White matter alterations related to P300 abnormalities in individuals at high risk for psychosis: an MRI-EEG study.
Psychosis onset is characterized by white matter and electrophysiologic abnormalities. The relation between these factors in the development of illness is almost unknown. We studied the relation between white matter volumes and P300 in prodromal psychosis. We assessed white matter volume (detected using magnetic resonance imaging) and electrophysiologic response during an oddball task (P300) in healthy controls and individuals at high clinical risk for psychosis (with an "at-risk mental state" [ARMS]). We included 41 controls and 39 patients with an ARMS in our study. A psychotic disorder developed in 26% of the ARMS group within the follow-up period of 2 years. The P300 amplitude was significantly lower in the ARMS group than in the control group. The ARMS group showed reduced volume of white matter underlying the left superior temporal gyrus and the left superior frontal gyrus and increased volume of white matter underlying the right insula and the right angular gyrus compared with controls. Relative to individuals who did not later become psychotic, the subgroup in whom psychosis subsequently developed had a smaller volume of white matter underlying the left precuneus and the right middle temporal gyrus and increased volume in the white matter underlying the right middle frontal gyrus. We observed a significant interaction in the right middle frontal gyrus: white matter volume was negatively associated with P300 amplitude in the ARMS group and positively associated with P300 amplitude in the control group. The voxel-based morphometry method alone cannot determine whether abnormal white matter volumes are due to an altered number of axonal connections or decreased myelination. P300 abnormalities precede the onset of psychosis and are directly related to white matter alterations, representing a correlate of an increased vulnerability to disease.


Exclusively Breastfeeding Modifies the Adverse Association of Late Preterm Birth and Gastrointestinal Infection: A Nationwide Birth Cohort Study.
Introduction: Late preterm infants (LPIs) are at greater risk for short- and long-term morbidity compared with term infants. However, little is known about whether breastfeeding can reduce the adverse effect of late preterm (LP) birth on various diseases. Therefore, we examined the association of LP birth with the risk of hospitalizations from 6 to 18 months of age, then explored the possible modification of this effect by breastfeeding. Materials and Methods: Data were extracted from a nationwide population-based longitudinal survey in Japan. We restricted our analysis to term and LPIs with information on hospitalization (n = 31,578). Multivariate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated to evaluate the association between LP birth and hospitalization using term birth as the reference. We then examined whether breastfeeding status modified the potential adverse effects of LP birth on each health outcome. Results: LPIs were more likely to be hospitalized for all-cause (aOR, 1.58; 95% CI, 1.35-1.86), respiratory (aOR, 1.52; 95% CI, 1.21-1.92) and gastrointestinal infections (aOR, 1.73; 95% CI, 1.14-2.62) than term infants. While LPIs had a higher risk of hospitalization for all-cause and respiratory infection regardless of breastfeeding status, we did not observe an increased risk of hospitalization for gastrointestinal infection among the exclusively breastfed LPIs, in contrast with increased risk among the non-exclusively breastfed LPIs. Conclusions: We found that LPIs had a higher risk of all-cause and cause-specific hospitalization compared with term infants. Moreover, exclusive breastfeeding probably reduced the adverse effect of LP birth on gastrointestinal infection.


New opportunities for an ancient material.
Spiders and silkworms generate silk protein fibers that embody strength and beauty. Orb webs are fascinating feats of bioengineering in nature, displaying magnificent architectures while providing essential survival utility for spiders. The unusual combination of high strength and extensibility is a characteristic unavailable to date in synthetic materials yet is attained in nature with a relatively simple protein processed from water. This biological template suggests new directions to emulate in the pursuit of new high-performance, multifunctional materials generated with a green chemistry and processing approach. These bio-inspired and high-technology materials can lead to multifunctional material platforms that integrate with living systems for medical materials and a host of other applications.


Developmental regulation of expression of C-reactive protein and serum amyloid A in Syrian hamsters.
The fetal and maternal concentration of various plasma proteins alters during pregnancy. Cells in the livers of fetal hamsters accumulate serum amyloid A (SAA) and C-reactive protein (CRP) mRNA, major acute phase reactants, when lipopolysaccharide is administered to the fetal circulation. No fetal SAA or CRP mRNA response is seen when the mother is stimulated at a remote site by endotoxin or a nonspecific inflammatory agent. In addition, cells of the fetal hamster liver do not respond by accumulating SAA mRNA when exposed to the specific cytokines, tumor necrosis factor, IL-1, and IL-6. CRP mRNA levels increased in fetal livers after administration of tumor necrosis factor and IL-1. These data suggest that cells contained in the fetal liver can respond during an acute phase reaction but that the capacity of some acute phase reactant genes to respond to cytokines may be developmentally regulated. Studies of immature hamsters after birth show that the responses of CRP and SAA genes to lipopolysaccharide, tumor necrosis factor, IL-1, and IL-6 are reduced when compared with induction of mRNA accumulation for these acute phase reactants in adult animals.


A new approach to test validity and clinical usefulness of the 2013 ACC/AHA guideline on statin therapy: A population-based study.
The ACC/AHA released a new guideline on the assessment of cardiovascular risk and management of hypercholesterolemia that some controversy exists concerning its usefulness. We examined the clinical usefulness of this guideline in a high incidence population using novel measures. First, we validated the new risk equation in a cohort of 2372 men and 2781 women aged 40-75 years. Then, high risk individuals for cardiovascular diseases (CVDs) were identified according to the ACC/AHA guideline at baseline (as a predictor) and CVD outcomes were detected during a 10-year follow-up. Discrimination of the guideline was quantified and the quality of decisions was evaluated by Net Benefit Fraction index considering the harm, for false-positive, and benefit, for true-positive predictions. Finally, net number needed to treat (NNT) for statin was estimated, using test tradeoff index, in diabetic and non-diabetic subjects. During follow-up, 726 CVD events including 298 hard CVDs occurred. The equation overestimated the risk by 57% in men and 48% in women. Based on the guideline, 73% of men and 44% of women were eligible for statin therapy. The lowest sensitivity was detected for intensive treatment in non-diabetic subgroups (82% in men and 41% in women; corresponding specificity, 52% and 90% respectively). The guideline had a significant net benefit for both moderate and intensive treatment, which resulted in estimated NNTs ranged 5-55; however, net benefit of intensive therapy was uncertain in non-diabetic women. We objectively showed that the ACC/AHA recommendations could be useful in our population but with some overtreatment in women.


Non-surgical management of stress urinary incontinence: ambulatory treatments for leakage associated with stress (ATLAS) trial.
Non-surgical treatment for stress urinary incontinence (SUI) is recommended as first-line therapy, yet few prospective studies and no randomized trials compare the most common non-surgical treatments for SUI. To present the design and methodology of the ambulatory treatments for leakage associated with stress (ATLAS) trial, a randomized clinical trial comparing three interventions for predominant SUI in women: intravaginal continence pessary; behavioral therapy (including pelvic floor muscle training and exercise and bladder control strategies); and a combination of the two treatments. Treatment outcome measures, collected at 12 weeks and six and 12 months post randomization, include the Patient Global Impression of Improvement (PGI-I), the Stress Incontinence Scale of the Pelvic Floor Distress Inventory (PFDI), seven-day bladder diaries, Pelvic Floor Impact Questionnaire (PFIQ), Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire (PISQ-12), Patient Satisfaction Questionnaire (PSQ) and the Medical Outcomes Study Short Form Health Survey (SF-36). The study design reduces most common biases, but some degree of selection bias may remain. This trial will provide useful information to help counsel women with stress and mixed incontinence about the relative efficacy and satisfaction with pessary, behavioral therapy and both treatments combined.


Assessing the discordance of multiple sequence alignments.
Multiple sequence alignments have wide applicability in many areas of computational biology, including comparative genomics, functional annotation of proteins, gene finding, and modeling evolutionary processes. Because of the computational difficulty of multiple sequence alignment and the availability of numerous tools, it is critical to be able to assess the reliability of multiple alignments. We present a tool called StatSigMA to assess whether multiple alignments of nucleotide or amino acid sequences are contaminated with one or more unrelated sequences. There are numerous applications for which StatSigMA can be used. Two such applications are to distinguish homologous sequences from nonhomologous ones and to compare alignments produced by various multiple alignment tools. We present examples of both types of applications.


Effects of crush and axotomy on oxidative stress and some trace element levels in phrenic nerve of rats.
This study was designed to investigate the effect of crush and axotomy on oxidative stress and some trace element levels in phrenic nerve of rats. Eighteen male Wistar-albino rats were divided randomly into three groups, each consisting of 6 rats. The animals in the first group were not crushed or axotomized and served as control. Phrenic nerves of the animals in the second and third groups were crushed and axotomized, respectively. Animals in all groups were sacrificed one week after the crush or axotomy, and degenerated phrenic nerves were harvested for the determination of tissue oxidative stress and trace element levels. Lipid peroxidation product malondialdehyde and antioxidant glutathione levels increased in both crushed and axotomized phrenic nerves. The activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase were lower in crushed and axotomized phrenic nerves than in controls. The levels of Fe, Pb, Mn, Cd and Co increased, and Mg and Cu levels decreased in crushed phrenic nerves. The levels of Fe and Mg decreased, Pb and Co levels increased in axotomized phrenic nerves. It was concluded that crushing or axotomizing the phrenic nerves may produce oxidative stress by increasing lipid peroxidation and decreasing antioxidant enzyme activities. It was also concluded that while crush to phrenic nerves causes accumulation of minerals, axotomizing phrenic nerves causes depletion of minerals in the tissues.


