Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway.
Oncolytic adenoviruses are promising therapies for the treatment of gliomas. However, untargeted viral replication and the paucity of coxsackie-adenovirus receptors (CARs) on tumor cells are major stumbling blocks for adenovirus-based treatment. We studied the antiglioma activity of the tumor-selective Delta-24 adenovirus, which encompasses an early 1 A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, and of the Delta-24-RGD adenovirus. Delta-24-RGD has an RGD-4C peptide motif inserted into the adenoviral fiber, which allows the adenovirus to anchor directly to integrins. CAR and integrin expression were examined by flow cytometry in six glioma cell lines and in normal human astrocytes (NHAs). Adenoviral vectors containing green fluorescent protein (GFP) (AdGFP and AdGFP-RGD) were used to infect glioma cell lines with high or low CAR expression. Viability of glioma cells infected with different adenoviruses was assessed by trypan blue staining. Adenovirus replication was quantified with the infection-dose replication assay. Athymic mice carrying glioma xenografts received intratumoral injections of Delta-24-RGD or Delta-24 and were followed for survival, which was analyzed by the Kaplan-Meier method and the log-rank test. All statistical tests were two-sided. Half the glioma cell lines expressed low levels of CAR (defined as <50% of cells expressing detectable CAR); all lines expressed integrins in more than 50% of cells. Infection of U-87 MG cells (a low-CAR-expressing line) with AdGFP-RGD resulted in approximately six times more GFP-positive cells than infection with AdGFP. Delta-24-RGD was more cytopathic to both low- and high-CAR-expressing glioma lines than Delta-24, and it replicated more efficiently in both cell lines. In the xenografted mice, intratumoral injection of Delta-24-RGD was associated with longer survival than intratumoral injection of Delta-24 (P<.001, log-rank test). Furthermore, 60% of Delta-24-RGD-treated mice but only 15% of Delta-24-treated mice survived more than 4 months (difference = 45%, 95% CI = 21% to 68%). The antitumor activity of Delta-24-RGD suggests that it has the potential to be an effective agent in the treatment of gliomas.


Na+, K(+)-ATPase inhibitory activity of fractionated urine during changes in dietary sodium intake in man.
Na+, K(+)-ATPase inhibitory activity in urine fractionated by HPLC was quantified in 7 normotensive male subjects during changes in dietary sodium intake. Subjects were studied on free sodium intake for 2 days, on low sodium intake (2 g/day) for 3 days, on high sodium intake (22 g/day) for 4 days and subsequently on normal sodium intake (6 g/day) for 2 days. Na+, K(+)-ATPase inhibitory activity in fraction 10 eluted with 17% acetonitrile by reverse-phase HPLC was 12.3 +/- 5.2% (mean +/- S.D.) on free sodium intake, 8.7 +/- 9.8% on the 3rd day of low sodium intake, 61.2 +/- 6.6% on the 4th day of high sodium intake, and 20.5% +/- 0.7% on the 2nd day of the normal sodium intake. Changes in Na+, K(+)-ATPase inhibitory activity of fraction 10 were closely associated with those in urinary sodium excretion. These results suggest that an endogenous Na+, K(+)-ATPase inhibitor(s) which plays a physiological role in the control of sodium and water balance may exist in this particular fraction.


Inflammatory pseudotumour of the liver presenting with obstructive jaundice.
Inflammatory pseudotumours are rare benign tumours characterized by an inflammatory process and can occur in any system. We present a case of inflammatory pseudotumours of the liver presenting with obstructive jaundice due to a mass forming lesion in the left lobe of the liver which was treated by left hepatic lobectomy. Inflammatory pseudotumour of the liver is a benign lesion and diagnosis with an image examination is difficult. Surgical management depends on the location of the lesion. Peripheral hepatic pseudotumours may be treated with simple observation or conservative therapy. In contrast to this, those involving the porta hepatis require treatment for obstructive jaundice.


Involvement of mammalian liver cytosols and aldehyde oxidase in reductive metabolism of zonisamide.
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide), an anticonvulsant agent, is primarily metabolized to 2-sulfamoylacetylphenol by reductive cleavage of the 1,2-benzisoxazole ring. Rabbit liver cytosol with an electron donor of aldehyde oxidase exhibited a significant zonisamide reductase activity that was sensitive to inhibition by menadione, an inhibitor of aldehyde oxidase. The result suggested that the cytosolic activity is caused by aldehyde oxidase, a cytosolic enzyme. In fact, rabbit and rat liver aldehyde oxidase had the ability to reduce zonisamide when supplemented with its electron donor. Apparent KM and Vmax values of aldehyde oxidase for zonisamide were 217 microM and 42 nmol/10 min/mg protein in the case of the rabbit liver enzyme, and 542 microM and 382 nmol/10 min/mg protein in the case of the rat liver enzyme, respectively. In rabbits, hamsters, mice, and guinea pigs, zonisamide reductase activity of the liver cytosols with 2-hydroxypyrimidine, an electron donor of aldehyde oxidase, was much higher than that of the liver microsomes with NADPH. In rats, zonisamide reductase activity was examined with liver microsomes and cytosols from seven strains. The 2-hydroxypyrimidine-dependent cytosolic activity exhibited marked strain differences, unlike the NADPH-dependent microsomal activity. 1,2-Benzisoxazole was also reduced to salicylaldehyde by rabbit liver cytosol and aldehyde oxidase in the presence of 2-hydroxypyrimidine. Stoichiometric studies showed that 2-sulfamoylacetylphenol was formed accompanying nearly equimolar ammonia from zonisamide.


Deformational Plagiocephaly: A Review.
Deformational plagiocephaly (DP) is a common condition and the leading cause of head shape abnormalities in infants. It is characterized by asymmetrical distortion of the skull resulting from external forces on the back of the head. DP has become more prevalent in infants and has increased dramatically since the introduction in 1994 of the "Back to Sleep" campaign. Management of this condition is not often covered by insurance, and can be costly and lengthy; However, DP can be prevented. Early recognition and management can make a significant difference in patients' outcomes and reduce the cost of treatment. Nurses play a key role in recognition and prevention, are instrumental in educating parents and caregivers, and have a significant impact on preventing and reducing the risk of DP. Current systematic approaches to clinical assessment, diagnosis, and management strategies of DP can help nurses who care for infants and their families understand DP and take the necessary steps to prevent it.


mTORC1/rpS6 and spermatogenic function in the testis-insights from the adjudin model.
mTORC1/rpS6 signaling complex promoted Sertoli blood-testis barrier (BTB) remodeling by perturbing Sertoli cell-cell adhesion site known as the basal ectoplasmic specialization (ES). mTORC1/rpS6 complex also promoted disruption of spermatid adhesion at the Sertoli-spermatid interface called the apical ES. Herein, we performed analyses using the adjudin (a non-hormonal male contraceptive drug under development) model, wherein adjudin was known to perturb apical and basal ES function when used at high dose. Through direct administration of adjudin to the testis, adjudin at doses that failed to perturb BTB integrity per se, overexpression of an rpS6 phosphomimetic (i.e., constitutively active) mutant (i.e., p-rpS6-MT) that modified BTB function considerably potentiated adjudin efficacy. This led to disorderly spatial expression of proteins necessary to maintain the proper cytoskeletal organization of F-actin and microtubules (MTs) across the seminiferous epithelium, leading to germ cell exfoliation and aspermatogenesis. These findings yielded important insights regarding the role of mTORC1/rpS6 signaling complex in regulating BTB homeostasis.


A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia.
Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS+IFNγ-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNγ-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5-4μM) significantly (p <0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling.


