Floral biology and ovule and seed ontogeny of Nymphaea thermarum, a water lily at the brink of extinction with potential as a model system for basal angiosperms.
Nymphaea thermarum is a member of the Nymphaeales, of one of the most ancient lineages of flowering plants. This species was only recently described and then declared extinct in the wild, so little is known about its reproductive biology. In general, the complete ontogeny of ovules and seeds is not well documented among species of Nymphaea and has never been studied in the subgenus Brachyceras, the clade to which N. thermarum belongs. Flowers and fruits were processed for brightfield, epifluorescence and confocal microscopy. Flower morphology, with emphasis on the timing of male and female functions, was correlated with key developmental stages of the ovule and the female gametophyte. Development of the seed tissues and dynamics of polysaccharide reserves in the endosperm, perisperm and embryo were examined. Pollen release in N. thermarum starts before the flower opens. Cell walls of the micropylar nucellus show layering of callose and cellulose in a manner reminiscent of transfer cell wall patterning. Endosperm development is ab initio cellular, with micropylar and chalazal domains that embark on distinct developmental trajectories. The surrounding maternal perisperm occupies the majority of seed volume and accumulates starch centrifugally. In mature seeds, a minute but fully developed embryo is surrounded by a single, persistent layer of endosperm. Early male and female function indicate that N. thermarum is predisposed towards self-pollination, a phenomenon that is likely to have evolved multiple times within Nymphaea. While formation of distinct micropylar and chalazal developmental domains in the endosperm, along with a copious perisperm, characterize the seeds of most members of the Nymphaeales, seed ontogenies vary between and among the constituent families. Floral biology, life history traits and small genome size make N. thermarum uniquely promising as an early-diverging angiosperm model system for genetic and molecular studies.


Effects of testosterone on differentiation and oxidative stress resistance in C1300 neuroblastoma cells.
Using undifferentiated mouse neuroblastoma cells (C1300), we have previously observed that testosterone (T) exerts a neuroprotective action against oxidative stress. Nitrogen intermediates induce the production of 3-nitro-L-tyrosine (3NT), an amino acid analogue involved in many neurodegenerative disorders. The aim of our work is to investigate T capability on C1300 cell differentiation. It is also evaluated whether differentiation could mitigate the nitrosative effects of 3NT. The effects of both T and 3NT were studied on an undifferentiated cell line of neural origin (C1300). For this purpose, cell cultures underwent morphometric investigation, blot analyses and catalase activity assay. All data obtained were expressed as mean+/-SD and tested by one-way ANOVA or Student's t test. The results were compared with those gathered by means of N6,2'-O-dibutyryl-adenosine-3',5'-cyclic-mono-phosphate (db-cAMP), a well-known differentiating agent. T-exposed cells showed an irregular shape and exhibited long branching cytoplasmic extensions, which were longer than in db-cAMP cells. Moreover, T-exposure induced an increase in the expression of tyrosinated and acetylated alpha-tubulin while 3NT-incorporation into tubulin was markedly reduced. The action of antioxidant defence systems, namely catalase activity, was enhanced in cells exposed to T. This work highlighted the effects of db-cAMP on differentiation and neuroprotection, but even indicated that T exposure induced differentiation in C1300 cells and this process matches a significant neuroprotective effect. This action seemed to be more effective than in db-cAMP-treated cells. T is suggested, like other substances having antioxidant properties, to be of potential interest in the experimental therapy of neuropathological conditions.


Development of non-oxide semiconductors as light harvesting materials in photocatalytic and photoelectrochemical water splitting.
Water splitting via photocatalysis and photoelectrolysis is a potential means to produce clean and renewable hydrogen as a storable high-density energy carrier. At present, the main concern is how to develop semiconductor materials for efficiently converting sunlight energy. The present perspective summarises recent developments in the use of new semiconductors as light-harvesting materials. Specifically, non-oxides, oxynitrides and oxysulfides have been demonstrated to be promising materials for water splitting under visible light. The design of such materials and their application to photocatalytic and photoelectrochemical water splitting are discussed.


Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity.
Innate immune responses to bacteria require cooperative interactions between host recognition molecules and phagocytes. The peptidoglycan recognition proteins (PGRPs) are a large group of proteins found in insects and mammals that bind to bacterial peptidoglycan (PGN). PGRP-S is located with other antimicrobial proteins, such as lysozyme, in the granules of human neutrophils. Whereas both PGRP-S and lysozyme recognize PGN, the exact binding specificity of human PGRP-S, its functional activity, and its potential synergy with other neutrophil-derived bactericidal proteins such as lysozyme have not been determined. Here we show that human PGRP-S binds to and inhibits the growth of Staphylococcus aureus (containing lysine-type PGN) and Escherichia coli (containing mesodiaminopimelic acid-type PGN). The binding affinity and thus antimicrobial activity of PGRP-S is determined by the third amino acid in the PGN stem peptide. Furthermore, the antimicrobial effect of PGRP-S against E coli is synergistic with lysozyme, and lysozyme and PGRP-S colocalize in neutrophil extracellular traps (NETs), suggesting that these granule-derived proteins act together to kill bacteria trapped in the NETs. Taken together, these results indicate that human PGRP-S plays a role in innate immunity in the context of neutrophils by contributing to the killing of intracellular and extracellular bacteria.


Creating a global dialogue on infectious disease surveillance: connecting organizations for regional disease surveillance (CORDS).
Connecting Organizations for Regional Disease Surveillance (CORDS) is an international non-governmental organization focused on information exchange between disease surveillance networks in different areas of the world. By linking regional disease surveillance networks, CORDS builds a trust-based social fabric of experts who share best practices, surveillance tools and strategies, training courses, and innovations. CORDS exemplifies the shifting patterns of international collaboration needed to prevent, detect, and counter all types of biological dangers - not just naturally occurring infectious diseases, but also terrorist threats. Representing a network-of-networks approach, the mission of CORDS is to link regional disease surveillance networks to improve global capacity to respond to infectious diseases. CORDS is an informal governance cooperative with six founding regional disease surveillance networks, with plans to expand; it works in complement and cooperatively with the World Health Organization (WHO), the World Organization for Animal Health (OIE), and the Food and Animal Organization of the United Nations (FAO). As described in detail elsewhere in this special issue of Emerging Health Threats, each regional network is an alliance of a small number of neighboring countries working across national borders to tackle emerging infectious diseases that require unified regional efforts. Here we describe the history, culture and commitment of CORDS; and the novel and necessary role that CORDS serves in the existing international infectious disease surveillance framework.


Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. A 2-year follow-up study.
This study examined how severe stress and depressive symptoms were related to changes in immune measures during a 2-year period in a sample of gay men with human immunodeficiency virus (HIV) infection. These analyses follow up our initial cross-sectional observations that severe stress was correlated with lower levels of natural killer (NK) cells and CD8+ T lymphocytes in these men. Data were collected in North Carolina as part of an ongoing, longitudinal study, the Coping in Health and Illness Project. Sixty-six HIV-infected gay men, who were asymptomatic at baseline, were assessed systematically at 6-month intervals. Severe stress and depressive symptoms were independently related to decreases on immune measures from entry to 2-year follow-up, that is, declines in CD8+ T cells and CD56+ and CD16+ NK cell subsets. Subjects most likely to have decreases on these immune measures were those who scored above the median on both stress and depressive symptoms. Our findings are among the first prospective data showing that stress and depressive symptoms, especially when they occur jointly, are associated with decreased number of NK and CD8+ T lymphocytes in HIV-infected men. Since these immune cells may play a protective role in the progression of HIV infection, our data suggest that stress and depressive symptoms may have clinical implications for the course of this disease.


Wildlife reservoirs of canine distemper virus resulted in a major outbreak in Danish farmed mink (Neovison vison).
A major outbreak of canine distemper virus (CDV) in Danish farmed mink (Neovison vison) started in the late summer period of 2012. At the same time, a high number of diseased and dead wildlife species such as foxes, raccoon dogs, and ferrets were observed. To track the origin of the outbreak virus full-length sequencing of the receptor binding surface protein hemagglutinin (H) was performed on 26 CDV's collected from mink and 10 CDV's collected from wildlife species. Subsequent phylogenetic analyses showed that the virus circulating in the mink farms and wildlife were highly identical with an identity at the nucleotide level of 99.45% to 100%. The sequences could be grouped by single nucleotide polymorphisms according to geographical distribution of mink farms and wildlife. The signaling lymphocytic activation molecule (SLAM) receptor binding region in most viruses from both mink and wildlife contained G at position 530 and Y at position 549; however, three mink viruses had an Y549H substitution. The outbreak viruses clustered phylogenetically in the European lineage and were highly identical to wildlife viruses from Germany and Hungary (99.29% - 99.62%). The study furthermore revealed that fleas (Ceratophyllus sciurorum) contained CDV and that vertical transmission of CDV occurred in a wild ferret. The study provides evidence that wildlife species, such as foxes, play an important role in the transmission of CDV to farmed mink and that the virus may be maintained in the wild animal reservoir between outbreaks.


Researcher liability for negligence in human subject research: informed consent and researcher malpractice actions.
Two sets of federal regulations, the "Common Rule" and Food and Drug Administration (FDA) regulations, govern human subject research that is either federally-funded or involves FDA regulated products. These regulations require, inter alia, that: (1) researchers obtain informed consent from human subjects, and (2) that an Institutional Review Board (IRB) independently review and approve the research protocol. Although the federal regulations do not provide an express cause of action against researchers, research subjects should be able to bring informed consent and malpractice actions against researchers by establishing a duty of care and standard of care. Researchers owe human subjects a duty of care analogous to the special relationship between physicians and patients. The federal regulations should provide the minimum standard of care for informed consent in human subject research, and complying with them should be a partial defense. In contrast, expert testimony should establish the standard of care for researcher malpractice, and IRB approval should be a partial defense.