Highly controllable direct femtosecond laser writing of gold nanostructures on titanium dioxide surfaces.
A highly reproducible and controllable deposition procedure for gold nanostructures on a titanium dioxide (TiO2) surface using femtosecond laser light has been demonstrated. This is realized by precisely focusing onto the TiO2 surface in the presence of a pure gold ion solution. The deposition is demonstrated both in dot arrays and line structures. Thanks to the multi-photon excitation, we observe that the deposition area of the nanostructures can be confined to a degree far greater than the diffraction limited focal spot. Finally, we demonstrate that catalytic activity with visible light irradiation is enhanced, proving the applicability of our new deposition technique to the catalytic field.


Restoration of podocyte structure and improvement of chronic renal disease in transgenic mice overexpressing renin.
Proteinuria is a major marker of the decline of renal function and an important risk factor of coronary heart disease. Elevated proteinuria is associated to the disruption of slit-diaphragm and loss of podocyte foot processes, structural alterations that are considered irreversible. The objective of the present study was to investigate whether proteinuria can be reversed and to identify the structural modifications and the gene/protein regulation associated to this reversal. We used a novel transgenic strain of mouse (RenTg) that overexpresses renin at a constant high level. At the age of 12-month, RenTg mice showed established lesions typical of chronic renal disease such as peri-vascular and periglomerular inflammation, glomerular ischemia, glomerulosclerosis, mesangial expansion and tubular dilation. Ultrastructural analysis indicated abnormal heterogeneity of basement membrane thickness and disappearance of podocyte foot processes. These structural alterations were accompanied by decreased expressions of proteins specific of podocyte (nephrin, podocin), or tubular epithelial cell (E-cadherin and megalin) integrity. In addition, since TGFbeta is considered the major pro-fibrotic agent in renal disease and since exogenous administration of BMP7 is reported to antagonize the TGFbeta-induced phenotype changes in kidney, we have screened the expressions of several genes belonging in the TGFbeta/BMP superfamily. We found that the endogenous inhibitors of BMPs such as noggin and Usag-1 were several-fold activated inhibiting the action of BMPs and thus reinforcing the deleterious action of TGFbeta.Treatment with an AT1 receptor antagonist, at dose that did not decrease arterial pressure, gradually reduced albuminuria. This decrease was accompanied by re-expression of podocin, nephrin, E-cadherin and megalin, and reappearance of podocyte foot processes. In addition, expressions of noggin and Usag-1 were markedly decreased, permitting thus activation of the beneficial action of BMPs. These findings show that proteinuria and alterations in the expression of proteins involved in the integrity and function of glomerular and renal epithelial phenotype are reversible events when the local action of angiotensin II is blocked, and provide hope that chronic renal disease can be efficiently treated.


Glasgow Early Treatment Arm Favirpiravir (GETAFIX) for adults with early stage COVID-19: A structured summary of a study protocol for a randomised controlled trial.
The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as: • greater than Child-Pugh grade A • AST or ALT > 5 x ULN • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. The current GETAFIX protocol is version 4.0 12th September 2020. GETAFIX opened to recruitment on 26th October 2020 and will recruit patients over a period of approximately six months. GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15th April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7th September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).


Course of cannabis use and clinical outcome in patients with non-affective psychosis: a 3-year follow-up study.
Prospective studies on the relationship between course of cannabis use and clinical outcome in patients with non-affective psychotic disorders are inconclusive. The current study examined whether (1) persistent, recently started, discontinued and non-cannabis-using patients with a psychotic disorder differed with regard to illness outcome at 3-year follow-up, and (2) whether timing of cannabis discontinuation was associated with course of clinical outcome. This 3-year follow-up study was part of a multi-center study in the Netherlands and Belgium (Genetic Risk and Outcome of Psychosis; GROUP). We used mixed-model analyses to investigate the association between pattern of cannabis use and symptoms, global functioning and psychotic relapse. In our sample of 678 patients, we found persistent users to have more positive and general symptoms, worse global functioning and more psychotic relapses compared with non-users and discontinued users [Positive and Negative Syndrome Scale (PANSS) positive, p < 0.001; PANSS general, p < 0.001; Global Assessment of Functioning (GAF) symptoms, p = 0.017; GAF disability, p < 0.001; relapses, p = 0.038]. Patients who started using cannabis after study onset were characterized by worse functioning at baseline and showed an increase in general symptoms (including depression and anxiety) at the 3-year follow-up (p = 0.005). Timing of cannabis discontinuation was not associated with clinical outcome. These findings suggest that cannabis use in patients with a psychotic disorder has a long-lasting negative effect on illness outcome, particularly when persistent. Treatment should focus on discouraging cannabis use.


Does Fetal Growth Restriction Cause Later Obesity? Pitfalls in Analyzing Causal Mediators as Confounders.
Recent studies finding that small-for-gestational-age (SGA) birth is associated with increased adiposity in childhood and adulthood have been based on analyses "adjusting" for height, weight, or body mass index (BMI; weight (kg)/height (m)2) measured concurrently with the adiposity measurement. To assess the potential for bias due to overadjustment for a causal mediator, we compared 2 approaches to analyzing the association between SGA birth and adiposity outcomes (skinfold thicknesses and bioelectrical impedance measurement of body fat) at age 11.5 years using the same data set in a cohort of Belarusian children followed from birth in 1996-1997 to age 11.5 years in 2008-2010. We 1) studied the association of SGA birth with adiposity, adjusting for baseline covariates only, and 2) made additional regression adjustment for concurrent height, weight, or BMI. The first approach yielded negative associations between SGA birth and all adiposity outcomes. Additional adjustment for concurrent weight or BMI reversed (i.e., to positive) the SGA-adiposity association. To explore the latter anthropometric measures as causal mediators, we also used marginal structural models to estimate the controlled direct effect of SGA birth. That effect was similar to the effect seen with the first approach when modeled on height, was null when modeled on BMI, but was confounded by differences in lean mass versus fat mass when modeled on weight.


Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis.
The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) β-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFNβ-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR. Trial registration number for study 25643: NCT00213135.


Characterization of the structural and functional determinants of MANF/CDNF in Drosophila in vivo model.
Mammalian MANF and CDNF proteins are evolutionarily conserved neurotrophic factors that can protect and repair mammalian dopaminergic neurons in vivo. In Drosophila, the sole MANF protein (DmManf) is needed for the maintenance of dopaminergic neurites and dopamine levels. Although both secreted and intracellular roles for MANF and CDNF have been demonstrated, very little is known about the molecular mechanism of their action. Here, by using a transgenic rescue approach in the DmManf mutant background we show that only full-length MANF containing both the amino-terminal saposin-like and carboxy-terminal SAP-domains can rescue the larval lethality of the DmManf mutant. Independent N- or C-terminal domains of MANF, even when co-expressed together, fail to rescue. Deleting the signal peptide or mutating the CXXC motif in the C-terminal domain destroys the activity of full-length DmManf. Positively charged surface amino acids and the C-terminal endoplasmic reticulum retention signal are necessary for rescue of DmManf mutant lethality when DmManf is expressed in a restricted pattern. Furthermore, rescue experiments with non-ubiquitous expression reveals functional differences between the C-terminal domain of human MANF and CDNF. Finally, DmManf and its C-terminal domain rescue mammalian sympathetic neurons from toxin-induced apoptosis in vitro demonstrating functional similarity of the mammalian and fly proteins. Our study offers further insights into the functional conservation between invertebrate and mammalian MANF/CDNF proteins and reveals the importance of the C-terminal domain for MANF activity in vivo.


Aromatherapy Improves Work Performance Through Balancing the Autonomic Nervous System.
This study analyzed the efficacy of aromatherapy in improving work performance and reducing workplace stress. The initial sample comprised 42 administrative university workers (Mage = 42.21 years, standard deviation = 7.12; 10 male). All sessions were performed in a university computer classroom. The participants were randomly assigned into an aromatherapy group (AG) and a control group (CG), and they were invited to participate in a specific session only once. They were seated in front of a computer. During the intervention period, some oil diffusers were switched on and were in operation throughout the session with petitgrain essential oil for AG sessions and a neutral oil (almond) for CG sessions. At the same time, participants completed a computer task on a specific Web site typing on their keyboard until they had finished it. The single times were different for all participants and were recorded on the Web site as "performance time." Before and after the intervention, participants completed anxiety and mood state questionnaires (the Stait-Trait Anxiety Inventory [STAI] and the Profile of Mood States [POMS]). Heart-rate variability (HRV) was measured before (PRE), during (20-25 min), and after (POS) the intervention to analyze autonomic nervous system regulation. The AG performed the Web site task 2.28 min faster than the CG (p = 0.05). The two groups showed differences in the following HRV parameters: low frequency (p = 0.05), high frequency (p = 0.02), standard deviation of all RR intervals (p = 0.05), and root mean square of differences (p = 0.02). All participants in all groups showed a decrease from PRE to POST for STAI (p < 0.001), Tension-POMS (p < 0.001), and Vigour-POMS (p = 0.01) scales. Aromatherapy (inhaling petitgrain essential oil) can improve performance in the workplace. These results could be explained by an autonomic balance on the sympathetic/parasympathetic system through a combined action of the petitgrain main components (linalyl acetate, linalool, and myrcene). The final effect could be an improvement of the mental and emotional condition by a combination of reducing the stress level and increasing the arousal level of the participants in terms of attentiveness and alertness.


Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) Trial.
The early effects of tissue-type plasminogen activator (t-PA) on the "culprit" coronary lesion in patients presenting with unstable angina or non-Q wave myocardial infarction were determined by quantitative arteriography. Of 391 such patients, 306 satisfied clinical and arteriographic requirements for eligibility and received a 90-minute front-loaded infusion of t-PA (0.8 mg/kg i.v.; maximum, 80 mg) or placebo plus conventional antianginal therapy. All patients received full heparinization and a follow-up arteriogram 18-48 hours after treatment. A non-Q wave myocardial infarction (MI) was diagnosed in 97 patients (32%) after entry. In the entire patient population, among t-PA- and placebo-treated patients, respectively, 25% versus 19% (p = 0.25) of all culprit lesions achieved the primary study end point, measurable improvement (by > or = 10% reduction of stenosis or two Thrombolysis in Myocardial Infarction [TIMI] flow grades) at follow-up. Substantial improvement (by > or = 20% reduction of stenosis or two TIMI grades) was seen with t-PA in 15% of all culprit lesions versus 5% with placebo (p < 0.003). Arteriographically apparent thrombus was present at baseline in the culprit lesion of 107 patients (35%). Substantial improvement was more frequent with t-PA among lesions containing apparent thrombus (in 36% with t-PA versus 15% with placebo; p < 0.01), as it was among patients evolving a non-Q wave MI (33% versus 8%; p < 0.005). By multivariate analysis, the significant, independent predictors of substantial improvement include apparent thrombus (p = 0.0001), non-Q wave MI (p = 0.003), and t-PA use (p = 0.01). Both non-Q wave MI status and thrombus had been specified a priori as important variables. Arteriographically apparent intraluminal thrombus and improvement of the culprit lesion with either of these regimens were only moderately frequent in patients with unstable angina or non-Q wave MI. Substantial improvement of culprit lesions was more frequent with t-PA than with placebo overall and in two prospectively defined subgroups. The clinical relevance of these observations is being tested in the larger, ongoing clinical TIMI IIIB study.


Vitamin C in health and disease.
Vitamins are essential to maintain normal metabolic processes and homeostasis within the body. The amount of a specific vitamin required by an individual varies considerably and it is influenced by such factors as body size, growth rate, physical activity, and pregnancy. Most vitamins are stored minimally in human cells, but some are stored in liver cells to a greater extent. Vitamins A and D, for example, may be stored in sufficient amounts to maintain an individual without any intake for 5 to 10 months and 2 to 4 months, respectively. However, a deficiency of vitamin B compounds (except vitamin B12) may be noted within days, and the lack of vitamin C will manifest within weeks and may result in death in 5 to 6 months. The current recommended dietary allowance (RDA) of vitamin C is 75 mg for woman and 90 mg for men, based on the vitamin's role as an antioxidant as well as protection from deficiency. High intakes of the vitamin are generally well tolerated, however, a Tolerable Upper Level (TUL) was recently set at 2 g based on gastrointestinal upset that sometimes accompanies excessive dosages. Several populations warrant special attention with respect to vitamin C requirements. These include patients with periodontal disease, smokers, pregnant and lactating women, and the elderly.


Admixture mapping of pelvic organ prolapse in African Americans from the Women's Health Initiative Hormone Therapy trial.
Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women's Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade ≥2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10-5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.


Antibody interactions with the capsule of Cryptococcus neoformans.
Monoclonal antibodies to the encapsulated fungus Cryptococcus neoformans produce different immunofluorescence (IF) patterns after binding to the polysaccharide capsule. To explore the relationship between the IF pattern and the location of antibody binding, two immunoglobulin M (IgM) monoclonal antibodies (MAbs) (12A1 and 13F1) that differ in protective efficacy and IF pattern and one protective IgG1 MAb (2H1) were studied by IF and electron microscopy (EM). Fixing C. neoformans cells in lung tissue for EM resulted in significantly better preservation of the capsule than fixing yeast cells in suspension. The localization of MAbs 12A1 and 13F1 by immunogold EM differed depending on whether the MAb was bound to cells in cut tissue sections embedded in plastic or to cells in solution. In cut tissue sections, MAbs 12A1 and 13F1 bound throughout the capsule, whereas in solution both MAbs bound near the capsule surface. To investigate whether antibody binding to the C. neoformans capsule affected the binding of other primary or secondary reagents, various combinations of MAbs 12A1, 13F1, and 2H1 were studied by direct and indirect IF. The IF pattern and location of binding for MAbs 12A1, 13F1, and 2H1 varied depending on the presence of other capsule-binding MAbs and the method of detection. The results show that (i) binding of MAbs to the C. neoformans polysaccharide capsule can modify the binding of subsequent primary or secondary antibodies; (ii) the IgM MAbs bind primarily to the outer capsule regions despite the occurrence of their epitopes throughout the capsule; and (iii) MAb 2H1 staining of newly formed buds is reduced, suggesting quantitative or qualitative differences in bud capsule.


ACR white paper on teleradiology practice: a report from the Task Force on Teleradiology Practice.
Teleradiology services are now embedded into the workflow of many radiology practices in the United States, driven largely by an expanding corporate model of services. This has brought opportunities and challenges to both providers and recipients of teleradiology services and has heightened the need to create best-practice guidelines for teleradiology to ensure patient primacy. To this end, the ACR Task Force on Teleradiology Practice has created this white paper to update the prior ACR communication on teleradiology and discuss the current and possible future state of teleradiology in the United States. This white paper proposes comprehensive best-practice guidelines for the practice of teleradiology, with recommendations offered regarding future actions.


Expression and regulation of the antimonite, arsenite, and arsenate resistance operon of Staphylococcus xylosus plasmid pSX267.
The arsenate, arsenite, and antimonite resistance region of the Staphylococcus xylosus plasmid pSX267 was subcloned in Staphylococcus carnosus. The sequenced DNA region revealed three consecutive open reading frames, named arsR, arsB, and arsC. Expression studies in Escherichia coli with the bacteriophage T7 RNA polymerase-promoter system yielded three polypeptides with apparent molecular weights of 8,000, 35,000, and 15,000, which very likely correspond to ArsR, ArsB, and ArsC, respectively. ArsB was distinguished by its overall hydrophobic character, suggesting a membrane association. The arsenate, arsenite, and antimonite resistance was shown to be inducible by all three heavy metal ions. Inactivation of the first gene, arsR, resulted in constitutive expression of resistance. Similar results were obtained with transcriptional fusions of various portions of the ars genes with a lipase reporter gene, indicating a function of ArsR as a negative regulator of a putative promoter in front of arsR. The inactivation of arsR also resulted in reduction of resistance to arsenite and antimonite, while arsenate resistance was unaffected. The three ars genes conferred arsenite resistance in E. coli and arsenite as well as arsenate resistance in Bacillus subtilis.


Learning a Health Knowledge Graph from Electronic Medical Records.
Demand for clinical decision support systems in medicine and self-diagnostic symptom checkers has substantially increased in recent years. Existing platforms rely on knowledge bases manually compiled through a labor-intensive process or automatically derived using simple pairwise statistics. This study explored an automated process to learn high quality knowledge bases linking diseases and symptoms directly from electronic medical records. Medical concepts were extracted from 273,174 de-identified patient records and maximum likelihood estimation of three probabilistic models was used to automatically construct knowledge graphs: logistic regression, naive Bayes classifier and a Bayesian network using noisy OR gates. A graph of disease-symptom relationships was elicited from the learned parameters and the constructed knowledge graphs were evaluated and validated, with permission, against Google's manually-constructed knowledge graph and against expert physician opinions. Our study shows that direct and automated construction of high quality health knowledge graphs from medical records using rudimentary concept extraction is feasible. The noisy OR model produces a high quality knowledge graph reaching precision of 0.85 for a recall of 0.6 in the clinical evaluation. Noisy OR significantly outperforms all tested models across evaluation frameworks (p < 0.01).