Hydrochemical data on groundwater quality for drinking and irrigation use around Dangila town, Northwest Ethiopia.
The groundwater of volcanic aquifers, dissected by various structures and affected by several volcanic eruption events, varies in quality. A large number of rural people depend on shallow aquifers tapped by shallow hand wells and springs. On the other hand, the urban population is dependant on deep aquifers using drilled boreholes. The location of springs, shallow hand-dug wells and boreholes inside or close to farmlands, and the advancement of irrigation water use from groundwater by the government entail the assessment of groundwater quality. Therefore, the focus of the present study is to determine the quality and suitability of groundwater around Dangila Town, Northwest Ethiopia, for drinking and irrigation uses. The water quality assessment was conducted by collecting groundwater samples from 14 shallow hand-dug wells, 4 springs, and 7 deep boreholes then analysing for different physical and chemical parameters. A total of 25 selected groundwater samples from shallow and deep aquifers were analysed in a laboratory for physical and chemical parameters. The physical parameters measured both in the field and the laboratory included pH, electrical conductivity (EC) and total dissolved solids (TDS). The chemical parameters analysed in the laboratory comprised cations of calcium (Ca2+), magnesium (Mg2+), sodium (Na+), potassium (K +), Iron (Fe), manganese (Mn2+) and anions of bicarbonate (HCO3 -), sulfate (SO4 2-), carbonate (CO3 2-), chlorine (Cl-), nitrate (NO3 -), fluoride (F-), and boron (B). Based on the laboratory results, the variation in groundwater facies, and major cation and anion sources were determined. Furthermore, the groundwater quality for human consumption was assessed and sodium adsorption ratio (SAR), Na%, and the residual sodium carbonate (RSC) values, which are crucial to determine the overall groundwater quality for irrigational uses, were calculated. Detailed interpretations of the data have been presented in the paper entitled "Hydrogeological framework of the volcanic aquifers and groundwater quality in Dangila Town and the surrounding area, Northwest Ethiopia" [1]. The presented dataset demonstrates the necessity of water quality assessments that would be helpful to water sectors, government, and policymakers for sustainable groundwater management.


The Evolving Role of Rituximab in Adult Minimal Change Glomerulopathy.
Minimal-change glomerulopathy is defined histologically by the presence of normal glomeruli on light microscopy and diffuse podocyte effacement on electron microscopy. Although effective in children, corticosteroid treatment in adults is more variable and time to response can be prolonged. Data to support rituximab use in adults with corticosteroid-dependent or resistant minimal-change glomerulopathy are limited. Here, we describe the clinical course of adults with corticosteroid-dependent or -resistant minimal-change glomerulopathy who received rituximab. Demographic and clinical data were collected and analyzed from all adult patients with native kidney, biopsy-proven, minimal-change glomerulopathy who were administered rituximab between 2009 and 2014 and cared for at the UNC Kidney Center. Ten patients with corticosteroid-resistant (n = 5) or corticosteroid-dependent (n = 5) idiopathic minimal-change glomerulopathy were treated with rituximab between 2009 and 2014. Rituximab treatment induced remission in all 10 patients with a median time to remission of 2 months. The median time from rituximab to corticosteroid discontinuation was 3.5 months. The median remission time was 29 months and follow-up time was 39.5 months. No serious adverse events attributable to rituximab were observed. Rituximab induced remission in all patients with corticosteroid-dependent or -resistant minimal-change glomerulopathy, and may hold great therapeutic potential with good efficacy and minimal toxicity. Mounting evidence implies that a well-conducted randomized controlled clinical trial using rituximab in adults with minimal-change glomerulopathy in both corticosteroid-resistant and corticosteroid-dependent patients is warranted.


Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus.
Vertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates. To address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age. As expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines. Our data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.


Plasma concentrations of midazolam in neonates receiving extracorporeal membrane oxygenation.
Drug disposition is affected during extracorporeal membrane oxygenation (ECMO). This study investigates the dose-concentration relationship of midazolam in neonates requiring ECMO during continuous infusion into the circuit (extracorporeally; n = 10) and intravenously (n = 10). Data on hourly doses and sedation scores were collected for 120 hours. Plasma concentrations were analyzed at times 0, 2, 4, 6, 12, 18, and 24, and every 12 hours thereafter. Both groups were clinically similar. Mean (standard deviation) dose for all patients was 250 (185) microg/kg/h, four times greater than previously reported. Doses administered in the first 24 hours were significantly greater extracorporeally [361 (300)] compared with intravenous [258 (190) microg/kg/h, p < 0.001]. Mean (standard deviation) plasma concentrations in all patients at 24, 48, and 72 hours were 1.4 (0.9), 1.8 (1.2), and 2.6 (1.8) microg/ml, respectively. Satisfactory sedation levels were achieved in all patients. Comparison of the actual observed with predicted (simulated) midazolam concentrations suggested significant attenuation of plasma levels during the first 24 hours of ECMO. However, at 48 hours, observed concentrations exceeded those predicted, suggesting accumulation. We conclude that in the first 24 hours of ECMO, because of an expanded circulating volume and sequestration by the circuit, significantly more midazolam is required to achieve adequate sedation. Subsequently, and because of circuit saturation, maintenance doses should be reduced.


Transmitting the message: intracellular mRNA localization.
The intracellular localization of mRNA is an important mechanism for targeting proteins to their sites of function. Localized transcripts play key roles ranging from body axis determination to synapse plasticity, and recent studies highlight how common localized transcripts are in a variety of model organisms. In this review, we consider the full range of known mechanisms for delivering transcripts and anchoring them at their site of function. Finally, we evaluate the progress that has been made in the nervous system in understanding the mechanism and function of mRNA localization and translation regulation.


Comparison of traditional and low sensitivity whiteners.
This placebo-controlled, double-blind randomized clinical trial compared five 10% carbamide peroxide tooth whitening formulations. Three products contained varying concentrations of potassium nitrate as desensitizers. One contained no desensitizers and one was a placebo. During the two weeks of active bleaching, participants used a daily diary to record the number of days of sensitivity from hot, cold, gums, tongue and/or throat. The total number of days of sensitivity experienced by the participants in each group was compared. Participants using the agent with no desensitizers did not experience any more sensitivity than those using the agent containing 3% potassium nitrate. The products that included 0.5% potassium nitrate and 0.5% potassium nitrate and 0.25% sodium fluoride were not associated with any more sensitivity than the placebo group. In addition, the shade tab change from baseline to 11 weeks following cessation of bleaching was compared. Using an active bleaching agent, no difference in color change was noted among the four groups. All four groups were associated with significantly higher color change than the placebo. The addition of a small percentage of potassium nitrate to a 10% carbamide peroxide tooth whitener was shown to significantly reduce postoperative sensitivity without reducing efficacy.


Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome.
Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivoSIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.


The role of family therapy in the management of schizophrenia: challenges and solutions.
Family interventions for schizophrenia have been amply demonstrated to be effective and are recommended by most of the international clinical guidelines. However, their implementation in the clinical setting as well as in treatment protocols of patients with psychosis has not been fully achieved yet. With the increasing deinstitutionalization of patients, family has begun to assume the role of care performed by psychiatric hospitals, with a high emotional cost for caregivers as well as the recognition of burden experiences. Families have been the substitute in the face of the scarcity of therapeutic, occupational, and residential resources. For this reason, the viability of patients' care by their families has become a challenge. This article aims to discuss the most important aspects of family interventions, their impact on families, and the most important challenges that need to be overcome in order to achieve well-being and recovery in both patients and caregivers.


Implementing Legislation to Improve Hospital Support of Breastfeeding, New York State, 2009-2013.
Increasing breastfeeding is a public health priority supported by strong evidence. In 2009, New York passed Public Health Law § 2505-a, requiring that hospitals support the World Health Organization's (WHO's) recommended "Ten Steps for Successful Breastfeeding" (Ten Steps). This legislation strengthened and codified existing New York State's hospital perinatal regulations. The purpose of this study was to assess hospital policy compliance with New York laws and regulations related to breastfeeding. In 2009, 2011, and 2013, we collected written breastfeeding policies from 129 New York hospitals that provided maternity services. A policy review tool was developed to quantify compliance with the 28 components of breastfeeding support specified in New York Codes, Rules, and Regulations and the new legislation. In 2010 and 2012, hospitals received individual feedback from the New York State Department of Health, which informed hospitals in 2012 that formal regulatory enforcement, including potential fines, would be implemented for noncompliance. The number of components included in hospital policies increased from a mean of 10.4 in 2009, to 16.8 in 2011, and to 27.1 in 2013) (P < .001); a greater increase occurred from 2011 through 2013 than from 2009 through 2011 (P < .001). The percentage of hospitals with fully compliant policies increased from 0% in 2009, to 5% in 2011, and to 75% in 2013 (P < .001), and the percentage that included all WHO's 10 steps increased from 0% to 9% to 87%, respectively (P < .001). Although legislation or regulations requiring certain practices are important, monitoring with enforcement accelerates, and may be necessary for, full implementation. Future research is needed to evaluate the impact of improved hospital breastfeeding policies on breastfeeding outcomes in New York.