The potential of GHK as an anti-aging peptide.
GHK (glycyl-L-histidyl-L-lysine) is a naturally occurring peptide found in human serum with levels averaging 200 ng/ml at age 20 but declining to an average of 80 ng/ml by age 60. The molecule has a very high affinity for copper and forms the chelate GHK-Cu. The peptide as well as its Cu (II) chelate have anti-inflammatory and tissue remodeling properties. GHK-Cu has been shown to promote skin remodeling, wound healing and regeneration, and has prominent antioxidant and anti-inflammatory effects in in vitro and in vivo studies. In addition, preliminary observations suggest GHK can partially reverse cognitive impairment in aging mice by targeting anti-inflammatory and epigenetic pathways. The evidence as presented provides the rationale to further investigate this naturally occurring peptide in preclinical and clinical aging studies.


Camelid nanobodies raised against an integral membrane enzyme, nitric oxide reductase.
Nitric Oxide Reductase (NOR) is an integral membrane protein performing the reduction of NO to N(2)O. NOR is composed of two subunits: the large one (NorB) is a bundle of 12 transmembrane helices (TMH). It contains a b type heme and a binuclear iron site, which is believed to be the catalytic site, comprising a heme b and a non-hemic iron. The small subunit (NorC) harbors a cytochrome c and is attached to the membrane through a unique TMH. With the aim to perform structural and functional studies of NOR, we have immunized dromedaries with NOR and produced several antibody fragments of the heavy chain (VHHs, also known as nanobodies). These fragments have been used to develop a faster NOR purification procedure, to proceed to crystallization assays and to analyze the electron transfer of electron donors. BIAcore experiments have revealed that up to three VHHs can bind concomitantly to NOR with affinities in the nanomolar range. This is the first example of the use of VHHs with an integral membrane protein. Our results indicate that VHHs are able to recognize with high affinity distinct epitopes on this class of proteins, and can be used as versatile and valuable tool for purification, functional study and crystallization of integral membrane proteins.


Characterization of human pineal gland proteome.
The pineal gland is a neuroendocrine gland located at the center of the brain. It is known to regulate various physiological functions in the body through secretion of the neurohormone melatonin. Comprehensive characterization of the human pineal gland proteome has not been undertaken to date. We employed a high-resolution mass spectrometry-based approach to characterize the proteome of the human pineal gland. A total of 5874 proteins were identified from the human pineal gland in this study. Of these, 5820 proteins were identified from the human pineal gland for the first time. Interestingly, 1136 proteins from the human pineal gland were found to contain a signal peptide domain, which indicates the secretory nature of these proteins. An unbiased global proteomic profile of this biomedically important organ should benefit molecular research to unravel the role of the pineal gland in neuropsychiatric and neurodegenerative diseases.


Roles for a lipid phosphatase in the activation of its opposing lipid kinase.
Fig4 is a phosphoinositide phosphatase that converts PI3,5P2 to PI3P. Paradoxically, mutation of Fig4 results in lower PI3,5P2, indicating that Fig4 is also required for PI3,5P2 production. Fig4 promotes elevation of PI3,5P2, in part, through stabilization of a protein complex that includes its opposing lipid kinase, Fab1, and the scaffold protein Vac14. Here we show that multiple regions of Fig4 contribute to its roles in the elevation of PI3,5P2: its catalytic site, an N-terminal disease-related surface, and a C-terminal region. We show that mutation of the Fig4 catalytic site enhances the formation of the Fab1-Vac14-Fig4 complex, and reduces the ability to elevate PI3,5P2. This suggests that independent of its lipid phosphatase function, the active site plays a role in the Fab1-Vac14-Fig4 complex. We also show that the N-terminal disease-related surface contributes to the elevation of PI3,5P2 and promotes Fig4 association with Vac14 in a manner that requires the Fig4 C-terminus. We find that the Fig4 C-terminus alone interacts with Vac14 in vivo and retains some functions of full-length Fig4. Thus, a subset of Fig4 functions are independent of its phosphatase domain and at least three regions of Fig4 play roles in the function of the Fab1-Vac14-Fig4 complex.


Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide.
Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1-3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.


Thrombospondin modulates focal adhesions in endothelial cells.
We examined the effects of thrombospondin (TSP) in the substrate adhesion of bovine aortic endothelial cells. The protein was tested both as a substrate for cell adhesion and as a modulator of the later stages of the cell adhesive process. TSP substrates supported the attachment of some BAE cells, but not cell spreading or the formation of focal adhesion plaques. In contrast, cells seeded on fibrinogen or fibronectin substrates were able to complete the adhesive process, as indicated by the formation of focal adhesion plaques. Incubation of cells in suspension with soluble TSP before or at the time of seeding onto fibronectin substrates resulted in an inhibition of focal adhesion formation. Furthermore, the addition of TSP to fully adherent cells in situ or prespread on fibronectin substrates caused a reduction in the number of cells, which were positive for focal adhesions, although there was no significant effect on cell spreading. In a dose-dependent manner, TSP reduced the number of cells with adhesion plaques to approximately 60% of control levels. The distribution of remaining adhesion plaques in TSP-treated cells was also altered: plaques were primarily limited to the periphery of cells and were not present in the central cell body, as in control cells treated with BSA. The observed effects were specific for TSP and were not observed with platelet factor 4, beta-thromboglobulin, or fibronectin. The TSP-mediated loss of adhesion plaques was neutralized by the addition of heparin, fucoidan, other heparin-binding proteins, and by a monoclonal antibody to the heparin binding domain of TSP, but not by antibodies to the core or carboxy-terminal regions of TSP. The interaction of the heparin-binding domain of TSP with cell-associated heparan sulfate appears to be an important mechanistic component for this activity of TSP. These data indicate that TSP may have a role in destabilizing cell adhesion through prevention of focal adhesion formation and by loss of preformed focal adhesions.


Long-term follow-up (four years) of unprotected left main coronary artery disease treated with paclitaxel-eluting stents (from the TRUE Registry).
Limited data are available on the long-term outcome following PCI with paclitaxel-eluting stent (PES) implantation in patients with unprotected left main coronary artery (LMCA). The objective of this study was to evaluate "real world" long-term outcome following paclitaxel-eluting stent (PES) implantation for unprotected LMCA disease in patients enrolled in the TRUE registry. From March 2003 to October 2004, 93 consecutive patients (81.7% male) underwent PCI for unprotected LMCA disease. Surveillance angiography was performed at 6.8+/-3.3 months follow-up. The target lesion involved the distal LMCA in 68 (73.1%) patients. Double stenting techniques were performed in 46 (67.6%) distal LMCA, of these 50% were stented using the Crush technique. Clinical follow-up was complete in all patients with 85.8% angiographic follow-up rate. In-segment restenosis occurred in 16 (20.3%) patients and was focal in 72.4% of cases and significantly higher in patients with distal LMCA (36.8% vs. 13.6%, p<0.04). At a median follow-up of 1,450 days (IQR 1281-1595), the overall incidence of MACE was 35.5% and the TLR rate was 25.8% and significantly higher in patients with bifurcation stenting (32.3% vs. 8%, p<0.02). The estimated cardiac survival rate at one and four years was 96.7% and 93.3%, respectively. Total mortality rate was 14.1% and cardiac was 6.5%. There was one (1.1%) definite stent thrombosis (ST) and one (1.1%) probable ST. Treatment of unprotected LMCA disease with PES, after four years follow-up, appears to be safe and effective with a low rate of cardiac mortality and overall risk of ST. The need for target lesion revascularisation in 25.8% of patients highlights the need for more effective PCI especially in patients with distal LMCA disease.


Prevalence of Inflammatory Bowel Disease Among Patients with Autism Spectrum Disorders.
The objective of this study was to measure the prevalence of inflammatory bowel disease (IBD) among patients with autism spectrum disorders (ASD), which has not been well described previously. The rates of IBD among patients with and without ASD were measured in 4 study populations with distinct modes of ascertainment: a health care benefits company, 2 pediatric tertiary care centers, and a national ASD repository. The rates of IBD (established through International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes) were compared with respective controls and combined using a Stouffer meta-analysis. Clinical charts were also reviewed for IBD among patients with ICD-9-CM codes for both IBD and ASD at one of the pediatric tertiary care centers. This expert-verified rate was compared with the rate in the repository study population (where IBD diagnoses were established by expert review) and in nationally reported rates for pediatric IBD. In all of case-control study populations, the rates of IBD-related ICD-9-CM codes for patients with ASD were significantly higher than that of their respective controls (Stouffer meta-analysis, P < 0.001). Expert-verified rates of IBD among patients with ASD were 7 of 2728 patients in one study population and 16 of 7201 in a second study population. The age-adjusted prevalence of IBD among patients with ASD was higher than their respective controls and nationally reported rates of pediatric IBD. Across each population with different kinds of ascertainment, there was a consistent and statistically significant increased prevalance of IBD in patients with ASD than their respective controls and nationally reported rates for pediatric IBD.