Characterization of probe binding and comparison of its influence on fluorescence lifetime of two pH-sensitive benzo[c]xanthene dyes using intensity-modulated multiple-wavelength scanning technique.
Quantitative pH imaging using the carboxy seminaphthofluorescein dyes SNAFL-1 and SNAFL-2 can be performed by measurement of intensity ratios or fluorescence lifetimes. However, there is a controversy as to whether the latter method has the practical advantage of a straightforward pH calibration in buffers compared to a cumbersome and time-consuming procedure in cells. In this study we have undertaken a systematic study of the potential factors influencing the fluorescence lifetime of the probes at different pH using confocal microscopy. In vitro results demonstrate that factors such as lipid and protein concentrations have a substantial influence on pH measurements based on fluorescence lifetime. The pH could be overestimated by more than 2 pH units. Studies in permeabilized COS-7 cells demonstrate the same trends as observed in the in vitro studies.


Life or death: prognostic value of a resting EEG with regards to survival in patients in vegetative and minimally conscious States.
To investigate the potentially prognostic value of a resting state electroencephalogram (EEG) with regards to the clinical outcome from vegetative and minimally conscious states (VS and MCS) in terms of survival six months after a brain injury. We quantified a dynamic repertoire of EEG oscillations in resting condition with eyes closed in patients in VS and MCS. The exact composition of EEG oscillations was assessed by analysing the probability-classification of short-term EEG spectral patterns. Results demonstrated that (a) the diversity and the variability of EEG for Non-Survivors were significantly lower than for Survivors; and (b) a higher probability of mostly delta and slow-theta oscillations occurring either alone or in combination were found during the first assessment for patients with a bad outcome (i.e., those who died) within six months of an injury compared to patients who survived. At the same time, patients with a good outcome (i.e., those who survived) after six months post-injury had a higher probability of mostly fast-theta and alpha oscillations occurring either alone or in combination during the first assessment when compared to patients who died within six months of an injury. Resting state EEGs properly analysed may have a potentially prognostic value with regards to the outcome from VS or MCS in terms of survival six months after a brain injury. This work may have implications for clinical care, rehabilitative programmes and medical-legal decisions for patients with impaired consciousness states after being in a coma due to acute brain injuries.


Active Aging Index in Vietnam Relative to China, South Korea, Taiwan, and 28 European Union Countries.
This study constructed an Active Aging Index (AAI) for Vietnam and compares Vietnam's AAI with those of China, Korea, Taiwan, and 28 countries in the European Union. A survey of 1,105 people aged 55 or above in three provinces from the northern, central, and southern parts of Vietnam was conducted. Active aging was measured using the AAI; its 22 indicators were grouped into four domains: employment, social participation, independent/healthy/secure living, and enabling environments. Of the 32 countries reviewed, Vietnam ranked 11th. It ranked high for employment (1st) and social participation (5th) but low for independent/healthy/secure living (32nd) and enabling environments (26th). Three policy priorities were identified: maintaining a high preference-driven social and workforce participation rate among older adults; promoting medical care and healthy behaviors among older adults; and improving other poorly performing aspects of active aging, including voluntary activities, poverty risk, Internet usage, and lifelong learning.


Applications and limits of theoretical adsorption models for predicting the adsorption properties of adsorbents.
The objective of this study is to evaluate the applicability of adsorption models for predicting the properties of adsorbents. The kinetics of the adsorption of NO3- ions on a PP-g-AA-Am non-woven fabric have been investigated under equilibrium conditions in both batch and fixed bed column processes. The adsorption equilibrium experiments in the batch process were carried out under different adsorbate concentration and adsorbent dosage conditions and the results were analyzed using adsorption isotherm models, energy models, and kinetic models. The results of the analysis indicate that the adsorption occurring at a fixed adsorbate concentration with a varying adsorbent dosage occur more easily compared to those under a fixed adsorbent dosage with a varying adsorbate concentration. In the second part of the study, the experimental data obtained using fixed bed columns were fit to Bed Depth Service Time, Bohart-Adams, Clark, and Wolborska models, to predict the breakthrough curves and determine the column kinetic parameters. The adsorption properties of the NO3- ions on the PP-g-AA-Am non-woven fabric were differently described by different models for both the batch and fixed bed column process. Therefore, it appears reasonable to assume that the adsorption properties were dominated by multiple mechanisms, depending on the experimental conditions.


OCT Angiography to Predict Geographic Atrophy Progression using Choriocapillaris Flow Void as a Biomarker.
To investigate the relationship between choriocapillaris (CC) flow void (FV) percentage and geographic atrophy (GA) growth rate, and study how variations in FV percentage surrounding GA predict regional GA growth. This prospective, longitudinal study enrolled subjects with GA secondary to nonexudative age-related macular degeneration. Optical coherence tomography angiography imaged the CC and FV percentage was evaluated using a validated algorithm. GA growth rate was measured as the difference in the square root of GA area divided by the months between baseline and follow-up imaging. Twelve eyes from 7 subjects with a mean age of 80 ± 5 years (range 74-86) were studied once at baseline and 7 to 16 months later. GA expansion rate was positively correlated with increased CC FV percentage (Spearman rank correlation coefficient r = 0.69 [P = 0.038] and 0.76 [P = 0.013]) within the 6 x 6 mm scanned macular region and the 2° margin surrounding each GA lesion, respectively. Regions with CC FV at baseline located within 480 µm from the GA margin showed 33% greater chance of becoming atrophic compared with regions within 480 µm from the GA margin that did not show CC FV at baseline. GA expansion rate and CC FV density throughout the macular region and surrounding the GA margin were significantly correlated. The regional magnitude of FV immediately surrounding GA was associated with GA growth into that region. CC FV analysis may facilitate prediction of GA growth over time for patients with advanced nonneovascular age-related macular degeneration.


Effects of Vitex agnus and Flaxseed on cyclic mastalgia: A randomized controlled trial.
Evidence on the effect of Vitex agnus and Flaxseed on cyclical mastalgia is not enough. This study aimed to assess the efficacy of V. agnus and Flaxseed on cyclical mastalgia. This randomized controlled trial was conducted on 159 women referred to health centers of Tabriz, Iran. Subjects were allocated into three groups (n=53 per group) using block randomization. Group I received 25g daily Flaxseed powder and placebo of V. agnus; group II received daily 3.2-4.8mg V. agnus tablet and placebo of Flaxseed and control group received both placebo. Nominal day breast pain was applied at baseline, first, and second month after the intervention. Data was analyzed using general linear model. There was no statistical significant difference between the three groups in terms of socio-demographic characteristics and baseline values. The breast pain improved significantly in both intervention groups during the first and second month after intervention. Mean NDBP score was significantly lower than that in the control group at the first month after the intervention in the Flaxseed [adjusted mean difference: -3.1 (95% CI: -4.2 to -2.0)] and V. agnus groups [-3.3 (-4.3 to -2.2)] and the second month after the intervention in Flaxseed [-7.0 (-8.1 to -5.9)] and V. agnus groups [-6.4 (-7.5 to -5.3)]. Flaxseed and V. agnus are effective in short-term period in decreasing cyclical mastalgia. However, further studies are needed to examine the long-term effectiveness and sustainability of the effects after stopping the treatment in order to decide whether these alternative treatments are suitable to treat mastalgia or not.


A novel role for the Fc receptor gamma subunit: enhancement of Fc gamma R ligand affinity.
The Fc receptors (FcR), which belong to the immunoglobulin (Ig) superfamily, bind to specific Ig isotypes with varying affinities triggering complex immune defense responses. Several of the FcR that lack signaling motifs in their cytoplasmic domains rely on associated subunits to transmit signals. Two classes of FcR that bind the Fc portion of IgG, Fc gamma RI, and Fc gamma RIIIa associate with a subunit shared among several FcR, the gamma chain, which is involved in receptor expression and signal transduction. In this report, we propose that a novel role for gamma chain is to enhance the affinity of Fc gamma R for ligand. Our findings demonstrate that Fc gamma RI requires gamma -chain association to attain high affinity binding for monomeric IgG, and suggest that the intermediate binding affinity of the Fc gamma RIIIa isoform results from its association with gamma chain. The affinity increase conferred by gamma chain appears to be mediated through the transmembrane domain of the Fc gamma R, with no requirement for the cytoplasmic domain of the receptor.


Assessment of the process of movement of Xylella fastidiosa within susceptible and resistant grape cultivars.
To better understand the processes contributing to symptoms and resistance to Pierce's disease of grape, we examined the movement and multiplication of a green fluorescent protein-marked strain of Xylella fastidiosa in the stems and petioles of Cabernet Sauvignon, Chenin Blanc, Roucaneuf, and Tampa grape cultivars that differ in their susceptibility to this disease. X. fastidiosa achieved much lower population sizes and colonized fewer xylem vessels in the stem of resistant cultivars compared with more susceptible cultivars. In contrast, X. fastidiosa achieved similarly high population sizes and colonized a similar proportion of the vessels in petioles of susceptible and resistant cultivars, suggesting that, compared with the stem, X. fastidiosa is relatively unrestricted in its movement and growth within the petiole. There was not a direct relationship between the population size of X. fastidiosa in the stem and the proportion of vessels colonized; a much higher population size of the pathogen was observed in susceptible cultivars than expected based on the proportion of vessels colonized. The high population sizes of X. fastidiosa in stems of susceptible genotypes were associated with both a high number of infected vessels and a much higher extent of colonization of those vessels that become infested than in more resistant cultivars. The formation of large cellular aggregates in vessels is not required for X. fastidiosa to move laterally in the stem to adjacent vessels because most vessels harbored only small assemblages, especially in resistant cultivars such as Roucaneuf, in which some intervessel movement was detected. Resistance to Pierce's disease is apparently not due to inhibitory compounds that circulate in the xylem because they might be expected to operate similarly in all tissues.