No millipede endemics north of the Alps? DNA-Barcoding reveals Glomeris malmivaga Verhoeff, 1912 as a synonym of G. ornata Koch, 1847 (Diplopoda, Glomerida, Glomeridae).
In order to evaluate the status of the only species of pill millipede (Glomerida) endemic to Germany, Glomeris malmivaga Verhoeff, 1912, a DNA barcoding study based on the COI mitochondrial gene was conducted. Sequences of G. malmivaga were compared to those of G. ornata Koch, 1847 from Slovenia, of which the former was previously described as a variety of the latter before being elevated to subspecies- and, recently, species-rank. Included in the analysis were specimens of G. helvetica Verhoeff, 1894, also originally described as a variety of G. ornata, which was supposed to be closely related to G. malmivaga based on its morphology, as well as geographical proximity of occurrence. Additionally, G. valesiaca Rothenbühler, 1899, which occurs in sympatry and looks quite similar to G. helvetica was also sequenced for the first time and included in the study. Sequences of four widespread Glomeris species, all occurring in close proximity to G. malmivaga, G. marginata Villers, 1789, G. connexa Koch, 1847, G. klugii Brandt, 1833 and G. intermedia Latzel, 1884 were downloaded from Genbank and incorporated in the analysis. While G. helvetica and G. valesiaca were found to be clearly separate from G. ornata (11.8-14.6% p-distance), G. malmivaga is almost identical to the latter (0.5% p-distance), despite the large geographical distance between both species. Because of their great morphological and genetical similarity, G. malmivaga n. syn. is synonymised under G. ornata.


Tanshinon IIA injection accelerates tissue expansion by reducing the formation of the fibrous capsule.
The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR), which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA) has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and transforming growth factor-β (TGF-β) were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.


Stabilization of antibody structure upon association to a human carbonic anhydrase IX epitope studied by X-ray crystallography, microcalorimetry, and molecular dynamics simulations.
Specific antibodies interfere with the function of human tumor-associated carbonic anhydrase IX (CA IX), and show potential as tools for anticancer interventions. In this work, a correlation between structural elements and thermodynamic parameters of the association of antibody fragment Fab M75 to a peptide corresponding to its epitope in the proteoglycan-like domain of CA IX, is presented. Comparisons of the crystal structures of free Fab M75 and its complex with the epitope peptide reveal major readjustments of CDR-H1 and CDR-H3. In contrast, the overall conformations and positions of CDR-H2 and CDR-L2 remain unaltered, and their positively charged residues may thus present a fixed frame for epitope recognition. Adoption of the altered CDR-H3 conformation in the structure of the complex is accompanied by an apparent local stabilization. Analysis of domain mobility with translation-libration-screw (TLS) method shows that librations of the entire heavy chain variable domain (V(H)) decrease and reorient in the complex, which correlates well with participation of the heavy chain in ligand binding. Isothermal titration microcalorimetry (ITC) experiments revealed a highly unfavorable entropy term, which can be attributed mainly to the decrease in the degrees of freedom of the system, the loss of conformational freedom of peptide and partially to a local stabilization of CDR-H3. Moreover, it was observed that one proton is transferred from the environment to the protein-ligand complex upon binding. Molecular dynamics simulations followed by molecular mechanics/generalized Born surface area (MM-GBSA) calculations of the ligand (epitope peptide) binding energy yielded energy values that were in agreement with the ITC measurements and indicated that the charged residues play crucial role in the epitope binding. Theoretical arguments presented in this work indicate that two adjacent arginine residues (ArgH50 and ArgH52) are responsible for the observed proton transfer.


The regulation of SV40 early gene expression in embryonal carcinoma stem cells--faithful transcriptional regulation in vitro.
We have derived from F9 murine embryonal carcinoma stem cells, and from differentiated derivatives induced with retinoic acid and cAMP, whole cell extracts which efficiently and accurately transcribe a variety of supercoiled DNA templates in vitro. These extracts and control elements from viral genomes have been used to study changes in transcriptional activity which accompany differentiation. The SV40 enhancer is inefficiently utilized in stem cells but is activated upon differentiation to parietal endoderm and the in vitro systems mimick this regulation. Mixing experiments demonstrate that the differentiated cell phenotype is dominant, suggesting that stem cells contain limiting amounts of factors required for enhancer activity. Our results may explain the developmental regulation of cellular genes with enhancer motifs in their control sequences.


Alcohol Consumption, Athlete Identity, and Happiness Among Student Sportspeople as a Function of Sport-Type.
To examine the differences in alcohol consumption and psychosocial antecedents between team and individual sportspeople via secondary data analysis. Questionnaires measured alcohol consumption, athlete identity and subjective happiness from a sample of UK university sportspeople (N = 1785; male = 1048, 58.7%), involved in team (77.9%) and individual sports. Team sports players were more likely to be categorized as hazardous drinkers, and reported significantly greater rates of alcohol consumption, stronger athlete identity and higher levels of happiness than individual sports players. Athlete identity was a significant predictor for alcohol consumption, however there was no significant relationship found between happiness and consumption. Further regression analyses revealed interactions between sport-type and athlete identity on alcohol consumption. For individual sport players, as athlete identity increased alcohol consumption significantly reduced; however, there was a positive association between identity and consumption for team sport players. Our findings implicate the role of identity as an important factor to consider when addressing the issue of hazardous drinking among sportspeople.


Why do patients get idiopathic pulmonary fibrosis? Current concepts in the pathogenesis of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown origin. Recent findings suggest that IPF results from multiple factors that eventually lead to interstitial lung injury. In the pathogenesis it is likely that complex relationships between genetic predispositions, environmental exposures, and lung infections promote the fibrotic processes causing IPF; it is this complexity and the multiplicity of causes that make the population and clinical course of IPF so heterogeneous. Thus, it is clear that one common factor driving IPF pathogenesis in all patients would be far too simplified of an understanding. In recent years, efforts have been made in finding therapeutic strategies that target disease progression rather than disease onset. The biochemical composition and abnormal stiffness of the matrix might be crucial in controlling the cellular phenotype in fibrotic lungs that promotes disease progression and persistence. Though there has been substantial progress in the IPF field in recent years, much more work is required in order to improve the prognosis associated with this disease.


Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. NCT01218802.


Survival of patients treated with intra-aortic balloon counterpulsation at a tertiary care center in Pakistan - patient characteristics and predictors of in-hospital mortality.
Intra-aortic balloon counterpulsation (IABC) has an established role in the treatment of patients presenting with critical cardiac illnesses, including cardiogenic shock, refractory ischemia and for prophylaxis and treatment of complications of percutaneous coronary interventions (PCI). Patients requiring IABC represent a high-risk subset with an expected high mortality. There are virtually no data on usage patterns as well as outcomes of patients in the Indo-Pakistan subcontinent who require IABC. This is the first report on a sizeable experience with IABC from Pakistan. Hospital charts of 95 patients (mean age 58.8 (+/- 10.4) years; 78.9% male) undergoing IABC between 2000-2002 were reviewed. Logistic regression was used to determine univariate and multivariate predictors of in-hospital mortality. The most frequent indications for IABC were cardiogenic shock (48.4%) and refractory ischemia (24.2%). Revascularization (surgical or PCI) was performed in 74 patients (77.9%). The overall in-hospital mortality rate was 34.7%. Univariate predictors of in-hospital mortality included (odds ratio [95% CI]) age (OR 1.06 [1.01-1.11] for every year increase in age); diabetes (OR 3.68 [1.51-8.92]) and cardiogenic shock at presentation (OR 4.85 [1.92-12.2]). Furthermore, prior CABG (OR 0.12 [0.04-0.34]), and in-hospital revascularization (OR 0.05 [0.01-0.189]) was protective against mortality. In the multivariate analysis, independent predictors of in-hospital mortality were age (OR 1.13 [1.05-1.22] for every year increase in age); diabetes (OR 6.35 [1.61-24.97]) and cardiogenic shock at presentation (OR 10.0 [2.33-42.95]). Again, revascularization during hospitalization (OR 0.02 [0.003-0.12]) conferred a protective effect. The overall complication rate was low (8.5%). Patients requiring IABC represent a high-risk group with substantial in-hospital mortality. Despite this high mortality, over two-thirds of patients do leave the hospital alive, suggesting that IABC is a feasible therapeutic device, even in a developing country.


Low-temperature atomic layer deposition of crystalline manganese oxide thin films.
We present a new low-temperature atomic layer deposition (ALD) process based on Mn2(CO)10 and ozone as precursors to fabricate crystalline α-Mn2O3 and Mn3O4 thin films; the phase composition is controlled by the deposition temperature such that the former phase forms in the range 60-100 °C and the latter in the range 120-160 °C. In both cases an appreciably high growth rate of ∼1.2 Å per cycle is achieved. The spinel-structured Mn3O4 thin films are shown to be ferrimagnetic with the transition temperature determined to be at ∼47 K.