Sex differences in mortality of admitted patients with personality disorders in North Norway--a prospective register study.
It is well established that patients with serious mental disorders have higher mortality than the general population, yet there are few studies on mortality of both natural and unnatural causes in patients with personality disorders. The aim of this study was to investigate the mortality of in-patients with personality disorder diagnosis in a 27-year follow-up cohort in North Norway, with a special focus on gender differences. Based on a hospital case register covering 1980 to 2006, 284 female and 289 male patients were included. The cohort was linked to the Norwegian Cause of Death Registry for information concerning mortality. The mortality rates were adjusted for age by applying a Poisson regression model. The relative mortality in men compared to women was tested with Cox regression with attained age as the time variable. The number of deaths to be expected among the patients if the mortality rates of the general population in Norway had prevailed was estimated and excess mortality, expressed by the standardized mortality ratio (SMR), calculated. When compared to the mortality in the general population, men and women with personality disorder diagnoses had 4.3 (95% CI: 3.2-5.9) and 2.9 (95% CI: 1.9-4.5) times, respectively, increased total mortality. Patients with personality disorder diagnoses have particularly high mortality for unnatural deaths; 9.7 (95% confidence interval (CI): 6.3-15.1) times higher for men and 17.8 (95% CI: 10.1-30.3) for women, respectively, and even higher for suicides--15 (95% CI: 9-27) for men and 38 (95% CI: 20-70) for women. The mortality due to natural causes was not statistically significantly increased in women, whereas men had 2.8 (95% CI: 1.8-4.4) times higher mortality of natural deaths than the general population. Compared to the general population, patients with a personality disorder have high mortality, particularly mortality from unnatural causes. The number of deaths caused by suicides is especially high for women. Men also have higher mortality of natural causes than the general population.


The role of innate APOBEC3G and adaptive AID immune responses in HLA-HIV/SIV immunized SHIV infected macaques.
The AID/APOBEC family (activation induced deaminase/apolipoprotein B mRNA editing cytokine deaminase) in B cells play important roles in adaptive and innate immunity. Whereas APOBEC3G has been studied in CD4+ T cells and myeloid cells its functional potential in B cells has received little attention. AID combines two critical functions of antibodies, class switching and affinity maturation and may serve as a functional surrogate of protection. These functions were studied following systemic immunization of rhesus macaques with recombinant HLA constructs, linked with HIV and SIV antigens and HSP70 to dextran. The results showed significant upregulation of AID in CD20+ B cells, APOBEC 3G in CD27+ memory B cells and CD4+ effector memory T cells. After immunization the upregulated APOBEC 3G and AID were directly correlated in B cells (p<0.0001). Following challenge with SHIV SF162.P4 the viral load was inversely correlated with AID in B cells and APOBEC 3G in B and T cells, suggesting that both deaminases may have protective functions. Investigation of major interactions between DC, T cells and B cells showed significant increase in membrane associated IL-15 in DC and CD40L in CD4+ T cells. IL-15 binds the IL-15 receptor complex in CD4+ T and B cells, which may reactivate the DC, T and B cell interactions. The overall results are consistent with AID inhibiting pre-entry SHIV by eliciting IgG and IgA antibodies, whereas APOBEC 3G may contribute to the post-entry control of SHIV replication and cellular spread.


Critical involvement of the phosphatidylinositol 3-kinase/Akt pathway in anchorage-independent growth and hematogeneous intrahepatic metastasis of liver cancer.
In the multistep process of metastasis, "anchorage-independent growth," where cancer cells need to survive without cell-substratum interaction, is supposed to be important. In this study, we found that anchorage-independent growth analyzed using the soft agar colony formation assay correlated with hematogeneous intrahepatic metastasis of liver cancer cell lines and also Akt activation status. Two highly metastatic liver cancer cell lines showed high Akt activity and formed many colonies in soft agar, whereas three nonmetastatic cell lines showed less Akt activity and formed fewer colonies. Inhibition of Akt activation in the highly metastatic cell line Li7 by transfection with kinase-dead Akt or the phosphatidylinositol 3-kinase inhibitor, LY294002, resulted in formation of fewer colonies in soft agar than was the case with control cells. Moreover, in orthotopic implantation model, this inhibition resulted in a reduced rate of hematogeneous intrahepatic metastasis. These findings indicated that anchorage-independent growth regulated by phosphatidylinositol 3-kinase/Akt pathway plays a critical role in metastasis, and that this could be a potential therapeutic target to combat metastasis.


Benefits of iron supplementation for low birth weight infants: a systematic review.
A number of studies have reported on the effects of iron supplementation in low birth weight infants; however, no systematic review of the available evidence has been conducted to date. Hence, we performed a systematic review of the literature to examine the effects of iron supplementation on hematologic iron status, growth, neurodevelopment, and adverse effects in low birth weight/premature infants. We searched the Cochrane Library, Medline, and PubMed for articles reporting on the effects of iron supplementation in low weight infants. The following search terms were used: "preterm born infant(s)/children"; "preterm infants"; "prematurely born children" "weight less than 1500 g at birth"; "born prematurely"; "low birth weight infant(s)"; "infants born preterm"; "prematurity"; "small-for-gestational age"; "very small gestational age infants"; "iron supplementation"; "iron intake"; "iron supplements"; "ferric and/or ferrous compounds"; and "ferrous sulphate/fumarate/sulfate". A total of 15 studies were identified and included in the systematic review. Supplemental iron was given orally or as an iron-fortified formula in 14/15 studies. The duration of treatment ranged from 1 week to 18 months. Iron supplementation significantly increased hematologic measures of iron status (including hemoglobin, hematocrit, serum ferritin) relative to placebo or over time in most studies. All controlled studies that examined iron-deficiency anemia (IDA)/ID reported a decreased prevalence of IDA/ID with iron supplementation. Dose dependent decreases in the prevalence of IDA/ID were reported in several studies. Of the 5 studies reporting on growth, none found any significant effect on growth-related parameters (length, height, weight, and head circumference). Only 2 studies reported on neurodevelopment; no marked effects were reported. There were no consistently reported adverse effects, including oxidative stress, inhibited nutrient absorption, morbidity, or the requirement for blood transfusion. The available data suggest that iron supplementation increases the levels of hematologic indicators of iron status and reduces the prevalence of IDA/ID in low birth weight/premature infants. There is insufficient evidence to make a definitive statement regarding the effects of iron supplementation on growth, neurodevelopment, or the occurrence of adverse effects in low birth weight/premature infants.


Clinical efficacy of turmeric use in gingivitis: A comprehensive review.
Gingivitis affects an estimated 80% of the population, and is characterized as the world's most predominant inflammatory periodontal disease. Without intervention, gingivitis can advance to alveolar bone loss. Therefore, the primary goal in patients suffering with gingivitis is to control plaque buildup and soft tissue inflammation. Current guidelines consider chlorhexidine as the gold standard in the prevention and treatment of gingivitis. However, negative side effects of chlorhexidine, including oral mucosal erosion, discoloration of teeth, and bitter taste, provide an opportunity for alternative medications. Turmeric, a commonly used herb, possesses anti-inflammatory, antioxidant, antibacterial, antiviral, and antifungal properties. By virtue of these properties, multiple controlled trials have been performed to investigate the efficacy of turmeric in gingivitis. The aim of this comprehensive review is to summarize and evaluate the evidence on the efficacy of turmeric as compared to chlorhexidine in the prevention and treatment of gingivitis. PubMed, MedLine (Web of Science), and EBSCO (academic search complete) were utilized as primary literature search tools. The following search strategy was used: ((turmeric OR curcumin OR curcuma) AND (gingivitis OR "gum inflammation")). Five reviewed studies show that both turmeric and chlorhexidine significantly decrease plaque index (PI) and gingival index (GI), and can therefore be used in the prevention and treatment of gingivitis. Both chlorhexidine and turmeric can be used as an adjunct to mechanical means in preventing and treating gingivitis. However, trials longer than 21 days with a greater number of patients are necessary to further evaluate the comparison between turmeric and chlorhexidine.


Detection of novel 3' untranslated region extensions with 3' expression microarrays.
The 3' untranslated regions (UTRs) of transcripts are not well characterized for many genes and often extend beyond the annotated regions. Since Affymetrix 3' expression arrays were designed based on expressed sequence tags, many probesets map to intergenic regions downstream of genes. We used expression information from these probesets to predict transcript extension beyond currently known boundaries. Based on our dataset encompassing expression in 22 different murine tissues, we identified 845 genes with predicted 3'UTR extensions. These extensions have a similar conservation as known 3'UTRs, which is distinctly higher than intergenic regions. We verified 8 of the predictions by PCR and found all of the predicted regions to be expressed. The method can be extended to other 3' expression microarray platforms as we demonstrate with human data. Additional confirming evidence was obtained from public paired end read data. We show that many genes have 3'UTR regions extending beyond currently known gene regions and provide a method to identify such regions based on microarray expression data. Since 3' UTR contain microRNA binding sites and other stability determining regions, identification of the full length 3' UTR is important to elucidate posttranscriptional regulation.


Focal therapy in prostate cancer: the current situation.
Prostate cancer is one of the most significant pathologies in the field of urology. The adoption of screening strategies and improvements in biopsies have resulted in an increase in early-stage tumour detection. Radical global therapies provide very good oncological results in localised prostate cancer. However, excess treatment in low- and, in some cases, intermediate-risk groups affects the quality of life of these patients. In the case of localised prostate cancer, focal therapies offer a minimally invasive option with good results with respect to established treatments. Although this is currently not a standard treatment, it represents the therapeutic approach with the greatest potential. THIS LITERATURE REVIEW HAS THE FOLLOWING OBJECTIVES: to define selection criteria for patients who are candidates for focal therapy, to assess the current situation and results of the different therapeutic options, and to define procedures in cases of recurrence and for follow-ups. We concluded that focal therapy is a viable therapeutic alternative for localised prostate cancer, specifically cryosurgery and high-intensity targeted ultrasound, which have acceptable oncologic results and a lower comorbidity compared with global treatments. Studies with a high level of scientific evidence are still needed to validate these results. A search was carried out on the Medline (PubMed), EMBASE, Web of Science and Cochrane databases of all papers published before 31 July 2013. We included clinical studies and literature reviews that evaluated primary focal therapy for prostate cancer confirmed by biopsy and excluded focal rescue therapy studies. The keywords used were focal therapy and prostate cancer. Initially, we found 42 articles; 15 studies were excluded because they did not meet the minimum criteria for inclusion. A total of 1350 cases were treated throughout 27 studies.


