Effectiveness of Universal Self-regulation-Based Interventions in Children and Adolescents: A Systematic Review and Meta-analysis.
Childhood and adolescence self-regulation (SR) is gaining importance as a target of intervention because of mounting evidence of its positive associations with health, social and educational outcomes. To conduct a systematic review and meta-analysis of rigorously evaluated interventions to improve self-regulation in children and adolescents. Keyword searches of the PsycINFO, PubMed, EMBASE, CINAHL Plus, ERIC, British Education Index, Child Development and Adolescent Studies, and CENTRAL were used to identify all studies published through July 2016. To be eligible for this review, studies had to report cluster randomized trials or randomized clinical trials, evaluate universal interventions designed to improve self-regulation in children and adolescents aged 0 to 19 years, include outcomes associated with self-regulation skills, and be published in a peer-reviewed journal with the full text available in English. A total of 14 369 published records were screened, of which 147 were identified for full-text review and 49 studies reporting 50 interventions were included in the final review. Results were summarized by narrative review and meta-analysis. Self-regulation outcomes in children and adolescents. This review identified 17 cluster randomized trials and 32 randomized clinical trials evaluating self-regulation interventions, which included a total of 23 098 participants ranging in age from 2 to 17 years (median age, 6.0 years). Consistent improvement in self-regulation was reported in 16 of 21 curriculum-based interventions (76%), 4 of the 8 mindfulness and yoga interventions (50%), 5 of 9 family-based programs (56%), 4 of 6 exercise-based programs (67%), and 4 of 6 social and personal skills interventions (67%), or a total of 33 of 50 interventions (66%). A meta-analysis evaluating associations of interventions with self-regulation task performance scores showed a positive effect of such interventions with pooled effect size of 0.42 (95% CI, 0.32-0.53). Only 24 studies reported data on distal outcomes (29 outcomes). Positive associations were reported in 11 of 13 studies (85%) on academic achievement, 4 of 5 studies on substance abuse (80%), and in all studies reporting on conduct disorders (n = 3), studies on social skills (n = 2), studies on depression (n = 2), studies on behavioral problems (n = 2), and study on school suspensions (n = 1). No effect was seen on 2 studies reporting on academic achievement, 1 study reporting on substance abuse, and 1 additional study reporting on psychological well-being. A wide range of interventions were successful in improving self-regulation in children and adolescents. There was improvement in distal academic, health, and behavioral outcomes in most intervention groups compared with controls.


Machine learning applications for the prediction of surgical site infection in neurological operations.
Surgical site infection (SSI) following a neurosurgical operation is a complication that impacts morbidity, mortality, and economics. Currently, machine learning (ML) algorithms are used for outcome prediction in various neurosurgical aspects. The implementation of ML algorithms to learn from medical data may help in obtaining prognostic information on diseases, especially SSIs. The purpose of this study was to compare the performance of various ML models for predicting surgical infection after neurosurgical operations. A retrospective cohort study was conducted on patients who had undergone neurosurgical operations at tertiary care hospitals between 2010 and 2017. Supervised ML algorithms, which included decision tree, naive Bayes with Laplace correction, k-nearest neighbors, and artificial neural networks, were trained and tested as binary classifiers (infection or no infection). To evaluate the ML models from the testing data set, their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), as well as their accuracy, receiver operating characteristic curve, and area under the receiver operating characteristic curve (AUC) were analyzed. Data were available for 1471 patients in the study period. The SSI rate was 4.6%, and the type of SSI was superficial, deep, and organ/space in 1.2%, 0.8%, and 2.6% of cases, respectively. Using the backward stepwise method, the authors determined that the significant predictors of SSI in the multivariable Cox regression analysis were postoperative CSF leakage/subgaleal collection (HR 4.24, p < 0.001) and postoperative fever (HR 1.67, p = 0.04). Compared with other ML algorithms, the naive Bayes had the highest performance with sensitivity at 63%, specificity at 87%, PPV at 29%, NPV at 96%, and AUC at 76%. The naive Bayes algorithm is highlighted as an accurate ML method for predicting SSI after neurosurgical operations because of its reasonable accuracy. Thus, it can be used to effectively predict SSI in individual neurosurgical patients. Therefore, close monitoring and allocation of treatment strategies can be informed by ML predictions in general practice.


Pattern and predictors of dairy consumption during adolescence.
We aimed to prospectively assess dairy intake among adolescents, and determine the predictors of adequate dairy consumption during adolescence. 634 Sydney schoolchildren (351 girls and 283 boys) who had dietary data at both age 12 and 17 were included for analyses. Dairy consumption was assessed from validated semi-quantitative food frequency questionnaires. At age 12, mean total dairy intake was 1.62 serves/day which decreased to 1.40 by age 17 (p<0.0001). Mean serves/day of milk decreased from 1.11 to 0.92 during adolescence. Moreover, 90% of the decrease in serves/day of total dairy was due to reduced milk consumption. At age 12, 8.5% of children consumed >=3.5 serves/day of total dairy and this decreased to 6.2%, 5 years later at age 17 (p=0.001). A lower proportion of girls compared with boys consumed >=3 serves/day of total dairy at both ages 12 (p=0.005) and 17 (p=0.01). Participants with tertiary qualified parents at baseline were 85% more likely to have intakes of the dairy food group above the median during the 5 years, OR 1.85 (95% CI 1.18-2.91). Frequent flavored milk consumption (>=2 serves/week) at baseline was associated with ~5-fold greater likelihood of maintaining intakes of dairy foods above the median during adolescence. Dairy food consumption decreased significantly during adolescence, driven primarily by a decrease in milk consumption. Most adolescents did not meet national recommended guidelines for the dairy food group intake. These findings highlight the need for further research into intervention strategies aimed at sustaining dairy consumption.


Comparison of methylene blue and methylene violet for photoinactivation of intracellular and extracellular virus in red cell suspensions.
Previous studies with methylene blue (MB) in red cell suspensions have demonstrated that extracellular, but not intracellular, virus can be readily photoinactivated. To test if the resistance of intracellular virus to inactivation is related to the permanent positive charge of the phenothiazine, a series of uncharged phenothiazine dyes, methylene violet (MV), monodemethylated MV and didemethylated MV, were studied. Values of the sensitivity of intracellular relative to extracellular vesicular stomatitis virus (VSV) inactivation for the three dyes (D10 extracellular/D10 intracellular) in buffer were 1.0, 0.60 and 0.33, respectively. In contrast, intracellular virus was resistant to inactivation with MB, with a D10 extracellular/D10 intracellular of 0.05 in buffer. Because virucidal activity of MV was inhibited by the presence of plasma, the red cells (30% hematocrit) were repeatedly washed prior to photoinactivation and storage. Under conditions where MB and MV inactivated approximately 5 log10 of extracellular VSV, intracellular VSV was inactivated by more than 4 log10 with MV compared to 0.88 log10 with MB. These phototreatment conditions did not significantly affect red cell morphology, extracellular pH, ATP or 2,3-diphosphoglycerol levels during 42 days of 1-6 degrees C storage. There was enhanced potassium efflux and hemolysis over values obtained from untreated control; the extent of change from controls was comparable for each phototreatment. These results indicate that the uncharged phenothiazine dye, MV, can inactivate both intracellular and extracellular virus yet exhibit similar in vitro red cell storage properties as MB phototreatment.


Quantitative properties and receptor reserve of the IP(3) and calcium branch of G(q)-coupled receptor signaling.
Gq-coupled plasma membrane receptors activate phospholipase C (PLC), which hydrolyzes membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This leads to calcium release, protein kinase C (PKC) activation, and sometimes PIP2 depletion. To understand mechanisms governing these diverging signals and to determine which of these signals is responsible for the inhibition of KCNQ2/3 (KV7.2/7.3) potassium channels, we monitored levels of PIP2, IP3, and calcium in single living cells. DAG and PKC are monitored in our companion paper (Falkenburger et al. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210887). The results extend our previous kinetic model of Gq-coupled receptor signaling to IP3 and calcium. We find that activation of low-abundance endogenous P2Y2 receptors by a saturating concentration of uridine 5'-triphosphate (UTP; 100 µM) leads to calcium release but not to PIP2 depletion. Activation of overexpressed M1 muscarinic receptors by 10 µM Oxo-M leads to a similar calcium release but also depletes PIP2. KCNQ2/3 channels are inhibited by Oxo-M (by 85%), but not by UTP (<1%). These differences can be attributed purely to differences in receptor abundance. Full amplitude calcium responses can be elicited even after PIP2 was partially depleted by overexpressed inducible phosphatidylinositol 5-phosphatases, suggesting that very low amounts of IP3 suffice to elicit a full calcium release. Hence, weak PLC activation can elicit robust calcium signals without net PIP2 depletion or KCNQ2/3 channel inhibition.