Assessment of Masseter Muscle Appearance and Thickness in Edentulous and Dentate Patients by Ultrasonography.
The purpose of the present study was to examine ultrasonographic appearances of Masseter Muscle (MM) in dentate and edentulous patients without Temporomandibular Disorder (TMD). The thickness of the MM in 25 dentate (mean age: 30,68 ± 10,49) and 24 edentulous (mean age: 61,46 ± 9,71) patients, who visited routine dental examination, was measured at rest and at maximum contraction bilaterally. Examinations were performed using an Aloka Prosound α6 (Hitachi Aloka Medical Systems, Tokyo, Japan) equipped with an 8 MHz-wide bandwidth linear active matrix transducer (ranging from 1 to 15 MHz). The visibility and width of the internal echogenic bands of the MM were also assessed and the muscle appearance was classified as I of III types. Type I, characterized by the clear visibility of the fine bands; Type II, thickening echogenicity of the bands; Type III, disappearance or reduction in a number of the bands. MM thickness at rest and contraction in the dentate group were significantly higher than the edentulous group (p <0.05). Type I was the most common echogenic type in both dentate (right:16 (64%), left; 15 (60%)) and edentulous patients (right; 22 (91.7%), left; 18 (75%)). In a dentate group, type II was significantly higher than the edentulous group in both the right and left sides (p <0.05; p <0.01, respectively). Age and gender seemed to have no significant effect on the echogenic type (p ˃0.05). There were significant differences in the thickness at rest and contraction between the dentate and edentulous groups. It was clarified that ultrasonographic features of the MM in dentate and edentulous patients were different.


Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model.
Accumulating evidence demonstrates the important role of oxytocin (OT) in the modulation of social cognition and behavior. This has led many to suggest that the intranasal administration of OT may benefit psychiatric disorders characterized by social dysfunction, such as autism spectrum disorders and schizophrenia. Here, we review nasal anatomy and OT pathways to central and peripheral destinations, along with the impact of OT delivery to these destinations on social behavior and cognition. The primary goal of this review is to describe how these identified pathways may contribute to mechanisms of OT action on social cognition and behavior (that is, modulation of social information processing, anxiolytic effects, increases in approach-behaviors). We propose a two-level model involving three pathways to account for responses observed in both social cognition and behavior after intranasal OT administration and suggest avenues for future research to advance this research field.


Update on bacteraemia in oncology and hematology.
The present article is an update of the literature on bacteraemia in onco-hematologic patients. A multidisciplinary group of Spanish physicians with an interest in this field selected the most important papers published recently. Papers from the fields of basic science, epidemiology, causative microorganisms and clinical syndromes are discussed. Important aspects of these studies include the assessment of different strategies in the management of fever in neutropenic patients and the validation of specific scores. Moreover, early identification of patients at risk of bacterial and of multi-drug resistant infections is a topic of increasing interest.


Executive dysfunction and autobiographical memory retrieval in recovered depressed women.
Depressed individuals have difficulty remembering specific autobiographical events. These deficits often persist after recovery of mood symptoms, but the mechanisms underlying impaired memory specificity in recovered depressed individuals remain unclear. Here, we sought to examine whether performance on two cognitive measures might be related to deficits in autobiographical memory retrieval in individuals with a history of depression. Twenty-four recovered depressed women (12 with more than one previous episode) and 24 never depressed women completed two cognitive measures (Digit Span and a Number Generation Task) and tests of autobiographical memory recall. Overall, the recovered depressed women did not show deficits in autobiographical retrieval. However, those with more than one previous episode had impaired retrieval of categorical autobiographical memories. Moreover, depression history moderated the relationship between Digit Span and retrieval of categoric autobiographical memories such that within the whole recovered depressed group (but not the never depressed group), those with lower Digit Span also had poorer retrieval of categorical autobiographical memories. Our sample size was small and included only women. Moreover, order effects may have been a significant factor. These findings support the notion that working memory is an important factor in impairing autobiographical memory in those who have recovered from depression, but suggest a complex relationship with autobiographical recall.


Ethnic density effects on health and experienced racism among Caribbean people in the US and England: a cross-national comparison.
Studies indicate an ethnic density effect, whereby an increase in the proportion of racial/ethnic minority people in an area is associated with reduced morbidity among its residents, though evidence is varied. Discrepancies may arise due to differences in the reasons for and periods of migration, and socioeconomic profiles of the racial/ethnic groups and the places where they live. It is important to increase our understanding of how these factors might promote or mitigate ethnic density effects. Cross-national comparative analyses might help in this respect, as they provide greater heterogeneity in historical and contemporary characteristics in the populations of interest, and it is when we consider this heterogeneity in the contexts of peoples' lives that we can more fully understand how social conditions and neighbourhood environments influence the health of migrant and racial/ethnic minority populations. This study analysed two cross-sectional nationally representative surveys, in the US and in England, to explore and contrast the association between two ethnic density measures (black and Caribbean ethnic density) and health and experienced racism among Caribbean people. Results of multilevel logistic regressions show that nominally similar measures of ethnic density perform differently across health outcomes and measures of experienced racism in the two countries. In the US, increased Caribbean ethnic density was associated with improved health and decreased experienced racism, but the opposite was observed in England. On the other hand, increased black ethnic density was associated with improved health and decreased experienced racism of Caribbean English (results not statistically significant), but not of Caribbean Americans. By comparing mutually adjusted Caribbean and black ethnic density effects in the US and England, this study examined the social construction of race and ethnicity as it depends on the racialised and stigmatised meaning attributed to it, and the association that these different racialised identities have on health.


Signals from the embryonic mouse pancreas induce differentiation of human embryonic stem cells into insulin-producing beta-cell-like cells.
The recent success in restoring normoglycemia in type 1 diabetes by islet cell transplantation indicates that cell replacement therapy of this severe disease is achievable. However, the severe lack of donor islets has increased the demand for alternative sources of beta-cells, such as adult and embryonic stem cells. Here, we investigate the potential of human embryonic stem cells (hESCs) to differentiate into beta-cells. Spontaneous differentiation of hESCs under two-dimensional growth conditions resulted in differentiation of Pdx1(+)/Foxa2(+) pancreatic progenitors and Pdx1(+)/Isl1(+) endocrine progenitors but no insulin-producing cells. However, cotransplantation of differentiated hESCs with the dorsal pancreas, but not with the liver or telencephalon, from mouse embryos resulted in differentiation of beta-cell-like cell clusters. Comparative analysis of the basic characteristics of hESC-derived insulin(+) cell clusters with human adult islets demonstrated that the insulin(+) cells share important features with normal beta-cells, such as synthesis (proinsulin) and processing (C-peptide) of insulin and nuclear localization of key beta-cell transcription factors, including Foxa2, Pdx1, and Isl1.


Plasma miRNA-506 as a Prognostic Biomarker for Esophageal Squamous Cell Carcinoma.
BACKGROUND MicroRNAs (miRNAs) are responsible for regulating proliferation, differentiation, apoptosis, invasion, and metastasis in tumor cells. miRNA-506 is abnormally expressed in multiple tumors, indicating that it might be oncogenic or tumor-suppressive. However, little is known about the association between miRNA-506 expression and esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS We examined the expression of miRNA-506 in the plasma of ESCC patients using quantitative real-time polymerase chain reaction (qRT-PCR) to determine the association between miRNA-506 expression and clinicopathological features of ESCC. ROC curves were produced for ESCC diagnosis by plasma miRNA-506 and the area under curve was calculated to explore its diagnostic value. RESULTS Average miRNA-506 expression levels were remarkably higher in the plasma of ESCC patients than in healthy volunteers (P<0.001). The expression of miRNA-506 in the plasma was closely associated with lymph node status (P=0.004), TNM stage (P=0.031), and tumor length (P<0.001). According to ROC curves, the area under the curve for plasma miRNA-506 was 0.835, indicating statistical significance for ESCC diagnosis by plasma miRNA-506 (P<0.001). Kaplan-Meier analysis showed that patients with high miRNA-506 expression had significantly shorter survival time than those with low miRNA-506 expression. Cox regression analysis demonstrated that T stage, N stage, tumor length, and miRNA-506 expression levels were significantly correlated with prognosis in ESCC patients. CONCLUSIONS miRNA-506 can serve as an important molecular marker for diagnosis and prognostic prediction of ESCC.