Chitosan and carboxymethyl cellulose based magnetic nanocomposites for application of peroxidase purification.
Recently, protein purification methods have a very wide area of research. Many of these methods are both expensive and multi-stage methods, that are needed in specific equipment. In this study, biopolymer coated magnetic nanoparticles, carboxymethyl cellulose (CMC) and chitosan (CH) coated Fe3O4 (magnetite) nanocomposites, are used in a new purification process. The structure of the synthesized magnetic nanocomposites were characterized by Fourier transform infrared (FTIR) spectrometry, X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), thermogravimetric (TGA) analysis and zeta potential for surface charge of magnetic nanocomposites. Molecular weight and purification degree of peroxidase were estimated with SDS-PAGE. Peroxidase enzyme was purified a yield of 82.55% with carboxymethyl cellulose and 76.72% with chitosan using this method.


Variable major proteins of Borrelia hermsii. Epitope mapping and partial sequence analysis of CNBr peptides.
The variable major proteins (VMP) of serotypes 7 and 21 of the relapsing fever agent Borrelia hermsii were isolated by detergent extraction and high performance liquid chromatography. Cyanogen bromide (CNBr) digestion of the isolated VMP yielded two peptides of apparent molecular weights 20,000 (20 K) and 16 K from VMP7, and three peptides of 14.5, 14, and 7 K mol wt from VMP21. Serotype-specific monoclonal antibodies bound in Western blots to one of each of the two or three CNBr fragments from the homologous VMP. A single monoclonal antibody bound to the whole cells, the isolated VMP, and a CNBr fragment of both serotype 7 and serotype 21. (This crossreactive antibody did not, however, bind to any of four other serotypes examined.) Regional conservation of structure between VMP7 and VMP21 was also shown by amino acid sequence analysis of the N-termini of the five CNBr fragments. One pair of aligned fragments from VMP7 and VMP21 had 80% amino acid homology in sequence; a second pair had 40% homology. The partial amino acid homologies between two VMP suggest that these proteins are products of members of a polygene family.


Efficacy of Short-term Treatment of Internet and Computer Game Addiction: A Randomized Clinical Trial.
Internet and computer game addiction represent a growing mental health concern, acknowledged by the World Health Organization. To determine whether manualized cognitive behavioral therapy (CBT), using short-term treatment for internet and computer game addiction (STICA), is efficient in individuals experiencing internet and computer game addiction. A multicenter randomized clinical trial was conducted in 4 outpatient clinics in Germany and Austria from January 24, 2012, to June 14, 2017, including follow-ups. Blinded measurements were conducted. A consecutive sample of 143 men was randomized to the treatment group (STICA; n = 72) or wait-list control (WLC) group (n = 71). Main inclusion criteria were male sex and internet addiction as the primary diagnosis. The STICA group had an additional 6-month follow-up (n = 36). Data were analyzed from November 2018 to March 2019. The manualized CBT program aimed to recover functional internet use. The program consisted of 15 weekly group and up to 8 two-week individual sessions. The predefined primary outcome was the Assessment of Internet and Computer Game Addiction Self-report (AICA-S). Secondary outcomes were self-reported internet addiction symptoms, time spent online on weekdays, psychosocial functioning, and depression. A total of 143 men (mean [SD] age, 26.2 [7.8] years) were analyzed based on intent-to-treat analyses. Of these participants, 50 of 72 men (69.4%) in the STICA group showed remission vs 17 of 71 men (23.9%) in the WLC group. In logistic regression analysis, remission in the STICA vs WLC group was higher (odds ratio, 10.10; 95% CI, 3.69-27.65), taking into account internet addiction baseline severity, comorbidity, treatment center, and age. Compared with the WLC groups, effect sizes at treatment termination of STICA were d = 1.19 for AICA-S, d = 0.88 for time spent online on weekdays, d = 0.64 for psychosocial functioning, and d = 0.67 for depression. Fourteen adverse events and 8 serious adverse events occurred. A causal relationship with treatment was considered likely in 2 AEs, one in each group. Short-term treatment for internet and computer game addiction is a promising, manualized, short-term CBT for a broad range of internet addictions in multiple treatment centers. Further trials investigating the long-term efficacy of STICA and addressing specific groups and subgroups compared with active control conditions are required. ClinicalTrials.gov identifier: NCT01434589.


Reducing the medical economic burden of health insurance in China: Achievements and challenges.
The aims of this study were to describe health insurance reforms initiated by the Chinese government over the past two decades, to review their achievements in reducing the medical economic burden, and to summarize the challenges that still exist regarding a further reduction in out-of-pocket expenditures in this country. China has successfully attained the goal of providing health insurance coverage to almost the entire population by developing a mixed health insurance system, which consists of Urban Employees Basic Medical Insurance (UEBMI), Urban Resident Basic Medical Insurance (URBMI), New Rural Cooperative Medical Scheme (NCMS), and supplementary Catastrophic Health Insurance. Despite this achievement, China is still facing the challenges of a disparity in the medical economic burden by region and by health insurance scheme, relatively little protection from financial risk compared to developed countries, as well as low efficiency and quality of care under current payment systems. To further reduce the disparity in the medical economic burden and to increase the overall protection from financial risk in China, the Government should increase central government transfers to NCMS and URBMI enrollees in poor regions and increase the total amount of government subsidies to NCMS. In addition, China should improve the efficiency and quality of health insurance by further reforming the payment system.


Low-loss polysilicon waveguides fabricated in an emulated high-volume electronics process.
We measure end-of-line polysilicon waveguide propagation losses of ~6-15 dB/cm across the telecommunication O-, E-, S-, C- and L-bands in a process representative of high-volume product integration. The lowest loss of 6.2 dB/cm is measured at 1550 nm in a polysilicon waveguide with a 120 nm x 350 nm core geometry. The reported waveguide characteristics are measured after the thermal cycling of the full CMOS electronics process that results in a 32% increase in the extracted material loss relative to the as-crystallized waveguide samples. The measured loss spectra are fit to an absorption model using defect state parameters to identify the dominant loss mechanism in the end-of-line and as-crystallized polysilicon waveguides.


Mechanisms Associated with Protective Effects of Ginkgo Biloba Leaf Extracton in Rat Cerebral Ischemia Reperfusion Injury.
Cerebral infarction occurs as a consequence of cerebral ischemia-reperfusion injury (CIRI). Ginkgo biloba leaf extract (GbE) is composed predominantly of active ingredients such as flavonoids and terpene lactones and often used to treat cerebrovascular diseases. However, the mechanisms underlying the use of this herbal extract to treat cerebrovascular-mediated damage are not known. The aim of this study was to examine the effectiveness of administration GbE to ameliorate the observed consequences of CIRI. The following parameters were measured: (1) behavioral score (2) infarct area (3) the content of serum malondialdehyde (MDA) as well as activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and (4) interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression levels in the infarcted brain tissue. Data demonstrated that treatment with GbE to CIRI rats resulted in significant reduction in cerebral-infarcted area associated with improvement in behavioral score. GbE was found to decrease serum MDA levels concomitant with elevated activity levels of SOD and GSH-PX. Immunohistochemistry and Western blot analysis showed that GbE significantly lowered the levels of IL-6 and TNF-α in the infarcted brain tissue. Data suggest that GbE may be therapeutically effective in improving behavioral score in CIRI rats through reduction of oxidative stress and anti-inflammation in the cerebral infarction region.


IDH1-mutated transgenic zebrafish lines: An in-vivo model for drug screening and functional analysis.
The gene encoding isocitrate dehydrogenase 1 (IDH1) is frequently mutated in several tumor types including gliomas. The most prevalent mutation in gliomas is a missense mutation leading to a substitution of arginine with histidine at the residue 132 (R132H). Wild type IDH1 catalyzes oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) whereas mutant IDH1 converts α-KG into D2-hydroxyglutarate (D2HG). Unfortunately, there are few in vivo model systems for IDH-mutated tumors to study the effects of IDH1 mutations in tumor development. We have therefore created transgenic zebrafish lines that express various IDH1 mutants. IDH1 mutations (IDH1R132H, IDH1R132C and loss-of-function mutation IDH1G70D), IDH1wildtype or eGFP were cloned into constructs with several brain-specific promoters (Nestin, Gfap or Gata2). These constructs were injected into fertilized zebrafish eggs at the one-cell stage. In total more than ten transgenic zebrafish lines expressing various brain-specific IDH1 mutations were created. A significant increase in the level of D2HG was observed in all transgenic lines expressing IDH1R132C or IDH1R132H, but not in any of the lines expressing IDH1wildtype, IDH1G70D or eGFP. No differences in 5-hydroxymethyl cytosine and mature collagen IV levels were observed between wildtype and mutant IDH1 transgenic fish. To our surprise, we failed to identify any strong phenotype, despite increased levels of the oncometabolite D2HG. No tumors were observed, even when backcrossing with tp53-mutant fish which suggests that additional transforming events are required for tumor formation. Elevated D2HG levels could be lowered by treatment of the transgenic zebrafish with an inhibitor of mutant IDH1 activity. We have generated a transgenic zebrafish model system for mutations in IDH1 that can be used for functional analysis and drug screening. Our model systems help understand the biology of IDH1 mutations and its role in tumor formation.