Ultrasensitive electrochemical detection of Dicer1 3'UTR for the fast analysis of alternative cleavage and polyadenylation.
Alternative cleavage and polyadenylation (APA) is involved in several important biological processes in animals, e.g. cell growth and development, and cancer progression. The increasing data show that cancer cells are inclined to produce mRNA isoforms with a shortened 3'UTR undergoing APA. For example, the Dicer1 isoform with a shorter 3'untranslated region (3'UTR) was found to be overexpressed in some cancer cells, which may be used as a potential novel prognostic biomarker for cancer. In the present work, a novel electrochemical biosensor for ultrasensitive determination of Dicer1 was designed by using gold nanoparticles and p-sulfonated calix[6]arene functionalized reduced graphene oxide (Au@SCX6-rGO) as nanocarriers. The results showed that the expressions of the shorter 3'UTR (Dicer1-S) both in BT474 and SKBR3 were obviously higher than those of the longer Dicer1 (Dicer1-L) by the constructed biosensor, which agreed well with the result analyzed by the RT-qPCR method. The detection ranges of Dicer1-S and Dicer1-L were 10-14-10-9 M and 10-15-10-10 M. The LODs were 3.5 and 0.53 fM. The specificity of the proposed biosensor was also very high. For the first time, the expressional analysis of different 3'UTRs caused by APA was studied by an electrochemical method. Moreover, the use of a macrocyclic host for constructing an electrochemical/biosensing platform has rarely been reported. The proposed electrochemical sensing strategy is thus expected to provide a new method for determination of novel biomarkers and a novel method for fast and cheap analysis of APA.


Beam propagation in parabolically tapered graded-index waveguides.
To a good approximation, the electromagnetic-propagation characteristics of graded-index waveguides can be written in terms of polynomial-Gaussian modes. For uniform quadratic-index waveguides the behavior of these modes is well known. However, there are sometimes practical reasons for using tapered waveguides, but detailed propagation solutions are known for only a few specific taper functions. The parabolic taper is perhaps the most important special case, and the solution-generating techniques that we generalize are used to obtain analytic solutions for this case.


The relationship between prenatal PCB exposure and intelligence (IQ) in 9-year-old children.
Several epidemiologic studies have demonstrated relationships between prenatal exposure to polychlorinated biphenyls (PCBs) and modest cognitive impairments in infancy and early childhood. However, few studies have followed cohorts of exposed children long enough to examine the possible impact of prenatal PCB exposure on psychometric intelligence in later childhood. Of the few studies that have done so, one in the Great Lakes region of the United States reported impaired IQ in children prenatally exposed to PCBs, whereas another found no association. This study was designed to determine whether environmental exposure to PCBs predicts lower IQ in school-age children in the Great Lakes region of the northeastern United States. We measured prenatal exposure to PCBs and IQ at 9 years of age in 156 subjects from Oswego, New York. We also measured > 50 potential predictors of intelligence in children, including repeated measures of the home environment [Home Observation for Measurement of the Environment (HOME)], socioeconomic status (SES), parental IQ, alcohol/cigarette use, neonatal risk factors, and nutrition. For each 1-ng/g (wet weight) increase in PCBs in placental tissue, Full Scale IQ dropped by three points (p = 0.02), and Verbal IQ dropped by four points (p = 0.003). The median PCB level was 1.50 ng/g, with a lower quartile of 1.00 ng/g and an upper quartile of 2.06 ng/g. Moreover, this association was significant after controlling for many potential confounders, including prenatal exposure to methylmercury, dichlorodiphenyldichloroethylene, hexachlorobenzene, and lead. These results, in combination with similar results obtained from a similar study in the Great Lakes conducted 10 years earlier, indicate that prenatal PCB exposure in the Great Lakes region is associated with lower IQ in children.


Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis.
Glucagon-like Peptide-1 receptor agonists (GLP1-ra) are a relatively new class of anti-hyperglycemic drugs which may positively affect bone metabolism and thereby decrease (osteoporotic) bone fracture risk. Data on the effect of GLP1-ra on fracture risk are scarce and limited to clinical trial data only. The aim of this study was to investigate, in a population-based cohort, the association between the use of GLP1-ra and bone fracture risk. We conducted a population-based cohort study, with the use of data from the Clinical Practice Research Datalink (CPRD) database (2007-2012). The study population (N = 216,816) consisted of all individuals with type 2 diabetes patients with at least one prescription for a non-insulin anti-diabetic drug and were over 18 years of age. Cox proportional hazards models were used to estimate the hazard ratio of fracture in GLP1-ra users versus never-GLP1-ra users. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and the use of other drugs. There was no decreased risk of fracture with current use of GLP1-ra compared to never-GLP1-ra use (adjusted HR 0.99, 95 % CI 0.82-1.19). Osteoporotic fracture risk was also not decreased by current GLP1-ra use (adjusted HR 0.97; 95 % CI 0.72-1.32). In addition, stratification according to cumulative dose did not show a decreased bone fracture risk with increasing cumulative GLP1-ra dose. We showed in a population-based cohort study that GLP1-ra use is not associated with a decreased bone fracture risk compared to users of other anti-hyperglycemic drugs. Future research is needed to elucidate the potential working mechanisms of GLP1-ra on bone.


eNOS overexpression exacerbates vascular closure in the obliterative phase of OIR and increases angiogenic drive in the subsequent proliferative stage.
In ischemic retinopathies, the misdirection of reparative angiogenesis away from the hypoxic retina leads to pathologic neovascularization. Thus, therapeutic strategies that reverse this trend would be extremely beneficial. Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is an important mediator of vascular endothelial growth factor (VEGF) function facilitating vascular growth and maturation. However, in addition to NO, eNOS can also produce superoxide (O(2)(-)), exacerbating pathology. Here, our aim was to investigate the effect of eNOS overexpression on vascular closure and subsequent recovery of the ischemic retina. Mice overexpressing eNOS-GFP were subjected to oxygen-induced retinopathy (OIR) and changes in retinal vascularization quantified. Background angiogenic drive was assessed during vascular development and in aortic rings. NOS activity was measured by Griess assay or conversion of radiolabeled arginine to citrulline, nitrotyrosine (NT), and superoxide by immunolabeling and dihydroethidium fluorescence and VEGF by ELISA. In response to hyperoxia, enhanced eNOS expression led to increased NOS-derived superoxide and dysfunctional NO production, NT accumulation, and exacerbated vessel closure associated with tetrahydrobiopterin (BH₄) insufficiency. Despite worse vaso-obliteration, eNOS overexpression resulted in elevated hypoxia-induced angiogenic drive, independent of VEGF production. This correlated with increased vascular branching similar to that observed in isolated aortas and during development. Enhanced recovery was also associated with neovascular tuft formation, which showed defective NO production and increased eNOS-derived superoxide and NT levels. In hyperoxia, reduced BH₄ bioavailability causes overexpressed eNOS to become dysfunctional, exacerbating vaso-obliteration. In the proliferative phase, however, eNOS has important prorepair functions enhancing angiogenic growth potential and recovery in ischemia.


Variation in Physician Spending and Association With Patient Outcomes.
While the substantial variation in health care spending across regions and hospitals is well known, key clinical decisions are ultimately made by physicians. However, the degree to which spending varies across physicians and the clinical consequences of that variation are unknown. To investigate variation in spending across physicians and its association with patient outcomes. For this retrospective data analysis, we analyzed a 20% random sample of Medicare fee-for-service beneficiaries 65 years and older who were hospitalized with a nonelective medical condition and treated by a general internist between January 1, 2011, and December 31, 2014. We first quantified the proportion of variation in Medicare Part B spending attributable to hospitals, physicians, and patients. We then examined the association between physician spending and patient outcomes, adjusted for patient and physician characteristics and hospital fixed effects (effectively comparing physicians within the same hospital). Our primary analysis focused on hospitalist physicians, whose patients are plausibly quasirandomized within a hospital based on physician work schedule. A secondary analysis focused on general internists overall. To ensure that patient illness severity did not directly affect physician spending estimates, we calculated physicians' spending levels in 2011 through 2012 and examined outcomes of their patients in 2013 and 2014. Physicians' adjusted Part B spending level in 2011 through 2012. Patients' 30-day mortality and readmission rates in 2013 and 2014. To determine the amount of variation across physicians we included 485 016 hospitalizations treated by 21 963 physicians at 2837 acute care hospitals for the analysis of hospitalists and 839 512 hospitalizations treated by 50 079 physicians at 3195 acute care hospitals for the analysis of general internists. Variation in spending across physicians within hospital was larger than variation across hospitals (for hospitalists, 8.4% across physicians vs 7.0% across hospitals; for general internists, 10.5% across physicians vs 6.2% across hospitals). Higher physician spending was not associated with lower 30-day mortality (adjusted odds ratio [aOR] for additional $100 in physician spending, 1.00; 95% CI, 0.98-1.01; P = .47) or readmissions (aOR, 1.00; 95% CI, 0.99-1.01; P = .54) for hospitalists within the same hospital. We observed similar patterns among general internists. Health care spending varies more across individual physicians than across hospitals. However, higher physician spending is not associated with better outcomes of hospitalized patients. Our findings suggest policies targeting both physicians and hospitals may be more effective in reducing wasteful spending than policies focusing solely on hospitals.