Indicators Used to Assess the Impact of Specialized Pediatric Palliative Care: A Scoping Review.
Specialized pediatric palliative care programs aim to improve quality of life and ease distress of patients and their families across the illness trajectory. These programs require further development, which should be based on how they improve outcomes for patients, families, health care professionals, and the health care system. To identify and compare definitions of indicators used to assess the impact of specialized pediatric palliative care programs. The scoping review protocol was prospectively registered on PROSPERO 2017 (CRD42017074090). MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL, Scopus, and Embase databases were searched from January 2000 to September 2018. Eligible studies included randomized controlled trials, experimental studies, or observational studies that compared specialized programs with usual care. Studies were excluded if most care recipients were older than 19 years or the article was not available in English, French, German, or Spanish. Forty-six studies were included; one was a randomized controlled trial. We identified 82 different indicators grouped into 14 domains. The most common indicators included the following: location of death, length of stay in hospital, and number of hospital admissions. Only 22 indicators were defined identically in at least 2 studies. Only one study included children's perspectives in assessing indicators. Many indicators were used to assess program outcomes with little definition consensus across studies. Development of a set of agreed-upon indicators to assess program impact concurrent with family and patient input is essential to advance research and practice in pediatric palliative care.


Inclusive inheritance for residual feed intake in pigs and rabbits.
Non-genetic information (epigenetic, microbiota, behaviour) that results in different phenotypes in animals can be transmitted from one generation to the next and thus is potentially involved in the inheritance of traits. However, in livestock species, animals are selected based on genetic inheritance only. The objective of the present study was to determine whether non-genetic inherited effects play a role in the inheritance of residual feed intake (RFI) in two species: pigs and rabbits. If so, the path coefficients of the information transmitted from sire and dam to offspring would differ from the expected transmission factor of 0.5 that occurs if inherited information is of genetic origin only. Two pigs (pig1, pig2) and two rabbits (rabbit1, rabbit2) datasets were used in this study (1,603, 3,901, 5,213 and 4,584 records, respectively). The test of the path coefficients to 0.5 was performed for each dataset using likelihood ratio tests (null model: transmissibility model with both path coefficients equal to 0.5, full model: unconstrained transmissibility model). The path coefficients differed significantly from 0.5 for one of the pig datasets (pig2). Although not significant, we observed, as a general trend, that sire path coefficients of transmission were lower than dam path coefficients in three of the datasets (0.46 vs 0.53 for pig1, 0.39 vs 0.44 for pig2 and 0.38 vs 0.50 for rabbit1). These results suggest that phenomena other than genetic sources of inheritance explain the phenotypic resemblance between relatives for RFI, with a higher transmission from the dam's side than from the sire's side.


Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons.
The Mas-related G-protein-coupled receptor D (Mrgprd) marks a distinct subset of sensory neurons that transmit polymodal nociceptive information from the skin epidermis to the substantia gelatinosa (SG, lamina II) of the spinal cord. Moreover, Mrgprd-expressing (Mrgprd(+)) neurons are required for the full expression of mechanical but not thermal nociception. While such anatomical and functional specificity suggests Mrgprd(+) neurons might synapse with specific postsynaptic targets in the SG, precisely how Mrgprd(+) neurons interface with spinal circuits is currently unknown. To study circuit connectivity, we genetically targeted the light-activated ion channel Channelrhodopsin-2-Venus (ChR2-Venus) to the Mrgprd locus. In these knock-in mice, ChR2-Venus was localized to nonpeptidergic Mrgprd(+) neurons and axons, while peptidergic CGRP(+) neurons were not significantly labeled. Dissociated Mrgprd(+) DRG neurons from mice expressing one or two copies of ChR2-Venus could be activated in vitro as evidenced by light-evoked currents and action potentials. In addition, illumination of Mrgprd-ChR2-Venus(+) axon terminals in spinal cord slices evoked EPSCs in half of all SG neurons. Within this subset, Mrgprd(+) neurons were monosynaptically connected to most known classes of SG neurons, including radial, tonic central, transient central, vertical, and antenna cells. This cellular diversity ruled out the possibility that Mrgprd(+) neurons innervate a dedicated class of SG neuron. Our findings set broad constraints on the types of spinal neurons that process afferent input from Mrgprd(+) polymodal nociceptors.


Refinement of particle detection by the hybrid method in digital in-line holography.
Digital in-line holography provides simultaneous particle size and three-dimensional position measurements. In general, the measurement accuracy varies locally, and tends to decrease where particles are closely spaced, due to noise resulting from diffraction by adjacent particles. Aggravating the situation is the identification of transversely adjoining particles as a single particle, which introduces significant errors in both size and position measurements. Here, we develop a refinement procedure that distinguishes such erroneous particles from accurately detected ones and further separates individual particles. Effectiveness of the refinement is characterized using simulations, experimental holograms of calibration fields, and a few practical applications to liquid breakup. Significant improvements in the accuracy of the measured particle sizes, positions, and displacements confirm the usefulness of the proposed method.


The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3.
We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045×10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563×10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526×10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8.


Overexpression of manganese superoxide dismutase gene changes the metastasis associated-character of the mouse fibrosarcoma, FSa-II.
The tumor metastatic ability and tumorigenicity of the mouse fibrosarcoma cell line (FSa-II) were significantly reduced due to overexpression of manganese superoxide dismutase (MnSOD) as reported previously. We investigated changes in the in vitro basic character of FSa-II cells transfected with the human MnSOD cDNA which was employed in the previous studies. FSa-II and the control vector-transfected cell line NEO, had no detectable MnSOD activity. SOD-H, into which MnSOD cDNA was transfected, is the cell line with high MnSOD activity. The malignant phenotype, characterized by serum-independence, was suppressed with elevated MnSOD activity. A quantitative comparison of transferrin receptor (TfR) by flow cytometry showed the amount of TfR on the membrane of SOD-H cells to be significantly less than that on the membrane of NEO cells. The amount of CD44 expression on SOD-H cells was almost the same as that on NEO cells. The results of this study suggest that the overexpression of MnSOD is related to suppression of the malignant phenotype and that changes of iron metabolism may play an important role in this process.


Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs.
A susceptibility locus for schizophrenia in the 'pseudo-autosomal' region has been proposed on the basis of the reported excess of sex-chromosome aneuploidies (e.g. XXY and XXX) among patients with schizophrenia and the finding that schizophrenic sib-pairs are more often of the same than of the opposite sex. This hypothesis has been tested in 83 sibships with two or more siblings fulfilling Research Diagnostic Criteria for schizophrenia or schizoaffective disorder. Alleles at the pseudo-autosomal telomeric locus DXYS14, which is unlinked with sex, were analysed using the method of affected sib-pairs. Affected sibs shared alleles at DXYS14 more frequently than expected by random Mendelian assortment, supporting genetic linkage between DXYS14 and schizophrenia.


Inference under Covariate-Adaptive Randomization.
This paper studies inference for the average treatment effect in randomized controlled trials with covariate-adaptive randomization. Here, by covariate-adaptive randomization, we mean randomization schemes that first stratify according to baseline covariates and then assign treatment status so as to achieve "balance" within each stratum. Our main requirement is that the randomization scheme assigns treatment status within each stratum so that the fraction of units being assigned to treatment within each stratum has a well behaved distribution centered around a proportion π as the sample size tends to infinity. Such schemes include, for example, Efron's biased-coin design and stratified block randomization. When testing the null hypothesis that the average treatment effect equals a pre-specified value in such settings, we first show the usual two-sample t-test is conservative in the sense that it has limiting rejection probability under the null hypothesis no greater than and typically strictly less than the nominal level. We show, however, that a simple adjustment to the usual standard error of the two-sample t-test leads to a test that is exact in the sense that its limiting rejection probability under the null hypothesis equals the nominal level. Next, we consider the usual t-test (on the coefficient on treatment assignment) in a linear regression of outcomes on treatment assignment and indicators for each of the strata. We show that this test is exact for the important special case of randomization schemes with π = 1 2 , but is otherwise conservative. We again provide a simple adjustment to the standard errors that yields an exact test more generally. Finally, we study the behavior of a modified version of a permutation test, which we refer to as the covariate-adaptive permutation test, that only permutes treatment status for units within the same stratum. When applied to the usual two-sample t-statistic, we show that this test is exact for randomization schemes with π = 1 2 and that additionally achieve what we refer to as "strong balance." For randomization schemes with π ≠ 1 2 , this test may have limiting rejection probability under the null hypothesis strictly greater than the nominal level. When applied to a suitably adjusted version of the two-sample t-statistic, however, we show that this test is exact for all randomization schemes that achieve "strong balance," including those with π ≠ 1 2 . A simulation study confirms the practical relevance of our theoretical results. We conclude with recommendations for empirical practice and an empirical illustration·.