Optimizing structural and mechanical properties of cryogel scaffolds for use in prostate cancer cell culturing.
Prostate cancer (PCa) currently is the second most diagnosed cancer in men and the second most cause of cancer death after lung cancer in Western societies. This sets the necessity of modelling prostatic disorders to optimize a therapy against them. The conventional approach to investigating prostatic diseases is based on two-dimensional (2D) cell culturing. This method, however, does not provide a three-dimensional (3D) environment, therefore impeding a satisfying simulation of the prostate gland in which the PCa cells proliferate. Cryogel scaffolds represent a valid alternative to 2D culturing systems for studying the normal and pathological behavior of the prostate cells thanks to their 3D pore architecture that reflects more closely the physiological environment in which PCa cells develop. In this work the 3D morphology of three potential scaffolds for PCa cell culturing was investigated by means of synchrotron X-ray computed micro tomography (SXCμT) fitting the according requirements of high spatial resolution, 3D imaging capability and low dose requirements very well. In combination with mechanical tests, the results allowed identifying an optimal cryogel architecture, meeting the needs for a well-suited scaffold to be used for 3D PCa cell culture applications. The selected cryogel was then used for culturing prostatic lymph node metastasis (LNCaP) cells and subsequently, the presence of multi-cellular tumor spheroids inside the matrix was demonstrated again by using SXCμT.


Gene expression and deletion analysis of mechanisms for electron transfer from electrodes to Geobacter sulfurreducens.
Geobacter sulfurreducens is one of the few microorganisms available in pure culture known to directly accept electrons from a negatively poised electrode. Microarray analysis was used to compare gene transcript abundance in biofilms of G. sulfurreducens using a graphite electrode as the sole electron donor for fumarate reduction compared with transcript abundance in biofilms growing on the same material, but not consuming current. Surprisingly, genes for putative cell-electrode connections, such as outer-surface cytochromes and pili, which are highly expressed in current-producing biofilms, were not highly expressed in current-consuming biofilms. Microarray analysis of G. sulfurreducens gene transcript abundance in current-consuming biofilms versus current-producing biofilms gave similar results. In both comparative studies current-consuming biofilms had greater transcript abundance for a gene (GSU3274) encoding a putative monoheme, c-type cytochrome. Deletion of genes for outer-surface proteins previously shown to be essential for optimal electron transfer to electrodes had no impact on electron transfer from electrodes. Deletion of GSU3274 completely inhibited electron transfer from electrodes, but had no impact on electron transfer to electrodes. These differences in gene expression patterns and the impact of gene deletions suggest that the mechanisms for electron transfer from electrodes to G. sulfurreducens differ significantly from the mechanisms for electron transfer to electrodes.


Practice parameter: treatment of the child with a first unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence regarding risks and benefits. This parameter reviews published literature relevant to the decision to begin treatment after a child or adolescent experiences a first unprovoked seizure and presents evidence-based practice recommendations. Reasons why treatment may be considered are discussed. Evidence is reviewed concerning risk of recurrence as well as effect of treatment on prevention of recurrence and development of chronic epilepsy. Studies of side effects of anticonvulsants commonly used to treat seizures in children are also reviewed. Relevant articles are classified according to the Quality Standards Subcommittee classification scheme. Treatment after a first unprovoked seizure appears to decrease the risk of a second seizure, but there are few data from studies involving only children. There appears to be no benefit of treatment with regard to the prognosis for long-term seizure remission. Antiepileptic drugs (AED) carry risks of side effects that are particularly important in children. The decision as to whether or not to treat children and adolescents who have experienced a first unprovoked seizure must be based on a risk-benefit assessment that weighs the risk of having another seizure against the risk of chronic AED therapy. The decision should be individualized and take into account both medical issues and patient and family preference.


Is the principle of minimization of secondary moments validated during various fingertip force production conditions?
During the application of fingertip forces with simultaneous flexion of the four fingers, namely index, middle, ring, and little fingers, a stable force sharing among fingers is adopted. Several studies have hypothesized that this stable force sharing is established to minimize unnecessary rotational moments (different from the main flexion moments). This principle labeled "minimization of secondary moments" is presented in the literature as a principle used by the central nervous system to solve musculoskeletal redundancy. However, this principle has only been tested with one solicited degree of freedom and in one finger posture. Our study tests this principle with various degrees of freedom solicited as secondary moments and in two different finger postures. Participants (n=6) were asked to apply a downward vertical force using their four fingers with the forearm placed in two different configurations: a "horizontal" condition (involving flexion/extension and pronation/supination at the wrist joint) and a "vertical" condition (involving flexion/extension and radial/ulnar deviation at the wrist joint). Additionally, two finger postures were tested in each forearm configuration: in the first, the distal inter-phalangeal joints (DIP) were extended and the proximal inter-phalangeal joints (PIP) highly flexed. In the second finger posture, both DIP and PIP joints were flexed. The resultant four-finger force and the relative involvement of each finger in the resultant four-finger force (force sharing) were analyzed. Results showed that the finger postures did not influence the finger force sharing, showing that the minimization of the secondary moment principle was stable among the finger joint angle configurations. Nonetheless, the relative involvement of each finger was dependent on the secondary degree of freedom solicited (pronation/supination vs. radial/ulnar). The modifications of the finger force sharing between the "horizontal" and "vertical" conditions were in accordance with the principle of minimization of the secondary moments.


Multiple independent fusions of glucose-6-phosphate dehydrogenase with enzymes in the pentose phosphate pathway.
Fusions of the first two enzymes in the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconolactonase (6PGL), have been previously described in two distant clades, chordates and species of the malarial parasite Plasmodium. We have analyzed genome and expressed sequence data from a variety of organisms to identify the origins of these gene fusion events. Based on the orientation of the domains and range of species in which homologs can be found, the fusions appear to have occurred independently, near the base of the metazoan and apicomplexan lineages. Only one of the two metazoan paralogs of G6PD is fused, showing that the fusion occurred after a duplication event, which we have traced back to an ancestor of choanoflagellates and metazoans. The Plasmodium genes are known to contain a functionally important insertion that is not seen in the other apicomplexan fusions, highlighting this as a unique characteristic of this group. Surprisingly, our search revealed two additional fusion events, one that combined 6PGL and G6PD in an ancestor of the protozoan parasites Trichomonas and Giardia, and another fusing G6PD with phosphogluconate dehydrogenase (6PGD) in a species of diatoms. This study extends the range of species known to contain fusions in the pentose phosphate pathway to many new medically and economically important organisms.


Macrophage depletion suppresses sympathetic hyperinnervation following myocardial infarction.
Myocardial infarction induces sympathetic axon sprouting adjacent to the necrotic region, and this has been implicated in the etiology of arrhythmias resulting in sudden cardiac death. Previous studies show that nerve growth factor (NGF) is essential for enhanced post-infarct sympathetic sprouting, but the cell types necessary to supply this neurotrophic protein are unknown. The objective of the present study was to determine whether macrophages, which are known to synthesize NGF, are necessary for post-infarct cardiac sympathetic sprouting. Ovariectomized female rats received left coronary artery ligation or sham operation, followed by intravenous injection of liposomes containing saline vehicle or clodronate, which kills macrophages. Sham-operated myocardium contained some sympathetic axons, few myofibroblasts and T cells and no CD-68-positive macrophages. In rats receiving saline liposomes through 7 days post-ligation, the posterolateral infarct border contained numerous myofibroblasts, macrophages and T cells, and sympathetic innervation was increased twofold. Treatment with clodronate liposomes reduced macrophage numbers by 69%, while myofibroblast area was reduced by 23% and T cell number was unaffected. Clodronate liposome treatment reduced sympathetic axon density to levels comparable to the uninfarcted heart. NGF protein content measured in western blots was reduced to 33% of that present in infarcts where rats received saline-containing liposomes. Tissue morphometry confirmed that NGF immunostaining was dramatically reduced, and this was attributable primarily to reduced macrophage content. These results show that macrophage destruction markedly reduces post-infarction levels of NGF and that the presence of elevated numbers of macrophages is obligatory for development of sympathetic hyperinnervation following myocardial infarction.


Citrate Anticoagulation during Continuous Renal Replacement Therapy.
During extracorporeal dialysis, some anticoagulation strategy is necessary to prevent the coagulation of blood. Heparin has historically been used as an anticoagulant because of its efficacy combined with low cost. However, a variable incidence of hemorrhagic complications (5-30%) has been documented in patients undergoing continuous renal replacement therapy (CRRT) with heparin as an anticoagulant. Citrate has anticoagulation properties secondary to its ability to chelate calcium, which is necessary for the coagulation cascade. Citrate may thus be used in a regional anticoagulation (RCA), limited to the extracorporeal circuit of CRRT, to avoid systemic anticoagulation. Recent meta-analysis confirmed the advantage of RCA over heparin in terms of incidence of bleeding during CRRT. Moreover, an increase in filter lifespan is documented, with a secondary advantage in reaching the prescribed dialysis dose. In our experience, we could confirm this positive effect. In fact, with a progressive increase in the proportion of CRRT with citrate as RCA, we obtained a reduction in the number of filters used for every 72 h of treatment (from 2.4 in 2011 to 1.3 in 2015), and most importantly, a reduction in the difference between the prescribed and delivered dialysis doses (from 22 to 7%). Citrate has an intense effect on the acid-base balance as well, if fully metabolized through the Krebs cycle, due to the production of bicarbonate. Even more severely ill patients, such as those with liver dysfunction, may be treated with RCA without severe complications, because modern machines for CRRT are equipped with simple systems that are able to manage the citrate infusion and control the calcium levels, with minimal risks of metabolic derangements.