Larvicidal and repellent potential of Moringa oleifera against malarial vector, Anopheles stephensi Liston (Insecta: Diptera: Culicidae).
To evaluate the larvicidal and pupicidal potential of the methanolic extracts from Moringa oleifera (M. oleifera) plant seeds against malarial vector Anopheles stephensi (A. stephensi) mosquitoes at different concentrations (20, 40, 60, 80 and 100 ppm). M. oleifera was collected from the area of around Bharathiar University, Coimbatore. The dried plant materials were powdered by an electrical blender. From each sample, 100 g of the plant material were extracted with 300 mL of methanol for 8 h in a Soxhlet apparatus. The extracts were evaporated to dryness in rotary vacuum evaporator to yield 122 mg and 110 mg of dark greenish material (residue) from Arcang amara and Ocimum basilicum, respectively. One gram of the each plant residue was dissolved separately in 100 mL of acetone (stock solution) from which different concentrations, i.e., 20, 40, 60, 80 and 100 ppm were prepared. Larvicidal activity of M. oleifera exhibited in the first to fourth instar larvae of the A. stephensi, and the LC50 and LC90 values were 57.79 ppm and 125.93 ppm for the first instar, 63.90 ppm and 133.07 ppm for the second instar, 72.45 ppm and 139.82 ppm for the third instar, 78.93 ppm and 143.20 ppm for the fourth instar, respectively. During the pupal stage the methanolic extract of M. oleifera showed that the LC50 and LC90 values were 67.77 ppm and 141.00 ppm, respectively. The present study indicates that the phytochemicals derived from M. oleifera seeds extracts are effective mosquito vector control agents and the plant extracts may be used for further integrated pest management programs.


Chemical Inhibition of Bromodomain Proteins in Insect-Stage African Trypanosomes Perturbs Silencing of the Variant Surface Glycoprotein Repertoire and Results in Widespread Changes in the Transcriptome.
The eukaryotic protozoan parasite Trypanosoma brucei is transmitted by the tsetse fly to both humans and animals, where it causes a fatal disease called African trypanosomiasis. While the parasite lacks canonical DNA sequence-specific transcription factors, it does possess histones, histone modifications, and proteins that write, erase, and read histone marks. Chemical inhibition of chromatin-interacting bromodomain proteins has previously been shown to perturb bloodstream specific trypanosome processes, including silencing of the variant surface glycoprotein (VSG) genes and immune evasion. Transcriptomic changes that occur in bromodomain-inhibited bloodstream parasites mirror many of the changes that occur as parasites developmentally progress from the bloodstream to the insect stage. We performed transcriptome sequencing (RNA-seq) time courses to determine the effects of chemical bromodomain inhibition in insect-stage parasites using the compound I-BET151. We found that treatment with I-BET151 causes large changes in the transcriptome of insect-stage parasites and also perturbs silencing of VSG genes. The transcriptomes of bromodomain-inhibited parasites share some features with early metacyclic-stage parasites in the fly salivary gland, implicating bromodomain proteins as important for regulating transcript levels for developmentally relevant genes. However, the downregulation of surface procyclin protein that typically accompanies developmental progression is absent in bromodomain-inhibited insect-stage parasites. We conclude that chemical modulation of bromodomain proteins causes widespread transcriptomic changes in multiple trypanosome life cycle stages. Understanding the gene-regulatory processes that facilitate transcriptome remodeling in this highly diverged eukaryote may shed light on how these mechanisms evolved. IMPORTANCE The disease African trypanosomiasis imposes a severe human and economic burden for communities in sub-Saharan Africa. The parasite that causes the disease is transmitted to the bloodstream of a human or ungulate via the tsetse fly. Because the environments of the fly and the bloodstream differ, the parasite modulates the expression of its genes to accommodate two different lifestyles in these disparate niches. Perturbation of bromodomain proteins that interact with histone proteins around which DNA is wrapped (chromatin) causes profound changes in gene expression in bloodstream-stage parasites. This paper reports that gene expression is also affected by chemical bromodomain inhibition in insect-stage parasites but that the genes affected differ depending on life cycle stage. Because trypanosomes diverged early from model eukaryotes, an understanding of how trypanosomes regulate gene expression may lend insight into how gene-regulatory mechanisms evolved. This could also be leveraged to generate new therapeutic strategies.


Disordered Eating, Food Insecurity, and Weight Status Among Transgender and Gender Nonbinary Youth and Young Adults: A Cross-Sectional Study Using a Nutrition Screening Protocol.
Purpose: The purpose of this study was to describe the prevalence of and relationships among disordered eating, food insecurity, and weight status among transgender and gender nonbinary youth and young adults. Methods: This cross-sectional study involved a screening protocol to assess disordered eating and food insecurity risk from September to December of 2019 at a gender clinic using five validated measures: (1) previous eating disorder diagnosis (yes/no); (2) Sick, Control, One Stone, Fat, Food Questionnaire (SCOFF); (3) Adolescent Binge Eating Disorder Questionnaire (ADO-BED); (4) Nine-Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS); and (5) Hunger Vital Sign. Age, assigned sex at birth, gender identity, stage of medical transition, and body mass index were collected. Pearson's r correlation coefficients, between-groups t-tests, one-way analysis of variance tests, and Tukey's honest significant difference test were used to characterize the relationships between variables. Results: A total of 164 participants ages 12-23 years completed the screener. Using assigned sex at birth, 1.8% were underweight, 53% were a healthy weight, 17.1% were overweight, and 28.0% were obese. An estimated 8.7% reported a previous eating disorder diagnosis, 28.0% screened positive on the SCOFF, 9.1% on the ADO-BED, 75.0% on the NIAS, and 21.2% on the Hunger Vital Sign. Transgender males scored higher on the NIAS than transgender females (p = 0.03). Those with a previous eating disorder diagnosis scored significantly higher on the Hunger Vital Sign (p < 0.05). Conclusion: Gender clinics should routinely screen for disordered eating, food insecurity, overweight, and obesity to identify patients in need of further evaluation and referral.


Initial characterization of an antineoplastic, polysaccharide-rich extract of Mycobacterium bovis BCG, Tice substrain.
A purified hot-water extract from Mycobacterium bovis (BCG vaccine) has been found to have significant antitumor activity against a murine sarcoma in vivo, but not in vitro, suggesting that the active compound is behaving as an immunostimulant. The material, termed PS1, has an average molecular weight of 22.4 kDa, is freely soluble in water, but has low solubility in acetone or ethanol, and is remarkably heat-stable, as is the parent BCG vaccine in terms of high-dose antitumor activity. PS1 contains at least 50% carbohydrate, consisting mainly of glucose, galactose and mannose, and about 10% lipid that may correspond to phosphatidylinositol. It shares chemical and biological properties with an arabinomannan isolated from M. tuberculosis, but it contains only trace quantities of lipoarabinomannan (LAM). Crossed immunoelectrophoresis indicated that PS1 contains the mycobacterial antigen 89, but only a single, non-migrating precipitin arc appeared on immunoelectrophoresis against a standard anti-BCG serum. PS1 appears to be non-toxic in mice up to a dose of 5 mg/kg, while as little as 70 micrograms/kg is sufficient to inhibit tumor formation significantly.


Damage criteria for cerebral cortex cells subjected to hyperthermia.
Temperatures above the normal physiological threshold may cause damage to cells and tissue. In this study, the response of a culture of dissociated cerebral cortex cells exposed to laser-induced temperature gradients was examined. The cellular response was evaluated using a fluorescent dye indicating metabolic activity. Furthermore, by using a finite element model of the heating during the pulsed laser application, threshold temperatures could be extracted for the cellular response at different laser pulse lengths. These threshold temperatures were used in an Arrhenius model to extract the kinetic parameters, i.e. the activation energy (Ea), and the frequency factor (Ac), for the system. A damage signal ratio was defined and calculated to 5% for the cells to increase their metabolism as a response to the heat. Furthermore, efficient stimulation with 20-ms long laser pulses did not evoke changes in metabolism. Thus, 20 ms could be a potential pulse length for functional stimulation of neural cells.


Development of an interprofessional competency model for healthcare leadership.
During the past decade, there has been a growing interest in competency-based performance systems for enhancing both individual and organizational performance in health professions education and the varied healthcare industry sectors. In 2003, the Institute of Medicine's report Health Professions Education: A Bridge to Quality called for a core set of competencies across the professions to ultimately improve the quality of healthcare in the United States. This article reviews the processes and outcomes associated with the development of the Health Leadership Competency Model (HLCM), an evidence-based and behaviorally focused approach for evaluating leadership skills across the professions, including health management, medicine, and nursing, and across career stages. The HLCM was developed from extensive academic research and widespread application outside healthcare. Early development included behavioral event interviewing, psychometric analysis, and cross-industry sector benchmarking. Application to healthcare was supported by additional literature review, practice analysis, expert panel inputs, and pilot-testing surveys. The model addresses three overarching domains subsuming 26 behavioral and technical competencies. Each competency is composed of prescriptive behavioral indicators, or levels, for development and assessment as individuals progress through their careers from entry-level to mid-level and advanced stages of lifelong development. The model supports identification of opportunities for leadership improvement in both academic and practice settings.


The Mechanisms Underlying Lipid Resuscitation Therapy.
The experimental use of lipid emulsion for local anesthetic toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than local anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.