Is the nasal tampon a suitable treatment for epistaxis in Accident & Emergency? A comparison of outcomes for ENT and A&E packed patients.
This retrospective observational study aimed to establish the outcome for patients packed with a nasal tampon as first-line therapy for epistaxis in Accident & Emergency compared to those packed by ENT. During our study period, 189 admissions were treated with a nasal tampon as first-line therapy; 89 were inserted by ENT and 100 by A&E. A significantly higher number of patients packed by A&E required further treatment to control bleeding (p = 0.004; 95 per cent CI 7-34) than those in the group packed by ENT. A significantly greater proportion from the A&E group required additional cautery alone to control bleeding (p = 0.005; 95 per cent CI 5-30). We suggest that this may be due to inadequate initial assessment and inappropriate first-line therapy in the A&E department. It is recommended that ENT review patients prior to packing, in order to reduce the morbidity associated with multiple treatments.


Influence of adrenocorticotropin on transport of a cholesteryl linoleate-low density lipoprotein complex into adrenal tumor cells.
The action of adrenocorticotropin (ACTH) on the specific (receptor-mediated) uptake of cholesteryl linoleate . low density lipoprotein complexes was examined in Y-1 mouse adrenal tumor cells. High affinity binding (KA 4.1 X 10(8) M) was observed with ACTH; lower affinity was seen in the absence of ACTH. The effect of ACTH was observed within 10 min at physiological concentrations of low density lipoprotein (100 microgram/ml). Binding was followed by uptake (internalization) of the ester . lipoprotein complex which was transported to lysosomes. The site of action of ACTH was localized to the uptake process (internalization) since no effect of ACTH was observed on binding to the cell membrane nor on movement of internalized complex to lysosomes. ACTH increases the transport of cholesterol derived from cholesterol ester to the mitochondria. This cholesterol is converted to 20 alpha-hydroxypregn-4-en-3-one and this conversion is accelerated by ACTH. Dibutyryl cyclic AMP (but not butyrate) also stimulates uptake of cholesteryl linoleate . low density lipoprotein. The process stimulated by ACTH and dibutyryl cyclic AMP is specific for low density (as opposed to high density) lipoprotein and for ACTH as distinct from other peptide hormones. The possible physiological importance of this response is considered.


Stomatal Conductance Measurement for Toxicity Assessment in Zero-Effluent Constructed Wetlands: Effects of Landfill Leachate on Hydrophytes.
In this research, we explore for the first time the use of leaf stomatal conductance (gs) for phytotoxicity assessment. Plants respond to stress by regulating transpiration. Transpiration can be correlated with stomatal conductance when the water vapor pressure gradient for transpiration is constant. Thus, our working hypothesis was that the gs measurement could be a useful indicator of the effect of toxic compounds on plants. This lab-scale study aimed to test the measurement of gs as a phytotoxicity indicator. Our model plants were two common hydrophytes used in zero-effluent constructed wetlands for treating landfill leachate. The toxic influence of two types of leachate from old landfills (L1, L2) on common reed (Phragmites australis (Cav.) Trin. ex Steud.) and sweet flag (Acorus calamus L.) was tested. The gs measurements correlated well with plant response to treatments with six solutions (0 to 100%) of landfill leachate. Sweet flag showed higher tolerance to leachate solutions compared to common reed. The estimated lowest effective concentration (LOEC) causing the toxic effect values for these leachates were 3.94% of L1 and 5.76% of L2 in the case of reed, and 8.51% of L1 and 10.44% of L2 in the case of sweet flag. Leachate L1 was more toxic than L2. The leaf stomatal conductance measurement can be conducted in vivo and in the field. The proposed approach provides a useful parameter for indicating plant responses to the presence of toxic factors in the environment.


The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.
Mivacurium consists of a mixture of three stereoisomers: cis-trans (34-40%), trans-trans (52-60%), and cis-cis (4-8%). These isomers differ in potency (the trans-trans and the cis-trans isomers are equipotent and the cis-cis isomer is 1/13th as potent a neuromuscular blocking agent) and in rates of in vitro hydrolysis (in vitro half-lives are less than 2 min for the cis-trans and trans-trans isomers and 276 min for the cis-cis isomer). The current study was undertaken to determine the pharmacokinetic profile of the individual stereoisomers of mivacurium, to evaluate the dose-proportionality of the more potent trans-trans and cis-trans isomers, and to evaluate the pharmacodynamics of mivacurium in healthy adult patients receiving a consecutive two-step infusion of mivacurium. Eighteen ASA physical status 1 or 2 adult male patients undergoing elective surgery under nitrous oxide/oxygen/fentanyl anesthesia were studied. Neuromuscular function was monitored using a mechanomyograph at a frequency of 0.15 Hz. An infusion of mivacurium was begun at 5 micrograms.kg-1.min-1. Sixty minutes later, the infusion rate was doubled to 10 micrograms.kg-1.min-1, and, 60 min after that, the infusion was discontinued. All patients were allowed to recover spontaneously from mivacurium-induced neuromuscular block. Venous blood samples were drawn for the determination of the plasma concentrations of each isomer of mivacurium by a stereospecific high performance liquid chromatographic method. Pharmacokinetic parameters were determined using noncompartmental analysis. During the 5-micrograms.kg-1.min-1 infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 micrograms.kg-1.min-1 increased the depth of block to 99.0 +/- 2.0%. After discontinuation of the infusion, patients returned to 25% of their baseline muscle strength in 9.3 +/- 3.7 min and had 25-75% and 5-95% recovery indexes of 7.2 +/- 1.8 and 16.8 +/- 3.7 min, respectively. The volumes of distribution (V beta) of the cis-trans, trans-trans, and cis-cis isomers were 0.29 +/- 0.24, 0.15 +/- 0.05, and 0.34 +/- 0.08 l/kg, respectively. During the 5-micrograms.kg-1.min-1 infusion, the steady-state clearances of the potent cis-trans and trans-trans isomers were 106 +/- 67 and 63 +/- 34 ml.min-1.kg-1, respectively; the clearance of the less potent cis-cis isomer was 4.6 +/- 1.1 ml.min-1.kg-1. The elimination half-lives of the cis-trans and trans-trans isomers were 1.8 +/- 1.1 and 1.9 +/- 0.7 min, respectively, and that of the cis-cis isomer was 52.9 +/- 19.8 min. Clearance of the cis-trans and trans-trans isomers did not vary with infusion rate. The short elimination half-lives and high metabolic clearances of the potent cis-trans and trans-trans isomers are consistent with the short duration of action of mivacurium. The cis-cis isomer does not appear to produce significant neuromuscular block as evident by the return of twitch height to baseline despite persistent cis-cis isomer concentrations.


Impact of telemonitoring on older adults health-related quality of life: the Tele-ERA study.
Telemonitoring is being increasingly used for chronic disease monitoring. While the primary aim of telemonitoring is to improve chronic disease management and decrease hospitalizations, the potential impact on patient's health-related quality of life may be an additional benefit. Two hundred and five patients aged 60 years and older with multiple medical conditions were enrolled in a one-year randomized controlled trial of daily home telemonitoring. Health-related quality of life was measured with the 12-Item Short-Form at the beginning and at the completion of the study. Per protocol analysis of the 166 patients responding to the follow-up survey was performed. Among the 166 responders, there were no significant differences at baseline in the physical component summary (PCS) scores (p value = 0.32), nor the mental component summary (MCS) scores (p value = 0.12) between the telemonitored group and the usual care group. There was also no difference in the 12-month PCS scores (p value = 0.39) or MCS scores (p value = 0.10) between groups. There was no difference in the change from baseline to 12-month MCS scores between groups (p value = 0.89); however, there was a significant difference in the baseline to 12-month change of PCS scores between groups, with the telemonitored group having a greater decrease in PCS scores (-4.3 ± 9.3), compared to the usual care group (-1.2 ± 8.5) over the course of the study (p value = 0.03). Home telemonitoring in older adults with multiple comorbidities does not significantly improve self-perception of mental well-being (as measured by MCS scores) and may worsen self-perception of physical health (as measured by PCS scores).