Predicting affinity and specificity of antigenic peptide binding to major histocompatibility class I molecules.
Major Histo-Compatibility (MHC) class I molecules are major agents of the mammalian adaptive immune system. Class I molecules bind short antigenic peptides with a length of 8-10 residues in the Endoplasmatic Reticulum (ER) and after transport to the cell surface the peptides are presented to T-lymphocytes. The binding site of class I molecules is formed by a deep cleft between two alpha-helices at top of an extended beta-sheet. Only tightly bound high-affinity peptides have a chance to reach the cell surface and trigger an immune response. It is therefore of great interest to identify possible high-affinity antigenic peptides that could be used as vaccines to help the immune system to detect viral infections or kill malignant cells. A large number of crystal structures of antigenic peptides in complex with class I alleles have been determined that allow to understand the structural details important for peptide binding. Biophysical and biochemical analysis of peptide-class I complexes has resulted in a number of rules concerning the selection of high-affinity peptides. However, an accurate prediction of allele specific peptide-binding is still not possible. This issue is currently addressed by various computational tools developed by the bioinformatics community. The computational efforts range from statistical analysis of peptide motifs stored in databases to application of neural network methods and support vector machine approaches. In addition, structure based approaches to predict class I binding specificity including molecular modeling and molecular dynamics (MD) simulations will also be presented.


Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation.
Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 μM, trypan blue exclusion assay). At a lower range (25 μM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 μM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.


Temporal interactions in the cat visual system. III. Pharmacological studies of cortical suppression suggest a presynaptic mechanism.
When tested with pairs of brief visual stimuli, neurons of the primary visual cortex of the cat show a long-lasting, orientation-selective suppression, termed "paired-pulse suppression." The hypothesis that this suppression is due to GABAA-mediated inhibition was tested by performing temporal interaction tests before, during, and after iontophoretic application of the selective antagonist bicuculline methiodide (BMI). In keeping with previous reports, BMI elevated the spontaneous and evoked firing rates of cortical neurons, and altered basic receptive field properties. Under the influence of BMI, most neurons showed a reduced or abolished selectivity for stimulus orientation and direction of movement. The effects on orientation selectivity required higher ejection currents than did the effects on directional selectivity. At high ejection currents, most cells did lose selectivity for the orientation of a moving stimulus, but retained some selectivity for the orientation of a stationary stimulus. BMI, even at very high ejection currents, did not abolish paired-pulse suppression. In some cells, BMI enhanced or prolonged paired-pulse suppression. In further experiments, temporal interaction tests were performed in which one or the other of the component stimuli was replaced with a pharmacological stimulus (a pulse of glutamate or potassium). A pharmacological stimulus did not produce suppression of the response to a subsequent visual stimulus, nor did a visual stimulus suppress the response to a subsequent pharmacological stimulus. Paired-pulse suppression occurred only when both stimuli were visual. Taken together with previous results, the present data indicate that paired-pulse suppression is most likely due to a presynaptic mechanism.


Subcutaneous Administration of Insulin is Associated With Regional Differences in Injection Depot Variability and Kinetics in The Rat.
In humans, subcutaneous administration of insulin in the abdominal region or arm is associated with a faster absorption compared to the thigh or buttocks. We hypothesised that this is partly caused by differences in injection depot structure and kinetics and that the variability in insulin exposure differs between injection sites. Regional effects on insulin pharmacokinetics were evaluated in a series of studies in Sprague Dawley rats dosed subcutaneously with insulin aspart in the neck or flank. Injection depots were visualised using µCT after subcutaneous dosing with insulin aspart mixed with the contrast agent iomeprol, and insulin exposure was determined between the scans by Luminescent Oxygen Channeling Immunoassay. Insulin absorption was significantly delayed by subcutaneous dosing in the flank compared to the neck region (p<0.01 or less). This delay was associated with smaller depots, as measured by reduced depot volume and surface area (p<0.001). Furthermore, the delayed absorption correlated with a slower depot disappearance (p<0.001). Regional differences in depot variability were not reflected by similar differences in pharmacokinetic variability. Structure and kinetics of subcutaneous injection depots-as detected by µCT scans-predict insulin exposure and may thus contribute to the regional differences in insulin pharmacokinetics. The present methodology is applicable for visualisation of insulin injection depots in vivo. Our results did however not support a link between the variability in depot size and insulin pharmacokinetics.


Can prenatal exposure to a 900 MHz electromagnetic field affect the morphology of the spleen and thymus, and alter biomarkers of oxidative damage in 21-day-old male rats?
We investigated the effects of a 900 Megahertz (MHz) electromagnetic field (EMF), applied during the prenatal period, on the spleen and thymus of 21-day-old male rat pups. Pregnant Sprague-Dawley rats were divided into control and EMF groups. We applied 900 MHz EMF for 1 h/day to the EMF group of pregnant rats. Newborn male rat pups were removed from their mothers and sacrificed on postnatal day 21. Spleen and thymus tissues were excised and examined. Compared to the control group, thymus tissue malondialdehyde levels were significantly higher in the group exposed to EMF, while glutathione levels were significantly decreased. Increased malondialdehyde and glutathione levels were observed in splenic tissue of rats exposed to EMF, while a significant decrease occurred in superoxide dismutase values compared to controls. Transmission electron microscopy showed pathological changes in cell morphology in the thymic and splenic tissues of newborn rats exposed to EMF. Exposure to 900 MHz EMF during the prenatal period can cause pathological and biochemical changes that may compromise the development of the male rat thymus and spleen.


Comparative evaluation of the ventricles in the Yorkshire Terrier and the German Shepherd dog using low-field MRI.
MR images provide for the exact assessment of the brain, including ventricular size. Still inter- and intrabreed comparison of ventricle size is difficult due to the varying anatomies in dogs. To compare the ventricle area of different sized breeds, 25 dogs (13 Yorkshire Terriers and 12 German Shepard dogs) were reviewed, retrospectively. Hemisphere and ventricle of each side were outlined manually three times. All measurements were averaged and their percentage (ventricle area by hemisphere area) was defined as the relative ventricle area. This value in Yorkshire Terriers (5.3) was significantly higher compared to German Shepard dogs (1.7). However, on the basis of the neurologically symptomatic sample (7 Yorkshire Terriers) in this study, threshold values of normal and abnormal relative ventricle areas could not be detected.


Women's experiences of cognitive changes or 'chemobrain' following treatment for breast cancer: a role for occupational therapy?
Changes to functioning and cognition are commonly reported following chemotherapy. These changes are highly individual, and may not be fully recognised or understood. Breast cancer is the most common cancer diagnosed in women worldwide, yet little is known about the impact of cognitive changes for these women following treatment and many do not benefit from occupational therapy services. The aim was to describe changes in cognitive function experienced by women who had undergone chemotherapy, and the strategies used to overcome the associated challenges. This was a qualitative phenomenological study conducted with nine women, aged between 39 and 67 years, from New South Wales. Participants were breast cancer survivors who had received chemotherapy treatment, and self-reported chemobrain symptoms. Data were collected through semi-structured in-depth telephone and face-to-face interviews. Data were transcribed, coded and thematically analysed. Six themes described the chemobrain experience for these women. They were: uncertainty about the origin of the chemobrain experience; persistent but inconsistent impacts on function; simple function turned complex; losing functional independence in family life; strategies to maintain function; and the need for recognition of the subjective experience of cancer treatment. The experiences of cognitive and functional changes following chemotherapy for those reporting chemobrain symptoms are highly individual, and include the need for adaptive strategies. Some similarities in the types of impairments were experienced. As breast cancer survivorship rates continue to rise, there is a need for occupational therapy services to assist women in returning to daily occupations during or following their cancer treatment.


Behavioral effects of progesterone associated with rapid modulation of oxytocin receptors.
The ventromedial nuclei of the hypothalamus (VMN) are important for the control of feminine mating behavior, and hormone action within these nuclei has been causally related to behavior. Estradiol induces receptors for oxytocin in the VMN and in the area lateral to these nuclei over the course of 1 to 2 days, and progesterone causes, within 30 minutes of its application, a further increase in receptor binding and an expansion of the area covered by these receptors lateral to the VMN. The rapid progesterone effect appears to be a direct and specific effect of this steroid on the receptor or membrane, because it was produced in vitro as well as in vivo and was not mimicked by a variety of other steroids. The effect of progesterone occurred in the posterior part of the VMN, where oxytocin infusion facilitated feminine mating behavior; it did not take place in the anterior part of the VMN, where oxytocin infusion had no effect on mating behavior.


Assessing white matter integrity as a function of abstinence duration in former cocaine-dependent individuals.
Current cocaine-dependent users show reductions in white matter (WM) integrity, especially in cortical regions associated with cognitive control that have been associated with inhibitory dysfunction. A key question is whether these white matter differences are present following abstinence from drug use. To address this, WM integrity was examined using diffusion tensor imaging (DTI) obtained on 43 cocaine abstinent patients (abstinence duration ranged between five days and 102 weeks) and 43 non-using controls. Additionally, a cross-sectional comparison separated the patients into three groups (short-term, mid-term and long-term) based upon duration of cocaine abstinence. The 43 cocaine abstinent patients showed lower fractional anisotropy (FA) in the left anterior callosal fibers, left genu of the corpus callosum, right superior longitudinal fasciculus, right callosal fibers and the superior corona radiata bilaterally when compared against non-using controls. Higher FA in the cocaine abstinent patients was observed in the splenium of the corpus callosum and right superior longitudinal fasciculus. Differences between the cocaine abstinent groups were observed bilaterally in the inferior longitudinal fasciculus, right anterior thalamic radiation, right ventral posterolateral nucleus of the thalamus, left superior corona radiata, superior longitudinal fasciculus bilaterally, right cingulum and the WM of the right precentral gyrus. The results identified WM differences between cocaine abstinent patients and controls as well as distinct differences between abstinent subgroups. The findings suggest that specific white matter differences persist throughout abstinence while other, spatially distinct, differences discriminate as a function of abstinence duration. These differences may, therefore, represent brain changes that mark recovery from addiction.