Efficacy and safety of dose-dense neoadjuvant chemotherapy with nab-paclitaxel followed by epirubicin and cyclophosphamide for operable breast cancer.
Dose-dense chemotherapy has shown a better prognosis than standard interval chemotherapy in adjuvant settings for high-risk breast cancer. This study aimed to evaluate the efficacy and safety of dose-dense nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide as neoadjuvant chemotherapy for human epidermal growth factor 2 (HER2)-negative operable breast cancer. Patients with histologically confirmed stage I-III HER2-negative breast cancer were enrolled in this study. Patients received nanoparticle albumin-bound paclitaxel (260 mg/m2) followed by epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks with pegfilgrastim. The primary endpoint was the pathological complete response rate. Patients also underwent prophylactic management for peripheral neuropathy, which involved a combination of cryotherapy, compression therapy using elastic stockings and medications including goshajinkigan. Among the 55 patients enrolled in this study, 13 (23.6%) achieved pathological complete response, of whom 10/26 (38.5%) patients had triple-negative disease and 3/29 (10.3%) had luminal disease. The objective response was observed in 46 (83.6%) patients. Of the 36 patients who were initially planned for mastectomy, 11 (30.6%) underwent breast-conserving surgery after neoadjuvant chemotherapy. The most common grade 3-4 adverse events were myalgia (14.5%), fatigue (12.7%) and elevated transaminase levels (9.1%). No patients experienced febrile neutropenia. Eight (14.5%) patients discontinued treatments due to adverse events. Neoadjuvant dose-dense biweekly nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide was effective, especially in patients with triple-negative disease, and feasible with pegfilgrastim support.


[Ways of reducing complications after the surgical treatment of peptic ulcer].
Variants of parcimonious resections of the stomach with the dissection of the lesser curvature or a selective vagotomy and the formation of the pyloric canal for the treatment of the ulcer disease of the stomach and duodenum are described. Indications for the operation have been developed. For the period from 1973 the operations were performed on 197 patients with fairly satisfactory remote results. Lethality was 0,5%.


Evidence from ion chromatography experiments that met-cars are hollow cage clusters.
Ion chromatography studies were performed to assess various models proposed for the structure of M(8)C(12) species, the met-cars. A laser desorption source was used to make a sequence of titanium-carbon clusters centered around Ti(8)C(12)(+). The Ti(8)C(12)(+) was determined to be a hollow cage cluster, with the dodechadron structure originally propposed termined to be a hollow cage cluster, with the dodecahedron structure originally proposed giving the best fit to experiment; cubic structures could be excluded. Collisional breakup of Ti(8)C(12)(+) yielded only Ti(7)C(12)(+) under the experimental conditions described herein, and modeling indicated that the cage structure was retained. Both Ti(8)C(11)(+) and Ti(8)C(13)(+) were made by the cluster source, and again, dodecahedral-type cage structures were consistent with experiment. The extra carbon atom in Ti(8)C(13)(+) was attached exohedrally to a single titanium atom. No evidence for an endohedral species was found.


Correlates of blood parasitism in a threatened marshland passerine: infection by kinetoplastids of the genus Trypanosoma is related to landscape metrics of habitat edge.
In birds, vector-borne parasites invading the bloodstream are important agents of disease, affect fitness and shape population viability, thus being of conservation interest. Here, we molecularly identified protozoan blood parasites in two populations of the threatened Aquatic Warbler Acrocephalus paludicola, a migratory passerine nesting in open marsh. We explored whether prevalence and lineage diversity of the parasites vary by population and whether infection status is explained by landscape metrics of habitat edge and individual traits (body mass, fat score, wing length and sex). Aquatic Warblers were infected by genera Plasmodium, Leucocytozoon and Trypanosoma, with seven, one and four lineages, and 29.9, 0.7 and 12.5% prevalence, respectively. No Haemoproteus infections were detected. Prevalence did not vary between the populations, but lineage diversity was higher in Polesie than in Biebrza for all the lineages pooled and for Plasmodium. Infection by Trypanosoma decreased with patch core area and increased with density of habitat edge. Infection status was not predicted by the individual traits. Our study is the first to show an association between edge-related landscape features and blood parasitism in an open habitat bird. This finding will support informed conservation measures for avian species of the globally shrinking marshland and other treeless habitats.


Poly(ethyleneimine)-mediated large-scale transient gene expression: influence of molecular weight, polydispersity and N-propionyl groups.
Three synthesis lots of linear poly(ethyleneimine) (PEI) are compared to a fully hydrolyzed linear PEI (commercially available as PEI "Max") regarding structure, polyplex formation with plasmid DNA, and transfection of suspension-adapted HEK-293E cells. PEI "Max" binds DNA more efficiently than the other PEIs, but it is the least effective in terms of transient recombinant protein yield. One PEI lot is fractionated by means of SEC. The fractions of high-M(n) PEI are the most efficient for complex formation and transfection. Nevertheless, the highest transient recombinant protein yields are achieved with unfractionated PEI. The results demonstrate that the polydispersity and charge density of linear PEI are important parameters for gene delivery to suspension-adapted HEK-293E cells.


Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease.
Vitamin D-deficient IL-10 knockout (KO) mice develop accelerated inflammatory bowel disease (IBD). Removing dietary calcium from the diets of vitamin D-deficient IL-10 KO mice increased the severity of IBD. The mice fed either calcium or active vitamin D (1 alpha,25-dihydroxyvitamin D3, 1,25D3), developed an intermediate form of IBD, while the mice fed both calcium and 1,25D3 had the mildest form of IBD. TNF-alpha secretion from Con A-stimulated splenocytes was reduced by dietary calcium or 1,25D3 treatment. The IL-10 KO mice that received both high calcium diets and 1,25D3 treatments had the lowest TNF-alpha production. In the colons, a TNF-alpha-inducing transcription factor, LPS-induced TNF-alpha factor (LITAF), was inhibited by 1,25D3, but not by calcium. The inhibition of several TNF-alpha-related genes was associated with the decreased colitis in 1,25D3-treated IL-10 KO mice. Furthermore, fulminating IBD in vitamin D receptor/IL-10 double-KO mice corresponded with the increased expression of TNF-alpha and LITAF in the colon. Our results suggest that dietary calcium has independent effects on IBD severity and that 1,25D3 and high calcium together result in the maximal suppression of experimental IBD. The data support a model where dietary calcium and 1,25D3 treatment directly and indirectly inhibit the TNF-alpha pathway and suppress IBD.


Effects of corticospinal tract integrity on upper limb motor function recovery in stroke patients treated with repetitive transcranial magnetic stimulation.
The bimodal balance-recovery model predicts that corticospinal tract (CST) integrity in the affected hemisphere influences the partterns of brain recovery after stroke. Repetitive transcranial magnetic stimulation (rTMS) has been used to promote functional recovery of stroke patients by modulating motor cortical excitability and inducing reorganization of neural networks. This study aimed to explore how to optimize the efficiency of repetitive transcranial magnetic stimulation to promote upper limb functional recovery after stroke according to bimodal balance-recovery model. 60 patients who met the inclusion criteria were enrolled to high CST integrity group (n = 30) or low CST integrity group (n = 30), and further assigned randomly to receive high-frequency rTMS (HF-rTMS), low-frequency rTMS (LF-rTMS) or sham rTMS in addition to routine rehabilitation, with 10 patients in each group. Outcome measures included Fugl-Meyer scale for upper extremity (FMA-UE), Wolf Motor Function (WMFT) scale and Modified Barthel Index (MBI) scale which were evaluated at baseline and after 21 days of treatment. For patients with high CST integrity, the LF group achieved higher FMA-UE, WMFT and MBI scores improvements after treatment when compared to the HF group and sham group. For patients with low CST integrity, after 21 days treatment, only the HF group showed significant improvements in FMA-UE and WMFT scores. For MBI assessment, the HF group revealed significantly better improvements than the LF group and sham group. For stroke patients with high CST integrity, low-frequency rTMS is superior to high-frequency rTMS in promoting upper limb motor function recovery. However, only high-frequency rTMS can improve upper limb motor function of stroke patients with low CST integrity.


Recreational drug use and risk of Kaposi's sarcoma in HIV- and HHV-8-coinfected homosexual men.
Experimental data suggested that exposure to recreational drugs might adversely affect antitumor immunity, which led us to examine the hypothesis that use of marijuana, cocaine, poppers, and amphetamines might increase the risk of Kaposi's sarcoma (KS) in HIV- and HHV-8-coinfected homosexual men. We analyzed data prospectively collected from the Multicenter AIDS Cohort Study (MACS) between 1984 and 2002. Among the 1335 HIV- and HHV-8-coinfected white men, 401 KS cases were identified. Multivariable Cox regression models were used to estimate the effects of time-varying recreational drug use on KS risk adjusting for potential confounders. The effects of both recent use (6 months prior) of recreational drugs and lagged exposure (i.e., use from 3 and 5 years prior) were examined. We did not observe any clear association with KS for recent use of any of the four drugs. In the analyses using lagged exposures, KS risk was associated with use of poppers 3-5 years prior [hazard ratio (HR)(3 years prior) = 1.27, 95% CI (0.97-1.67), HR(5 years prior) = 1.46 (1.01-2.13)]. However, no clear dose-response relationship was observed. These findings do not support a biological association between use of these substances and KS development in HIV- and HHV-8-coinfected homosexual men.