Challenging the 48-Hour Rule-Out for Central Line-Associated Bloodstream Infections in the Pediatric Intestinal Failure Population: A Retrospective Pilot Study.
While parenteral nutrition (PN) has revolutionized the management of patients with intestinal failure (IF), central line-associated bloodstream infections (CLABSIs) remain a leading cause of mortality and morbidity in this population. The objective of this study is to characterize the presentation of CLABSIs in pediatric IF and to determine the time to positivity of blood cultures. A retrospective cohort study of children with IF who presented to our institution for evaluation of a possible CLABSI from January 1, 2012, to December 31, 2012, was performed. Sixty patients with IF were identified. There were 33 cases of CLABSI in 16 patients, with a rate of 1.5 infections per 1000 catheter days. There were no significant differences in age, growth parameters, or catheter days between patients with or without CLABSI. Fever was documented in 85% of patients with CLABSI. These patients demonstrated an increased percentage of neutrophils and higher C-reactive protein levels compared with patients without CLABSI. The mean time to culture positivity was 13.2 hours, and 97% of cultures were positive within 24 hours. Our data suggest that most pediatric patients with IF who have CLABSI develop positive cultures within 24 hours, and the absence of fever and leukocytosis does not necessarily indicate the absence of infection. These findings may support clinical practice guidelines in favor of shorter hospital stay when CLABSI is suspected; however, a prospective analysis of CLABSI in this population is recommended to determine the safety and appropriate setting prior to any practice change.


Evaluation of the validity of preemptive therapy against cytomegalovirus disease based on antigenemia assay with a cutoff of 20 positive cells per two slides.
Preemptive therapy with ganciclovir (GCV) based on the results of a cytomegalovirus (CMV) antigenemia assay is a standard strategy for preventing CMV disease after allogeneic hematopoietic cell transplantation (HCT). However, the appropriate threshold of antigenemia-positive cells for deciding when to start GCV remains unclear. This retrospective study included 80 recipients who received HCT from an alternative donor between 2007 and 2011. In 2009, we switched the threshold from 3 (3A group, n=24) to 20 (20A group, n=56) antigenemia-positive cells per two slides for preemptive therapy after HCT from an alternative donor. Early CMV disease within 100 days after HCT was observed in one patient in the 20A group. Antiviral agents including GCV, val-GCV, and foscarnet were given in 17 (71%) and 36 (64%) patients in the 3A and 20A groups, respectively (p=0.23). In 13 (23%) patients in the 20A group, the initiation of preemptive therapy was avoided because of the change in the cutoff value for CMV antigenemia. However, the total dose of GCV was not different between the two groups. The use of steroid was significantly associated with CMV antigenemia of at least 20 positive cells among patients with low-level antigenemia at the first detection. The increased threshold up to 20 positive cells for starting preemptive therapy was not associated with a significant increase in CMV disease, but the total dose of GCV was not reduced and there was one early CMV disease in the 20A group. We should explore how to identify patients who are at high risk for increased antigenemia among patients with low-level antigenemia, but at least, preemptive therapy should not be withheld in patients who are already receiving systemic steroid.


The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.
Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.


Co-application of biochar and microorganisms improves soybean performance and remediate cadmium-contaminated soil.
Sole biochar addition or microbial inoculation as a soil amendment helps to reduce cadmium (Cd) toxicity in polluted agricultural soils. Yet the synergistic effects of microorganisms and biochar application on Cd absorption and plant productivity remain unclear. Therefore, a pot experiment was conducted to investigate the combined effect of microorganisms (Trichoderma harzianum L. and Bacillus subtilis L.), biochar (maize straw, cow manure, and poultry manure), and Cd (0, 10, and 30 ppm) on plant physiology and growth to test how biochar influences microbial growth and plant nutrient uptake, and how biochar ameliorates under Cd-stressed soil. Results showed that in comparison to non-Cd polluted soil, the highest reduction in chlorophyll content, photosynthetic rate, transpiration rate, stomatal conductance, water use efficiency, and intercellular CO2 were observed in Cd2 (30 ppm), which were 9.34%, 22.95%, 40.45%, 29.07%, 20.67%, and 22.55% respectively less than the control Cd0 (0 ppm). Among sole inoculation of microorganisms, highest stomatal conductance, water use efficiency, and intercellular CO2 were recorded with combined inoculation of both microorganisms (M3), which were 5.92%, 7.65%, and 7.28% respectively higher than the control, and reduced the Cd concentration in soil, root, and shoot by 21.34%, 28.36%, and 20.95%, respectively, compared to the control. Similarly, co-application of microorganisms and biochar ameliorated the adverse effect of Cd in soybean as well as significantly improved plant biomass, photosynthetic activity, nutrient contents, and antioxidant enzyme activities, and minimized the production of reactive oxygen species and Cd content in plants. Soil amended with poultry manure biochar had significantly improved the soil organic carbon, total nitrogen, total phosphorous, and available potassium by 43.53%, 36.97%, 22.28%, and 4.24%, respectively, and decreased the concentration of Cd in plant root and shoot by 34.68% and 47.96%, respectively, compared to the control. These findings indicate that the combined use of microorganisms and biochar as an amendment have important synergistic effects not only on the absorption of nutrients but also on the reduction of soybean Cd intake, and improve plant physiology of soybean cultivated in Cd-polluted soils as compared to sole application of microorganisms or biochar.


[Immunosuppressive effect of cultured Cordyceps sinensis on cellular immune response].
The immunosuppressive effect of cultured Cordyceps sinensis (Bei Lin Capsule) was studied in vitro and in vivo. When the drug was added from 0.6 mg/ml to 5 mg/ml a significant dose-dependent inhibition effect was shown in the following immune reactions of mice (P less than 0.05-0.01): phagocytic function of peripheral blood leucocytes assayed by chemiluminescence; mitogenic response of spleen lymphocytes to Con A; mixed lymphocyte culture and LPS induced interleukin-1 release of macrophages. The survival rate of mice spleen lymphocytes cultured with Cordyceps sinensis 5 mg/ml in 37 degrees C 5% CO2 for 5 days was more than 80%. Cordyceps sinensis 4 g/kg daily significantly prolonged the mice skin allograft survival time (12.7 +/- 2.2 days v.s. 8.3 +/- 0.7 days in the control, P less than 0.01) and its immunosuppressive effect was close to that of Cyclosporin A 5 mg/kg daily on skin allograft.


Automatic Background Removal and Correction of Systematic Error Caused by Noise Expecting Bio-Raman Big Data Analysis.
Spectral pretreatments, such as background removal from Raman big data, are crucial to have a smooth link to advanced spectral analysis. Recently, we developed an automated background removal method, where we considered the shortest length of a spectrum by changing the scaling factor of the background spectrum. Here, we propose a practical way to correct the systematic error caused by noise from measurements. This correction has been realized to be more effective and accurate for automatic background removal.


A perspective on food energy standards for nutrition labelling.
Food energy values used for nutrition labelling and other purposes are traditionally based on the metabolisable energy (ME) standard, which has recent support from. By reference to current practices and published data, the present review critically examines the ME standard and support for it. Theoretical and experimental evidence on the validity of ME and alternatives are considered. ME and alternatives are applied to 1189 foods to assess outcomes. The potential impact of implementing a better standard in food labelling, documentation of energy requirements and food tables, and its impact on users including consumers, trade and professionals, are also examined. Since 1987 twenty-two expert reviews, reports and regulatory documents have fully or partly dropped the ME standard. The principal reason given is that ME only approximates energy supply by nutrients, particularly fermentable carbohydrates. ME has been replaced by net metabolisable energy (NME), which accounts for the efficiency of fuel utilisation in metabolism. Data collated from modern indirect calorimetry studies in human subjects show NME to be valid and applicable to each source of food energy, not just carbohydrates. NME is robust; two independent approaches give almost identical results (human calorimetry and calculation of free energy or net ATP yield) and these approaches are well supported by studies in animals. By contrast, the theoretical basis of ME is totally flawed. ME incompletely represents the energy balance equation, with substantial energy losses in a missing term. In using NME factors an account is made of frequent over-approximations by the ME system, up to 25 % of the NME for individual foods among 1189 foods in British tables, particularly low-energy-density traditional foods. A new simple general factor system is possible based on NME, yet the minimal experimental methodology is no more than that required for ME. By accounting for unavailable carbohydrate the new factor system appears as specific to foods as the USA's food-specific Atwater system, while it is more representative of energy supply from food components. The NME content of foods is readily calculable as the sum from fat (37 kJ/g), protein (13 kJ/g), available carbohydrate (16 kJ/g), fully-fermentable carbohydrate (8 kJ/g), alcohol (26 kJ/g) and other components. Obstacles to the implementation of NME appear to be subjective and minor. In conclusion, the ME standard is at best an approximate surrogate for NME, and inadequately approximates food energy values for the purpose of informing the consumer about the impact on energy balance of the energy supply for equal intake of individual foods. NME is superior to ME for nutrition labelling and other purposes.