A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial.
The naturally-occurring omega (ω)-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA) reduces colorectal adenoma (polyp) number and size in patients with familial adenomatous polyposis. The safety profile and potential cardiovascular benefits associated with ω-3 PUFAs make EPA a strong candidate for colorectal cancer (CRC) chemoprevention, alone or in combination with aspirin, which itself has recognized anti-CRC activity. Colorectal adenoma number and size are recognized as biomarkers of future CRC risk and are established as surrogate end-points in CRC chemoprevention trials. The seAFOod Polyp Prevention Trial is a randomized, double-blind, placebo-controlled, 2×2 factorial 'efficacy' study, which will determine whether EPA prevents colorectal adenomas, either alone or in combination with aspirin. Participants are 55-73 year-old patients, who have been identified as 'high risk' (detection of ≥5 small adenomas or ≥3 adenomas with at least one being ≥10 mm in diameter) at screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Exclusion criteria include the need for more than one repeat endoscopy within the three-month BCSP screening period, malignant change in an adenoma, regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs, regular use of fish oil supplements and concomitant warfarin or anti-platelet agent therapy. Patients are randomized to either EPA-free fatty acid 1 g twice daily or identical placebo AND aspirin 300 mg once daily or identical placebo, for approximately 12 months. The primary end-point is the number of participants with one or more adenomas detected at routine one-year BCSP surveillance colonoscopy. Secondary end-points include the number of adenomas (total and 'advanced') per patient, the location (left versus right colon) of colorectal adenomas and the number of participants re-classified as 'intermediate risk' for future surveillance. Exploratory end-points include levels of bioactive lipid mediators such as ω-3 PUFAs, resolvin E1 and PGE-M in plasma, urine, erythrocytes and rectal mucosa in order to gain insights into the mechanism(s) of action of EPA and aspirin, alone and in combination, as well as to discover predictive biomarkers of chemopreventive efficacy. The recruitment target is 904 patients. Current Controlled Trials ISRCTN05926847.


Fate of trace organic compounds during vadose zone soil treatment in an onsite wastewater system.
During onsite wastewater treatment, trace organic compounds are often present in the effluents applied to subsurface soils for advanced treatment during vadose zone percolation and groundwater recharge. The fate of the endocrine-disrupting surfactant metabolites 4-nonylphenol (NP), 4-nonylphenolmonoethoxylate (NP1EO), and 4-nonylphenolmonoethoxycarboxylate (NP1EC), metal-chelating agents ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA), antimicrobial agent triclosan, stimulant caffeine, and antibiotic sulfamethoxazole during transport through an unsaturated sandy loam soil was studied at a field-scale test site. To assess the effects of effluent quality and hydraulic loading rate (HLR) on compound fate in the soil profile, two effluents (septic tank or textile biofilter) were applied at two design HLRs (2 or 8 cm/d). Chemical concentrations were determined in the two effluents and soil pore water at 60, 120, and 240 cm below the soil infiltrative surface. Concentrations of trace organic compounds in septic tank effluent were reduced by more than 90% during transport through 240 cm (often within 60 cm) of soil, likely due to sorption and biotransformation. However, the concentration of NP increased with depth in the shallow soil profile. Additional treatment of anaerobic septic tank effluent with an aerobic textile biofilter reduced effluent concentrations of many compounds, but generally did not affect any changes in pore water concentrations. The soil profile receiving septic tank effluent (vs. textile biofilter effluent) generally had greater percent removal efficiencies. EDTA, NP, NP1EC, and sulfamethoxazole were measured in soil pore water, indicating the ability of some trace organic compounds to reach shallow groundwater. Risk is highly dependent on the degree of further treatment in the saturated zone and the types and proximity of uses for the receiving groundwater environment.


Solution structures of DNA.RNA hybrids with purine-rich and pyrimidine-rich strands: comparison with the homologous DNA and RNA duplexes.
The structures of d(GAAGAGAAGC).d(GCTTCTCTTC), d(GAAGAGAAGC). r(GCUUCUCUUC), r(GAAGAGAAGC).d(GCTTCTCTTC), and r(GAAGAGAAGC). r(GCUUCUCUUC) have been determined in solution from NMR data. Globally, the pure DNA and RNA duplexes were in the B and A forms, respectively. The two DNA.RNA hybrids were neither A nor B, but closer globally to the A than the B form. However, the thermodynamically less stable d(GAAGAGAAGC).r(GCUUCUCUUC) duplex has a significantly different conformation from r(GAAGAGAAGC). d(GCTTCTCTTC). Structures were calculated based on the NMR data, using restrained molecular dynamics. A new approach to the treatment of conformational averaging based on a prioriprobabilities has been used. The nucleotides were treated by fitting the scalar coupling data and NOE time courses to a two-state model comprising N and S sugar puckers each with a different glycosidic torsion angle, and the mole fraction of the S state. Restraint sets for different distributions of N and S states within molecules were constructed, such that each nucleotide was weighted in the ensemble according to the mole fractions (or a prioriprobabilities). The individual nucleotide conformations were strongly restrained, whereas the internucleotide restraints were set relatively loosely. Ensembles of conformations were generated and assessed by comparison of the NOEs calculated from ensemble-averaged relaxation matrices with the experimental NOEs. The ensemble averages accounted for the experimental data much better than any individual member, or for structures calculated assuming a single unique conformation. The two hybrids populated different degrees of conformational space. There was a general trend in minor and major groove widths in the order d(GAAGAGAAGC).d(GCTTCTCTTC), d(GAAGAGAAGC).r(GCUUCUCUUC), r(GAAGAGAAGC).d(GCTTCTCTTC), r(GAAGAGAAGC).r(GCUUCUCUUC) and a similar progression in global character from B-like to A-like structures. Furthermore, r(GAAGAGAAGC).d(GCTTCTCTTC) showed a greater dispersion of conformations in the ensemble than d(GAAGAGAAGC).r(GCUUCUCUUC), reflecting the greater flexibility of the sugars. If conformational averaging of the nucleotides is ignored, incorrect virtual structures are produced that nevertheless are able to satisfy a substantial fraction of the experimental data.


Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies.
Many SARS-CoV-2-infected individuals remain asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mildly symptomatic, and 21 hospitalized patients with COVID-19. We measure anti-spike immunoglobulin G (IgG), IgA, and IgM levels with the S-Flow assay and map IgG-targeted epitopes with a Luminex assay. We also evaluate neutralization, complement deposition, and antibody-dependent cellular cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC, and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than they are in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.


Software and hardware infrastructure for research in electrophysiology.
As in other areas of experimental science, operation of electrophysiological laboratory, design and performance of electrophysiological experiments, collection, storage and sharing of experimental data and metadata, analysis and interpretation of these data, and publication of results are time consuming activities. If these activities are well organized and supported by a suitable infrastructure, work efficiency of researchers increases significantly. This article deals with the main concepts, design, and development of software and hardware infrastructure for research in electrophysiology. The described infrastructure has been primarily developed for the needs of neuroinformatics laboratory at the University of West Bohemia, the Czech Republic. However, from the beginning it has been also designed and developed to be open and applicable in laboratories that do similar research. After introducing the laboratory and the whole architectural concept the individual parts of the infrastructure are described. The central element of the software infrastructure is a web-based portal that enables community researchers to store, share, download and search data and metadata from electrophysiological experiments. The data model, domain ontology and usage of semantic web languages and technologies are described. Current data publication policy used in the portal is briefly introduced. The registration of the portal within Neuroscience Information Framework is described. Then the methods used for processing of electrophysiological signals are presented. The specific modifications of these methods introduced by laboratory researches are summarized; the methods are organized into a laboratory workflow. Other parts of the software infrastructure include mobile and offline solutions for data/metadata storing and a hardware stimulator communicating with an EEG amplifier and recording software.


Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds.
Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the alpha1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.