Formation of normal surface plasmon modes in small sodium nanoparticles.
Formation of surface plasmon modes in sodium nanoclusters containing 20-300 atoms was studied using the G0W0 approximation. It is shown that in the small Na nanoparticles up to 2 nm in size, the loss function Im[ε-1] is dominated by a single peak corresponding to localized surface plasmon resonance (LSPR). For particles of 2 nm and more, a resonance corresponding to surface plasmon polariton (SPP) oscillations begins to form, as well as a resonance corresponding to volume plasmon (VP) excitations. Considering the above, the linear size of a particle in the range of 0.7-3.7 nm can be estimated as the lower limit for metal nanodevices operating with SPPs. On the example of spherical nanoparticles consisting of a silicon core coated with sodium atoms, it is shown that the LSPR mode is selectively suppressed while the SPP mode is not. Such composite structures can be considered as an example of nanoplasmonic devices with selectively tuned characteristics.


Visual mismatch negativity and its importance in visual cognitive sciences.
This review paper on visual mismatch negativity (MMN), an event-related brain potential component, provides arguments in favor of its theoretical importance in visual cognitive sciences. We propose that (a) previous visual MMN findings can be regarded as ample evidence for the existence of unintentional prediction about the next state of a visual object in the immediate future on the basis of its temporal context ('unintentional temporal-context-based prediction in vision'); (b) such predictive processes may be qualitatively similar to those revealed by behavioral phenomena, such as representational momentum, flash-lag effect, and perceptual sequence learning; (c) such predictive processes may provide advantages for our adaptation to the visual environment at the computational, neural, and behavioral levels, and (d) in concert with such behavioral phenomena, visual MMN could be a unique and powerful tool for tapping into the predictive power of the human visual system.


Fractal analysis of the effects on mandibular bone of botulinum toxin therapy of the masseter muscle in patients with bruxism.
We examined changes in the mandibular angle, ramus, and condylar neck of patients with bruxism after botulinum toxin-A (BTX-A) injection into the masseter muscle as calculated with fractal analysis (FA) on panoramic radiographs (PRs). We examined the PRs of 3 groups of 22 patients each (n = 66) obtained upon presentation and 6 months later. One group included healthy controls without bruxism, one group included patients with untreated bruxism, and one group included patients with bruxism who had undergone BTX-A injection into the masseter muscle. We performed FA of the bilateral angle, ramus, and condylar neck of the PRs to calculate fractal dimension (FD). The FD values of the angle on the second PRs of the untreated bruxism group were significantly higher than those of the other groups (P = .026), specifically when compared to the BTX-A injection group (P = .017). The FD values in the angle and ramus of the bruxism group were significantly higher on the second PRs (P ≤..005)) Conversely, the FD values in the angle of the BTX-A injection group were significantly lower on the second PR (P = .039). Masseter muscle hyperactivity due to bruxism increases bone density in masseter muscle attachment regions. BTX-A injection restricts muscle activity, thereby chnging bone structure and decreasing FD.


Safety, tolerability and efficacy of peginterferon alpha-2a and ribavirin in chronic hepatitis C in clinical practice: The German Open Safety Trial.
The combination treatment of peginterferon alpha-2a (PEG-IFN alpha-2a; Pegasys) plus ribavirin (RBV) is recommended as a standard care for HCV infections. Side effects and aspects of efficacy and safety have to be balanced. This study evaluates clinical practice data on safety and efficacy of HCV treatment with PEG-IFN in combination with RBV over 24 and 48 weeks. This study was a phase III, multi-centre, open-label study with two treatment groups: PEG-IFN in combination with RBV for 24 or 48 weeks. The allocation to the treatment groups was at the discretion of the investigator; 309 patients entered active treatment: 90 patients received PEG-IFN plus RBV for 24 weeks and 219 patients PEG-IFN plus RBV for 48 weeks. A sustained virological response (SVR) was achieved in 48.9% of all patients. Genotype 1 patients with a 48-week combination treatment achieved an SVR of 39.9%. In the 48-week group a low baseline viral load was associated with a higher SVR rate (47.0% vs. 32.4%). For genotype 2 or 3 patients, the SVR was 67.9%. For these patients there was no relevant difference between patients with low and high viral loads; 97.7% of the patients experienced at least one adverse event. The incidence of serious adverse events was distinctly lower in the 24-week group (4.4% vs. 10.5%). This investigation confirms the well-known risk-benefit ratio found in controlled studies in a clinical practice setting. The safety profile is similar and shows the highest incidence of adverse events in the first 12 weeks of treatment.


Examination of neurons in wild type and mutants of Caenorhabditis elegans using antibodies to horseradish peroxidase.
Antibodies to horseradish peroxidase (HRP) recognize 27 of 302 neurons and several non-neuronal cells in adult hermaphrodites of the soil nematode Caenorhabditis elegans and can be used to label these cells for cytological analysis in whole animals. The antibodies bind to the anterior members, but not to the posterior members of a set of mechanosensory neurons in wild type animals. Binding to one of the posterior mechanosensory neurons (PVM) occurs when this neuron migrates to an abnormal anterior position in mab-5 mutant animals, suggesting that expression of the epitope recognized by these antibodies is position dependent or that mab-5 mutations transform PVM into AVM intrinsically. The antibodies were used to characterize morphologies of two pairs of lumbar neurons (PHC and PVN) in uncoordinated mutants representing 95 unc genes. PHC and PVN morphologies were normal in most of the unc mutants examined, however, in mutants of 9 unc genes (unc-6, unc-13, unc-33, unc-44, unc-51, unc-61, unc-71, unc-73, and unc-98), misdirected PHC and/or PVN processes were observed at a high frequency. The morphologies of 2 other lumbar neurons, PHA and PHB, were determined previously in these mutants (Hedgecock et al., 1985). Mutations in most, but not all of these 9 unc genes affect the growth of the embryonic lumbar neurons PHA and PHB differently than they affect the growth of the postembryonic lumbar neurons PHC and PVN, indicating that these neurons require different, but overlapping sets of genes for different stages of normal growth and guidance.


A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis.
Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset. To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10(-8) was used to determine significance. Replication was performed in 1523 additional patients from the POSH study. Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10(-6). These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27-1.75, P = 1.1×10(-6)), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67-0.85, P = 1.8×10(-6)), and rs1728400 which is between LINC00917 and FOXF1. In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study.


[Vaccination against yellow fever among patients on immunosuppressors with diagnoses of rheumatic diseases].
Yellow fever is endemic in some countries. The anti-yellow fever vaccine is the only effective means of protection but is contraindicated for immunocompromised patients. The aim of this paper was to report on a case series of rheumatological patients who were using immunosuppressors and were vaccinated against this disease. This was a retrospective study by means of a questionnaire applied to these patients, who were vaccinated 60 days before the investigation. Seventy patients of mean age 46 years were evaluated. Most of them were female (90%). There were cases of rheumatoid arthritis (54), systemic lupus erythematosus (11), spondyloarthropathy (5) and systemic sclerosis (2). The therapeutic schemes included methotrexate (42), corticosteroids (22), sulfasalazine (26), leflunomide (18), cyclophosphamide (3) and immunobiological agents (9). Sixteen patients (22.5%) reported some minor adverse effect. Among the eight patients using immunobiological agents, only one presented a mild adverse effect. Among these patients using immunosuppressors, adverse reactions were no more frequent than among immunocompetent individuals. This is the first study on this topic.


Increase in daytime symptoms is a sensitive and specific criterion for predicting corticosteroid-treated exacerbations in a clinical asthma trial.
To determine which diary card variables are the most predictive for administration of additional courses of corticosteroids using the TRUST (The Regular Use of Salbutamol Trial) data set. Logistic regression models were used to identify the extent to which a change in diary card variable affected the odds ratio (OR) for administering a course of oral or increased inhaled corticosteroids. The complete TRUST diary card data were used with over 200,000 days of diary card observations from 983 mild to moderate asthmatic subjects. An increase in daytime symptoms of 1-5 U over baseline was associated with an increase in the OR for starting all types of corticosteroids from two- to 60-fold. These results indicate that an increase in daytime symptoms of two or more over baseline strongly predicts the administration of additional corticosteroids. The results have significant implications for both clinical practice and design of clinical trials in asthma.


[Endogenous and neurotic depression again III: support for a sequence hypothesis].
The sequential hypothesis about depression tells: "neurotic" and "endogenous" depression are not different diseases, but two different moments in the evolution of a unique disorder (initial and terminal, respectively). The authors use Kiloh and Garside's (1963) and Carney et al's (1965) data to support this hypothesis. The bibliographic data are analyzed in that way to show that biological correlates of endogeneity are the final pathway of an ontogenic evolution of biological modifications in depression less obvious in initial episodes ("neurotiforms") and more evident in subsequent episodes ("endogeniforms").


Urine 6-Bromotryptophan: Associations with Genetic Variants and Incident End-Stage Kidney Disease.
Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (<median level: cause-specific hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.51 to 0.97; ≥median level: HR 0.50, 95% CI 0.34 to 0.74). Upon adjustment for baseline eGFR, this association became attenuated, suggesting that urine 6-bromotryptophan may represent a correlated marker of kidney health.


Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin.
The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ∼15-40% and increases HDL-C by ∼40-140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (-59 to -100%, P < 0.001), thereby decreasing non-HDL-C (-24 to -45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (-41 to -92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (-95%, P < 0.001) and severity. Analysis of covariance showed that both anacetrapib (P < 0.05) and non-HDL-C (P < 0.001), but not HDL-C (P = 0.76), independently determined lesion size. Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability.


Groundwater derived arsenic in high carbonate wetland soils: sources, sinks, and mobility.
Wetlands and organic soils have been recognized as important sinks for arsenic in the environment, yet sources and immobilization mechanisms of As are often unclear. To begin rectifying this deficiency, we investigated As retention and binding mechanisms at a degraded, minerotrophic wetland site in contact with groundwater rich in As and Fe. Arsenic occurred in high dissolved concentrations of up to 467 microg L(-1) in the groundwater, but dropped to values below 10 microg L(-1) towards the surface. The solid phase As content instead was high in the topsoil with up to 3400 mg kg(-1) and decreased with depth to 15 mg kg(-1). A similar pattern was observed with respect to Fe. Amorphous and crystalline iron precipitates were the main sorbents for arsenic in the soil horizons according to results from wet chemical sequential extractions. Arsenic was apparently not associated with inorganic carbon phases, but a substantial portion of up to 31% of As(tot) could be mobilized by dispersion of soil organic matter. Ratios of dissolved As(III)/As(V) decreased from the deeper As(III) dominated groundwater to the As(V) dominated soil porewaters, where As was apparently immobilized in its oxidized form. Concentrations of the organic species DMA and MMA were negligible. According to the results of simple one-dimensional estimates the vertical arsenic transport from the source in the groundwater to the topsoil was slow given an extrapolation of current conditions. These results suggest that As accumulation started before the beginning of drainage in the now degraded peatland soils and the degradation and mass loss of organic matter under oxic conditions caused the very high As concentrations found in the topsoil horizon today.


Validity and reliability of instruments to assess potential mediators of children's physical activity: A systematic review.
This paper aimed to (1) identify potential mediators reported in children's physical activity interventions; and (2) review the psychometric properties of measures of potential mediators included in such interventions. A systematic search of the literature was conducted and studies that reported potential mediators and/or the psychometric properties of measures of potential mediators were retrieved and reviewed. The studies were reviewed for the following psychometric properties: face/logical, construct, and criterion validity; and test-retest and internal consistency (factor analysis and Cronbach's alpha) reliability. Twenty-one potential mediators were identified from 24 published children's physical activity intervention studies; 17 individual, three social, and one physical environmental. Overall, there was considerable variation in the reporting of the psychometric properties of these measures. Reliability properties (specifically Cronbach's alpha) were more commonly reported than validity properties; however, for many potential mediators, the quality of these measures was low. Future studies should examine the psychometric properties of measures of potential mediators to ensure appropriate, valid and reliable instruments are used. This will assist in the ability to accurately determine the efficacy of physical activity interventions among children.


SPPs coupling induced interference in metal/dielectric multilayer waveguides and its application for plasmonic lithography.
We present the analyses of surface plasmon polaritons (SPPs) coupling induced interference in metal/dielectric (M/D) multilayer metamaterials and techniques to improve the performance of sub-wavelength plasmonic lithography. Expressions of beam spreading angles and interference patterns are derived from analyses of numerical simulations and the coupled mode theory. The new understandings provide useful guidelines and design criteria for plasmonic lithography. With proper layer structure design, sub-wavelength uniform periodic patterns with feature size of 1/12 of the mask's period can be realized. High pattern contrast of 0.8 and large field depth of 80 nm are also demonstrated numerically by considering the SPPs coupling in the photoresist. Both high contrast and large image depth are crucial for practical application of plasmonic lithography.


The firewater myth and response to alcohol in Mission Indians.
This study aimed to assess empirically the intensity of reaction to alcohol in a group of Native Americans. Forty healthy, nonalcoholic Mission Indian men between the ages of 18 and 25 years were tested before and after ingestion of placebo and 0.75 ml/kg of alcohol. Subjective (self-report of feelings) and objective (blood pressure, pulse rate, and plasma cortisol level) measures of intoxication were taken before ingestion of alcohol and placebo and at 15, 30, 60, 90, and 120 minutes after ingestion. Overall effects of alcohol were evaluated, and the responses of subjects with less than 50% Native American heritage (N = 19) were compared with the responses of subjects with at least 50% Native American heritage (N = 21). Alcohol did not produce any significant effects on any of the objective measures of intoxication; however, the subjects reported significant subjective effects of alcohol. Subjects with at least 50% Native American heritage reported less intense effects of alcohol than did those with less than 50% Native American heritage, despite equivalent blood alcohol concentrations. These results contradict the "firewater myth"--the theory that Native Americans are more sensitive to the effects of alcohol. Rather, the data indicate that Mission Indian men generally may be less sensitive to alcohol's effects, a physiological characteristic that has been shown to be associated with a greater risk for alcoholism in Caucasian populations. In addition, individuals with a greater percentage of Native American heritage may be less sensitive to the subjective effects of alcohol than individuals with a smaller percentage of Native American heritage.


Readout of three-dimensional optical memories.
The method of recording data in a volume memory determines the spatial frequency content. We use a threedimensional transfer function approach to show that this has serious implications for the choice of readout system. In particular, one cannot use a ref lection confocal system to read a photopolymer-based memory. A solution to this problem is proposed.


Serum progranulin to TNF-α ratio in patients with gonarthrosis.
Progranulin (PGRN) is a growth factor that has antiinflammatory, immunosuppressive, and chondroprotective effects. It blocks Tumor Necrosis Factor-α (TNF-α) signal pathway by binding its receptor. Recently, it has been claimed that PGRN may be overexpressed in patients with Osteoarthritis (OA). However, these patients tend to be obese and obesity also may be one of the factors that affect PGRN levels. The aim of this study was to compare the PGRN levels of patients with Knee OA (KOA) with that of healthy controls by eliminating the effect of obesity and to evaluate PGRN-to-Tumor Necrosis Factor-α (TNF-α) ratio in KOA, both of which were investigated first in literature by this study. A total of 80 individuals (40 patients with KOA and 40 healthy controls) were included in this study. The patients and controls were divided into two groups according to their Body Mass Indexes (BMI): nonobese (BMI between 18.5 and 24.9) and obese (BMI of 30 or higher). Each of the groups included 20 subjects and had an equal number of men and women. Blood samples were obtained from all participants, and the serum PGRN and TNF-α levels were measured using commercial ELISA kits. There was no difference among groups in terms of age (P = 0.416) and gender distribution. There was no statistical difference among study groups with regard to serum PGRN levels. Serum TNF-α levels were significantly higher in obese controls (P < 0.001) and nonobese patients (P = 0.003) compared to that of nonobese healthy controls. Correspondingly, serum PGRN-to-TNF-α ratio was considerably lower in obese controls (P < 0.001) and nonobese patients (P < 0.001) by comparison with that of nonobese healthy controls. We determined that both obesity and KOA increased serum TNF-α levels and concordantly decreased serum PGRNto- TNF-α ratio. The results of the study suggest that the activation of the PGRN pathway and/or the inhibition of the TNFα pathway may be essential in terms of the reestablishment of the disrupted inflammatory balance in patients with KOA. Level III, Diagnostic study.


Identifying the cause of toxicity of a saline mine water.
Elevated major ions (or salinity) are recognised as being a key contributor to the toxicity of many mine waste waters but the complex interactions between the major ions and large inter-species variability in response to salinity, make it difficult to relate toxicity to causal factors. This study aimed to determine if the toxicity of a typical saline seepage water was solely due to its major ion constituents; and determine which major ions were the leading contributors to the toxicity. Standardised toxicity tests using two tropical freshwater species Chlorella sp. (alga) and Moinodaphnia macleayi (cladoceran) were used to compare the toxicity of 1) mine and synthetic seepage water; 2) key major ions (e.g. Na, Cl, SO4 and HCO3); 3) synthetic seepage water that were modified by excluding key major ions. For Chlorella sp., the toxicity of the seepage water was not solely due to its major ion concentrations because there were differences in effects caused by the mine seepage and synthetic seepage. However, for M. macleayi this hypothesis was supported because similar effects caused by mine seepage and synthetic seepage. Sulfate was identified as a major ion that could predict the toxicity of the synthetic waters, which might be expected as it was the dominant major ion in the seepage water. However, sulfate was not the primary cause of toxicity in the seepage water and electrical conductivity was a better predictor of effects. Ultimately, the results show that specific major ions do not clearly drive the toxicity of saline seepage waters and the effects are probably due to the electrical conductivity of the mine waste waters.