Anti-inflammatory effects of Citrus sinensis L., Citrus paradisi L. and their combinations.
Citrus bioflavonoids embrace a wide group of phenolic compounds effecting the production and scavenging of reactive oxygen species and the processes relating free radical-mediated injury. Keeping in view of the antioxidant and anti-inflammatory properties of Citrus sinensis and Citrus paradisi, present study was undertaken to explore the effects of C. sinensis (orange juice) and C. paradisi (grapefruit juice) at three different doses alone and their two combinations with the objective to examine the effects of these compounds in an experimental model of rat colitis induced by trinitrobenzenesulphonic acid (TNBS). Hence biochemical parameters e.g. myeloperoxidase, alkaline phosphatase, C-reactive protein (CRP) and glutathione were assessed. Data entry and analysis was accomplished by Statistical Package for the Social Sciences version 17 and was presented as mean ± S.E.M with 95% confidence interval. Present result shows that these juices, mainly C. paradisi, may be efficacious for the management of inflammatory bowel disease. In acute colitis model, C. paradise encouraged a decrease in the extension of the lesion escorted by a decrease in the occurrence of diarrhea and reinstatement of the glutathione content. Related effects were produced by the administration of C. sinensis, which also prevented the myeloperoxidase and alkaline phosphatase actions in acute intestinal inflammatory process. The effect of the citrus juices on the inflammatory process may be associated to their antioxidant and anti-inflammatory properties, as revealed in present investigation. The favorable effects exerted were demonstrated both by histological and biochemical changes and were related with a progress in the colonic oxidative status.


Breast self-examination: resistance to change.
To investigate whether Canadian family practitioners routinely teach breast self-examination (BSE) after publication of the 2001 Canadian Preventive Health Task Force guideline advising them to exclude teaching BSE from periodic health examinations. Self-administered cross-sectional mailed survey. Canada. A random sample of English-speaking general practitioners and physicians certified by the College of Family Physicians of Canada. Current and past BSE practices and opinions on the value of BSE. Response rate was 47.4%. Most respondents (88%) were aware of the new recommendations, yet only 16% had changed their usual practice of routinely teaching BSE. Most physicians agreed that before the recommendation they almost always taught BSE (74.3%). Only 9.5% agreed that physicians should follow the recommendation and not routinely teach BSE. A few also agreed that they now spend less time discussing BSE (25.7%) and that the recommendation has influenced them to stop teaching (12.4%) and encouraging (12.9%) women to practise BSE. Physicians who had changed their BSE practices were less likely to agree that BSE increases early detection of breast cancer and more likely to agree that BSE increases benign breast biopsies. They were also more likely to agree that screening mammography in women older than 50 decreases mortality from breast cancer. This survey, which assessed routine teaching of BSE, revealed poor adherence by Canadian family physicians to a well publicized evidence-based guideline update. Resistance to change could in part be attributed to a lack of knowledge of the supporting evidence, a lack of confidence in the evidence to date, and personal experiences with patients within their practices.


Networks in plant epidemiology: from genes to landscapes, countries, and continents.
There is increasing use of networks in ecology and epidemiology, but still relatively little application in phytopathology. Networks are sets of elements (nodes) connected in various ways by links (edges). Network analysis aims to understand system dynamics and outcomes in relation to network characteristics. Many existing natural, social, and technological networks have been shown to have small-world (local connectivity with short-cuts) and scale-free (presence of super-connected nodes) properties. In this review, we discuss how network concepts can be applied in plant pathology from the molecular to the landscape and global level. Wherever disease spread occurs not just because of passive/natural dispersion but also due to artificial movements, it makes sense to superimpose realistic models of the trade in plants on spatially explicit models of epidemic development. We provide an example of an emerging pathosystem (Phytophthora ramorum) where a theoretical network approach has proven particularly fruitful in analyzing the spread of disease in the UK plant trade. These studies can help in assessing the future threat posed by similar emerging pathogens. Networks have much potential in plant epidemiology and should become part of the standard curriculum.


Cardiovascular Drug Therapy for Human Newborn: Review of Pharmacodynamic Data.
Circulatory failure in preterm and term newborn infants is commonly treated with inotropes or vasoactive medications. In this structured literature review, the available data on pharmacodynamic effects of the inotropes adrenaline, dobutamine, dopamine, levosimendan, milrinone, noradrenaline, and the vasoactive drugs vasopressin and hydrocortisone are presented. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria which were human clinical trials published after 2000. Out of 101 identified eligible studies only 22 studies met the criteria for evidence based practice guidelines level I to IV. The most prevalent pharmacodynamic effects were increase in blood pressure and/or heart rate, which were also the most frequently studied circulatory parameters. This review demonstrates the need for further systematic studies on all reviewed drugs with incorporation of novel non-invasive biomarkers in this vulnerable patient group, for more timely and appropriate treatment for clinical efficacy.


Photoabsorption of acridine yellow and proflavin bound to human serum albumin studied by means of quantum mechanics/molecular dynamics.
Attempting to unravel mechanisms in optical probing of proteins, we have performed pilot calculations of two cationic chromophores-acridine yellow and proflavin-located at different binding sites within human serum albumin, including the two primary drug binding sites as well as a heme binding site. The computational scheme adopted involves classical molecular dynamics simulations of the ligands bound to the protein and subsequent linear response polarizable embedding density functional theory calculations of the excitation energies. A polarizable embedding potential consisting of point charges fitted to reproduce the electrostatic potential and isotropic atomic polarizabilities computed individually for every residue of the protein was used in the linear response calculations. Comparing the calculated aqueous solution-to-protein shifts of maximum absorption energies to available experimental data, we concluded that the cationic proflavin chromophore is likely not to bind albumin at its drug binding site 1 nor at its heme binding site. Although agreement with experimental data could only be obtained in qualitative terms, our results clearly indicate that the difference in optical response of the two probes is due to deprotonation, and not, as earlier suggested, to different binding sites. The ramifications of this finding for design of molecular probes targeting albumin or other proteins is briefly discussed.


Genetic testing and Parkinson disease: assessment of patient knowledge, attitudes, and interest.
The most common genetic contributor to late-onset Parkinson disease (PD) is the LRRK2 gene. In order to effectively integrate LRRK2 genetic testing into clinical practice, a strategy tailored to the PD population must be developed. We assessed 168 individuals with PD for baseline knowledge of genetics, perceived risk, and interest and opinions regarding genetic counseling and testing. Most participants felt that they were familiar with general genetics terms but overall knowledge levels were low, with an average score of 55%. The majority of participants thought it was likely they inherited a PD gene (72%), believed genetic testing for PD would be useful (86%), and were interested in genetic testing (59%) and genetic counseling (56%). However, only a few participants had heard of any genetic tests for PD (29%) or LRRK2 (10%). There appears to be a significant level of interest in genetics and genetic testing within the PD population, but a considerable deficit in genetics knowledge and an over-estimation of risk. Genetic education and counseling tools to address these needs were developed to provide patients with the ability to make informed and knowledgeable genetic testing decisions.


Revision of failed traditional fundoplication using EsophyX transoral fundoplication.
Laparoscopic revision of failed traditional fundoplication is difficult and involves risk of gastric, esophageal, and vagal nerve injury that is higher than that of the primary fundoplication. This study assessed feasibility and clinical outcomes of the transoral approach to revision of loose Nissen. Between November 2009 and August 2011, a total of 11 patients underwent transoral repair as opposed to 70 patients who underwent laparoscopic or open revision of a failed fundoplication. Subjective and objective outcomes were evaluated with the GERD health-related quality of life (GERD-HRQL) questionnaire and the reflux symptom index (RSI) questionnaire and ambulatory pH testing. The competency of the new antireflux barrier was evaluated by endoscopy. Wilcoxon signed-rank test was used to compare pre- and postoperative variables. All 11 patients evidenced loosening of the Nissen fundoplication without evidence of hiatal failure. Mean age was 57 years, BMI was 25.1 kg/m(2), and 4 of 11 (36 %) were female. Indications for operation were abnormal pH-metry off PPIs (6), impedance/pH on PPIs (3), esophagitis (1), and evidence of free reflux on barium swallow (1). One patient developed a postoperative bleed requiring transfusion. Two patients had laparoscopic revision at 6 and 8 months after the transoral procedure. At a median follow-up of 14 (range = 6-28) months, 8/10 patients reported resolution of their primary symptoms. Eight patients had pH testing off PPIs both pre- and postoperatively; median % time with pH <4 improved by dropping from 8.1 % (21-4.8 %) to 0.6 % (13.4-0.01 %) (p = 0.008). Esophageal acid exposure normalized in 5/6 patients. Mean GERD-HRQL score improved significantly by dropping from 28.6 (10.6) preoperatively to 6.7 (6.1) post-TIF (p = 0.016). Mean RSI score improved more than 50 % in 5/7 patients. Transoral revision of failed traditional fundoplication without herniation is technically feasible. It results in symptomatic and objective improvement of GERD without the risks of laparoscopic dissection for a majority of patients.


Identification of NF-κB related genes in channel catfish and their expression profiles in mucosal tissues after columnaris bacterial infection.
Interactions of NF-κB family, IκB family and IKK complex are the key components of NF-κB pathway that is essential for many biological processes including innate and adaptive immunity, inflammation and stress responses. In spite of their importance, systematic analysis of these genes in fish has been lacking. Here we report a systematic study of the NF-κB related genes in channel catfish. Five NF-κB family genes, five IκB family genes and three IKK complex genes were identified in the channel catfish genome. Annotation of these 13 NF-κB related genes was further confirmed by phylogenetic and syntenic analysis. Negative selection was found to play a crucial role in the adaptive evolution of these genes. Expression profiles of NF-κB related genes after Flavobacterium columnare (columnaris) infection were determined by analysis of the existing RNA-Seq dataset. The majority of NF-κB related genes were significantly regulated in mucosal tissues of gill, skin and intestine after columnaris infection, indicating their potential involvement in host defense responses. Distinct expression patterns of NF-κB related genes were observed in susceptible and resistant catfish in response to columnaris infection, suggesting that expression of these genes may contribute to the variations in disease resistance/susceptibility of catfish.