Are there moral differences between maternal spindle transfer and pronuclear transfer?
This paper examines whether there are moral differences between the mitochondrial replacement techniques that have been recently developed in order to help women afflicted by mitochondrial DNA diseases to have genetically related children absent such conditions: maternal spindle transfer (MST) and pronuclear transfer (PNT). Firstly, it examines whether there is a moral difference between MST and PNT in terms of the divide between somatic interventions and germline interventions. Secondly, it considers whether PNT and MST are morally distinct under a therapy/creation optic. Finally, it investigates whether there is a moral difference between MST and PNT from a human embryo destruction point of view. I conclude, contra recent arguments, that regarding the first two points there is no moral differences between PNT and MST; and that regarding the third one MST is morally preferable to PNT, but only if we hold a gradualist account of the moral value of human embryos where zygotes have slight moral value.


Water and trehalose: how much do they interact with each other?
The observation made by early naturalists that some organisms could tolerate extreme environmental condisions and "enjoy the advantage of real resurrection after death" [ Spallanzani , M. Opuscules de Physique Animale et Vegetale 1776 (translated from Italian by Senebier , J. Opuscules de Physique Animale et Vegetale 1787 , 2 , 203 - 285 )] stimulated research that still continues to this day. Cryptobiosis, the ability of an organism to tolerate adverse environments, such as dehydration and low temperatures, still represents an unsolved and fascinating problem. It has been shown that many sugars play an important role as bioprotectant agents, and among the best performers is the disaccharide trehalose. The current hypothesis links the efficiency of its protective role to strong modifications of the tetrahedral arrangement of water molecules in the sugar hydration shell, with trehalose forming many hydrogen bonds with the solvent. Here, we show, by means of state-of-the-art neutron diffraction experiments combined with EPSR simulations, that trehalose solvation induces very minor modifications of the water structure. Moreover, the number of water molecules hydrogen-bonded to the sugar is surprisingly small.


The effect of immediate and delayed cold immersion on burn edema formation and resorption.
Massive wound edema after a burn may impair healing and help to convert partial to full-thickness injury. Cold treatment (usually by immersion) has been reported to decrease wound edema and is useful in first-aid treatment of burns. Reliable quantitative data have been lacking and frequently a superficial burn has been studied. Since cold by decreasing peripheral blood flow could actually be harmful to a deep burn, especially if applied late, we measured the effect of cold immediately and 2 minutes postburn on edema formation and resorption in a deep second-degree burn in sheep hindlimbs. We used Dichromatic Absorptiometry, a noninvasive, reliable method for measuring tissue fluid, to quantitate edema. Immediate application of cold by immersion in 15 degrees C saline for 30 minutes reduced the edema of a deep second-degree burn and did not impair resorption rate compared with control limbs, fluid content returning to baseline after 1 week. Cold treatment beginning 2 minutes after the burn did not decrease edema formation and did impair resorption. Fifteen per cent of the edema fluid was still present 1 week postburn, suggesting further injury to the burn wound vasculature with use of cold immersion 2 minutes postburn.


In vitro anti-leukaemia activity of pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs).
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by unregulated growth of myeloid leukemia cells in the bone marrow and accumulation of these cells in the blood. CML represents approximately 15-20% of all adult leukemia and the disease development is clearly linked to the constitutively active tyrosine kinase of the chimeric protein BCR-ABL. It is encoded by the Bcr-Abl fusion gene sequence as the result of chromosome 9/22 translocation (Philadelphia chromosome) or other aberrant cytogenetic events. The development of targeted agents that specifically inhibit the tyrosine kinase (TK) activity of BCR-ABL has revolutionized the treatment of CML. Imatinib is now the first-line treatment for chronic phase CML, and several newer tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have been added to the pharmacologic compendium. Despite the proven efficacy of TKIs to induce hematological and cytogenetic remission, the large majority of patients still have molecularly detectable disease. Therefore, new options are needed to improve therapeutic success in the treatment of leukemia. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxides (PBTDs) induced apoptosis in human BCR-ABL expressing leukemia cells. The apoptotic activity was also observed in primary leukemic blasts, obtained from CML patients at onset or from patients in blast crisis and who were imatinib- dasatinib- and nilotinib resistant. These results suggests that these compounds are promising agent for the treatment of leukemia. Due to the fact that the phenomenon of resistance to TKIs remains a major issue in the treatment of patients with CML, the identification of new drugs may be of clinical relevance. This review summarises patents and papers dealing with the present understanding of mechanism of action and the most relevant data concerning TKs inhibition.


Fortilin reduces apoptosis in macrophages and promotes atherosclerosis.
Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient (fortilin(+/-)) mice and wild-type counterparts (fortilin(+/+)) on a LDL receptor (Ldlr)(-/-) apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)(-/-) hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin(+/-) mice exhibited significantly less atherosclerosis in their aortae than their fortilin(+/+) littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin(+/-) mice contained fewer macrophages than those of fortilin(+/+) mice. In addition, there were more apoptotic cells in the intima of fortilin(+/-) mice than in the intima of fortilin(+/+) mice. Furthermore, peritoneal macrophages from fortilin(+/-) mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr(-/-)Apobec1(-/-) mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.


Organic and Polymeric Semiconductors Enhanced by Noncovalent Conformational Locks.
Constructing highly planar, extended π-electron systems is an important strategy for achieving high-mobility organic semiconductors. In general, there are two synthetic strategies for achieving π-conjugated systems with high planarity. The conventional strategy connects neighboring aromatic rings through covalent bonds to restrict the rotation about single bonds. However, this usually requires a complex sequence of synthetic steps to achieve this target, which can be costly and labor-intensive. More recently, noncovalent through-space intramolecular interactions, which are defined here as noncovalent conformational locks, have been employed with great success to increase the planarity and rigidity of extended π-electron systems; this has become a well-known and important strategy to design and synthesize highly planar π-conjugated systems for organic electronics. This review offers a comprehensive and general summary of conjugated systems with such noncovalent conformational locks, including O···S, N···S, X···S (where X = Cl, Br, F), and H···S through-space interactions, together with analysis by density functional theory computation, X-ray diffraction, and microstructural characterization, as well as by evaluation of charge transport in organic thin-film transistors and solar cells.


The Kalanchoë genome provides insights into convergent evolution and building blocks of crassulacean acid metabolism.
Crassulacean acid metabolism (CAM) is a water-use efficient adaptation of photosynthesis that has evolved independently many times in diverse lineages of flowering plants. We hypothesize that convergent evolution of protein sequence and temporal gene expression underpins the independent emergences of CAM from C3 photosynthesis. To test this hypothesis, we generate a de novo genome assembly and genome-wide transcript expression data for Kalanchoë fedtschenkoi, an obligate CAM species within the core eudicots with a relatively small genome (~260 Mb). Our comparative analyses identify signatures of convergence in protein sequence and re-scheduling of diel transcript expression of genes involved in nocturnal CO2 fixation, stomatal movement, heat tolerance, circadian clock, and carbohydrate metabolism in K. fedtschenkoi and other CAM species in comparison with non-CAM species. These findings provide new insights into molecular convergence and building blocks of CAM and will facilitate CAM-into-C3 photosynthesis engineering to enhance water-use efficiency in crops.


Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses.
To resolve discrepancies in previous systematic overviews and provide estimates of the effect of stress ulcer prophylaxis on gastrointestinal bleeding, pneumonia, and mortality in critically ill patients. Computerized search of published and unpublished research, bibliographies, pharmaceutical and personal files, and conference abstract reports. Independent review of 269 articles identified 63 relevant randomized trials for inclusion. We made independent, duplicate assessment of the methodologic quality, population, intervention, and outcomes of each trial. The source of discrepancies between prior meta-analyses included incomplete identification of relevant studies, differential inclusion of non-English language and nonrandomized trials, different definitions of bleeding, provision of additional information through direct correspondence with authors, and different statistical methods. The current overview demonstrates that prophylaxis with histamine2-receptor antagonists decreases the incidence of overt gastrointestinal bleeding (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.42 to 0.79) and clinically important bleeding (OR, 0.44; 95% CI, 0.22 to 0.88). There is a trend toward decreased overt bleeding when antacids are compared with no therapy (OR, 0.66; 95% CI, 0.37 to 1.17). Histamine2-receptor antagonists and antacids are associated with a trend toward lower clinically important bleeding rates than sucralfate is. There is a trend toward an increased risk of pneumonia associated with histamine2-receptor antagonists as compared with no prophylaxis (OR, 1.25; 95% CI, 0.78 to 2.00). Sucralfate is associated with a lower incidence of nosocomial pneumonia when compared with antacids (OR, 0.80; 95% CI, 0.56 to 1.15) and histamine2-receptor antagonists (OR, 0.77; 95% CI, 0.60 to 1.01). Sucralfate is also associated with a reduced mortality rate (OR, 0.73; 95% CI, 0.54 to 0.97) relative to antacids and to histamine2-receptor antagonists (OR, 0.83; 95% CI, 0.63 to 1.09). Our results emphasize the need for registries to include all randomized trials and demonstrate the importance of explicit methodology for systematic reviews. There is strong evidence of reduced clinically important gastrointestinal bleeding with histamine2-receptor antagonists. Sucralfate may be as effective in reducing bleeding as gastric pH-altering drugs and is associated with lower rates of pneumonia and mortality. However, the data are insufficient to determine the net effect of sucralfate compared with no prophylaxis.