Evaluation of gene prediction software using a genomic data set: application to Arabidopsis thaliana sequences.
The annotation of the Arabidopsis thaliana genome remains a problem in terms of time and quality. To improve the annotation process, we want to choose the most appropriate tools to use inside a computer-assisted annotation platform. We therefore need evaluation of prediction programs with Arabidopsis sequences containing multiple genes. We have developed AraSet, a data set of contigs of validated genes, enabling the evaluation of multi-gene models for the Arabidopsis genome. Besides conventional metrics to evaluate gene prediction at the site and the exon levels, new measures were introduced for the prediction at the protein sequence level as well as for the evaluation of gene models. This evaluation method is of general interest and could apply to any new gene prediction software and to any eukaryotic genome. The GeneMark.hmm program appears to be the most accurate software at all three levels for the Arabidopsis genomic sequences. Gene modeling could be further improved by combination of prediction software. The AraSet sequence set, the Perl programs and complementary results and notes are available at http://sphinx.rug.ac.be:8080/biocomp/napav/. firstname.lastname@example.com.


Aorta in Pathologies May Function as an Immune Organ by Upregulating Secretomes for Immune and Vascular Cell Activation, Differentiation and Trans-Differentiation-Early Secretomes may Serve as Drivers for Trained Immunity.
To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel-Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang-II induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase 1 SGs play roles at early MERS-CoV infected ECs whereas caspase 4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase 1 SGs may function as drivers for trained immunity (innate immune memory); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.


Patient perspectives of Internet-delivered cognitive behavior therapy for psychosocial issues post spinal cord injury.
Many individuals with a spinal cord injury (SCI) report significant symptoms of depression and/or anxiety post-SCI; however, access to mental health services can be limited. The purpose of this study was to evaluate patient perspectives on the acceptability of an 8-week guided Internet-delivered cognitive behavior therapy (ICBT) course (Chronic Conditions Course) for people with SCI. In particular, we sought to understand patient perceptions of facilitators and barriers of engaging in ICBT and strengths and weaknesses of ICBT program content. Semistructured interviews were conducted with 8 SCI patients after completion of the ICBT course. The interviews were audio-recorded, transcribed verbatim, and examined by means of thematic analysis by 2 coders. Eight participants (mean age = 53.2 years; males = 50%; paraplegia = 67.5%) were interviewed. Four major themes emerged when examining facilitators to completing the program: accessibility, flexibility, motivation, and guided support. Barriers to completing the program included course timeframe and physical health. Strengths of the course included effective skill development and mental health prioritization. Suggested changes to the course included improved breadth of case stories, development of extra resources, adjusting the course timeframe to account for the SCI, and more support from the guide. ICBT was overall highlighted as an acceptable method of receiving care for people with SCI. The study provides direction for improving delivery of ICBT to ensure this method of treatment meets the needs of individuals with SCI. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Impact of ticagrelor monotherapy on two-year clinical outcomes in patients with long stenting: a post hoc analysis of the GLOBAL LEADERS trial.
The aim of this study was to evaluate the impact of a novel antiplatelet regimen in patients with increasing total stent length (TSL). This is a post hoc analysis of the GLOBAL LEADERS trial, a prospective, multicentre, open-label, randomised trial, investigating the impact of the experimental strategy (one-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus the reference regimen (12-month DAPT followed by 12-month aspirin monotherapy) in patients with a Biolimus A9-eluting stent (BES). The primary endpoint was the composite of all-cause death and new Q-wave myocardial infarction (MI), and the secondary endpoint was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding at two years. To investigate the association between total stent length and outcomes, groups were compared in quartiles according to TSL; the fourth quartile group was at significantly higher ischaemic risk at two years. In that stratum (TSL ≥46 mm), the experimental strategy significantly reduced the risk of the primary endpoint (hazard ratio [HR] 0.67, 95% confidence interval [CI]: 0.49-0.90; pinteraction=0.043), while demonstrating a similar risk of BARC type 3 or 5 bleeding (HR 0.99, 95% CI: 0.66-1.49; pinteraction=0.975). Ticagrelor monotherapy could potentially balance ischaemic and bleeding risks, thereby achieving a net clinical benefit in patients with a TSL ≥46 mm with a BES.


Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.
Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.


CE: Original Research: End-of-Life Care Behind Bars: A Systematic Review.
: To conduct a systematic review of the published research literature on end-of-life (EOL) care in prisons in order to determine the current state of the science and suggest implications for nursing practice and areas for future research.Applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a comprehensive search of the literature using the following databases: CINAHL, Criminal Justice Abstracts, the National Criminal Justice Reference Service, PsycINFO, PubMed, and Sociological Abstracts. All databases were searched from the time of their inception through June 2014. All English-language articles that reported on original quantitative and qualitative research involving EOL or palliative care delivered to prisoners were included. We abstracted data, using the matrix method, and independently reviewed and graded the evidence on its level of strength and quality in accordance with the Johns Hopkins Nursing Evidence-Based Practice rating scales.Nineteen articles, all published between 2002 and 2014, met the inclusion criteria. Of these, 53% were published between 2009 and 2014, and 58% reported findings from qualitative research. One article reported on research conducted in the United Kingdom; the remaining 18 reported on research conducted in the United States. Capacity (that is, the number of prisoners requiring EOL care and the ability of the prison to accommodate them) and the site of EOL care delivery varied across studies, as did the criteria for admission to EOL or hospice services. Care was provided by prison health care staff, which variously included numerous professional disciplines, corrections officers, and inmate caregivers. The inmate caregivers, in particular, provided a wide array of services and were viewed positively by both EOL patients and health care staff. There are insufficient data to characterize the patients' and inmate caregivers' perceptions of the EOL care staff and the quality of care they provided. The screening criteria applied to inmate caregivers and the training they received varied widely among care programs. Inmates providing EOL care viewed caregiving as a transformational experience. Likewise, prison administrators and health care staff viewed inmate participation positively.This literature review reveals the challenges of providing EOL care to prisoners and may inspire nurses to consider steps they can take individually or within nursing organizations to improve this care and address the unique challenges faced by dying inmates. By being aware of these issues and advocating for best practices, nurses can help inmates at the end of life to have a dignified death.


[Prospective study of 288 cases of acute appendicitis during childhood: characteristics in preschool children].
The purpose of this study was to verify that preschool children with acute appendicitis show some clinical characteristics which, associated with the faster evolution of the infection at this age, result in a higher incidence of perforations, peritonitis and complications. A group of 288 children between 9 months and 17 years of age with acute appendicitis was studied over a 17-month period, ending July 1993. They were divided into two age groups: Group I (< 5 years: n = 45) and Group II (5 or more years: n = 243). Comparisons between clinical, laboratory and radiological findings, appendiceal pathology, microbiology and complications were made. Children fro Group I showed a higher incidence of perforations (29% vs 7.8%), peritonitis (69% vs 36%), appendiceal masses (37% vs 10.2%), positive cultures (66% vs 18%) and complications (24% vs 9.8%) than those from Group II. All differences were found to be significant (p < 0.05). Children from Group I more frequently showed a set of clinical characteristics forming an atypical picture consisting of: 1) Diffuse abdominal pain (69% vs 30%); 2) Associated infections with non-specific symptoms (33% vs 11.5%); 3) Previous therapy with antimicrobial agents (40% vs 9.8%); 4) X-ray findings compatible with gastroenteritis (27% vs 7.4%); and 5) Inability of the child to specify the intensity and location of pain. All these factors justified the delay in the diagnosis and its significant relationship with the higher incidence of peritonitis in this age group.


The Impingement-free, Prosthesis-specific, and Anatomy-adjusted Combined Target Zone for Component Positioning in THA Depends on Design and Implantation Parameters of both Components.
Lewinnek's recommendation for orienting the cup in THA is criticized because it involves a static assessment of the safe zone and because it does not consider stem geometry. A revised concept of the safe zone should consider those factors, but to our knowledge, this has not been assessed. (1) To determine the shape, size, and location of target zones for combined cup and stem orientation for a straight stem/hemispheric cup THA to maximize the impingement-free ROM and (2) To determine whether and how these implant positions change as stem anteversion, neck-shaft angle, prosthetic head size and target range of movements are varied. A three-dimensional computer-assisted design model, in which design geometry was expressed in terms of parameters, of a straight stem/hemispheric cup hip prosthesis was designed, its design parameters modified systematically, and each prosthesis model was implanted virtually at predefined component orientations. Functional component orientation referencing to body planes was used: cups were abducted from 20° to 70°, and anteverted from -10° to 40°. Stems were rotated from -10° to 40° anteversion, neck-shaft angles varied from 115° to 143°, and head sizes varied from 28 to 40 mm. Hip movements up to the point of prosthetic impingement were tested, including simple flexion/extension, internal/external rotation, ab/adduction, combinations of these, and activities of daily living that were known to trigger dislocation. For each combination of parameters, the impingement-free combined target zone was determined. Maximizing the size of the combined target zone was the optimization criterion. The combined target zones for impingement-free cup orientation had polygonal boundaries. Their size and position in the diagram changed with stem anteversion, neck-shaft angle, head size, and target ROM. The largest target zones were at neck-shaft angles from 125° to 127°, at stem anteversions from 10° to 20°, and at radiographic cup anteversions between 17° and 25°. Cup anteversion and stem anteversion were inverse-linearly correlated supporting the combined-anteversion concept. The range of impingement-free cup inclinations depended on head size, stem anteversion, and neck-shaft angle. For a 127°-neck-shaft angle, the lowest cup inclinations that fell within the target zone were 42° for the 28-mm and 35° for the 40-mm head. Cup anteversion and combined version depended on neck-shaft angle. For head size 32-mm cup, anteversion was 6° for a 115° neck-shaft angle and 25° for a 135°-neck-shaft angle, and combined version was 15° and 34° respectively. The shape, size, and location of the combined target zones were dependent on design and implantation parameters of both components. Changing the prosthesis design or changing implantation parameters also changed the combined target zone. A maximized combined target zone was found. It is mandatory to consider both components to determine the accurate impingement-free prosthetic ROM in THA. This study accurately defines the hypothetical impingement-free, design-specific component orientation in THA. Transforming it into clinical precision may be the case for navigation and/or robotics, but this is speculative, and as of now, unproven.