Myotropic activity and immunolocalization of selected neuropeptides of the burying beetle Nicrophorus vespilloides (Coleoptera: Silphidae).
Burying beetles (Nicrophorus sp.) are necrophagous insects with developed parental care. Genome of Nicrophorus vespilloides has been recently sequenced, which makes them interesting model organism in behavioral ecology. However, we know very little about their physiology, including the functioning of their neuroendocrine system. In this study, one of the physiological activities of proctolin, myosuppressin (Nicve-MS), myoinhibitory peptide (Trica-MIP-5) and the short neuropeptide F (Nicve-sNPF) in N. vespilloides have been investigated. The tested neuropeptides were myoactive on N. vespilloides hindgut. After application of the proctolin increased hindgut contraction frequency was observed (EC50 value was 5.47 × 10-8 mol/L). The other tested neuropeptides led to inhibition of N. vespilloides hindgut contractions (Nicve-MS: IC50 = 5.20 × 10-5 mol/L; Trica-MIP-5: IC50 = 5.95 × 10-6 mol/L; Nicve-sNPF: IC50 = 4.08 × 10-5 mol/L). Moreover, the tested neuropeptides were immunolocalized in the nervous system of N. vespilloides. Neurons containing sNPF and MIP in brain and ventral nerve cord (VNC) were identified. Proctolin-immunolabeled neurons only in VNC were observed. Moreover, MIP-immunolabeled varicosities and fibers in retrocerebral complex were observed. In addition, our results have been supplemented with alignments of amino acid sequences of these neuropeptides in beetle species. This alignment analysis clearly showed amino acid sequence similarities between neuropeptides. Moreover, this allowed to deduce amino acid sequence of N. vespilloides proctolin (RYLPTa), Nicve-MS (QDVDHVFLRFa) and six isoforms of Nicve-MIP (Nicve-MIP-1-DWNRNLHSWa; Nicve-MIP-2-AWQNLQGGWa; Nicve-MIP-3-AWQNLQGGWa; Nicve-MIP-4-AWKNLNNAGWa; Nicve-MIP-5-SEWGNFRGSWa; Nicve-MIP-6- DPAWTNLKGIWa; and Nicve-sNPF-SGRSPSLRLRFa).


Volcanic sulfur dioxide and acute respiratory symptoms on Miyakejima island.
Following a volcanic eruption in 2000, high concentrations of ambient sulfur dioxide (SO2) are still observed on Miyakejima, Japan despite the reversal 2 years ago of the ban on residents living on the island. This study examines the association between current levels of volcanic SO2 and the incidence of acute subjective symptoms in volunteers on Miyakejima. The authors conducted a follow-up study on 611 healthy volunteers, on a person-hour basis (28 413 person-hours), who visited the island to provide support to residents from February to July 2005. Adverse health symptoms were measured by self-administered diary and exposure was approximated using monitoring data across 14 sites. Associations between incidence rates and increasing SO2 levels (reference (the lowest), very low, low, middle and high) were examined using Poisson regression. Hourly incidence of cough, scratchy throat, sore throat and breathlessness showed clear exposure-response relationships with SO2 concentrations. There were statistically significant risks of those symptoms at relatively low SO2 levels. Thus, rate ratios in the 0.6-2.0 ppm exposure band (vs <0.01 ppm) were: for cough, 3.4 (95% CI 1.8 to 6.6) in men and 9.8 (3.9 to 24.9) in women; for sore throat, 3.2 (1.7 to 6.2) in men and 5.8 (2.0 to 16.5) in women; and for breathlessness, 10.5 (4.2 to 26.6) in men and 18.5 (4.6 to 74.3) in women. Little evidence of SO2 effects on sputum and nasal discharge/congestion was observed in this study. Eye and skin irritations showed inconsistent results between hourly maximal and hourly mean SO2 concentrations. The authors observed strong evidence of an exposure-response relationship between volcanic SO2 and subjective acute respiratory symptoms among a healthy population on Miyakejima. The results are consistent with reports that females and non-smokers are more sensitive to irritant gas than males and smokers, respectively.


Thermus sediminis sp. nov., a thiosulfate-oxidizing and arsenate-reducing organism isolated from Little Hot Creek in the Long Valley Caldera, California.
Thermus species are widespread in natural and artificial thermal environments. Two new yellow-pigmented strains, L198T and L423, isolated from Little Hot Creek, a geothermal spring in eastern California, were identified as novel organisms belonging to the genus Thermus. Cells are Gram-negative, rod-shaped, and non-motile. Growth was observed at temperatures from 45 to 75 °C and at salinities of 0-2.0% added NaCl. Both strains grow heterotrophically or chemolithotrophically by oxidation of thiosulfate to sulfate. L198T and L423 grow by aerobic respiration or anaerobic respiration with arsenate as the terminal electron acceptor. Values for 16S rRNA gene identity (≤ 97.01%), digital DNA-DNA hybridization (≤ 32.7%), OrthoANI (≤ 87.5%), and genome-to-genome distance (0.13) values to all Thermus genomes were less than established criteria for microbial species. The predominant respiratory quinone was menaquinone-8 and the major cellular fatty acids were iso-C15:0, iso-C17:0 and anteiso-C15:0. One unidentified phospholipid (PL1) and one unidentified glycolipid (GL1) dominated the polar lipid pattern. The new strains could be differentiated from related taxa by β-galactosidase and β-glucosidase activity and the presence of hydroxy fatty acids. Based on phylogenetic, genomic, phenotypic, and chemotaxonomic evidence, the novel species Thermus sediminis sp. nov. is proposed, with the type strain L198T (= CGMCC 1.13590T = KCTC XXX).


Mutagenic replication in a human cell extract of DNAs containing site-specific and stereospecific benzo(a)pyrene-7,8-diol-9,10-epoxide DNA adducts placed on the leading and lagging strands.
The environmental carcinogen benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE) forms DNA adducts with unique stereochemistries that may have divergent biological fates, depending on how they are processed within a cell. To investigate the effect of DNA bulky adduct stereoisomerism on the mutagenic outcome of translesion DNA replication in a human cell extract, oligonucleotides were synthesized that contained (+)- and (-)-anti-cis-BPDE enantiomers on N6 adenine at position 2 of the human N-ras 61 codon. Both the nonadducted and BPDE-adducted oligonucleotides were introduced into two double-stranded vectors, replicative forms M13mp2SVoriL and M13mp2SVoriR, which contain SV40 origins of replication in two different orientations relative to the adduct insertion site. Nonadducted and adduct-containing vector DNA constructs were replicated in HeLa cytoplasmic extracts and then screened in bacteria for base substitutions at the adduct site. The mutation frequencies for the adducted DNAs were at least 10 times higher than for the nonadducted DNA and ranged from 5.5 x 10(-4) to 1.5 x 10(-3). The (-)anti-cis enantiomer was more than twice as mutagenic as the (+)-enantiomer. All three possible base mutations were present, with the A-->G being the predominant one. No dramatic differences in replication fidelity were found when the adducts were placed on the leading versus the lagging strand of the vector.


Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations.
Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones - significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer.


Urinary Tartaric Acid, a Biomarker of Wine Intake, Correlates with Lower Total and LDL Cholesterol.
Postmenopausal women are at higher risk of developing cardiovascular diseases due to changes in lipid profile and body fat, among others. The aim of this study was to evaluate the association of urinary tartaric acid, a biomarker of wine consumption, with anthropometric (weight, waist circumference, body mass index (BMI), and waist-to-height ratio), blood pressure, and biochemical variables (blood glucose and lipid profile) that may be affected during the menopausal transition. This sub-study of the PREDIMED (Prevención con Dieta Mediterránea) trial included a sample of 230 women aged 60-80 years with high cardiovascular risk at baseline. Urine samples were diluted and filtered, and tartaric acid was analyzed by liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Correlations between tartaric acid and the study variables were adjusted for age, education level, smoking status, physical activity, BMI, cholesterol-lowering, antihypertensive, and insulin treatment, total energy intake, and consumption of fruits, vegetables, and raisins. A strong association was observed between wine consumption and urinary tartaric acid (0.01 μg/mg (95% confidence interval (CI): 0.01, 0.01), p-value < 0.001). Total and low-density lipoprotein (LDL) cholesterol were inversely correlated with urinary tartaric acid (-3.13 μg/mg (-5.54, -0.71), p-value = 0.016 and -3.03 μg/mg (-5.62, -0.42), p-value = 0.027, respectively), whereas other biochemical and anthropometric variables were unrelated. The results suggest that wine consumption may have a positive effect on cardiovascular health in postmenopausal women, underpinning its nutraceutical properties.


Neural Responses to Musical Rhythm in Chinese Children With Reading Difficulties.
The perception of the musical rhythm has been suggested as one of the predicting factors for reading abilities. Several studies have demonstrated that children with reading difficulties (RD) show reduced neural sensitivity in musical rhythm perception. Despite this prior evidence, the association between music and reading in Chinese is still controversial. In the present study, we sought to answer the question of whether the musical rhythm perception of Chinese children with RD is intact or not, providing further clues on how reading and music might be interlinked across languages. Oddball paradigm was adapted for testing the difference of musical rhythm perception, including predictable and unpredictable omission, in elementary school children with RD and typically developing age-controlled children with magnetoencephalography (MEG). We used the cluster-based permutation tests to examine the statistical difference in neural responses. The event-related field (ERF) components, mismatch negativity (MMNm) and P3a(m), were elicited by the rhythmical patterns with omitted strong beats. Specifically, differential P3a(m) components were found smaller in children with RD when comparing the rhythmical patterns between predictable and unpredicted omission patterns. The results showed that brain responses to the omission in the strong beat of an unpredicted rhythmic pattern were significantly smaller in Chinese children with RD. This indicated that children with RD may be impaired in the auditory sensitivity of rhythmic beats. This also suggests that children with reading difficulties may have atypical neural representations of rhythm that could be one of the underlying factors in dysfluent reading development.


Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.
Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.


Levels of batrachotoxin and lack of sensitivity to its action in poison-dart frogs (Phyllobates).
Batrachotoxin is present in remarkably high amounts in the skin of Phyllobates terribilis. Levels of batrachotoxin tend to be reduced when P. terribilis is maintained in captivity, but even after being confined for up to 6 years, these frogs were still at least five times more toxic than other Phyllobates species used by natives for poisoning blowgun darts. Batrachotoxin was not detectable in F1 progeny reared to maturity in captivity. Nerve and muscle preparations from wild-caught frogs and from the nontoxic F1 frogs were both insensitive to batrachotoxin. The regulatory site controlling sodium-channel activation and permeability appears to have been minimally altered to prevent interaction with batrachotoxin, but is still sensitive to other sodium conductance activators (veratridine, grayanotoxin) to which the frogs arenot exposed naturally.


Award for Distinguished Contributions of Applications of Psychology to Education and Training.
The Board of Educational Affairs is pleased to bestow the Award for Distinguished Contributions of Applications of Psychology to Education and Training. This award acknowledges psychologists who contribute to new teaching methods or solutions to learning problems through the use of research findings or evidence-based practices. Particular emphasis is placed on the use of psychological knowledge to improve learning in educational settings, including prekindergarten to Grade 12, or in communities. The 2018 recipients of the APA Education and Training Contributions Awards were selected by the 2017 Education and Training Awards Committee appointed by the Board of Educational Affairs (BEA). (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Enhanced green luminescence in Ce-Tb-Ca codoped sintered porous glass.
We report on a new kind of green-emitting high silica luminous glass, which is fabricated by sintering of Ce(3+)-Tb(3+) co-doped porous glass. The spectra show that there are energy transfer between Ce(3+) and Tb(3+), and cross-relaxation between (5)D(3) and (5)D(4) energy level of Tb(3+). The energy transfer process can be adjusted by addition of Ca(2+) into the Ce(3+)-Tb(3+) co-doped porous glass, and the transfer rate can be enhanced about four times than that of Ce(3+)-Tb(3+) co-doped porous glass. The role of Ca(2+) has been discussed, and the fluorescence decay curve reveals that the Ca(2+) play an important role in energy transfer.


Genitourinary medicine and surgery in Nelson's navy.
Surgeons of the Royal Navy during the Napoleonic and revolutionary wars, between 1793 and 1815, were solely responsible for all health care of the officers, men, and boys of their ships. This paper examines the genitourinary medicine and surgery encountered by the naval surgeons at the time of Nelson. Primary sources are examined to explore the presentation, case mix, and management of genitourinary disease during this period. A general overview is given of the life and work of the Royal Naval surgeons at the end of the 18th century. The documents that were examined contained 39 surgeon's journals, these were written by 26 surgeons on 13 different ships. The journals contained 446 presentations to the sick list of men with genitourinary symptoms. The presenting symptoms are grouped together under the following headings; venereal disease, penile pathology, scrotal pain and swelling, urinary symptoms and retention, stone disease and trauma. Examination of these journals permits a glimpse of medical life in the Royal Navy during the time of Nelson. The case load and management of genitourinary disease shows the diversity of presentation to these surgeons.


A qualitative descriptive study of new graduate nurses' experiences supporting breastfeeding women in neonatal settings.
The aim was to explore the experiences of new graduate nurses who provide support to breastfeeding women in neonatal care settings. The objective of this study was to explore the enablers and barriers that influenced new graduate nurses' self-efficacy. Nurses have important roles in promoting and educating breastfeeding women in neonatal care settings. Although there are many studies that focused on nursing students and registered nurses' experiences in supporting breastfeeding women, there is limited research about the experiences of new graduate nurses during their transition from universities to neonatal care settings as a registered nurse where they learn how to educate and support breastfeeding women. A qualitative descriptive study. Nine new graduate nurses who support breastfeeding women in neonatal care settings within Australia were recruited. Data was collected through semi-structured interviews via videoconference or telephone. Braun & Clarke's thematic analysis was used to analyse the data. This study found four themes: Preparedness, Emotions, Ongoing Learning, and Confidence. Barriers and enablers included support, time, consistency of information, and impact of stereotyping. The new graduate nurses did not initially feel prepared to support breastfeeding women due to their lack of knowledge. Participants' self-efficacy enhancing strategies to help build knowledge and confidence supporting breastfeeding women included: a) frequent practice, b) having role models and seeking support, c) receiving encouragement and positive feedback, and d) interpreting their emotional feelings as a normal reaction to the learning process. Additional education should be provided during pre-registration education and on commencement of employment in neonatal settings to improve new graduate nurses'knowledge supporting breastfeeding women. Self-efficacy enhancing strategies can be used in partnerships between educational institutions and hospitals to support new graduate nurses to feel more confident providing breastfeeding support in neonatal care settings.


The presence of "ghost" citations in an applicant pool of an integrated plastic surgery residency program.
In today's morally flexible society, breaches in professionalism abound. Professionalism and integrity are core values required of all physicians. Falsification of application information has been demonstrated in some applicant populations. As one of the most competitive fields among residency training programs, applications to an integrated plastic surgery residency program were analyzed to determine whether nonverifiable or "ghost" publications were being included by applicants. The study population included 232 applicants to the University of Wisconsin integrated plastic surgery program in 2008 to 2009. In each application, citation information for journal articles, book chapters, and other publications were reviewed for accuracy. The protocol included verifying citation accuracy in the PubMed/MEDLINE database. Citations that could not be verified were submitted to the department of surgery librarian for further review. Other applicant data were also collected to identify potential predictive factors for including ghost publications. Two hundred thirty-two applications listed 876 citations that were reviewed. Two hundred sixty (30 percent) were identified as citations for which publication was pending and were excluded from analysis. A primary search successfully verified 415 citations (47 percent). A secondary search successfully verified 148 citations (17 percent) as well as identified citations that were complicated, incorrectly cited, or ghost publications. There were 14 ghost publications (2 percent). The inclusion of nonverifiable citations among plastic surgery applicants is low. Nonetheless, we should insist on professionalism and integrity as core values in medical students pursuing plastic surgery, as any "ghost" publication raises an index of suspicion for potentially fraudulent activity.


Residential proximity to industrial facilities and risk of non-Hodgkin lymphoma.
Industrial pollution has been suspected as a cause of non-Hodgkin lymphoma (NHL), based on associations with chemical exposures in occupational studies. We conducted a case-control study of NHL in four SEER regions of the United States, in which residential locations of 864 cases and 684 controls during the 10 years before recruitment were used to characterize proximity to industrial facilities reporting chemical releases to the Environmental Protection Agency's Toxics Release Inventory (TRI). For each of 15 types of industry (by 2-digit SIC code), we evaluated the risk of NHL associated with having lived within 2 miles of a facility, the distance to the nearest facility (miles categories of < or =0.5, >0.5-1.0, >1.0-2.0, >2 [referent]), and the duration of residence within 2miles (years categories of 10, 1-9, 0 [referent]), using logistic regression. Increased risk of NHL was observed in relation to lumber and wood products facilities (SIC 24) for the shortest distance of residential proximity (< or =0.5 mile: odds ratio [OR]=2.2, 95% confidence interval [CI]: 0.4-11.8) or the longest duration (10 years: OR=1.9, 95% CI: 0.8-4.8); the association with lumber facilities was more apparent for diffuse large B-cell lymphoma (lived within 2 miles: OR=1.7, 95% CI: 1.0-3.0) than for follicular lymphoma (OR=1.1, 95% CI: 0.5-2.2). We also observed elevated ORs for the chemical (SIC 28, 10 years: OR=1.5, 95% CI: 1.1-2.0), petroleum (SIC 29, 10 years: OR=1.9, 95% CI: 1.0-3.6), rubber/miscellaneous plastics products (SIC 30, < or =0.5mile: OR=2.7, 95% CI: 1.0-7.4), and primary metal (SIC 33, lived within 2miles: OR=1.3, 95% CI: 1.0-1.6) industries; however, patterns of risk were inconsistent between distance and duration metrics. This study does not provide strong evidence that living near manufacturing industries increases NHL risk. However, future studies designed to include greater numbers of persons living near specific types of industries, along with fate-transport modeling of chemical releases, would be informative.