimally large enough to accommodate a TCE molecule. The pressure-induced uptake appeared to result primarily from an increase in the packing density in the smallest pores. Ab initio calculations showed that small distortions of a TCE molecule from its low energy conformation require high activation energies. Results from this study indicate that activated adsorption requiring bond angle distortions in the adsorbate may be responsible forthe slow attainment of adsorptive equilibrium of HOCs on microporous solids. Likewise, activated desorption from molecular-sized adsorption sites may contribute to the slow release of HOCs from aquifer sediments.


Preparation of silver nanoparticles by Osbeckia stellata aqueous extract via green synthesis approach: Characterization and assessment of their antioxidant, antidiabetic, cytotoxicity, and antibacterial properties.
Silver nanoparticles (Ag NPs) via green synthesis using medicinal plants have been widely used in natural product research due to the economical and eco-friendly properties of NPs. The plant-derived Ag NPs biosynthesis comprises the interaction between silver nitrate (precursor) and bioactive components of plant extract (reducing agents). In this work, Ag NPs were biosynthesized using Osbeckia stellata leaves aqueous extract. Characterization of Ag NPs was done by using ultraviolet-visible absorption (UV-Vis) spectroscopy, dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy-dispersive X-ray analysis (EDX). Further, antioxidant, antidiabetic, cytotoxicity, and antimicrobial activities were evaluated to establish the pharmacological properties of Ag NPs. UV-Vis spectroscopy and FTIR showed an absorption peak of Ag NPs due to the surface plasmonic resonance. In contrast, the particle size in the nanometer range was analyzed by XRD and DLS. The size of the particle was confirmed by the SEM, TEM, and EDX in the nanometer range. This study showed the spherical shape and crystalline nature of NPs. Zeta potential was used to determine the stability of Ag NPs. Biosynthesized Ag NPs showed significantly potent antioxidant, antidiabetic, and cytotoxicity activity. Ag NPs also showed effectiveness against gram-positive (Escherichia coli) and gram-negative (Staphylococcus aureus) bacteria in the antimicrobial activity study. The result concluded that these Ag NPs might be used in biomedical and pharmacological fields.


[Pathologic wall changes in the gallbladder in patients with gallstones and in healthy probands. Imaging using high frequency annular array sector transducers].
2154 computerized ultrasound diagnoses of 1623 patients were evaluated retrospectively from January 1st to October 31st 1987. The frequency of pathologic gallbladder wall changes in patients with stones and normal controls was examined applying 5 MHz annular array sector transducer. The occurrence of polyps, septae, sludge, kinking, carcinoma and adenomyomatosis was noted separately. The prevalence of polyps and septae in gallstone patients was increased fourfold if compared to the total number of examined patients. Sludge was found in 5.9% of gallstone patients compared to 2.2% in normal controls. Carcinoma and adenomyomatosis were present only in cases of cholelithiasis; the prevalence of these pathologic wall changes is obviously rare. The importance of polyps and septae in biliary lithogenicity is discussed.


Hospital cost of care, quality of care, and readmission rates: penny wise and pound foolish?
Hospitals face increasing pressure to lower cost of care while improving quality of care. It is unclear if efforts to reduce hospital cost of care will adversely affect quality of care or increase downstream inpatient cost of care. We conducted an observational cross-sectional study of US hospitals discharging Medicare patients for congestive heart failure (CHF) or pneumonia in 2006. For each condition, we examined the association between hospital cost of care and the following variables: process quality of care, 30-day mortality rates, readmission rates, and 6-month inpatient cost of care. Compared with hospitals in the lowest-cost quartile for CHF care, hospitals in the highest-cost quartile had higher quality-of-care scores (89.9% vs 85.5%) and lower mortality for CHF (9.8% vs 10.8%) (P < .001 for both). For pneumonia, the converse was true. Compared with low-cost hospitals, high-cost hospitals had lower quality-of-care scores (85.7% vs 86.6%, P = .002) and higher mortality for pneumonia (11.7% vs 10.9%, P < .001). Low-cost hospitals had similar or slightly higher 30-day readmission rates compared with high-cost hospitals (24.7% vs 22.0%, P < .001 for CHF and 17.9% vs 17.3%, P = .20 for pneumonia). Nevertheless, patients initially seen in low-cost hospitals incurred lower 6-month inpatient cost of care compared with patients initially seen in hospitals with the highest cost of care ($12 715 vs $18 411 for CHF and $10 143 vs $15 138 for pneumonia, P < .001 for both). The associations are inconsistent between hospitals' cost of care and quality of care and between hospitals' cost of care and mortality rates. Most evidence did not support the "penny wise and pound foolish" hypothesis that low-cost hospitals discharge patients earlier but have higher readmission rates and greater downstream inpatient cost of care.


[Congestive cardiomyopathy (pathologo-anatomic study of the heart)].
A pathomorphologic study of 40 cases of congestive cardiomyopathy (CCMP) demonstrated that circulatory insufficiency was the cause of death in 70% of cases, while sudden death occurred in 25%. Morphometric investigation identified 3 CCMP patterns: cardiosclerosis-free and accompanied with small-focal (diffuse) and large-focal cardiosclerosis. The mean duration of the disease and the mean age at death were the smallest in the cardiosclerosis-free group where the dilatation of heart cavities was found to be the greatest. A direct relationship was demonstrated between the duration of the disease and the myocardial fibrous tissue content. Blood flow deceleration due to circulatory insufficiency in CCMP cases was shown to be conducive to thrombogenesis both in heart cavities, and in minor pulmonary arteries and myocardial veins.


Role prediction using Electronic Medical Record system audits.
Electronic Medical Records (EMRs) provide convenient access to patient data for parties who should have it, but, unless managed properly, may also provide it to those who should not. Distinguishing the two is a core security challenge for EMRs. Strategies proposed to address these problems include Role Based Access Control (RBAC), which assigns collections of privileges called roles to users, and Experience Based Access Management (EBAM), which analyzes audit logs to determine access rights. In this paper, we integrate RBAC and EBAM through an algorithm, called Roll-Up, to manage roles effectively. In doing so, we introduce the concept of "role prediction" to identify roles from audit data. We apply the algorithm to three months of logs from Northwestern Memorial Hospital's Cerner system with approximately 8000 users and 140 roles. We demonstrate that existing roles can be predicted with 50% accuracy and intelligent grouping of roles through Roll-Up can facilitate 65% accuracy.