Eukaryotic initiation factor 5A plays an essential role in luteinizing hormone receptor regulation.
Down-regulation of LH receptor (LHR) in the ovary by its ligand is mediated by a specific RNA-binding protein, designated LH receptor mRNA-binding protein (LRBP), through translational suppression and mRNA degradation. Using yeast 2-hybrid screens, we previously identified eukaryotic initiation factor 5A (eIF5A) as one of the proteins that interacts with LRBP during LHR mRNA down-regulation. The present study examined the role of eIF5A and its hypusination in the context of LHR mRNA down-regulation. The association of eIF5A with LRBP or LHR mRNA was determined using immunoprecipitation and RNA immunoprecipitation assays. The results showed that the association of eIF5A with the LHR mRNA-LRBP complex increased significantly during down-regulation. Furthermore, gel fractionation and the hypusination activity assay both showed increased hypusination of eIF5A during LHR mRNA down-regulation. Abolishment of hypusination by pretreatment with the chemical inhibitor GC7 prevented the association of eIF5A with LHR mRNA and LRBP. Inhibition of hypusination also reduced the extent of ligand-induced down-regulation of LHR mRNA as well as the expression of functional LHRs assessed by real-time PCR and (125)I-human chorionic gonadotropin (hCG) binding assays, respectively. The loss of human chorionic gonadotropin-mediated downstream signaling during LHR down-regulation was also restored by inhibition of hypusination of eIF5A. Thus, the present study, for the first time, reveals the crucial role of eIF5A and its hypusination in the regulation of LHR expression in the ovary.


Diagnosis of foot-and mouth disease by real time reverse transcription polymerase chain reaction under field conditions in Brazil.
Foot-and-mouth disease (FMD) is an economically important and highly contagious viral disease that affects cloven-hoofed domestic and wild animals. Virus isolation and enzyme-linked immunosorbent assay (ELISA) are the gold standard tests for diagnosis of FMD. As these methods are time consuming, assays based on viral nucleic acid amplification have been developed. A previously described real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay with high sensitivity and specificity under laboratorial and experimental conditions was used in the current study. To verify the applicability of this assay under field conditions in Brazil, 460 oral swabs from cattle were collected in areas free of FMD (n = 200) and from areas with outbreaks of FMD (n = 260). Three samples from areas with outbreaks of FMD were positive by real-time RT-PCR, and 2 of those samples were positive by virus isolation and ELISA. Four other samples were considered inconclusive by real-time RT-PCR (threshold cycle [Ct] > 40); whereas all 200 samples from an area free of FMD were real-time RT-PCR negative. real-time RT-PCR is a powerful technique for reliable detection of FMDV in a fraction of the time required for virus isolation and ELISA. However, it is noteworthy that lack of infrastructure in certain areas with high risk of FMD may be a limiting factor for using real-time RT-PCR as a routine diagnostic tool.


Lauric acid induce cell death in colon cancer cells mediated by the epidermal growth factor receptor downregulation: An in silico and in vitro study.
Coconut oil (CO) is enriched with medium chain saturated fatty acids like lauric acid (LA), capric acid and caprylic acid, which are known to have several health benefits. LA, the predominant fatty acid in CO, is reported to possess anticancer activity mediated through oxidative stress-induced apoptosis; however, there is no clear information on its cellular signalling mechanism. The present study screened the anticancer potential of various fatty acids present in CO (capric acid, caprylic acid and LA) using in silico tools such as CDOCKER in Accelrys Discovery Studio by targeting proteins like epidermal growth factor receptor (EGFR), cyclin-dependent kinase and thymidine synthase (TS). The results were further confirmed using cell culture-based studies and quantitative PCR. Among the tested compounds, LA was found to be the most active and showed a higher affinity towards EGFR and TS. Corroborating with these results, LA-induced dose-dependent cytotoxicity towards HCT-15 (human colon cancer), HepG2 (human hepatocellular carcinoma) and Raw 264.7 (murine macrophages) cells exhibiting morphological characteristics of apoptosis. Further, in HCT-15 cells exposed to LA (30 and 50 µg/mL), the expression of EGFR was found to be downregulated by 1.33- and 1.58-fold. The study thus concludes that the anticancer activity of LA may be partially mediated by the downregulation of EGFR signalling and consequent reduction in cell viability through apoptosis. Since EGFR signalling is crucial in cancer cell survival and is a prime target in drug development, the present study has pharmacological significance.


Two-year outcome of treatment with central stimulant medication in adult attention-deficit/hyperactivity disorder: a prospective study.
Given that adults with ADHD continue to use stimulants for extended periods of time, studies on the long-term effectiveness and adverse events are warranted. The aims of this study were to investigate factors associated with persistence in treatment in an exploratory manner and to document side effects and reasons for discontinuation. The current study describes the systematic follow-up of 133 psychiatric patients with DSM-IV-diagnosed ADHD treated with central stimulants at a specialized outpatient unit between January 1, 2001, and August 31, 2006. A standardized questionnaire, derived from the Targeted Attention-deficit Disorder Symptoms Rating Scale, was used in order to measure improvement of the following target symptoms: hyperactivity, impulsivity, irritability, distractibility, structure/organization problems, inattention, and restlessness. Eighty percent of the patients were successfully treated with stimulants at the 6- to 9-month follow-up. Fifty percent remained in treatment after 2 years or more. Forty-five percent were treated for comorbid anxiety and/or depression during the study period. Only 15% dropped out because of lack of efficacy. The amount of clinical response over the first 6 to 9 months (but not at 6 weeks) predicted adherence to treatment at 2 years. The patients' heart rate increased from a least squares mean ± SE of 70 ± 2.2 to 80 ± 2.1 bpm (P = .00003) while blood pressure remained unchanged at the ≥ 2-year follow-up. Severe side effects or drug abuse were not detected in this cohort. The long-term treatment outcome shows that stimulants are effective in adult ADHD and side effects tend to be mild.


Emerging Frontiers in Drug Delivery.
Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.


Effect of Preventive Chlamydia abortus Vaccination in Offspring Development in Sheep Challenged Experimentally.
Ovine enzootic abortion, caused by Chlamydia abortus, leads to important economic losses worldwide. In addition to reproductive failures, infection may impact lamb growth during the first weeks after birth, yet this effect has not been well characterized. Vaccination can help to control the disease but variable efficacy values have been described, possibly related with factors associated with the host, the vaccine, the parameter used for efficacy determination, and the challenge conditions. In this context, we evaluated the efficacy of an inactivated standard commercial vaccine and a 1/2 diluted dose in pregnant sheep challenged with C. abortus by examining multiple indicators of vaccine effect (including incidence of reproductive failures, bacterial excretion, and evolution of weight gain of viable lambs during the first month of life). Three groups of ewes [control non-vaccinated, C (n = 18); vaccinated with standard dose, SV (n = 16); and vaccinated with 1/2 dose, DV (n = 17)], were challenged approximately 90 days post-mating and tested using direct PCR (tissue samples and vaginal swabs) and ELISA (serum) until 31 days post-reproductive outcome. There were not significant differences in the proportions of reproductive failures or bacterial shedding after birth/abortion regardless the vaccination protocol. However, a beneficial effect of vaccination on offspring growth was detected in both vaccinated groups compared with the controls, with a mean increase in weight measured at 30 days of life of 1.5 and 2.5 kg (p = 0.056) and an increase in the geometric mean of the daily gain of 8.4 and 9.7% in lambs born from DV and SV ewes compared with controls, respectively. Our results demonstrate the effect of an inactivated vaccine in the development of the offspring of C. abortus-infected ewes at a standard and a diluted dose, an interesting finding given the difficulty in achieving sufficient antigen concentration in the production of enzootic abortion of ewes-commercial vaccines.