Trainable COSFIRE filters for keypoint detection and pattern recognition.
Keypoint detection is important for many computer vision applications. Existing methods suffer from insufficient selectivity regarding the shape properties of features and are vulnerable to contrast variations and to the presence of noise or texture. We propose a trainable filter which we call Combination Of Shifted FIlter REsponses (COSFIRE) and use for keypoint detection and pattern recognition. It is automatically configured to be selective for a local contour pattern specified by an example. The configuration comprises selecting given channels of a bank of Gabor filters and determining certain blur and shift parameters. A COSFIRE filter response is computed as the weighted geometric mean of the blurred and shifted responses of the selected Gabor filters. It shares similar properties with some shape-selective neurons in visual cortex, which provided inspiration for this work. We demonstrate the effectiveness of the proposed filters in three applications: the detection of retinal vascular bifurcations (DRIVE dataset: 98.50 percent recall, 96.09 percent precision), the recognition of handwritten digits (MNIST dataset: 99.48 percent correct classification), and the detection and recognition of traffic signs in complex scenes (100 percent recall and precision). The proposed COSFIRE filters are conceptually simple and easy to implement. They are versatile keypoint detectors and are highly effective in practical computer vision applications.


Quantitative evaluation of a low-cost noninvasive hybrid interface based on EEG and eye movement.
This paper describes a low-cost noninvasive brain-computer interface (BCI) hybridized with eye tracking. It also discusses its feasibility through a Fitts' law-based quantitative evaluation method. Noninvasive BCI has recently received a lot of attention. To bring the BCI applications into real life, user-friendly and easily portable devices need to be provided. In this work, as an approach to realize a real-world BCI, electroencephalograph (EEG)-based BCI combined with eye tracking is investigated. The two interfaces can be complementary to attain improved performance. Especially to consider public availability, a low-cost interface device is intentionally used for test. A low-cost commercial EEG recording device is integrated with an inexpensive custom-built eye tracker. The developed hybrid interface is evaluated through target pointing and selection experiments. Eye movement is interpreted as cursor movement and noninvasive BCI selects a cursor point with two selection confirmation schemes. Using Fitts' law, the proposed interface scheme is compared with other interface schemes such as mouse, eye tracking with dwell time, and eye tracking with keyboard. In addition, the proposed hybrid BCI system is discussed with respect to a practical interface scheme. Although further advancement is required, the proposed hybrid BCI system has the potential to be practically useful in a natural and intuitive manner.


Risk of behavioral and adaptive functioning difficulties in youth with previous and current sleep disordered breathing.
To examine the rates of behavioral and adaptive functioning difficulties among youth who never had sleep disordered breathing (SDB), had remitted SDB, had incident SDB, or had persistent SDB; and to determine if there were increased odds of behavioral difficulties among youth with varying SDB histories relative to those who never had SDB. 263 youth had valid polysomnography and neurobehavioral data at two time points approximately 5 years apart from the prospective Tucson Children's Assessment of Sleep Apnea study. Primary outcomes were the behavior assessment scale for children-2(nd) Edition parent report form (BASC-PRF) and Self-Report of Personality (SRP), and the Adaptive Behavior Assessment System-2(nd) Edition (ABAS-2). Compared to those who never had SDB, individuals with persistent SDB had significant odds and met more cutoff scores on the BASC-2-PRF externalizing problems composite (odds ratio [OR] 3.29; 8.92% vs. 35.3%), behavioral symptoms index (OR 6.82; 7.4% vs. 35.3%) and Hyperactivity subscale (OR 6.82; 11.1% vs. 41.2%). Similarly, greater difficulties was seen for the group with persistent SDB (relative to never) on the ABAS-2 social domain (OR 3.39; 22% vs. 50%), and Communication (OR 4.26; 15% vs. 42.9%) and Self-Care subscales (OR = 2.97; 25.2% vs. 50%). Relative to youth who never had SDB, youth who developed SDB at Time 2 had compromised adaptive skills as evidenced by the BASC-2 PRF adaptive behavior composite (OR 3.34; 15.6% vs. 38.1%) and the ABAS-2 general adaptive composite (OR 2.83; 20.5% vs. 42.1%). Youth with current SDB exhibited hyperactivity, attention problems, aggressivity, lower social competency, poorer communication, and/or diminished adaptive skills.


The assessment of insemination success in yellow dung flies using competitive PCR.
In spite of considerable interest in postcopulatory sexual selection, separating the effects of sperm competition from cryptic female choice remains difficult because mechanisms underlying postcopulatory processes are poorly understood. One methodological challenge is to quantify insemination success for individual males within the sperm stores of multiply mated females to discover how insemination translates into eventual paternity. Any proposed method must be applicable in organisms without extensive DNA sequence information (which include the majority of model species for sexual selection). Here, we describe the development and application of microsatellite competitive-multiplex-PCR for quantifying relative contributions to a small number of sperm in storage. We studied how DNA template characteristics affect PCR amplification of known concentrations of mixed DNA and generated regressions for correcting observations of allelic signal strength based on such characteristics. We used these methods to examine patterns of sperm storage in twice-mated female yellow dung flies, Scathophaga stercoraria. We confirm previous findings supporting sperm displacement and demonstrate that average paternity for the last mate accords with the mean proportion of sperm stored. We further find consistent skew in storage across spermathecae, with more last male sperm stored in the singlet spermatheca on one side of the body than in the doublet on the opposite side. We also show that the time between copulations may be important for effectively sorting sperm. Finally, we demonstrate that male size may influence the opportunity for sperm choice, suggesting future work to disentangle the roles of male competition and cryptic female choice.


Recognition of mono-ADP-ribosylated ARTD10 substrates by ARTD8 macrodomains.
ADP-ribosyltransferases (ARTs) catalyze the transfer of ADP-ribose from NAD(+) onto substrates. Some ARTs generate in an iterative process ADP-ribose polymers that serve as adaptors for distinct protein domains. Other ARTs, exemplified by ARTD10, function as mono-ADP-ribosyltransferases, but it has been unclear whether this modification occurs in cells and how it is read. We observed that ARTD10 colocalized with ARTD8 and defined its macrodomains 2 and 3 as readers of mono-ADP-ribosylation both in vitro and in cells. The crystal structures of these two ARTD8 macrodomains and isothermal titration calorimetry confirmed their interaction with ADP-ribose. These macrodomains recognized mono-ADP-ribosylated ARTD10, but not poly-ADP-ribosylated ARTD1. This distinguished them from the macrodomain of macroH2A1.1, which interacted with poly- but not mono-ADP-ribosylated substrates. Moreover, Ran, an ARTD10 substrate, was also read by ARTD8 macrodomains. This identifies readers of mono-ADP-ribosylated proteins, defines their structures, and demonstrates the presence of this modification in cells.


A pilot evaluation of a nasal expiratory resistance device for the treatment of obstructive sleep apnea.
Obstructive sleep apnea (OSA) is a major problem in need of new treatment approaches. The present pilot study tests the hypothesis that the application of expiratory resistance via a nasal valve device would improve breathing during sleep in subjects with OSA and in primary snorers. Thirty men and women were recruited from the community and from the Stanford University Sleep Disorders Clinic. Twenty-four had at least mild OSA (AHI >5), and 6 were primary snorers. Subjects underwent 2 nights of polysomnographic evaluation, one with and one without a new nasal resistance device with the order of nights counterbalanced across participants. The device consisted of a small valve inserted into each nostril calibrated to provide negligible inspiratory resistance, but increased expiratory resistance with a back pressure between 60 and 90 cm H2O*sec/Liter (at 100 mL/sec flow). Standard polysomnography was conducted to compare participants' sleep both with and without the device, with the scoring conducted blind to treatment condition. The apnea-hypopnea (AHI) (p < 0.001) and oxygen desaturation (O2DI) (p < 0.01) indices both significantly decreased, and the percentage of the night spent above 90% saturation (p < 0.05) significantly increased with device use. The observed amount of snoring (p < 0.001) was significantly decreased with device use, and there were no significant changes in measures of sleep architecture. The results of this pilot study are suggestive of a therapeutic effect of expiratory nasal resistance for some OSA patients and indicate that this technique is worthy of further clinical study.


A qualitative case study of LifeGuide: users' experiences of software for developing Internet-based behaviour change interventions.
Previously, behavioural scientists seeking to create Internet-based behaviour change interventions have had to rely on computer scientists to actually develop and modify web interventions. The LifeGuide software was designed to enable behavioural researchers to develop and adapt Internet-based behavioural interventions themselves. This article reports a qualitative case study of users' experiences and perceptions of the LifeGuide software. The aim was to explore users' experiences and their perceptions of the benefits and limitations of this approach to intervention development. Twenty LifeGuide users took part in semi-structured interviews and one provided feedback via email. Thematic analysis identified three overarching themes: 'Recognising LifeGuide's potential', 'I'm not a programmer' and 'Knowledge sharing - the future of LifeGuide'. Users valued LifeGuide's potential to allow them to flexibly develop and modify interventions at little cost. However, users noted that their lack of programming experience meant that they needed to learn new skills for using the software, and they varied in the extent to which they felt able to develop interventions without any input from programmers. Respondents saw the potential of using the LifeGuide Community Website to share technical support and examples of intervention components to support their use of LifeGuide.