Ripples on rolandic spikes: A marker of epilepsy severity.
Children with rolandic spikes may or may not have seizures, ranging from benign rolandic epilepsy to severe atypical rolandic epilepsy. We investigated whether ripples (80-250 Hz), superimposed on rolandic spikes in surface electroencephalography (EEG), can differentiate between different entities. In this cohort study we analyzed the EEG studies of children with rolandic spikes without other EEG or magnetic resonance imaging (MRI) abnormalities. They were divided into the following three groups: (1) rolandic spikes but no epilepsy, (2) typical rolandic epilepsy, and (3) atypical and symptomatic rolandic epilepsy. Ripples superimposed on rolandic spikes were marked in 10 minutes of EEG, and compared to the number of seizures before the EEG. Receiver operating characteristic (ROC) curves were constructed to determine the predictive value of ripples and spikes for having epilepsy (groups 2 and 3) and for differentiating benign courses (groups 1 or 2) from atypical and symptomatic epilepsy (group 3). Ripples were also marked in the time frequency spectrum of averaged rolandic spikes. Ripples were found in 13 of 22 children. Children without epilepsy showed no ripples, except for a single child with only one ripple. The number of ripples showed a significant positive correlation with the number of seizures (ρ = 0.70, p = 0.001), whereas spikes had a borderline significant correlation (ρ = 0.43, p = 0.05). Presence of more than two ripples was a predictor for having seizures (area under the curve [AUC] 0.84), whereas spikes could not predict having seizures (AUC 0.53). More than five ripples predicted the difference between benign courses and atypical and symptomatic epilepsy (AUC 0.91, sensitivity 63%, specificity 100%). Ripples in the time frequency spectra appeared in all children and were not related to seizures. Absence of ripples on top of rolandic spikes predicts a relative benign clinical entity, whereas in the presence of several ripples, the child is likely to have more seizures than classical rolandic epilepsy, and pharmacologic treatment might be needed.


Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications.
Diabetic retinopathy (DR), commonly classified as a microvascular complication of diabetes, is now recognized as a neurovascular complication or sensory neuropathy resulting from disruption of the neurovascular unit. Current therapies for DR target the vascular complication of the disease process, including neovascularization and diabetic macular edema. Since neurodegeneration is an early event in the pathogenesis of DR, it will be important to unravel the mechanisms that contribute to neuroretinal cell death in order to develop novel treatments for the early stages of DR. In this review we comment on how inflammation, the metabolic derangements associated with diabetes, loss of neuroprotective factors, and dysregulated glutamate metabolism may contribute to retinal neurodegeneration during diabetes. Promising potential therapies based on these specific aspects of DR pathophysiology are also discussed. Finally, we stress the importance of developing and validating new markers of visual function that can be used to shorten the duration of clinical trials and accelerate the delivery of novel treatments for DR to the public.


In vitro adsorption of possible aetiological factors of hepatic encephalopathy.
Four different adsorbents (activated charcoal, XAD-4, a strong base anion and a strong acid cation-exchange resin) were tested in vitro for their capacity to remove substances that may be important in the development of hepatic encephalopathy. Separate columns packed with one of these adsorbents were perfused for three hours with a reconstituted plasma solution containing simultaneously high concentrations of amino-acids, ammoniumchloride, short-chain fatty acids, octopamine and bile salts. Effective removal of all these substances was only obtained when either activated charcoal, or XAD-4, were combined with the cation-exchange resin. Possible implications for the treatment of hepatic coma are discussed.


Histochemical localization of aldehyde dehydrogenase during rat hepatocarcinogenesis.
Significant changes in aldehyde dehydrogenase (ALDH) activity occur during chemically induced rat hepatocarcinogenesis. We have developed a procedure for the histochemical localization of hepatic ALDH which has proven extremely useful as an additional probe for studying changes in this enzyme during hepatocarcinogenesis. Frozen sections of fresh tissue were stained for ALDH using either propionaldehyde-NAD to detect normal liver ALDH or benzaldehyde-NADP to detect tumor ALDH. Histochemically, normal liver ALDH activity is strongly centrilobular with only slight periportal activity and produces a characteristic staining pattern. During hepatocarcinogenesis, ALDH staining patterns in grossly normal liver range from normal-appearing to patterns of distinct, intense focal hepatocyte staining with propionaldehyde-NAD and/or benzaldehyde-NADP. ALDH-positive foci are found both in normal regions of tumor-bearing livers and prior to the appearance of gross neoplasms. Neoplastic nodules and carcinomas possess a wide variety of ALDH staining patterns between and within lesions. Neoplasms with elevated ALDH activity with propionaldehyde-NAD and/or benzaldehyde-NADP, as well as with no detectable ALDH, have been observed. Changes in ALDH can be identified histochemically at a time in hepatocarcinogenesis when other analytical methods cannot detect significant changes. Moreover, considerable heterogeneity in expression of tumor ALDH is demonstrable by histochemistry.


Evaluation of end-to-side v end-to-end proximal anastomosis in aortobifemoral bypass.
The cumulative graft-limb patency rate was significantly higher after aortobifemoral bypass with a proximal end-to-end anastomosis (E-E-AN) than with a proximal end-to-side anastomosis (E-S-AN), 100% v 93%, respectively, after 1.5 years in a consecutive series of 38 E-S-ANs followed by 41 E-E-ANs. The two operations were equally effective in relieving hip claudication, but impotence occurred more frequently after E-E-AN (27%) than after E-S-AN (13%). This difference was not significant, but six of ten patients with E-E-AN who became impotent had arteriographic patterns predicting that graft flow into hypogastric arteries might be compromised. Intraoperative studies demonstrated that acute bilateral occlusion of hypogastric arteries significantly decreases penile BP, but branches of the external iliac arteries also contribute to penile flow and may become the major route of supply in patients with hypogastric occlusive disease.


Betulin-derived compounds as inhibitors of alphavirus replication.
This paper describes inhibition of Semliki Forest virus (SFV) replication by synthetic derivatives of naturally occurring triterpenoid betulin (1). Chemical modifications were made to OH groups at C-3 and C-28 and to the C-20-C-29 double bond. A set of heterocyclic betulin derivatives was also assayed. A free or acetylated OH group at C-3 was identified as an important structural contributor for anti-SFV activity, 3,28-di-O-acetylbetulin (4) being the most potent derivative (IC50 value 9.1 microM). Betulinic acid (13), 28-O-tetrahydropyranylbetulin (17), and a triazolidine derivative (41) were also shown to inhibit Sindbis virus, with IC50 values of 0.5, 1.9, and 6.1 microM, respectively. The latter three compounds also had significant synergistic effects against SFV when combined with 3'-amino-3'-deoxyadenosine. In contrast to previous work on other viruses, the antiviral activity of 13 was mapped to take place in virus replication phase. The efficacy was also shown to be independent of external guanosine supplementation.


Suppression of VMH-lesion-induced reactivity and aggressiveness in the rat by stimulation of lateral septum, but not medial septum or cingulate cortex.
Animals made vicious with bilateral ventromedial hypothalamic lesions had bipolar electrodes implanted unilaterally in the lateral septum, medial septum, or cingulate cortex. Four days later, the animals' reactivity and aggressiveness were evaluated 5 min before, during, and 5 min after stimulation at 20 micronA (60 Hz, sine wave). Lateral septal stimulation suppressed reactivity and aggressiveness by almost 80% compared with pre- and poststimulation levels. Stimulation of neither the cingulate cortex nor the medial septum produced a change reliably different from that seen in unstimulated control animals. Further tests with stimulation of the lateral septum at the 20-micronA level showed that neither rewarding self-stimulation nor disruption of ongoing water drinking was produced. These results are congruent with evidence from lesion studies that the lateral septum normally acts to suppress reactivity and aggressiveness in the rat; they do not support previous suggestions that the medial septum is involved in the modulation of these behaviors.


Bariatric surgery outcomes in a European Centre of Excellence (CoE).
Bariatric Surgery Centres of Excellence have been promoted by the International Federation for the Surgery of Obesity and Metabolic Disorders European Chapter to improve outcomes and security of patients. A retrospective analysis of our prospective database has been performed. Between May 2001 and September 2012, we operated on 690 patients, first with open gastric bypass (2001-2005), then laparoscopy (2006-2009), introduced robotics and finally the Centre of Excellence period (2012). Complication rate was 18.9 % in the first period and 3 % in the last. We reoperated on 9 % of patients in two early periods and none in the last. Mortality rate was 2, 0.85, 0.47 and 0 % in the four periods. Teams that are just at the beginning of their experience in bariatric surgery in order to avoid complications and deal with better long-term results.


Options for handling missing data in the Health Utilities Index Mark 3.
The Health Utilities Index Mark 3 (HUI3) is a tool composed of 41 questions, covering 8 attributes: vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. Responses to these questions can define more than 972,000 health situations. This tool allows respondents to answer "Don't Know," for which there is no scoring instruction, to any given question. This situation creates a break in the scoring algorithm and leads to considerable amounts of missing data. The goal of this study is to develop strategies to deal with HUI3 scores for participants who have missing data. The authors used data from 248 individuals enrolled in the Cataract Management Trial, focusing on the HUI3 vision and ambulation attributes, which had 19% and 10% of attribute levels missing, respectively. Inspection and deduction were used to fill in values independent of the value of the missing data, then alternative analytic techniques were compared, including mean substitution, model scoring, hot deck, multiple imputation, and regression imputation. Inspection and logical deduction reduced the percentage of missing information in the HUI3 by 49% to 87%. A comparison of analytic techniques used for the remaining HUI3 vision data missing demonstrated the value of building models based on internal response patterns and that simple analytic techniques fare as well as more complicated ones when the number of missing cases is small. Analyzing the pattern of responses in cases where the attribute level score is missing reduces the amount of missing data and can simplify the analytic process for the remaining missing data.